Ophthalmic preparations

Details Ophthalmic preparations Ophthalmic preparations

1998-03-09

2001-05-15

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S573000, C514S913000

Reexamination Certificate

active

06232343

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an ophthalmic preparation having an effect of decreasing ocular tension, which has a therapeutic and prevention effects against various ophthalmic diseases such as glaucoma, hypertonia oculi or cataract.
BACKGROUND ART
Beraprost (the general name of (±)-1R*, 2R*, 3aS*, 8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S* )-3-hydroxy-4-methyl-1-octene-6-ynyl)-1H-cyclopentane[b]benzofuran-5-butyric acid) is a stable derivative of prostaglandin I
2
(PGI
2
) and has a wide variety of physiological actions such as strong antithrombotic activity and peripheral vasodilator action. Thus, beraprost has been attracting attention as a drug for improving peripheral circulatory disturbance.
However, application of beraprost to ophthalmic preparations has not been started. Research and development of application of beraprost to therapeutic agents of ophthalmic diseases, especially glaucoma, cataract and the like, is waited for.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide an ophthalmic preparation which exhibits excellent pharmacological effect against the above-mentioned ophthalmic diseases.
The present inventors discovered usefulness of beraprost and salts thereof as a therapeutic drug for glaucoma, hypertonia oculi, or postoperative hypertonia oculi by administering an ophthalmic preparation containing beraprost or a salt thereof, and discovered usefulness of the beraprost and salts thereof as a therapeutic drug for cataract by discovering the activity of beraprost to inhibit the swelling of crystalline lens and to inhibit the decrease of reduced glutathione in crystalline lens when crystalline lens is cultured with high concentration of galactose, thereby completing the present invention.
That is, the present invention provides an ophthalmic preparation comprising as an effective ingredient a 4,8-inter-m-phenylene prostaglandin I
2
derivative of the formula (I):
(wherein R
1
is
(A) COOR
2
(wherein R
2
is
1) hydrogen or a pharmaceutically acceptable cation,
2) C
1
-C
12
straight alkyl or C
3
-C
14
branched alkyl,
3) —Z—R
3
(wherein Z is a valence bond or straight or branched alkylene represented by C
t
H
2t
wherein t is an integer of 1-6, R
3
is C
3
-C
12
cycloalkyl or C
3
-C
12
cycloalkyl substituted with 1 to 3 R
4
wherein R
4
is hydrogen or C
1
-C
5
alkyl),
4) —(CH
2
CH
2
O)
n
CH
3
(wherein n is an integer of 1-5),
5) —Z—Ar
1
(wherein Z represents the same meaning as described above, Ar
1
is phenyl, &agr;-naphthyl, &bgr;-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, &agr;-furyl, &bgr;-furyl, &agr;-thienyl, &bgr;-thienyl or substituted phenyl (wherein the substituent is at least one selected from the group consisting of chlorine, bromine, fluorine, iodine, trifluoromethyl, C
1
-C
4
alkyl, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, —CH═N—NH—C(═O)—NH
2
, —NH—C(═O)—Ph, —NH—C(═O)—CH
3
and —NH—C(═O)—NH
2
—,
6) —C
t
H
2t
COOR
4
(wherein C
t
H
2t
and R
4
represent the same meanings as described above),
7) —C
t
H
2t
N(R
4
)
2
(wherein C
t
H
2t
and R
4
represent the same meanings as described above),
8) —CH(R
5
)—C(═O)—R
6
(wherein R
5
is hydrogen or benzoyl, R
6
is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidephenyl or 2-naphthyl),
9) —C
p
H
2p
—W—R
7
(wherein W is —CH═CH—, —CH═CR
7
— or —C≡C—, R
7
is hydrogen, C
1
-C
30
straight or branched alkyl or aralkyl, p is an integer of 1-5), or
10) —CH (CH
2
OR
8
)
2
(wherein R
8
is C
1
-C
30
alkyl or acyl)
(B) —CH
2
OH
(C)—C(═O)N(R
9
)
2
(wherein R
9
is hydrogen, C
1
-C
12
straight alkyl, C
3
-C
12
branched alkyl, C
3
-C
12
cycloalkyl, C
4
-C
13
cycloalkylalylene, phenyl, substituted phenyl (wherein the definition of the substituents are the same as (A)5) described above), C
7
-C
12
aralkyl or —SO
2
R
10
, wherein R
10
is C
1
-C
