Composition containing PGI2 analogs stabilized

Claim 2

A stabilized composition which contains a PGI 2 analogue in solution in a solvent consisting essentially of at least one pharmacologically-acceptable alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, hexamethylphosphoramide, dimethyl sulphoxide, or a middle chain triglyceride, or which is a cyclodextrin clathrate of a PGI 2 analogue, said PGI 2 analogue being selected from the group consisting of PGI 2 compounds in which the carboxyl group of PGI 2 , 5(E)PGI 2 , 11-deoxy-PGI 2 , 13,14-dihydro-PGI 2 , trans-delta2-PGI 2 , 16-chloro-PGI 2 , 7-methyl-PGI 2 and 7a-homo-PGI 2 is esterified or replaced by CH 2 OH, compounds differing from PGI 2 5(E)-PGI 2 , 11-deoxy-PGI 2 , 13,14-dihydro-PGI 2 , and trans-delta2-PGI 2 by having a longer or shorter side chain attached to the 6- or 12-position, and in which the side chain attached to the 6-position may carry an alkyl substituent and the side chain attached to the 12-position may carry an alkyl, hydroxy, cycloalkyl, phenyl or phenoxy substituent, and such compounds in which the carboxyl group is esterified or replaced by CH 2 OH.

Claim 3

A pharmaceutical composition useful for the treatment of arteriosclerosis, cardiac failure or thrombosis which comprises, as active ingredient, an effective amount of a cyclodextrin clathrate of a PGI 2 analogue as specified in claim 1 in association with a pharmaceutically acceptable carrier.

Claim 4

A cyclodextrin clathrate of a PGI 2 analogue, said PGI 2 analogue being selected from the group consisting of compounds in which the carboxy group of PGI 2 is esterified or replaced by an alcohol group (--CH 2 OH), compounds which possess carbon skeletons similar to that of PGI 2 with a corresponding carboxy group but in which the side chains attached to the 6- and 12-positions may be longer or shorter than those of PGI 2 , and in which the side chain attached to the 6-position may carry an alkyl substituent and the side chain attached to the 12-position may carry an alkyl, hydroxy, cycloalkyl, phenyl or phenoxy substituent, and such compounds in which the carboxy group is esterified or replaced by an alcohol group, and corresponding 5(E)-PGI 2 compounds, corresponding 11-deoxy-PGI 2 compounds, corresponding 13,14-dihydro-PGI 2 compounds, corresponding trans-Δ 2 -PGI 2 compounds, corresponding 16-chloro-PGI 2 compounds, corresponding 7-methyl-PGI 2 compounds, and corresponding 7a-homo-PGI 2 compounds.

Claim 5

A cyclodextrin clathrate of a PGI 2 analogue, said PGI 2 analogue being selected from the group consisting of compounds in which the carboxy group of PGI 2 is esterified or replaced by an alcohol group (--CH 2 OH), compounds which possess carbon skeletons similar to that of PGI 2 with a corresponding carboxy group but in which the side chains attached to the 6- and 12-positions may be longer or shorter than those of PGI 2 , and in which the side chain attached to the 6-position may carry an alkyl substituent and the side chain attached to the 12-position may carry an alkyl, hydroxy, cycloalkyl, phenyl or phenoxy substituent, and such compounds in which the carboxy group is esterified or replaced by an alcohol group, and corresponding 5(E)-PGI 2 compounds, corresponding 11-deoxy-PGI 2 compounds, corresponding 13,14-dihydro-PGI 2 compounds, corresponding trans-Δ 2 -PGI 2 compounds, corresponding 16-chloro-PGI 2 compounds, corresponding 7-methyl-PGI 2 compounds, and corresponding 7a-homo-PGI 2 compounds.

