STABLE MEDICINAL COMPOSITIONS CONTAINING 4,5-EPOXYMORPHINANE DERIVATIVES

Abstract

A stable pharmaceutical composition includes a 4,5-epoxy-morphinan derivative, and includes at least one of the group consisting of a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, and a surfactant.

Description

TECHNICAL FIELD

[0001] The present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative or pharmacologically acceptable acid-addition salts thereof. More particularly, the present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative which includes 4,5-epoxy-morphinan derivative as an effective component and includes a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, or a surfactant, and also relates to a method for stabilizing the pharmaceutical composition.

BACKGROUND ART

[0002] Morphine has a significant analgesic effect and is indicated for conditions such as postoperative pain and cancer pain. However, the drug has severe adverse reactions such as being addictive and causing respiratory depression and constipation, which induces clinical problems. Therefore, morphine is an analgesic which demands meticulous care.

[0003] Recently, it has become clear that opiate receptors may be classified into three types, that is, μ, δ, and κ receptor, which function as central analgesic receptors. In addition, an opiate σ receptor has also been elucidated which affects mental function.

[0004] The severe adverse reactions accompanied by administration of morphine are specific to the μ receptor agonist and to the σ receptor agonist. The δ receptor agonist and the κ receptor agonist seem not to show the above-mentioned adverse reactions.

[0005] A 4,5-epoxy-morphinan derivative does not induce the severe adverse reactions accompanied by the administration of morphine. In addition, the 4,5-epoxy-morphinan derivative is agonistic to the κ receptor or to the δ receptor, and shows significant analgesic and diuretic activities. Furthermore, the 4,5-epoxy-morphinan derivative does not show cross-tolerance with morphine or the like, and does not show an affinity for the σ receptor. Therefore, the 4,5-epoxy-morphinan derivative is a promising analgesic and a promising diuretic (WO93/15081).

[0006] However, the 4,5-epoxy-morphinan derivatives are chemically unstable to heat, light, and oxygen. Thus, means such as low-temperature storage, light protection, and displacement by an inert gas are necessary to store them.

[0007] Therefore, it is significantly useful that a stable pharmaceutical preparation including these 4,5-epoxy-morphinan derivatives is prepared.

[0008] With respect to a conventional stabilizing method for morphine, that is, a morphinan derivative, for example, in Japanese Unexamined Patent Publication No. 2-160719, an attempt to improve stability of a pharmaceutical preparation is made by adding a basic component to morphine. In addition, a stabilized pharmaceutical composition (DE29719704) or the like is known in which an antioxidant such as sodium thiosulfate or tocopherol is accompanied by naloxone. However, with respect to a 4,5-epoxy-morphinan derivative, a stabilized composition and a method of stabilization therefore has not been determined heretofore.

[0009] An object of the present invention is to provide a stable pharmaceutical composition including a 4,5-epoxy-morphinan derivative and also to provide a method for stabilizing it.

DISCLOSURE OF INVENTION

[0010] The present invention relates to a pharmaceutical composition including a 4,5-epoxy-morphinan derivative and at least one substance selected from the group consisting of the following materials (1), (2), (3), (4) and (5).

[0011] (1) A water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate.

[0012] (2) A fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole.

[0013] (3) A synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin.

[0014] (4) A sugar selected from the group consisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose.

[0015] (5) A surfactant selected from the group consisting of sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The present invention relates to stable pharmaceutical compositions including a 4,5-epoxy-morphinan derivative and at least one component selected from the group consisting of a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, and a surfactant.

[0017] A 4,5-epoxy-morphinan derivative in accordance with the present invention can be prepared by the method disclosed in WO93/15081 and is a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 1

[0018] wherein . . . is a double bond, or a single bond; R1 is an alkyl group having from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl group having from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbon atoms; R2 is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or —NR7R8; R7 is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R8 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or —C(═O)R9—; R9 is a hydrogen atom, a phenyl group, or an alkyl group having from 1 to 5 carbon atoms; R3 is a hydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is —N(R4)C(═X)—, —N(R4)C(═X)Y—, —N(R4)—, or —N(R4)SO2— (wherein X and Y are, independently of one another, NR4, S, or O; and R4 is a hydrogen atom, a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R4 may be identical or different in the formula); B is a valence bond, a straight-chain or branched-chain alkylene group having from 1 to 14 carbon atoms (wherein the alkylene group may be substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the alkylene group may be replaced with carbonyl groups), a straight-chain or branched-chain acyclic unsaturated hydrocarbon containing from one to three double bonds and/or triple bonds and having from 2 to 14 carbon atoms (wherein the acyclic unsaturated hydrocarbon may be substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the acyclic unsaturated hydrocarbon may be replaced with carbonyl groups), or a straight-chain or branched-chain saturated or unsaturated hydrocarbon containing from one to five thioether, ether and/or amino bonds and having from 1 to 14 carbon atoms (wherein no hetero atoms are bonded directly to A, and one to three methylene groups of the hydrocarbon may be replaced with carbonyl groups); and R5 is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of following formulas: 2

Organic Groups Represented by R5

[0019] wherein the organic group may have at least one substituent selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group; R6 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms.

[0020] In the general formula (I), R1 is preferably a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, an allyl group, a benzyl group, or a phenethyl group, and more preferably a cyclopropylmethyl group or an allyl group.

[0021] R2 and R3 are preferably a hydrogen atom, a hydroxy group, an acetoxy group, or a metoxy group, independently.

[0022] A is preferably —N (R4)C(═O)—, —N(R4)C(═O)O—, —N(R4)—, or —N(R4)SO2— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms). Among them A is more preferably —N(R4)C(═O)— or —N(R4)C(═O)O— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms).

