JPH08310955A - Therapeutic agent for retinopathy - Google Patents

Abstract

PURPOSE: To obtain the subject therapeutic agent comprising a dihydro- prostaglandin F2 β derivative or its salt as an active ingredient, having excellent vasodilating action on constriction of blood vessel of retina, effective for retinal circulatory disorder. CONSTITUTION: This therapeutic agent for retinopathy comprises a 13,14-dihydro- prostaglandin F2 β derivative of the formula (R is H, a lower alkyl, a cycloalkyl, phenyl or a phenyl lower alkyl) or its salt as an active ingredient. A compound wherein R is H or isopropyl is preferable among the compounds of the formula. The objective therapeutic agent, for example, can be prepared as an eye drop by using an isotonizing agent such as concentrated glycerol, a buffering agent such as sodium phosphate, etc., an antiseptic such as paraben, etc. The preparation is preferably carried out at pH4 to pH8. A daily dose is preferably 0.1-50mg in the case of an injection and administered once or several times dividedly. In the case of an eye drop, 0.02-0.1% solution is dropped once to several times daily.

Description

Detailed Description of the Invention

[0001]

This invention relates to 13,14-dihydro-
The present invention relates to a retinopathy therapeutic agent containing a prostaglandin F ₂ β derivative as an active ingredient.

[0002]

2. Description of the Related Art The retina has a function of receiving light from the outside and plays an important role in visual function.
This is structurally composed of 10 layers such as the retinal pigment epithelium layer, the inner granular layer, the nerve fiber layer, and the thickness of 0.1 to 0.1.
It has a tissue of 0.5 mm.

The blood vessels of the retina are branches of the central retinal arteries and veins, run in the nerve fiber layer, and play a role of supplying oxygen and nutrients to the optic nerve.

When a retinal blood vessel is occluded or narrowed due to factors such as convulsions, thrombus and emboli, the retinal circulation is impaired, and the supply of oxygen and nutrients to the optic nerve is blocked. Retinal circulation disorders occupy a particularly important position in retinal diseases,
Representative examples of symptoms associated with retinal circulation disorders are retinal vascular occlusion, hypertensive retinopathy, and diabetic retinopathy.

Retinal vascular occlusion includes central retinal vein occlusion in which retinal vein is occluded and branch retinal vein occlusion, central retinal artery occlusion in which retinal artery is occluded or narrowed, and central retinal artery occlusion. , The current treatments are as follows. Laser photocoagulation has been the main treatment method for central retinal vein occlusion and branch retinal vein occlusion (Am. J. Ophthalmol., 98 , 271-282).
(1984)). In addition, drug treatment with a fibrinolytic enzyme agent or an anticoagulant has been attempted. On the other hand, central retinal artery occlusion and central retinal artery branch occlusion are treated with eye massage, inhalation of amyl nitrite, administration of isosorbide nitrate and the like. However, these treatment methods may not be able to be sufficiently treated, and the detailed treatment methods are currently in flux.

[0006] Iloprost, a prostaglandin (hereinafter referred to as PG) derivative having a platelet aggregation inhibitory action, a vasodilatory action and the like, was administered to central retinal vein occlusion and branch retinal vein occlusion. However, a satisfactory effect was not obtained (Oki, 40 , 2267-2272 (198
9)). In addition, PGF ₂ α, PGE ₂ and 6-keto-
Although the involvement of PGF ₁ α in the regulation of retinal blood flow has been investigated, no clear relationship has been observed (Invest. Ophthalmol. Vis. Sci., 33, 3378-3384 (199
2)), The therapeutic effects of these drugs on retinal vascular occlusion are unknown.

On the other hand, 13,14-dihydro-PGF ₂ β
Alternatively, salts thereof or isopropyl esters thereof are disclosed to be useful as preventive agents and / or therapeutic agents for glaucoma because they exhibit an intraocular pressure-lowering effect (JP-A-7-61965).

However, 13,14-dihydro-P
No studies have been conducted on the action of the GF ₂ β derivative on the retina, particularly the retinal circulation.

[0009]

DISCLOSURE OF THE INVENTION It has been a very interesting subject to find a compound useful for the treatment of retinal circulatory disorders, which are particularly important in retinal diseases.

[0010]

The present inventors have searched for a compound that dilates retinal blood vessels in order to find a new therapeutic agent for retinal circulatory disorders that occupy a particularly important position in retinal diseases. As a result, 13,14-dihydro-P
GF ₂ β and its ester were found to dilate retinal blood vessels. That is, 13,14-dihydro-PG
It was confirmed that F ₂ β and its ester are effective for retinal circulation disorders and are useful as therapeutic agents for retinal diseases.

[0011]

DISCLOSURE OF THE INVENTION The present invention is represented by the following general formula [I].
The present invention relates to a therapeutic agent for retinal diseases, which comprises a 3,14-dihydro-PGF ₂ β derivative or a salt thereof (hereinafter referred to as the present compound) as an active ingredient.