Claim 6

A pharmaceutical composition useful for the treatment of arteriosclerosis, cardiac failure or thrombosis which comprises, as active ingredient, an effective amount of a cyclodextrin clathrate of a PGI 2 analogue in association with a pharmaceutically acceptable carrier, said PGI 2 analogue being selected from the group consisting of compounds in which the carboxy group of PGI 2 is esterified or replaced by an alcohol group (--CH 2 OH), compounds which possess carbon skeletons similar to that of PGI 2 with a corresponding carboxy group but in which the side chains attached to the 6- and 12-positions may be longer or shorter than those of PGI 2 , and in which the side chain attached to the 6-position may carry an alkyl substituent and the side chain attached to the 12-position may carry an alkyl, hydroxy, cycloalkyl, phenyl or phenoxy substituent, and such compounds in which the carboxy group is esterified or replaced by an alcohol group, and corresponding 5(E)-PGI 2 compounds, corresponding 11-deoxy-PGI 2 compounds, corresponding 13,14-dihydro-PGI 2 compounds, corresponding trans-Δ 2 -PGI 2 compounds, corresponding 16-chloro-PGI 2 compounds, corresponding 7-methyl-PGI 2 compounds, and corresponding 7a-homo-PGI 2 compounds.

Claim 7

A pharmaceutical composition useful for the treatment of arteriosclerosis, cardiac failure or thrombosis which comprises, as active ingredient, an effective amount of a cyclodextrin clathrate of a PGI 2 analogue in association with a pharmaceutically acceptable carrier, said PGI 2 analogue being selected from the group consisting of compounds in which the carboxy group of PGI 2 is esterified or replaced by an alcohol group (--CH 2 OH), compounds which possess carbon skeletons similar to that of PGI 2 with a corresponding carboxy group but in which the side chains attached to the 6- and 12-positions may be longer or shorter than those of PGI 2 , and in which the side chain attached to the 6-position may carry an alkyl substituent and the side chain attached to the 12-position may carry an alkyl, hydroxy, cycloalkyl, phenyl or phenoxy substituent, and such compounds in which the carboxy group is esterified or replaced by an alcohol group, and corresponding 5(E)-PGI 2 compounds, corresponding 11-deoxy-PGI 2 compounds, corresponding 13,14-dihydro-PGI 2 compounds, corresponding trans-Δ 2 -PGI 2 compounds, corresponding 16-chloro-PGI 2 compounds, corresponding 7-methyl-PGI 2 compounds, and corresponding 7a-homo-PGI 2 compounds.

Claim 8

A cyclodextrin clathrate of a PGI 2 analogue in the form of an ester or alcohol derivative of PGI 2 , 2a-homo-PGI 2 , 7a-homo-PGI 2 , 2-nor-PGI 2 , 2-methyl-PGI 2 , 3-methyl-PGI 2 , 5-methyl-PGI 2 , 7-methyl-PGI 2 , 15 methyl-PGI 2 , 16-methyl-PGI 2 , 17-methyl-PGI 2 , 16,16-dimethyl-PGI 2 , 17,20-dimethyl-PGI 2 , 17-ethyl-PGI 2 , 20 hydroxy-PGI 2 , 16-chloro-PGI 2 , 15-cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(1 butyl)cyclobutyl-16,17,18,19,20-pentanor-PGI 2 , 15-(2-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 16-cyclohexyl-17,18,19,20-tetranor-PGI 2 , 16-cyclopentyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-19,20-dinor-PGI 2 , 16-methyl-17-cyclohexyl-18,19,20-trinor-PGI 2 , 19-cyclohexyl-20-nor-PGI 2 , 16-phenyl-17,18,19,20-tetranor-PGI 2 , 16-phenoxy-17,18,19,20-tetranor-PGI 2 , 16-(4-chlorophenoxy)-17,18,19,20-tetranor-PGI 2 , 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGI 2 or of a corresponding (5E)-PGI 2 analogue, corresponding 11-deoxy-PGI 2 analogue, corresponding 13,14-dihydro-PGI 2 analogue or corresponding trans-Δ 2 -PGI 2 analogue.