[0023] B is preferably a straight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH2O— or —CH2S—. Among them, B is more preferably a straight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—, or —C≡C—.

[0024] R5 is preferably a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 3

Organic Groups Represented by R5

[0025] wherein the organic group may be substituted with one or more substituents selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group.

[0026] R6 is preferably a hydrogen atom.

[0027] 17-(cyclopropyl methyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (hereinafter referred to as “Compound 1”) and 17-(cyclopropyl methyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan hydrochloride (hereinafter referred to as “Compound 2”) are particularly preferred. 4

[0028] The pharmacologically acceptable acid-addition salts thereof are inorganic acid salts, such as chlorides, 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 camphor-sulfonates. Among them, chlorides, hydrobromides, phosphates, tartrates, malates, and methanesulfonates are preferred, but of course the pharmacologically acceptable acid-addition salts thereof are not limited to these compounds.

[0029] With respect to a composition content of the 4,5-epoxy-morphinan derivative, that is, an effective component, any content may be available, even if the content of the effective component in a pharmaceutical composition is sufficient for a treatment. For example, the content may range from 0.01 to 10000 μg/pharmaceutical composition. Ordinarily, the content preferably ranges from 0.1 to 1000 μg/pharmaceutical composition.

[0030] In the present invention, sulfites, nitrites, ascorbic acids, thiol derivatives, hydroxyquinoline sulfate, or the like is used as a water soluble antioxidant. Phenolic compounds, fat soluble vitamins, ascorbic acid esters, fat soluble vitamins, nordihydroguaiaretic acid, mercaptobenzimidazole, or the like is used as a fat soluble antioxidant. EDTA, salts thereof, citric acid, salts thereof, lecithin, or the like is used as a synergist. The above-mentioned synergist shows a weak antioxidant effect by itself. However, the effect can be increased in combination with other antioxidants.

[0031] Specifically, a sulfite such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, or Rongalite, a nitrite such as sodium nitrite, a ascorbic acid such as L-ascorbic acid or erysorbic acid, and a thiol derivative such as sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, or hydroxyquinoline sulfate is used as a water soluble antioxidant. Among them, sodium thiosulfate is most preferable.

[0032] A phenolic compound such as propyl gallate, butyl hydroxytoluene, or butyl hydroxyanisole, a fat soluble vitamin such as tocopherol or a fat soluble vitamin such as ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, or mercaptobenzimidazole is used as a fat soluble antioxidant. Among them, propyl gallate, butyl hydroxytoluene or butyl hydroxyanisole is preferable.

[0033] For example, EDTA, salts thereof, citric acid, salts thereof, lecithin, or the like is used as a synergist. With respect to salts, sodium salts, calcium salts, potassium salts, or magnesium salts are preferable. Among them, EDTA or citric acid is more preferable.

[0034] At least one selected from the group consisting of above-described water soluble antioxidants, fat soluble antioxidants, and synergists is used as an antioxidant. In addition, at least one sugar or at least one surfactant can be mixed therein.

[0035] The content of the antioxidant ranges from 0.00001 to 10 percent by weight of the total pharmaceutical composition, preferably ranges from 0.001 to 10 percent by weight of the total pharmaceutical composition, and more preferably 0.001 to 1 percent by weight of the total pharmaceutical composition.

[0036] It is confirmed that the antioxidant is sufficiently effective when it is solved or dispersed in a solution, or when it is dispersed in a semisolid or in a solid. The antioxidant is effective for stabilization of all dosage forms such as syrups, powders, fine granules, granules, tablets, hard capsules, soft capsules, injections, freeze-drying dosage forms, ointments, tapes, lotions, nose drops, ophthalmic solutions, aerosols, suspensions, emulsions, plasters, and suppositories.

[0037] Specifically, a sugar used in the present invention, for example, is D-mannitol, D-sorbitol, xylitol, glucose, maltose, fructose, sucrose, or white soft sugar.

[0038] Preferably, D-mannitol, D-sorbitol, xylitol, glucose, or fructose is used alone or used in a mixture of at least two thereof. Furthermore, at least one of water soluble antioxidants, fat soluble antioxidants, synergists, and surfactants can be mixed therein.

[0039] The content of the sugar ranges from 0.01 to 20 percent by weight of the total pharmaceutical composition, preferably ranges from 0.1 to 20 percent by weight of the total pharmaceutical composition, and more preferably 1 to 20 percent by weight of the total pharmaceutical composition.

[0040] It is confirmed that addition of sugars is particularly useful for stabilization of injections. In addition, it has been shown that when a water soluble antioxidant, a fat soluble antioxidant, or a synergist as an antioxidant is added, a greater stabilization effect can be obtained. Among them, D-mannitol, D-sorbitol, xylitol, and glucose are useful for stabilization of the injections. With respect to the accompanying antioxidant, sodium thiosulfate, that is, a water soluble antioxidant and citric acid, that is, a synergist, are particularly preferable.

[0041] Specifically, a surfactant used in the present invention, for example, is sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

[0042] Preferably, glyceryl myristate or polyoxyethylene nonylphenyl ether is used alone or used as a mixture of at least two thereof. Furthermore, at least one of water soluble antioxidants, fat soluble antioxidants, synergists, and sugars can be mixed therein.

[0043] The content of the surfactant ranges from 0.0001 to 20 percent by weight of the total pharmaceutical composition, preferably ranges from 0.001 to 20 percent by weight of the total pharmaceutical composition, and more preferably 0.01 to 10 percent by weight of the total pharmaceutical composition.