10
alkyl, C
3
-C
12
cycloalkyl, phenyl, substituted phenyl (wherein the definition of the substituents are the same as (A)5) described above) or C
7
-C
12
aralkyl, with the proviso that although the two R
9
may be the same or different, when one is —SO
2
R
10
, the other R
9
is not —SO
2
R
10
), or
(D) —CH
2
OTHP (wherein THP represents tetrahydropyranyl),
Y is hydrogen, C
1
-C
4
alkyl, chlorine, bromine, fluorine, formyl, methoxy or nitro,
B is —X—C(R
11
) (R
12
) OR
13
(wherein R
11
is hydrogen or C
1
-C
4
alkyl, R
13
is hydrogen, C
1
-C
14
acyl, C
6
-C
15
aroyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl,
X is
1) —CH
2
—CH
2
—
2) —CH═CH—, or
3) —C≡C—,
R
12
is
1) C
1
-C
12
straight alkyl or C
3
-C
14
branched alkyl,
2) —Z—Ar
2
(wherein Z represents the same meaning as described above, Ar
2
represents phenyl, &agr;-naphthyl, &bgr;-naphthyl or phenyl substituted with at least one selected from the group consisting of chlorine, bromine, fluorine, iodine, trifluoromethyl, C
1
-C
4
alkyl, nitro, cyano, methoxy, phenyl and phenoxy),
3) —C
t
H
2t
OR
14
(wherein C
t
H
2t
represents the same meaning as described above, R
14
is C
1
-C
6
straight alkyl, C
3
-C
6
branched alkyl, phenyl or substituted phenyl substituted with at least one selected from the group consisting of chlorine, bromine, fluorine, iodine, trifluoromethyl, C
1
-C
4
alkyl, nitro, cyano, methoxy, phenyl and phenoxy, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1 to 4 C
1
-C
4
straight alkyl),
4) —Z—R
3
(wherein Z and R
3
represent the same meanings as described above),
5) —C
t
H
2t
—CH═C(R
15
)R
16
(wherein C
t
H
2t
represents the same meaning as described above, R
15
and R
16
independently represent hydrogen, methyl, ethyl, propyl or butyl), or
6) —C
u
H
2u
—C≡C—R
17
(wherein u is an integer of 1-7, C
u
H
2u
is straight or branched alkylene, R
17
is C
1
-C
6
straight alkyl, E is hydrogen or —OR
18
(wherein R
18
is C
1
-C
12
acyl, C
7
-C
15
aroyl or R
2
(wherein R
2
represents the same meaning as described above), the formula represents d-isomer, l-isomer and racemic body) or a pharmaceutically acceptable salt thereof.
The ophthalmic preparation according to the present invention has excellent therapeutic and preventive effects against various ophthalmic diseases such as glaucoma, hypertonia oculi or cataract.
BEST MODE FOR CARRYING OUT THE INVENTION
The ophthalmic preparation according to the present invention contains the PGI
2
derivative represented by the formula (I) as an effective ingredient. The PGI
2
derivative may be not only racemic body but also d-isomer or l-isomer.
Preferred examples of the PGI
2
derivatives include beraprost and salts thereof. The salts are pharmaceutically acceptable salts including alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; primary, secondary or tertiary ammonium salt; and basic amino acid. Preferred examples of the PGI
2
derivative also include Compounds 2 to 6 described in the examples described below.
The above-described PGI
2
derivatives per se employed in the ophthalmic preparation according to the present invention, as well as production processes thereof are known and described in, for example, U.S. Pat. No. 4,474,802.
By adding a cyclodextrin to the ophthalmic preparation containing the above-described PGI
2
derivative or a salt thereof, ophthalmic topical irritation, such as conjunctival hyperemia, chemosis or abnormal egesta, which is observed when a high concentration of PGI
2
derivative is applied may be prevented. Further, by adding a vasoconstrictor to the ophthalmic preparation containing the PGI
2
derivative, the ophthalmic topical irritation which is a side effect may be prevented without adding a cyclodextrin. By adding a vasoconstrictor to an ophthalmic preparation containing a cyclodextrin, the ophthalmic topical irritation may be better prevented.
Examples of the cyclodextrin include &agr;-cyclodextrin, &bgr;-cyclodextrin, &ggr;-cyclodextrin, dimethyl-&bgr;-cyclodextrin, trime

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