Claim 9

A cyclodextrin clathrate of a PGI 2 analogue in the form of an ester or alcohol derivative of PGI 2 , 2a-homo-PGI 2 , 7a-homo-PGI 2 , 2-nor-PGI 2 , 2-methyl-PGI 2 , 3-methyl-PGI 2 , 5-methyl-PGI 2 , 7-methyl-PGI 2 , 15 methyl-PGI 2 , 16-methyl-PGI 2 , 17-methyl-PGI 2 , 16,16-dimethyl-PGI 2 , 17,20-dimethyl-PGI 2 , 17-ethyl-PGI 2 , 20 hydroxy-PGI 2 , 16-chloro-PGI 2 , 15-cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(1 butyl)cyclobutyl-16,17,18,19,20-pentanor-PGI 2 , 15-(2-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 16-cyclohexyl-17,18,19,20-tetranor-PGI 2 , 16-cyclopentyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-19,20-dinor-PGI 2 , 16-methyl-17-cyclohexyl-18,19,20-trinor-PGI 2 , 19-cyclohexyl-20-nor-PGI 2 , 16-phenyl-17,18,19,20-tetranor-PGI 2 , 16-phenoxy-17,18,19,20-tetranor-PGI 2 , 16-(4-chlorophenoxy)-17,18,19,20-tetranor-PGI 2 , 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGI 2 or of a corresponding (5E)-PGI 2 analogue, corresponding 11-deoxy-PGI 2 analogue, corresponding 13,14-dihydro-PGI 2 analogue or corresponding trans-Δ 2 -PGI 2 analogue.

Claim 10

A cyclodextrin clathrate according to claim 5 wherein the ester is a straight- or branched-chain alkyl ester containing from 1 to 12 carbon atoms in the esterifying alkyl moiety, a carboalkoxyalkyl ester in which the esterifying moiety is of the general formula --C n H 2n COOR 1 (wherein n represents an integer from 1 to 12 and R 1 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms), a hydroxy- or alkoxy-alkyl ester in which the esterifying moiety is of the general formula --C n H 2n OR 2 (wherein R 2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), a mono- or di-alkylaminoalkyl ester in which the esterifying moiety is of the general formula ##STR3## (wherein R 3 and R 4 , which may be the same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), an aralkyl ester containing from 7 to 12 carbon atoms, a cycloalkyl ester containing from 4 to 7 carbon atoms in the ring, which may be unsubstituted or substituted by at least one alkyl group containing from 1 to 4 carbon atoms, or a phenyl ester in which the phenyl group is unsubstituted or carries at least one substituent selected from chlorine atoms, trifluoromethyl groups, straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms and phenyl groups.

Claim 11

A cyclodextrin clathrate according to claim 6 wherein the ester is an alkyl ester containing from 1 to 4 carbon atoms in the esterifying alkyl moiety.

Claim 12

A cyclodextrin clathrate of a PGI 2 analogue as specified in claim 5 in which the molar ratio of cyclodextrin to PGI 2 analogue is from 1 to 25:1.

Claim 13

A cyclodextrin clathrate according to claim 8 in which the molar ratio is from 3 to 15:1.

Claim 14

A cyclodextrin clathrate of a PGI 2 analogue specified in claim 6 or 7 in which the molar ratio of cyclodextrin to PGI 2 analogue is from 1 to 25:1.

Claim 15

A pharmaceutical composition useful for the treatment of arteriosclerosis, cardiac failure or thrombosis which comprises, as active ingredient, an effective amount of a cyclodextrin clathrate of a PGI 2 analogue as specified in claim 5 in association with a pharmaceutically acceptable carrier.