[0044] It is confirmed that addition of the surfactant is particularly useful for stabilization of external preparations such as ointments, gels, tapes, lotions, nose drops, ophthalmic solutions, aerosols, and suppositories. In addition, it is shown that when a water soluble antioxidant, a fat soluble antioxidant, or a synergist as an antioxidant is added, a greater stabilization effect can be obtained. Among them, glyceryl myristate and polyoxyethylene nonylphenyl ether are useful for stabilization of the external preparations. With respect to the accompanying antioxidant, citric acid, that is, a synergist, is particularly preferable.

[0045] An available additive such as vehicles, binders, thickener, solubilizer, solvents, isotonizing agents, buffers, preservatives, or bases may be added to the pharmaceutical compositions in accordance with the present invention, if necessary.

[0046] The additives in the present invention are not particularly limited, even though they are pharmaceutically acceptable. Examples of a vehicle are lactose, white soft sugar, sucrose, sorbitol, microcrystalline cellulose, corn starch, gelatin, dextrans and the like. Examples of a binder are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, methyl cellulose, and the like. Examples of a thickener are gum arabic, sodium hyaluronate, xanthan gum, and the like. Examples of a solvent are water, ethanol, propylene glycol, polyethylene glycol, Polysorbate 80, glycerin, soybean oil and the like. Examples of an isotonizing agent are sodium chloride, D-mannitol, xylitol, glucose and the like. Examples of a solubilizer are cyclodextrin and the like. Examples of a nonionic surfactant are polyoxyethylene hydrogenated castor oil, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl oleate, glyceryl myristate, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, and the like. Examples of a buffer are tartaric acid, citric acid, maleic acid, phosphoric acid, succinic acid, lactic acid, acetic acid, sodium hydrogencarbonate, boric acid, sodium borate, magnesium oxide, magnesium hydroxide, and the like. Examples of a preservative are methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzalkonium chloride, and the like. Examples of a base are white petrolatum, Witepsol, Plastibase, liquid paraffin, and the like.

[0047] The pharmaceutical compositions in accordance with the present invention are not particularly limited, even though they have pharmaceutically acceptable dosage forms for administration. The pharmaceutical compositions in accordance with the present invention are available for all dosage forms such as syrups, powders, fine granules, granules, tablets, hard capsules, soft capsules, injections, freeze-drying dosage forms, ointments, gels, tapes, lotions, nose drops, ophthalmic solutions, aerosols, suspensions, emulsions, plasters, and suppositories.

EXAMPLES

[0048] Advantages of the present invention will become clear from the following description of examples. However, it is to be understood that the invention is not limited thereto.

Example 1

[0049] In measuring flasks, aqueous solutions containing Compound 1 (10 μg/mL) which were added a predetermined concentration of a variety of antioxidants, and an aqueous solution containing the compound with no additives were prepared. Test 1, Test 2, and Comparative Example are shown in Table 1.

TABLE 1
		Drug
Example 1	Dosage Form	Content	Antioxidant	Additive Rate
Comparative	Aqueous	10 μg/mL	None
Example	solution
Test 1	Aqueous	10 μg/mL	Citric acid	0.10%
	solution
Test 2	Aqueous	10 μg/mL	Sodium	0.10%
	solution		thiosulfate

[0050] Stability test: The aqueous solutions of Test 1, Test 2, and Comparative example were sealed in ampoules. Then, after storing them at a temperature of 80° C. for five days, the concentrations of Compound 1 were measured using a HPLC method (an UV method). The residual rates were calculated, so that stability of the aqueous solutions was estimated.

TABLE 2
		Additive	Storage	Residual
Example 1	Antioxidant	Rate	Conditions	Rate (%)
Comparative	None		Seal/80° C./5d	41.4
Example
Test 1	Citric acid	0.10%	Seal/80° C./5d	93.5
Test 2	Sodium	0.10%	Seal/80° C./5d	90.8
	thiosulfate

[0051] As shown in Table 2, the residual rates of Test 1 and Test 2 to which the antioxidant was added by 0.1% were higher than that of Comparative Example to which no antioxidant was added, so that a significant stabilizing effect on Compound 1 was shown.

Example 2

[0052] As shown in Prescription Example 1, injections were prepared by adding a predetermined amount of an isotonizing agent to Compound 1 (10 μg/mL). Tests 1 to 4 and Comparative Example are shown in Table 3.

Compound 1          1 mg
Isotonizing agent   0.9 to 5 g
Water for injection Balance volume
Total               100 mL

(Prescription Example 1)

Injection

[0053]

TABLE 3
		Drug	Isotonizing	Additive
Example 2	Dosage Form	Content	Agent	Rate
Comparative	Injection	10 μg/mL	Sodium chloride	0.90%
Example
Test 1	Injection	10 μg/mL	Glucose	5.00%
Test 2	Injection	10 μg/mL	Xylitol	5.00%
Test 3	Injection	10 μg/mL	Mannitol	5.00%
Test 4	Injection	10 μg/mL	D-sorbitol	5.00%

[0054] Stability test: After the aqueous solutions of Tests 1 to 4, and Comparative Example were subjected to nitrogen bubbling, they were sealed in ampoules. Then, after storage at a temperature of 80° C. for seven days, the residual rates of Compound 1 were measured using a HPLC method (an UV method). Thus, stability after accelerated storage was estimated.