[0012]

Embedded image [In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl lower alkyl group. same as below. The group used in the present specification will be described in detail. Lower alkyl means methyl, ethyl, propyl, butyl, pentyl,
Hexyl, isopropyl, isobutyl, sec.-butyl, t
ert.-Butyl, isopentyl, neopentyl, tert.-pentyl, isohexyl and the like are linear or branched alkyl having 1 to 6 carbon atoms. Cycloalkyl refers to cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The salt in the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, a salt with an alkali metal or alkaline earth metal such as sodium, potassium and calcium, ammonium salt, diethylamine, triamine. Examples thereof include salts with organic amines such as ethanolamine.

Of these compounds, preferred compounds are:
The compound in which R is a hydrogen atom, an isopropyl group, a cyclohexyl group, a phenyl group, or a benzyl group is mentioned, and the compound in which R is a hydrogen atom or an isopropyl group is particularly preferable.

The present compound is, for example, disclosed in JP-A-7-61965.
It is manufactured by the method described in the publication.

The term "retinal disease" as used in the present invention means central retinal vein occlusion, branch retinal vein occlusion, central retinal artery occlusion, central retinal occlusion in which retinal blood vessels are occluded due to various factors and retinal circulation is impaired. Branch artery occlusion etc.

The retinal circulation disorder is effectively resolved by restoring the contracted retinal blood vessels to a normal state.

The present inventors examined the action of this compound on retinal blood vessels. As a result, although detailed data will be described in the section of the effect of the invention, it was confirmed that this compound dilates retinal blood vessels and restores contracted retinal blood vessels to a normal state, and this compound is effective for retinal circulation disorder. Therefore, it was confirmed that it may be useful as a therapeutic agent for retina.
Of these compounds, compounds derived from esters are expected to play a role as prodrugs.

Examples of the dosage form of the present compound include eye drops, injections and the like, and the present compound can be formulated using a commonly used technique. For example, in the case of eye drops, sodium chloride, isotonic agents such as concentrated glycerin, sodium phosphate, buffering agents such as sodium acetate, sodium citrate, stabilizers such as sodium edetate, benzalkonium chloride, The compound can be formulated using a preservative such as paraben and the like, and the pH may be in a range acceptable for ophthalmic preparations, but a range of 4 to 8 is preferable.

Further, the compound of the present invention can be prepared by a known method using α
It can also be converted into an inclusion compound of-, β- or γ-cyclodextrin.

The dose may be appropriately selected depending on the symptoms, age, dosage form, etc., but in the case of an injection, it is usually 0.01 to 500 per day.
mg, preferably 0.1 to 50 mg, can be administered once or in several divided doses. If it is an eye drop, it is 0.
001% to 1%, preferably 0.02 to 0.1% may be instilled once to several times a day.

The formulation examples of the present invention are shown below, but these examples are for the purpose of better understanding the present invention, and do not limit the scope of the present invention.

[0023]

【Example】

 [Formulation Example] An example of the formulation of the compound is shown below.

1) Eye drops Formulation 1 In 10 ml 13,14-dihydro-PGF ₂ β isopropyl ester 2 mg Polysorbate 80 15 mg Sodium chloride 80 mg

Formulation 2 10 ml 13,14-Dihydro-PGF ₂ β isopropyl ester 6 mg Polysorbate 80 50 mg Sodium chloride 80 mg

Formulation 3 13 14-dihydro-PGF ₂ β isopropyl ester 10 mg Polysorbate 80 75 mg Sodium chloride 80 mg in 10 ml

2) Injectable formulation 1 10 ml 13,14-dihydro-PGF ₂ β 10 to 100 mg sodium chloride 90 mg sodium hydroxide suitable amount sterile purified water suitable amount

[0028]

【The invention's effect】

[Pharmacological test] Sakagami et al. Can evaluate the action of a drug on a retinal blood vessel by taking photographs of the fundus including the retinal blood vessel over time and measuring the blood vessel diameter of the retinal blood vessel, and Endothelin-1 (hereinafter referred to as ET- It has been reported that retinal blood vessels contract due to (1) (Nippon Shimbun, 96 , 469-472 (199).
2)). Therefore, according to the method described in this document, the action of the present compound on retinal blood vessels was examined in rabbits by the following method.

1) Retinal vasodilatory effect (Experimental method) 24 male Japanese white rabbits (body weight: 1.9-
2.5 kg), the test compound solution was administered to the left eye and the base to the right eye.

The fundus was photographed immediately before administration and 0.5, 1, 2, 4 and 24 hours after administration. When photographing the fundus of the eye, rabbits were supplemented with 0.5% tropicamide and 0.
An ophthalmic solution (trade name: Midrin P) containing 5% phenylephrine was applied to the eyes to cause dilation, and the photograph was taken using a fundus camera.

