Aqueous liquid composition for external use

Claim 2

An aqueous liquid composition for external use characterized in that the composition contains a tricyclo compound of the formula: wherein each vicinal pair of substituents [R¹ and R²], [R³ and R⁴], [R⁵ and R⁶] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R² may represent an alkyl group; R⁷ represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R¹ it may represent =0; R⁸ and R⁹ independently represent H or OH; R¹⁰ represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =0; X represents O, (H,OH)), (H,H) or -CH₂O-; Y represents O, (H,OH), (H,H), N-NR¹¹R¹² or N-OR¹³; R¹¹ and R¹² independently represent H, alkyl, aryl or tosyl; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²², and R²³ independently represent H or alkyl; R²⁰ and R²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H) respectively; R²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₃ or R²¹a is protected hydroxy; in addition, R²⁰a and R²¹a may together represent an oxygen atom in an epoxide ring; N is 1, 2 or 3; in addition to their significances above, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a 5- or 6-­membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅); or a pharmaceutically acceptable salt thereof and a water-soluble solubilizer.

Claim 3

The aqueous liquid composition of claim 1, which is an aqueous eye drop.

Claim 4

The aqueous eye drop of claim 2, which is aqueous suspending eye drop.

Claim 5

The aqueous suspending eye drop of claim 3, wherein the water-soluble solubilizer is a water-soluble cellulose polymer.

Claim 6

The aqueous suspending eye drop of claim 4, wherein the water-soluble cellulose polymer is hydroxypropylmethyl­cellulose.

Claim 7

The aqueous suspending eye drop of claim 5, wherein the tricyclo compound is 17-allyl-1,14-dihydroxy-12-[2-(4-­hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-­13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo­[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.

Claim 8

A process for preparing an aqueous liquid composition comprising a tricyclo compound of the formula: wherein each vicinal pair of substituents [R¹ and R²], [R³ and R⁴], [R⁵ and R⁶] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R² may represent an alkyl group; R⁷ represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R¹ it may represent =0; R⁸ and R⁹ independently represent H or OH; R¹⁰ represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =0; X represents O, (H,OH), (H,H) or -CH₂O-; Y represents O, (H,OH), (H,H), N-NR¹¹R¹² or N-OR¹³; R¹¹ and R¹² independently represent H, alkyl, aryl or tosyl; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ independently represent H or alkyl; R²⁰ and R²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H) respectively; R²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₃ or R²¹a is protected hydroxy; in addition, R²⁰a and R²¹a may together represent an oxygen atom in an epoxide ring; N is 1, 2 or 3; in addition to their significances above, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a 5- or 6-­membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅); or a pharmaceutically acceptable salt thereof and a water-soluble solubilizer, which is characterized by (1) (i) dissolving the tricyclo compound (I) in an organic solvent, and (ii) adding a water-soluble solubilizer to the resultant solution, and (iii) removing the solvent therefrom, and (iv) if necessary, adding additives in the resultant residue, and then (v) adding physiological saline or distilled water in the resultant mixture, (2) (i) dissolving a water-soluble solubilizer in physiological saline or distilled water, and (ii) if necessary, adding additives in the resultant solution, and then (iii) adding the tricyclo compound (I) in the resultant solution, or (3) (i) dissolving the tricyclo compound (I) in a water-soluble solubilizer, and (ii) if necessary, adding additives in the resulting mixture, and then (iii) adding physiological saline or distilled water in the resulting mixture.

Claim 9

A process for preparing an aqueous liquid composition comprising a tricyclo compound of the formula: wherein each vicinal pair of substituents [R¹ and R²], [R³ and R⁴], [R⁵ and R⁶] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R² may represent an alkyl group; R⁷ represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R¹ it may represent =0; R⁸ and R⁹ independently represent H or OH; R¹⁰ represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =0; X represents O, (H,OH), (H,H) or -CH₂O-; Y represents O, (H,OH), (H,H), N-NR¹¹R¹² or N-OR¹³; R¹¹ and R¹² independently represent H, alkyl, aryl or tosyl; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ independently represent H or alkyl; R²⁰ and R²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H) respectively; R²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₃ or R²¹a is protected hydroxy; in addition, R²⁰a and R²¹a may together represent an oxygen atom in an epoxide ring; N is 1, 2 or 3; in addition to their significances above, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a 5- or 6-­membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅); or a pharmaceutically acceptable salt thereof and a water-soluble solubilizer, which is characterized by (1) (i) dissolving the tricyclo compound (I) in an organic solvent, and (ii) adding a water-soluble solubilizer to the resultant solution, and (iii) removing the solvent therefrom, and (iv) if necessary, adding additives in the resultant residue, and then (v) adding physiological saline or distilled water in the resultant mixture, (2) (i) dissolving a water-soluble solubilizer in physiological saline or distilled water, and (ii) if necessary, adding additives in the resultant solution, and then (iii) adding the tricyclo compound (I) in the resultant solution, or (3) (i) dissolving the tricyclo compound (I) in a water-soluble solubilizer, and (ii) if necessary, adding additives in the resulting mixture, and then (iii) adding physiological saline or distilled water in the resulting mixture.