Pharmaceutical composition
View Patent ↗The present invention relates to a pharmaceutical composition containing a cycloalkene compound, a salt thereof or a prodrug thereof, and a nonionic surfactant and/or a cyclodextrin derivative readily soluble in water, and a method for improving solubility, stability or coloring property of the compound, a salt thereof or a prodrug thereof.
1. A pharmaceutical composition comprising a compound represented by the formula (I):
wherein R is an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1 (wherein R 1 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula:
wherein R 1b is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 1c is the same as or different from R 1b and is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 0 is a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination represent a bond, ring A 1 is a cycloalkene optionally substituted by 1 to 4 substituents selected from (1) an aliphatic hydrocarbon group optionally having substituents, (2) an aromatic hydrocarbon group optionally having substituents, (3) a group represented by the formula: —OR 1 (wherein R 1 is as defined above) and (4) a halogen atom, Ar is an aromatic hydrocarbon group optionally having substituents, a group represented by the formula:
represents a group represented by the formula:
and n is an integer of 1 to 4, a salt thereof or a prodrug thereof, a nonionic surfactant and ethanol, wherein said nonionic surfactant is polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil.
2. The composition of claim 1 , wherein the compound is (A) d-ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (B) d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (C) ethyl 6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (D) ethyl 6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, or a salt thereof.
3. The composition of claim 1 , wherein a content of the nonionic surfactant is about 10 wt %-about 70 wt % of the whole composition.
4. The composition of claim 1 , wherein a content of the ethanol is about 30 wt %-about 90 wt % of the whole composition.
5. The composition of claim 1 , wherein a mixing ratio of the nonionic surfactant and ethanol is about 90 parts by weight-about 10 parts by weight of ethanol relative to about 10 parts by weight-about 90 parts by weight of the nonionic surfactant.
6. The composition of claim 1 , which is used as an injectable composition.
7. The composition of claim 6 , which is a non-emulsified composition.
8. The composition of claim 1 , which is clear.
9. A method for improving solubility, stability or coloring property of a compound represented by the formula (I):
wherein R is an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1 (wherein R 1 is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula:
wherein R 1b is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 1c is the same as or different from R 1b and is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 0 is a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination represent a bond, ring A 1 is a cycloalkene optionally substituted by 1 to 4 substituents selected from (1) an aliphatic hydrocarbon group optionally having substituents, (2) an aromatic hydrocarbon group optionally having substituents, (3) a group represented by the formula: —OR 1 (wherein R 1 is as defined above) and (4) a halogen atom, Ar is an aromatic hydrocarbon group optionally having substituents, a group represented by the formula:
represents a group represented by the formula:
and n is an integer of 1 to 4, a salt thereof or a prodrug thereof, which comprises mixing said compound, a salt thereof or a prodrug thereof, with a nonionic surfactant.
10. A method for the treatment of a cardiac disease, an autoimmune disease or septic shock, which comprises administrating an effective amount of the composition of claim 1 to a mammal.