Ophthalmic preparations

An ophthalmic preparation which exhibits excellent pharmacological effects for various ophthalmic diseases is disclosed. The ophthalmic preparation according to the present invention contains a 4,8-inter-m-phenylene prostaglandin I.sub.2 derivative represented by the formula (I): ##STR1## or a pharmaceutically acceptable salt thereof as an effective ingredient.

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-butyr
 ic acid) is a stable derivative of prostaglandin I.sub.2 (PGI.sub.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.sub.2 derivative of the formula (I):
 ##STR2##
 (wherein R.sup.1 is
 (A) COOR.sup.2
 (wherein R.sup.2 is
 1) hydrogen or a pharmaceutically acceptable cation,
 2) C.sub.1 -C.sub.12 straight alkyl or C.sub.3 -C.sub.14 branched alkyl,
 3) --Z--R.sup.3
 (wherein Z is a valence bond or straight or branched alkylene represented
 by C.sub.t H.sub.2t wherein t is an integer of 1-6, R.sup.3 is C.sub.3
 -C.sub.12 cycloalkyl or C.sub.3 -C.sub.12 cycloalkyl substituted with 1 to
 3 R.sup.4 wherein R.sup.4 is hydrogen or C.sub.1 -C.sub.5 alkyl),
 4) --(CH.sub.2 CH.sub.2 O).sub.n CH.sub.3
 (wherein n is an integer of 1-5),
 5) --Z--Ar.sup.1
 (wherein Z represents the same meaning as described above, Ar.sup.1 is
 phenyl, .alpha.-naphthyl, .beta.-naphthyl, 2-pyridyl, 3-pyridyl,
 4-pyridyl, .alpha.-furyl, .beta.-furyl, .alpha.-thienyl, .beta.-thienyl or
 substituted phenyl (wherein the substituent is at least one selected from
 the group consisting of chlorine, bromine, fluorine, iodine,
 trifluoromethyl, C.sub.1 -C.sub.4 alkyl, nitro, cyano, methoxy, phenyl,
 phenoxy, p-acetamidobenzamide, --CH.dbd.N--NH--C(.dbd.O)--NH.sub.2,
 --NH--C(.dbd.O)--Ph, --NH--C(.dbd.O)--CH.sub.3 and
 --NH--C(.dbd.O)--NH.sub.2 --,
 6) --C.sub.t H.sub.2t COOR.sup.4
 (wherein C.sub.t H.sub.2t and R.sup.4 represent the same meanings as
 described above),
 7) --C.sub.t H.sub.2t N(R.sup.4).sub.2
 (wherein C.sub.t H.sub.2t and R.sup.4 represent the same meanings as
 described above),
 8) --CH(R.sup.5)--C(.dbd.O)--R.sup.6
 (wherein R.sup.5 is hydrogen or benzoyl, R.sup.6 is phenyl, p-bromophenyl,
 p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidephenyl or
 2-naphthyl),
 9) --C.sub.p H.sub.2p --W--R.sup.7
 (wherein W is --CH.dbd.CH--, --CH.dbd.CR.sup.7 -- or --C.tbd.C--, R.sup.7
 is hydrogen, C.sub.1 -C.sub.30 straight or branched alkyl or aralkyl, p is
 an integer of 1-5), or
 10) --CH (CH.sub.2 OR.sup.8).sub.2
 (wherein R.sup.8 is C.sub.1 -C.sub.30 alkyl or acyl)
 (B) --CH.sub.2 OH
 (C)--C(.dbd.O)N(R.sup.9).sub.2
 (wherein R.sup.9 is hydrogen, C.sub.1 -C.sub.12 straight alkyl, C.sub.3
 -C.sub.12 branched alkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.13
 cycloalkylalylene, phenyl, substituted phenyl (wherein the definition of
 the substituents are the same as (A)5) described above), C.sub.7 -C.sub.12
 aralkyl or --SO.sub.2 R.sup.10, wherein R.sup.10 is C.sub.1 -C.sub.10
 alkyl, C.sub.3 -C.sub.12 cycloalkyl, phenyl, substituted phenyl (wherein
 the definition of the substituents are the same as (A)5) described above)
 or C.sub.7 -C.sub.12 aralkyl, with the proviso that although the two
 R.sup.9 may be the same or different, when one is --SO.sub.2 R.sup.10, the
 other R.sup.9 is not --SO.sub.2 R.sup.10), or
 (D) --CH.sub.2 OTHP (wherein THP represents tetrahydropyranyl),
 Y is hydrogen, C.sub.1 -C.sub.4 alkyl, chlorine, bromine, fluorine, formyl,
 methoxy or nitro,
 B is --X--C(R.sup.11) (R.sup.12) OR.sup.13
 (wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sup.13 is
 hydrogen, C.sub.1 -C.sub.14 acyl, C.sub.6 -C.sub.15 aroyl,
 tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl,
 X is
 1) --CH.sub.2 --CH.sub.2 --
 2) --CH.dbd.CH--, or
 3) --C.tbd.C--,
 R.sup.12 is
 1) C.sub.1 -C.sub.12 straight alkyl or C.sub.3 -C.sub.14 branched alkyl,