TABLE 4
	Isotonizing		Storage	Residual
Example 2	Agent	Additive Rate	Conditions	Rate (%)
Comparative	Sodium	0.90%	Seal/80° C./7d	66.6
Example	chloride
Test 1	Glucose	5.00%	Seal/80° C./7d	90.3
Test 2	Xylitol	5.00%	Seal/80° C./7d	97.9
Test 3	Mannitol	5.00%	Seal/80° C./7d	98.9
Test 4	D-sorbitol	5.00%	Seal/80° C./7d	97.4

[0055] As shown in Table 4, the residual rates of Tests 1 to 4 were significantly higher than that of Comparative Example to which sodium chloride as the isotonizing agent was added. Therefore, with respect to the accelerated storage of the injections, sugars as isotonizing agents showed significant stabilizing effects on Compound 1.

Example 3

[0056] As shown in Prescription Example 2, injections were prepared by adding a predetermined amount of sodium thiosulfate to a 5% aqueous solution of mannitol containing Compound 1 (10 μg/mL) and a injection to which no sodium thiosulfate was added was also prepared. Tests 1 to 3 and Comparative Example are shown in Table 5.

Compound 1          1 mg
Sodium thiosulfate  0 to 1 g
Mannitol            5 g
Water for injection Balance volume
Total               100 mL

(Prescription Example 2)

Injection

[0057]

TABLE 5
				Additive
Example 3	Dosage Form	Drug Content	Antioxidant	Rate
Comparative	Injection	10 μg/mL	None
Example
Test 1	Injection	10 μg/mL	Sodium	0.10%
			thiosulfate
Test 2	Injection	10 μg/mL	Sodium	0.50%
			thiosulfate
Test 3	Injection	10 μg/mL	Sodium	1.00%
			thiosulfate

[0058] Stability test: The aqueous solutions of Tests 1 to 3, and that of Comparative Example were sealed in ampoules. Then, after sterilization by heating at a temperature of 120° C. for 60 minutes, the purities of Compound 1 in the samples were measured using a HPLC method (an UV method). Thus, pharmaceutical stability after sterilization was estimated.

TABLE 6
		Additive		Purity
Example 3	Antioxidant	Rate	Storage Conditions	(%)
Comparative	None		Seal/120° C./60 min	98.95
Example
Test 1	Sodium	0.10%	Seal/120° C./60 min	99.57
	thiosulfate
Test 2	Sodium	0.50%	Seal/120° C./60 min	99.44
	thiosulfate
Test 3	Sodium	1.00%	Seal/120° C./60 min	99.53
	thiosulfate

[0059] As shown in Table 6, the purities of Tests 1 to 3 were significantly higher than that of Comparative Example to which no antioxidant was added. With respect to the sterilization process of the injections, sodium thiosulfate showed a significant stabilizing effect on Compound 1. The difference of the effects due to the amounts of the sodium thiosulfate was not seen in the range of 0.1 to 1.0%, and any additive amount showed the same stabilizing effect.

Example 4

[0060] Aqueous solutions containing Compound 1 and a predetermined amount of antioxidants, or an aqueous solution, to which no antioxidant was added, were added dropwise and mixed to a mixture of lactose and Avicel PH101, so that granulated substances were obtained. After drying the above-mentioned substances at a temperature of 40° C. for 12 hours, so that the granules shown in Prescription Example 3 were prepared. Tests 1 to 9 and Comparative Example are shown in Table 7.

(Prescription Example 3)

Granule

[0061]

Compound 1         100 mg
Sodium thiosulfate 0 to 1 g
Avicel PH-101      31 g
Lactose            Balance volume
Total              100 g

[0062]

TABLE 7
	Dosage			Additive
Example 4	Form	Drug Content	Antioxidant	Rate
Comparative	Granule	100 μg/100 mg	None
Example
Test 1	Granule	100 μg/100 mg	EDTA	0.10%
Test 2	Granule	100 μg/100 mg	Citric acid	0.10%
Test 3	Granule	100 μg/100 mg	Propyl gallate	0.10%
Test 4	Granule	100 μg/100 mg	Butyl	0.10%
			Hydroxyanisole
Test 5	Granule	100 μg/100 mg	Tocopherol	0.10%
Test 6	Granule	100 μg/100 mg	Sodium	0.10%
			thiosulfate
Test 7	Granule	100 μg/100 mg	Sodium	0.20%
			thiosulfate
Test 8	Granule	100 μg/100 mg	Sodium	0.50%
			thiosulfate
Test 9	Granule	100 μg/100 mg	Sodium	1.00%
			thiosulfate

[0063] Stability test: Immediately after manufacturing the granules of Tests 1 to 9 and that of Comparative Example, the purities of Compound 1 were measured using a HPLC method (an UV method). Thus, pharmaceutical stability was estimated.

TABLE 8
		Additive		Purity
Example 4	Antioxidant	Rate	Storage Conditions	(%)
Comparative	None		Immediately after	98.48
Example			Manufacturing
Test 1	EDTA	0.10%	Immediately after	98.75
			Manufacturing
Test 2	Citric acid	0.10%	Immediately after	98.56
			Manufacturing
Test 3	Propyl gallate	0.10%	Immediately after	99.33
			Manufacturing
Test 4	Butyl	0.10%	Immediately after	98.62
	Hydroxyanisole		Manufacturing
Test 5	Tocopherol	0.10%	Immediately after	99.20
			Manufacturing
Test 6	Sodium	0.10%	Immediately after	99.49
	thiosulfate		Manufacturing
Test 7	Sodium	0.20%	Immediately after	99.49
	thiosulfate		Manufacturing
Test 8	Sodium	0.50%	Immediately after	99.30
	thiosulfate		Manufacturing
Test 9	Sodium	1.00%	Immediately after	98.99
	thiosulfate		Manufacturing

[0064] As shown in Table 8, the purities of the compound in the granules of Tests 1 to 9 were significantly higher than that of Comparative Example to which no antioxidant was added. Thus, the stabilizing effects on Compound 1 were also shown in the granules. In addition, when the difference of the effects due to the amounts of the sodium thiosulfate was studied in Tests 6 to 9, the highest stabilizing effect can be seen in the range of 0.1 to 0.2%.