On the photograph, the retinal blood vessel diameter near the teat edge (at two locations on the ear side and the nose side) and the longitudinal diameter of the teat were measured, and the relative retinal blood vessel diameter was determined by the following formula.

[0032]

(Equation 1) (Results) In Tables 1 and 2, as an example of the experimental results, 10
^-4 M and 10 ^-3 M 13,14-dihydro-PGF ₂
Relative when β (hereinafter referred to as the free body) is administered by intravitreous injection of 10 μl (inhalation anesthesia with 0.4% oxybuprocaine hydrochloride ophthalmic solution (brand name: benoxyl 0.4% solution) is performed beforehand) 4 shows a temporal change in the retinal blood vessel diameter. The relative retinal blood vessel diameter after administration was expressed as a percentage of the blood vessel diameter immediately before administration.

[0033]

[Table 1]

[Table 2] As shown in Table 1 and Table 2, the retinal blood vessels were significantly expanded by the administration of the free body, and the action was concentration-dependent.

From this, it became clear that this compound dilates retinal blood vessels.

2) Effect of ET-1 on retinal vasoconstriction (Experimental method) 12 male Japanese white rabbits (body weight: 1.9-
2.2 kg), 10 μl of 10 ⁻⁷ M ET-1 was added to both eyes.
Administered by intravitreal injection (0.4% oxybuprocaine hydrochloride ophthalmic solution in advance (trade name: benoxir 0.4%
Solution) was used for eye anesthesia). One hour after the administration of ET-1, the test compound solution was administered to the left eye and the base was administered to the right eye.

Immediately before ET-1 administration, immediately before test compound administration,
The fundus was photographed at 1, 2, 4 and 23 hours after administration of the test compound. When photographing the fundus of the eye, rabbits were instilled with eye drops (trade name: Midrin P) containing 0.5% tropicamide and 0.5% phenylephrine, and dilated and photographed using a fundus camera.

On the photograph, the retinal blood vessel diameter near the teat rim (at two locations on the ear side and the nose side) and the longitudinal diameter of the teat were measured, and the relative retinal blood vessel diameter was obtained from the above-mentioned formula 1.

(Results) Table 3 shows an example of the experimental results:
Administration of 0 ^-3 M free body by intravitreous injection of 10 μl (prior to eye anesthesia with 0.4% oxybuprocaine hydrochloride ophthalmic solution (brand name: benoxir 0.4% solution))
The time-dependent change of the relative retinal blood vessel diameter is shown. In addition,
The relative retinal blood vessel diameter after administration was expressed as a percentage of the blood vessel diameter immediately before ET-1 administration.

[0039]

[Table 3] As shown in Table 3, the retinal blood vessels contracted by ET-1 expanded more than 1 hour after the administration of the free body, and the recovery of the blood vessel diameter was recognized earlier than in the vehicle administration group. It was revealed that the retinal blood vessels contracted by 1 rapidly expanded.

From the above, the compound has an excellent dilating effect on retinal vasoconstriction, which is an abnormal tonic factor, and has central retinal vein occlusion, branch retinal vein occlusion, central retinal artery occlusion. It has been confirmed that it is effective for retinal circulation disorders such as central retinal artery branch occlusion and may be useful as a therapeutic agent for retinal diseases.

Claims (9)

[Claims] 1. A compound represented by the following general formula [I]: 13,14
-A retinopathy therapeutic agent containing a dihydro-prostaglandin F ₂ β derivative or a salt thereof as an active ingredient. Embedded image [In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl lower alkyl group. ] 2. The therapeutic agent for retinal disease according to claim 1, wherein the disease is retinal circulation disorder. 3. The therapeutic agent for retinal diseases according to claim 1, wherein R is a hydrogen atom, an isopropyl group, a cyclohexyl group, a phenyl group or a benzyl group. 4. The therapeutic agent for retinal diseases according to claim 1, wherein R is a hydrogen atom or an isopropyl group. 5. The therapeutic agent for retinal diseases according to claim 1, wherein R is a hydrogen atom, an isopropyl group, a cyclohexyl group, a phenyl group or a benzyl group, and the disease is retinal circulation disorder. 6. The therapeutic agent for retinal diseases according to claim 1, wherein R is a hydrogen atom or an isopropyl group, and the disease is retinal circulation disorder. 7. A compound represented by the following general formula [I]: 13,14
-A retinal vasodilator containing a dihydro-prostaglandin F ₂ β derivative or a salt thereof as an active ingredient. Embedded image [In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl lower alkyl group. ] 8. The retinal vasodilator according to claim 3, wherein R is a hydrogen atom, an isopropyl group, a cyclohexyl group, a phenyl group or a benzyl group. 9. The retinal vasodilator according to claim 3, wherein R is a hydrogen atom or an isopropyl group.