 2) --Z--Ar.sup.2
 (wherein Z represents the same meaning as described above, Ar.sup.2
 represents phenyl, .alpha.-naphthyl, .beta.-naphthyl or phenyl substituted
 with at least one selected from the group consisting of chlorine, bromine,
 fluorine, iodine, trifluoromethyl, C.sub.1 -C.sub.4 alkyl, nitro, cyano,
 methoxy, phenyl and phenoxy),
 3) --C.sub.t H.sub.2t OR.sup.14
 (wherein C.sub.t H.sub.2t represents the same meaning as described above,
 R.sup.14 is C.sub.1 -C.sub.6 straight alkyl, C.sub.3 -C.sub.6 branched
 alkyl, phenyl or substituted phenyl substituted with at least one selected
 from the group consisting of chlorine, bromine, fluorine, iodine,
 trifluoromethyl, C.sub.1 -C.sub.4 alkyl, nitro, cyano, methoxy, phenyl and
 phenoxy, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted
 with 1 to 4 C.sub.1 -C.sub.4 straight alkyl),
 4) --Z--R.sup.3
 (wherein Z and R.sup.3 represent the same meanings as described above),
 5) --C.sub.t H.sub.2t --CH.dbd.C(R.sup.15)R.sup.16
 (wherein C.sub.t H.sub.2t represents the same meaning as described above,
 R.sup.15 and R.sup.16 independently represent hydrogen, methyl, ethyl,
 propyl or butyl), or
 6) --C.sub.u H.sub.2u --C.tbd.C--R.sup.17
 (wherein u is an integer of 1-7, C.sub.u H.sub.2u is straight or branched
 alkylene, R.sup.17 is C.sub.1 -C.sub.6 straight alkyl, E is hydrogen or
 --OR.sup.18 (wherein R.sup.18 is C.sub.1 -C.sub.12 acyl, C.sub.7 -C.sub.15
 aroyl or R.sup.2 (wherein R.sup.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.sub.2 derivative represented by the formula (I) as an effective
 ingredient. The PGI.sub.2 derivative may be not only racemic body but also
 d-isomer or l-isomer.
 Preferred examples of the PGI.sub.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.sub.2 derivative also include Compounds 2 to 6
 described in the examples described below.
 The above-described PGI.sub.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.sub.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.sub.2 derivative is
 applied may be prevented. Further, by adding a vasoconstrictor to the
 ophthalmic preparation containing the PGI.sub.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 .alpha.-cyclodextrin,
 .beta.-cyclodextrin, .gamma.-cyclodextrin, dimethyl-.beta.-cyclodextrin,
 trimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin,
 glucosyl-cyclodextrin, maltosyl-cyclodextrin and the like. Examples of the
 vasoconstrictor include naphazoline hydrochloride, naphazoline nitrate,
 tetrahydrozoline hydrochloride, phenylephrine hydrochloride and the like.
 The concentration of the PGI.sub.2 derivative or a salt thereof used in the
 present invention varies depending on the ophthalmic disease and any
 concentration may be employed as long as its effect is exhibited. Thus,
 although the concentration is not restricted, a concentration of 0.0001 to
 1.0 wt % (in the present specification, all "%" means weight/volume %
 unless otherwise specified) is preferred. The concentrations of the
 cyclodextrin and vasoconstrictor vary depending on the concentration of
 the PGI.sub.2 derivative or the salt thereof. In cases where the
 concentration of the PGI.sub.2 derivative or the salt thereof is not more
 than 0.001%, ophthalmic topical irritation is not exhibited, so that there
 is no need to add a cyclodextrin or a vasoconstrictor. In cases where the
 concentration of the PGI.sub.2 derivative or the salt thereof is not less
 than 0.003%, the cyclodextrin and/or the vasoconstrictor may be added in
 an amount by which ophthalmic topical irritation may be prevented.
 Although the concentrations are not restricted, usually, the concentration
 of the cyclodextrin is preferably 0.001 to 10.0%, and the concentration of
 the vasoconstrictor is preferably 0.0005 to 0.1%.