Claim 16

A stabilized composition which contains a PGI 2 analogue in the form of an ester or alcohol derivative of PGI 2 , 2a-homo-PGI 2 , 7a-homo-PGI 2 , 2-nor-PGI 2 , 2-methyl-PGI 2 , 3-methyl-PGI 2 , 5-methyl-PGI 2 , 7-methyl-PGI 2 , 15-methyl-PGI 2 , 16-methyl-PGI 2 , 17-methyl-PGI 2 , 16,16-dimethyl-PGI 2 , 17,20-dimethyl-PGI 2 , 17-ethyl-PGI 2 , 20-hydroxy-PGI 2 , 16-chloro-PGI 2 , 20-chloro-PGI 2 , 16-methyl-20-chloro-PGI 2 , 15-cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(1 butyl)cyclobutyl-16,17,18,19,20-pentanor-PGI 2 , 15-(2-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 16-cyclohexyl-17,18,19,20-tetranor-PGI 2 , 16-cyclopentyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-19,20-dinor-PGI 2 , 16-methyl-17-cyclohexyl-18,19,20-trinor-PGI 2 , 19-cyclohexyl-20-nor-PGI 2 , 16-phenyl-17,18,19,20-tetranor-PGI.sub. 2, 16-phenoxy-17,18,19,20-tetranor-PGI 2 , 16-(4-chlorophenoxy)-17,18,19,20-tetranor-PGI 2 , 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGI 2 or of a corresponding (5E)-PGI 2 analogue, corresponding 11-deoxy-PGI 2 analogue, corresponding 13,14-dihydro-PGI 2 analogue or corresponding trans-Δ 2 -PGI 2 analogue in solution in a pharmacologically-acceptable alcohol, N,N-dimethyl acetamide, N,N-dimethylformamide, hexamethyl phosphoramide, dimethyl sulphoxide, or a middle chain triglyceride.

Claim 17

A stabilized composition which contains a PGI 2 analogue in the form of an ester or alcohol derivative of PGI 2 , 2a-homo-PGI 2 , 7a-homo-PGI 2 , 2-nor-PGI 2 , 2-methyl-PGI 2 , 3-methyl-PGI 2 , 5-methyl-PGI 2 , 7-methyl-PGI 2 , 15-methyl-PGI 2 , 16-methyl-PGI 2 , 17-methyl-PGI 2 , 16,16-dimethyl-PGI 2 , 17,20-dimethyl-PGI 2 , 17-ethyl-PGI 2 , 20-hydroxy-PGI 2 , 16-chloro-PGI 2 , 20-chloro-PGI 2 , 16-methyl-20-chloro-PGI 2 , 15-cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(1 butyl)cyclobutyl-16,17,18,19,20-pentanor-PGI 2 , 15-(2-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanor-PGI 2 , 15-(3-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanor-PGI 2 , 16-cyclohexyl-17,18,19,20-tetranor-PGI 2 , 16-cyclopentyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-18,19,20-trinor-PGI 2 , 17-cyclohexyl-19,20-dinor-PGI 2 , 16-methyl-17-cyclohexyl-18,19,20-trinor-PGI 2 , 19-cyclohexyl-20-nor-PGI 2 , 16-phenyl-17,18,19,20-tetranor-PGI.sub. 2, 16-phenoxy-17,18,19,20-tetranor-PGI 2 , 16-(4-chlorophenoxy)-17,18,19,20-tetranor-PGI 2 , 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGI 2 or of a corresponding (5E)-PGI 2 analogue, corresponding 11-deoxy-PGI 2 analogue, corresponding 13,14-dihydro-PGI 2 analogue or corresponding trans-Δ 2 -PGI 2 analogue in solution in a pharmacologically-acceptable alcohol, N,N-dimethyl acetamide, N,N-dimethylformamide, hexamethyl phosphoramide, dimethyl sulphoxide, or a middle chain triglyceride.

Claim 18

A composition according to claim 12 wherein the solvent is ethanol.

Claim 19

A composition according to claim 12 wherein the solvent is dimethyl sulphoxide.

Claim 20

A composition according to claim 12 wherein the solvent is N,N-dimethylacetamide.

Claim 21

A composition according to claim 12 wherein the solvent consists of at least one middle chain triglyceride which is liquid at ambient temperature and in which the esterifying acid or acids, which may be the same or different, may be saturated or unsaturated.

Claim 22

A composition according to claim 12 wherein the solvent is tricaproin.

Claim 23

A composition according to claim 12 wherein the solvent is tricaprylin.

Claim 24

A composition according to claim 12 wherein the concentration of PGI 2 analogue in solution is from 0.01 mg/ml to 100 mg/ml.

Claim 25

A composition according to claim 19 wherein the concentration in solution is from 0.5 mg/ml to 10 mg/ml.