Example 5

[0065] Aqueous solutions containing Compound 1 and a predetermined amount of antioxidants, or an aqueous solution, to which no antioxidant was added, were added dropwise and mixed to a mixture of lactose, Avicel PH101, and HPC-SL, so that granulated substances were obtained. After drying the above-mentioned substances at a temperature of 40° C. for 12 hours, sieving them, mixing with magnesium stearate, and compressing tablets, the tablets shown in Prescription Example 4 were prepared. Tests 1 and Comparative Example are shown in Table 9.

(Prescription Example 4)

Tablet

[0066]

Compound 1         100 mg
Sodium thiosulfate 0 to 1 g
Avicel PH-101      30 g
HPC-SL             3 g
Magnesium stearate 0.5 g
Lactose            Balance volume
Total              100 g

[0067]

TABLE 9
				Additive
Example 5	Dosage Form	Drug Content	Antioxidant	Rate
Comparative	Tablet	100 μg/tablet	None
Example
Test 1	Tablet	100 μg/tablet	Sodium	0.10%
			thiosulfate

[0068] Stability test: After the tablets of Test 1 and Comparative Example were sealed in bottles, they were stored at a temperature of 40° C. and at a relative humidity (R.H.) by 75% for three months. Then, the residual rates were measured using a HPLC method (an UV method), so that pharmaceutical stability was estimated.

TABLE 10
		Additive		Purity
Example 5	Antioxidant	Rate	Storage Conditions	(%)
Comparative	None		Seal/40° C./75%	98.12
Example			R.H./3m
Test 1	Sodium	0.10%	Seal/40° C./75%	99.20
	thiosulfate		R.H./3m

[0069] As shown in Table 10, the residual rates of Test 1 was higher than that of Comparative Example to which no antioxidant was added, so that with respect to a tablet, a significant stabilizing effect on Compound 1 was also seen.

Example 6

[0070] Aqueous solutions containing Compound 1 and a predetermined amount of antioxidants, or an aqueous solution, to which no antioxidant was added, were dissolved in Polyethylene glycol 400, so that filling fluids for soft capsules shown in Prescription Example 5 were prepared. Tests 1 to 3 and Comparative Example are shown in Table 11.

(Prescription Example 5)

Filling Fluid For Soft Capsules

[0071]

Compound 1              40 mg
Sodium thiosulfate      0 to 0.1 g
Purified water          2 g
Polyethylene glycol 400 Balance volume
Total                   100 g

[0072]

TABLE 11
	Dosage			Additive
Example 6	Form	Drug Content	Antioxidant	Rate
Comparative	Filling fluid	40 μg/100 mg	None	0.00%
Example	for soft
	capsules
Test 1	Filling fluid	40 μg/100 mg	Sodium	0.01%
	for soft		thiosulfate
	capsules
Test 2	Filling fluid	40 μg/100 mg	Sodium	0.05%
	for soft		thiosulfate
	capsules
Test 3	Filling fluid	40 μg/100 mg	Sodium	0.10%
	for soft		thiosulfate
	capsules

[0073] Stability test: After the filling fluids for the soft capsules of Test 1 to 3 and that of Comparative Example were sealed in ampoules, the filling fluids for the soft capsules were stored at a temperature of 80° C. for one week. Then, the residual rates of compound 1 were measured using a HPLC method (an UV method), so that pharmaceutical stability of the filling fluid was estimated.

TABLE 12
		Additive		Residual
Example 6	Antioxidant	Rate	Storage Conditions	Rate (%)
Comparative	None	0.00%	Seal/80 ° C./1w	19.3
Example
Test 1	Sodium	0.01%	Seal/80 ° C./1w	23.4
	thiosulfate
Test 2	Sodium	0.05%	Seal/80 ° C./1w	88.3
	thiosulfate
Test 3	Sodium	0.10%	Seal/80 ° C./1w	85.1
	thiosulfate

[0074] As shown in Table 12, the residual rates of Test 1 to 3 were higher than that of Comparative Example to which no antioxidant was added, so that with respect to the above-described filling fluids a significant stabilizing effect on Compound 1 was shown. In addition, the difference of the effects due to the amounts of the sodium thiosulfate was studied. It has been clear that the greater the additional amount, the higher the stabilizing effect.

Example 7

[0075] The filling fluid for the soft capsules of Test 1 and that of Comparative Example were degassed by nitrogen bubbling. Then, 100 mg of the filling fluid for the soft capsule was packed in the gelatin capsule shown in Prescription Example 6, so that the soft capsule was prepared. Test 1 and Comparative Example are shown in Table 13.

(Prescription Example 6)

Gelatin Capsule For Soft Capsules

[0076]

Gelatin           21 g
Gelatin succinate 21 g
Glycerin          23 g
Titanium oxide    0.7 g
Purified water    Balance volume
Total             100 g

[0077]

TABLE 13
	Dosage			Additive
Example 7	Form	Drug Content	Antioxidant	Rate
Comparative	Soft capsule	40 μg/capsule	None	0.00%
Example
Test 1	Soft capsule	40 μg/capsule	Sodium	0.10%
			thiosulfate

[0078] Stability test: After the capsule of Test 1 and that of Comparative Example were sealed in bottles, the capsules were stored at a temperature of 40° C. and at a R.H. by 75% for one month. Then, the residual concentrations of the drug were measured using a HPLC method (an UV method), so that stability of the soft capsule was estimated.