 The ophthalmic preparation according to the present invention may not only
 be dropped or applied to cornea or conjunctiva, but also be injected into
 corps or anterior chamber. The effective ingredient may be blended with an
 ophthalmic ointment base such as petrolatum, liquid paraffin and
 Macrogold; fatty emulsion base such as soybean oil, egg yolk lecithin and
 soybean lecithin; isotonic agent such as sodium chloride, potassium
 chloride and glycerin; buffer such as borate buffer, phosphate buffer,
 citrate buffer and acetate buffer; stabilizer such as sodium edetate,
 sodium sulfite, propylene glycol, polyoxyethylene (20) sorbitan monoleate
 (polysorbate 80) and polyvinylpyrrolidone; viscosity increaser such as
 polyvinyl alcohol, carboxymethyl cellulose, hydroxyethyl cellulose and
 sodium chondroitin sulfate; pH regulator such as sodium hydroxide and
 hydrochloric acid; and antiseptic such as benzalkonium chloride,
 chlorobutanol, methylparaben and propylparaben.
 The administration dose of the ophthalmic preparation according to the
 present invention may be appropriately selected depending on the type of
 disease, symptom, and purpose of administration. Usually, about 5 .mu.l to
 200 .mu.l per one time is administered one to five times a day.
 The ophthalmic preparation according to the present invention has an
 activity to decrease ocular tension, and has therapeutic and preventive
 effects for various ophthalmic diseases. Especially, it is effective as an
 agent for decreasing ocular tension, and thus exhibits excellent
 therapeutic and preventive effects against glaucoma, hypertonia oculi or
 postoperative hypertonia oculi. Further, it has an excellent therapeutic
 and preventive effects against cataract.

EXAMPLES
 The present invention will now be described in more detail by way of
 examples and test examples. It should be noted that the ophthalmic
 preparation according to the present invention is not restricted to the
 prescriptions described in the examples.

Formulation Example 1
 Beraprost 0.0005 g
 White petrolatum 77.0 g
 Liquid paraffin 22.96 g
 Methylparaben 0.0265 g
 Propylparaben 0.013 g
 Total 100.0 g
 Formulation Example 2
 Beraprost 0.001 g
 Purified Soybean Oil 10.0 g
 Purified Egg Yolk Lecithin 1.2 g
 Conc. glycerin 2.5 g
 Sodium hydroxide or Amount necessary
 diluted hydrochloric acid for adjusting pH
 Water for injection Balance
 Total 100.0 ml
 Formulation Example 3
 Sodium beraprost 0.001 g
 Sodium chloride 0.9 g
 Water for injection Balance
 Total 100.0 ml
 Formulation Example 4
 Sodium beraprost 0.001 g
 Boric acid 0.02 g
 Borax 1.7 g
 Chlorobutanol 0.35 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 5
 Sodium beraprost 0.003 g
 .beta.-cyclodextrin 0.3 g
 Sodium chloride 0.9 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 6
 Sodium beraprost 0.01 g
 .alpha.-cyclodextrin 0.8 g
 Sodium dihydrogen phosphate 1.0 g
 (dodecahydrate)
 Sodium dihydrogen phosphate 0.2 g
 (anhydride)
 Sodium chloride 0.6 g
 Chlorobutanol 0.4 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 7
 Sodium beraprost 0.01 g
 Tetrahydrozoline hydrochloride 0.1 g
 Boric acid 2.0 g
 Borax 0.1 g
 Benzalkonium chloride 0.001 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 8
 Sodium beraprost 0.05 g
 Dimethyl-.beta.-cyclodextrin 3.0 g
 Boric acid 0.4 g
 Borax 1.7 g
 Chlorobutanol 0.4 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 9
 Sodium beraprost 0.05 g
 .gamma.-cyclodextrin 3.0 g
 Boric acid 2.0 g
 Borax 0.1 g
 Benzalkonium chloride 0.002 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Formulation Example 10
 Sodium beraprost 0.1 g
 Hydroxypropyl-.beta.-cyclodextrin 3.0 g
 Naphazoline hydrochloride 0.03 g
 Sodium dihydrogen phosphate 1.0 g
 (dodecahydrate)
 Sodium dihydrogen phosphate 0.2 g
 (anhydride)
 Sodium edetate 0.01 g
 Sodium chloride 0.6 g
 Benzalkonium chloride 0.002 g
 Sterilized Purified Water Balance
 Total 100.0 ml
 Test Example 1
 Action to Decrease Ocular Tension
 Activities of test compounds were tested using 2-3 New Zealand White
 Rabbits per group, whose body weights were 2-3.5 kg. As the test
 compounds, Compound 1 (sodium beraprost) to Compound 6 shown in Table 1
 were used. The symbols R.sup.1, E, B and Y in Table 1 indicate the same
 meanings as in Formula (I).
