Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-19
2002-04-16
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06372755
ABSTRACT:
This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/JP98/03096 which has an International filing date of Jul. 10, 1998, which designated the United States of America.
TECHNICAL FIELD
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
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.
Recently, it has become clear that opiate receptors may be classified into three types, that is, &mgr;, &dgr;, and &kgr; receptor, which function as central analgesic receptors. In addition, an opiate &sgr; receptor has also been elucidated which affects mental function.
The severe adverse reactions accompanied by administration of morphine are specific to the &mgr; receptor agonist and to the &sgr; receptor agonist. The &dgr; receptor agonist and the &kgr; receptor agonist seem not to show the above-mentioned adverse reactions.
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 &kgr; receptor or to the &dgr; 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 &sgr; receptor. Therefore, the 4,5-epoxy-morphinan derivative is a promising analgesic and a promising diuretic (WO93/15081).
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.
Therefore, it is significantly useful that a stable pharmaceutical preparation including these 4,5-epoxy-morphinan derivatives is prepared.
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.
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
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).
(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.
(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.
(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
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.
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:
wherein - - - is a double bond or a single bond; R
1
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; R
2
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 —NR
7
R
8
; R
7
is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R
8
is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or —C(═O)R
9
; R
9
is a hydrogen atom, a phenyl group, or an alkyl group having from 1 to 5 carbon atoms; R
3
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(R
4
)C(═X)—, —N(R
4
)C(═X)Y—, —N(R
4
)—, or —N(R
4
)SO
2
— (wherein X and Y are, independently of one another, NR
4
, S, or O; and R
4
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 R
4
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
Aoki Takao
Hanamura Nobuyuki
Hara Michio
Horiuchi Yasuhide
Yoshii Ryoji
Jarvis William R. A.
Toray Industries Inc.
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