TABLE 14
		Additive		Residual
Example 7	Antioxidant	Rate	Storage Conditions	Rate (%)
Comparative	None	0.00%	Seal/40° C./75%	98.8
Example			R.H./1m
Test 1	Sodium	0.10%	Seal/40° C./75%	99.1
	thiosulfate		R.H./1m

[0079] As shown in Table 14, the residual rate of Test 1 was higher than that of Comparative Example to which no antioxidant was added, so that with respect to a soft capsule, a significant stabilizing effect on Compound 1 due to the antioxidant was seen.

Example 8

[0080] Hydroxypropylmethylcellulose as a gelatinizing agent, Polyethylene glycol 4000 as a humectant, and ethyl paraoxybenzoate and butyl paraoxybenzoate as preservatives were dissolved in an aqueous solution containing Compound 1 and a predetermined amount of antioxidants, or were dissolved in an aqueous solution to which no antioxidant was added. Thus, aqueous gels shown in Prescription Example 7 were prepared. Tests 1 and Comparative Example are shown in Table 15.

(Prescription Example 7)

Aqueous Gel

[0081]

Compound 1                   1 mg
Hydroxypropylmethylcellulose 2 g
Polyethylene glycol 4000     15 g
Sodium thiosulfate           0 to 0.1 g
Ethyl paraoxybenzoate        0.03 g
Butyl paraoxybenzoate        0.02 g
Purified water               Balance volume
Total                        100 g

[0082]

TABLE 15
				Additive
Example 8	Dosage Form	Drug Content	Antioxidant	Rate
Comparative	Aqueous gel	10 μg/g	None	0.00%
Example
Test 1	Aqueous gel	10 μg/g	Sodium	0.10%
			thiosulfate

[0083] Stability test: After the aqueous gel of Test 1 and that of Comparative Example were sealed in aluminized tube, the aqueous gels were stored at a temperature of 60° C. and at a R.H. by 75% for one month. Then, the purities of Compound 1 in the aqueous gels were measured using a HPLC method (an UV method), so that stability of the aqueous gel was estimated.

TABLE 16
		Additive		Purity
Example 8	Antioxidant	Rate	Storage Conditions	(%)
Comparative	None	0.00%	Seal/60° C./75%	19.3
Example			R.H./l m
Test 1	Sodium	0.10%	Seal/60° C./75%	99.6
	thiosulfate		R.H./l m

[0084] As shown in Table 16, the purity of Test 1, to which sodium thiosulfate was added at a concentration of 0.1%, was higher than that of Comparative Example, to which sodium thiosulfate was not added, during storage under a severe condition. Thus, with respect to an aqueous gel, a significant stabilizing effect on Compound 1 due to sodium thiosulfate was seen.

Example 9

[0085] As shown in Prescription Example 8, Compound 1 was dissolved in a heated surfactant, and the mixture was mixed with liquid paraffin and white petrolatum. Thus, petrolatum ointments were obtained. Tests 1 to 6 and Comparative Example are shown in Table 17.

(Prescription Example 8)

Petrolatum Ointment

[0086]

Compound 1       1 mg
Surfactant       5 g
Liquid paraffin  15 g
White petrolatum Balance volume
Total            100 g

[0087]

TABLE 17
				Addi-
		Drug		tive
Example 9	Dosage Form	Content	Solubilizer	Rate
Comparative	Petrolatum	10 μg/g	Glyceryl monooleate	5.00%
Example	ointment
Test 1	Petrolatum	10 μg/g	Sorbitan	5.00%
	ointment		sesquioleate
Test 2	Petrolatum	10 μg/g	Sorbitan monolaurate	5.00%
	ointment
Test 3	Petrolatum	10 μg/g	Sorbitan	5.00%
	ointment		monopalmitate
Test 4	Petrolatum	10 μg/g	Polyoxyethylene (2)	5.00%
	ointment		lauryl ether
Test 5	Petrolatum	10 μg/g	Glyceryl	5.00%
	ointment		monomyristate
Test 6	Petrolatum	10 μg/g	polyoxyethylene (3)	5.00%
	ointment		nonylphenyl ether

[0088] Stability test during manufacturing: Yields of the major degradation products (N-oxides) in the ointments of Test 1 to 6 and that of Comparative Example were measured using a HPLC method (an UV method) immediately after the preparation therefor. Thus, stability during manufacturing was estimated.

TABLE 18
				Yield of
		Addi-		major
		tive	Storage	degradation
Example 9	Solubilizer	Rate	Conditions	product (%)
Comparative	Glyceryl	5.00%	Stability	5.6
Example	monooleate		immediately
			after
			manufacturing
Test 1	Sorbitan	5.00%	Stability	1
	sesquioleate		immediately
			after
			manufacturing
Test 2	Sorbitan	5.00%	Stability	0.7
	monolaurate		immediately
			after
			manufacturing
Test 3	Sorbitan	5.00%	Stability	0.8
	monopalmitate		immediately
			after
			manufacturing
Test 4	Polyoxyethylene	5.00%	Stability	1.6
	(2) lauryl ether		immediately
			after
			manufacturing
Test 5	Glyceryl	5.00%	Stability	0
	monomyristate		immediately
			after
			manufacturing
Test 6	polyoxyethylene	5.00%	Stability	0
	(3) nonylphenyl		immediately
	ether		after
			manufacturing

[0089] As shown in Table 18, the yields of the major degradation products of Tests 1 to 6 were lower than that of Comparative Example to which a surfactant was added. In particular, the addition of glyceryl monomyristate or polyoxyethylene nonylphenyl, that is, Test 5 or 6, respectively, showed a significant stabilizing effect.