 TABLE 1
 Compound 1 R.sup.1 COON.sub.a
 (Sodium beraprost) E
 ##STR3##
 B
 ##STR4##
 Y H
 Compound 2 R.sup.1 COOCH.sub.3
 E
 ##STR5##
 B
 ##STR6##
 Y H
 Compound 3 R.sup.1 COOH
 E
 ##STR7##
 B
 ##STR8##
 Y H
 C
 Compound 4 R.sup.1
 ##STR9##
 E
 ##STR10##
 B
 ##STR11##
 Y H
 Compound 5 R.sup.1
 ##STR12##
 E
 ##STR13##
 B
 ##STR14##
 Y H
 Compound 6 R.sup.1
 ##STR15##
 E
 ##STR16##
 B
 ##STR17##
 Y H
 The test compound was dropped into one eye and 30 .mu.l of solvent was
 dropped to the other eye. The ocular tensions up to 4 hours or 6 hours
 from the administration of the compounds were measured with time with a
 pneumatic ophthalmotonometer (NIPPON ALCON). When measuring the ocular
 tension, 4% oxybuprocaine hydrochloride was dropped to the eyes as a
 surface anesthetic. Compound 1 was dissolved in 100 mM phosphate buffer
 and other compounds were dissolved in 2% polyoxyethylene(20)sorbitan
 monoleate, and the solutions were dropped to the eyes. The results are
 shown in Table 2.
 TABLE 2
 Maximum Decrease
 in Ocular
 Compound Concentration Tension (mmHg)
 Compound 1 0.03% 4.7
 (Sodium beraprost)
 Compound 2 0.01% 4.2
 Compound 3 0.01% 2.8
 Compound 4 0.01% 1.7
 Compound 5 0.01% 6.5
 Compound 6 0.01% 3.8
 From the above-described results, it was proved that the ophthalmic
 preparations according to the present invention have activities to
 decrease ocular tension.
 Test Example 2
 To confirm activity of sodium beraprost to decrease ocular tension, a test
 was carried out using white male rabbits. Sodium beraprost was dissolved
 in physiological saline to a concentration shown in Table 2 below, and the
 obtained solution was dropped to the eyes of white male rabbits in an
 amount of 50 .mu.l per time. Under anesthesia by dropping 4% oxybuprocaine
 hydrochloride to the eyes, ocular tension was measured with time. The
 results are shown in Table 3.
 TABLE 3
 Ocular Tension
 after
 Concentration Number Before Instillation
 of Sodium of Instillation (mmHg)
 beraprost Rabbits (mmHg) 1 hr 2 hr 3 hr
 0% 12 16.3 16.5 17.1 17.4
 0.001% 6 16.2 14.3 14.3 14.5
 0.003% 6 16.5 14.0 13.8 14.0
 0.01% 12 16.6 15.2 13.8 13.3
 As shown in Table 3, activity of sodium beraprost to decrease ocular
 tension was observed at a very low concentration of as low as 0.001%.
 Irritation of eye mucosa was not substantially observed at concentrations
 not more than 0.001%, while it was observed at concentrations not lower
 than 0.003%.
 Test Example 3
 The effects of cyclodextrins and a vasoconstrictor to prevent irritation of
 eye mucosa caused by sodium beraprost were tested using white male
 rabbits. As representative examples of cyclodextrins, .alpha.-cyclodextrin
 (.alpha.CyD), .beta.-cyclodextrin (.beta.CyD), .gamma.-cyclodextrin
 (.gamma.CyD), hydroxypropyl-.beta.-cyclodextrin (HP.beta.CyD) and
 dimethyl-.beta.-cyclodextrin (DM.beta.CyD) were used, and as a
 representative example of vasoconstrictors, naphazoline hydrochloride
 (NZH) was used.
 Sodium beraprost (BPS) was dissolved in physiological saline and the
 cyclodextrin or vasoconstrictor was dissolved therein to prepare test
 compositions. Each of the test compositions was dropped to eyes of white
 male rabbits in an amount of 50 .mu.l per time, and the irritation of eye
 mucosa was observed with time and evaluated based on the scores given
 according to the following criteria:

Scores
 (A) Flare of conjunctiva
 Normal (no congestion) 0
 Accentuation of congestion 1
 Congestion in deep red color is 2
 observed in large area and blood
 vessels are hardly distinguished
 (B) Chemosis of conjunctiva
 Normal (no chemosis) 0
 Accentuation of chemosis 1
 Chemosis accompanying partial 2
 evagination of eyelid
 (C) Egesta
 Normal amount 0
 Abnormal amount 1
 Eyelid and eyelash were wetted 2
 Evaluation (A) + (B) + (C)
 As shown in Table 4, in rabbits who received 0.01% sodium beraprost,
 conjunctival hyperemia, chemosis of conjunctiva and abnormality in egesta
 were observed. However, with the test compounds to which the cyclodextrin
 or the vasoconstrictor was blended, irritation of eye mucosa was not
 substantially observed. As for the activity to decrease ocular tension
 shown in Table 5, the activity was not influenced by the cyclodextrin or
 the vasoconstrictor, and activity to decrease ocular tension was observed.
 TABLE 4
 Average
 Score
 before Score after
 Instilla- Instillation
 Test Drug NOR* tion 1 hr 2 hr 3 hr
 Physiological Saline 6 0 0 0 0
 0.01% BPS 6 0 1.2 3.2 3.2
 0.01% BPS + 1.8% .alpha. CyD 6 0 0.2 0.2 0
 0.01% BPS + 1.8% .beta. CyD 6 0 0.2 0 0
 0.01% BPS + 1.8% .gamma. CyD 6 0 0 0.2 0
 0.01% BPS + 1.8% HP .beta. CyD 6 0 0.2 0 0
 0.01% BPS + 1.8% DM .beta. CyD 6 0 0 0 0
 0.01% BPS + 0.01% NZH 6 0 0 0.2 0.2
 *Number of Rabbits
 TABLE 4
 Average
 Score
 before Score after
 Instilla- Instillation
 Test Drug NOR* tion 1 hr 2 hr 3 hr
 Physiological Saline 6 0 0 0 0
 0.01% BPS 6 0 1.2 3.2 3.2
 0.01% BPS + 1.8% .alpha. CyD 6 0 0.2 0.2 0
 0.01% BPS + 1.8% .beta. CyD 6 0 0.2 0 0
 0.01% BPS + 1.8% .gamma. CyD 6 0 0 0.2 0
 0.01% BPS + 1.8% HP .beta. CyD 6 0 0.2 0 0
 0.01% BPS + 1.8% DM .beta. CyD 6 0 0 0 0
 0.01% BPS + 0.01% NZH 6 0 0 0.2 0.2
 *Number of Rabbits
 Test Example 4
 To confirm the potential of sodium beraprost as a drug for cataract,
 crystalline lenses of rats were cultured in a culture medium containing 50
 mM galactose and sodium beraprost for 48 hours, and the wet weight of each
 crystalline lens was measured. The content of reduced glutathione (GSH) in
 each crystalline lens was also measured. The results are shown in Tables 6
 and 7.
 TABLE 6
 Ratio of
 Test Group Inhibition
 Galactose BPS Number of Wet Weight of Swelling
 (mM) (%) Cases (mg) (%)
 -- 0 5 28.5 --
 50 0 5 33.5 --
 50 0.0004 5 32.2 26.0
 50 0.0042 5 31.5 40.0
 50 0.0420 5 28.3 104.0
 TABLE 6
 Ratio of
 Test Group Inhibition
 Galactose BPS Number of Wet Weight of Swelling
 (mM) (%) Cases (mg) (%)
 -- 0 5 28.5 --
 50 0 5 33.5 --
 50 0.0004 5 32.2 26.0
 50 0.0042 5 31.5 40.0
 50 0.0420 5 28.3 104.0
 As shown in Table 6, when the lenses were cultured in a culture medium
 containing no galactose, swelling of the lenses was not substantially
 observed, while when the lenses were cultured in a culture medium
 containing a high concentration of galactose, swelling of about 18% was
 observed. On the other hand, when the lenses were cultured in a culture
 medium containing a high concentration of galactose and sodium beraprost,
 swelling of the lenses was inhibited dose-dependently. Further, as shown
 in Table 7, the amount of the reduced glutathione in the lenses was
 clearly decreased by culturing the lenses in a culture medium containing
 high concentration of galactose, and it was confirmed that sodium
 beraprost inhibits decrease in the reduced glutathione in the lenses.
 From the above-described results, it was shown that the above-described
 PGI.sub.2 derivatives such as beraprost are useful for various ophthalmic
 diseases. Further, an excellent effect was shown that the irritation of
 eye mucosa caused by high concentration of beraprost can be prevented by
 blending a cyclodextrin or a vasoconstrictor.