Example 10

[0090] As shown in Prescription Example 9, Compound 1 and citric acid were dissolved in heated glycerin monomyristate, and the mixture was mixed with liquid paraffin and white petrolatum. Thus, petrolatum ointments to which a predetermined amount of citric acid was added, and a petrolatum ointment to which citric acid was not added were obtained. Tests 1, Test 2, and Comparative Example are shown in Table 19.

(Prescription Example 9)

Petrolatum Ointment

[0091]

Compound 1             1 mg
Glyceryl monomyristate 5 g
Citric acid            0 to 0.1 g
Liquid paraffin        15 g
White petrolatum       Balance volume
Total                  100 g

[0092]

TABLE 19
		Drug		Additive
Example 10	Dosage Form	Content	Antioxidant	Rate
Comparative	Petrolatum	10 μg/g	None	—
Example	ointment
Test 1	Petrolatum	10 μg/g	Citric acid	0.001%
	ointment
Test 2	Petrolatum	10 μg/g	Citric acid	0.10%
	ointment

[0093] Stability test: After the ointments of Test 1, Test 2 and Comparative Example were sealed in aluminized tubes, the ointments were stored at a temperature of 60° C. and at a R.H. by 75% for a half month. Then, the purities of Compund 1 in the ointments were measured using a HPLC method (an UV method), so that stability of the ointment was estimated.

TABLE 20
		Additive		Purity
Example 10	Antioxidant	Rate	Storage Conditions	(%)
Comparative	None	0.00%	Seal/60° C./75%	89.4
Example			R.H./0.5 m
Test 1	Citric acid	0.001%	Seal/60° C./75%	98.4
			R.H./0.5 m
Test 2	Citric acid	0.10%	Seal/60° C./75%	96.2
			R.H./0.5 m

[0094] As shown in Table 20, the purities of the drug of Tests 1 and 2 were higher than that of Comparative Example to which citric acid was not added. With respect to a petrolatum ointment, citric acid (a synergist) showed a significant stabilizing effect on Compound 1.

Example 11

[0095] As shown in Prescription Example 10, injections were prepared by adding a predetermined amount of an isotonizing agent to Compound 2 (50 μg/mL). Tests 1 to 3 and Comparative Example are shown in Table 21.

(Prescription Example 10)

Injection

[0096]

Compound 2          5 mg
Isotonizing agent   0.9 to 5 g
Water for injection Balance volume
Total               100 mL

[0097]

TABLE 21
		Drug	Isotonizing	Additive
Example 11	Dosage Form	Content	Agent	Rate
Comparative	Injection	50 μg/mL	Sodium chloride	0.90%
Example
Test 1	Injection	50 μg/mL	Glucose	5.00%
Test 2	Injection	50 μg/mL	Xylitol	5.00%
Test 3	Injection	50 μg/mL	Mannitol	5.00%

[0098] Stability test: The aqueous solutions of Tests 1 to 3, and that of Comparative Example were sealed in ampoules. After sterilization by high-pressure steam at a temperature of 121° C. for 30 minutes, the residual rates of Compound 2 in the samples were measured using a HPLC method (an UV method). Thus, pharmaceutical stability after sterilization was estimated.

TABLE 22
Example	Isotonizing	Additive	Storage	Residual
11	Agent	Rate	Conditions	Rate (%)
Com-	Sodium	0.90%	Seal/121° C./30 mim	94.7
parative	chloride
Example
Test 1	Glucose	5.00%	Seal/121° C./30 mim	100.0
Test 2	Xylitol	5.00%	Seal/121° C./30 mim	98.0
Test 3	Mannitol	5.00%	Seal/121° C./30 mim	100.0

[0099] As shown in Table 22, the residual rates of Tests 1 to 3 were significantly higher than that of Comparative Example to which sodium chloride as an isotonizing agent was added. Therefore, with respect to the high-pressure steam sterilization process, sugars as isotonizing agents showed significant stabilizing effects on Compound 2.

Industrial Applicability

[0100] As shown in the results of the above-described examples, a pharmaceutical composition including a 4,5-epoxy-morphinan derivative in accordance with the present invention is a stable pharmaceutical preparation in which stability of the 4,5-epoxy-morphinan derivative is improved. Furthermore, the stability thereof is significantly improved by optimizing compound ratio and ingredients thereof. In addition, since a stabilization effect is seen, in spite of variations in the dosage form of the drug, it is suggested that the handling during manufacturing the drug and storing thereof can be improved, and effectiveness, stability, and handling during administration can also be improved. Furthermore, a variety of dosage forms and administration routes can be selected, and indications for treatments for various diseases can be expanded.

Claims

1. A pharmaceutical composition comprising, a 4,5-epoxy-morphinan derivative and at least one substance selected from the group consisting of the following materials (1), (2), (3), (4) and (5): (1) a water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate; (2) a fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole; (3) a synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin; (4) a sugar selected from the group consisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose; and (5) a surfactant selected from the group consisting of sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

2. A pharmaceutical composition according to claim 1, wherein the 4,5-epoxy-morphinan derivative is a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 5

3. A pharmaceutical composition according to claim 2, wherein in the general formula (I), R1 is a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, an allyl group, a benzyl group, or a phenethyl group; R2 and R3 are, independently of one another, a hydrogen atom, a hydroxy group, an acetoxy group, or a metoxy group; A is —N(R4)C(═O)—, —N(R4)C(═O)O—, —N(R4)—, or —N(R4)SO2— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms); B is a straight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH2O— or —CH2S—; R5 is the same as that in claim 2; and R6 is a hydrogen atom.

4. A pharmaceutical composition according to claim 3, wherein in the general formula (I), R5 is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 7

5. A pharmaceutical composition according to claim 4, wherein in the general formula (I), R1 is a cyclopropylmethyl group or an allyl group; A is —N(R4)C(═O)— or —N(R4)C(═O)O— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms); and B is a straight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—, or —C≡C—.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein each content of the water soluble antioxidant, the fat soluble antioxidant, and the synergist ranges from 0.00001 to 10 percent by weight of the total pharmaceutical composition.

7. An injection preparation comprising: a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 8wherein . . . is a double bond, or a single bond; R1 is an alkyl group having from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl group having from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbon atoms; R2 is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or —NR7R8; R7 is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R8 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or —C((═O)R9—; R9 is a hydrogen atom, a phenyl group, or an alkyl group having from 1 to 5 carbon atoms; R3 is a hydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is —N(R4)C(═X)—, —N(R4)C(═X)Y—, —N(R4)—, or —N(R4)SO2— (wherein X and Y are, independently of one another, NR4, S, or O; and R4 is a hydrogen atom, a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R4 is identical or different in the formula); B is a valence bond, a straight-chain or branched-chain alkylene group having from 1 to 14 carbon atoms (wherein the alkylene group is optionally substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the alkylene group is optionally replaced with carbonyl groups), a straight-chain or branched-chain acyclic unsaturated hydrocarbon containing from one to three double bonds and/or triple bonds and having from 2 to 14 carbon atoms (wherein the acyclic unsaturated hydrocarbon is optionally substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the acyclic unsaturated hydrocarbon is optionally replaced with carbonyl groups), or a straight-chain or branched-chain saturated or unsaturated hydrocarbon containing from one to five thioether, ether, and/or amino bonds and having from 1 to 14 carbon atoms (wherein no hetero atoms are bonded directly to A, and one to three methylene groups of the hydrocarbon is optionally replaced with carbonyl groups); and R5 is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 9Organic Groups Represented by R5 wherein the organic group has optionally at least one substituent selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group; R6 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoyl group having from 1 to 5 carbon atoms; and at least one sugar selected from the group consisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose.

8. An injection preparation according to claim 7, further comprising, at least one substance selected from the group consisting of the following materials (1), (2), and (3): (1) a water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate; (2) a fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole; and (3) a synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin.

9. An external preparation comprising: a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 10wherein . . . is a double bond, or a single bond; R1 is an alkyl group having from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl group having from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbon atoms; R2 is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or —NR7R8; R7 is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R8 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or —C((═O)R9—; R9 is a hydrogen atom, a phenyl group, or an alkyl group having from 1 to 5 carbon atoms; R3 is a hydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is —N(R4)C(═X)—, —N(R4)C(═X)Y—, —N(R4)—, or —N(R4)SO2— (wherein X and Y are, independently of one another, NR4, S, or O; and R4 is a hydrogen atom, a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R4 is identical or different in the formula); B is a valence bond, a straight-chain or branched-chain alkylene group having from 1 to 14 carbon atoms (wherein the alkylene group is optionally substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the alkylene group is optionally replaced with carbonyl groups), a straight-chain or branched-chain acyclic unsaturated hydrocarbon containing from one to three double bonds and/or triple bonds and having from 2 to 14 carbon atoms (wherein the acyclic unsaturated hydrocarbon is optionally substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the acyclic unsaturated hydrocarbon is optionally replaced with carbonyl groups), or a straight-chain or branched-chain saturated or unsaturated hydrocarbon containing from one to five thioether, ether, and/or amino bonds and having from 1 to 14 carbon atoms (wherein no hetero atoms are bonded directly to A, and one to three methylene groups of the hydrocarbon is optionally replaced with carbonyl groups); and R5is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 11Organic Groups Represented by R5 wherein the organic group has optionally at least one substituent selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group; R6 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoyl group having from 1 to 5 carbon atoms; and at least one surfactant selected from the group consisting of sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

10. An external preparation according to claim 9, further comprising, at least one substance selected from the group consisting of the following materials (1), (2), and (3): (1) a water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate; (2) a fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole; and (3) a synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin.

11. A method for stabilizing a 4,5-epoxy-morphinan derivative, wherein at least one substance selected from the group consisting of the following materials (1), (2), (3), (4), and (5) is used; (1) a water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate; (2) a fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole; (3) a synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin; (4) a sugar selected from the group consisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose; and (5) a surfactant selected from the group consisting of sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

12. A method for stabilizing a 4,5-epoxy-morphinan derivative according to claim 11, wherein the 4,5-epoxy-morphinan derivative is a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 12

13. A method for stabilizing a 4,5-epoxy-morphinan derivative according to claim 12, wherein in the general formula (I), R1 is a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, an allyl group, a benzyl group, or a phenethyl group; R2 and R3 are, independently of one another, a hydrogen atom, a hydroxy group, an acetoxy group, or a metoxy group; A is —N(R4)C(═O)—, —N(R4)C(═O)O —, —N(R4)—, or —N(R4)SO2— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms); B is a atoms, —CH═CH—, —C≡C—, —CH2O— or —CH2S—; R5 is the same as that in claim 2; and R6 is a hydrogen atom.

14. A method for stabilizing a 4,5-epoxy-morphinan derivative according to claim 13, wherein in the general formula (I), R5 is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 14

15. A method for stabilizing a 4,5-epoxy-morphinan derivative according to claim 14, wherein in the general formula (I), R1 is a cyclopropylmethyl group or an allyl group; A is —N(R4)C(═O)— or —N(R4)C(═O)O— (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms); and B is a straight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—, or —C≡C—.