WO2008023784A1

WO2008023784A1 - Agent for amelioration of ophthalmic circulatory disorder

Info

Publication number: WO2008023784A1
Application number: PCT/JP2007/066430
Authority: WO
Inventors: Masahiko Ayaki
Original assignee: Showa University; Ono Pharmaceutical Co., Ltd.
Priority date: 2006-08-25
Filing date: 2007-08-24
Publication date: 2008-02-28

Abstract

Disclosed is an agent for ameliorating an ophthalmic circulatory disorder for orally administering limaprost to a patient with the ophthalmic circulatory disorder in an amount of 5 to 50 μg per day for a period of 2 to 72 weeks. The agent can be administered orally to ameliorate the ophthalmic circulatory disorder, and treat a symptom induced by the ophthalmic circulatory disorder and/or prevent the progress of the symptom. Further, the agent can shorten the period required for disappearance of the hemorrhage of the optic fundus associated with the ophthalmic circulatory disorder and also shorten the period required for the recovery of decreased visual acuity and/or the amelioration of a visual field disorder.

Description

Specification

Agent for improving ocular circulation disorder

Technical field

[0001] The present invention relates to an agent for improving ocular circulation disorder. More specifically, the present invention relates to an agent for ameliorating ocular circulatory disorder, which is for oral administration of 5 to 50 g of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorder.

Background art

[0002] The blood vessels of the eyeball include the retinal vasculature and the ciliary vasculature. In the retinal vasculature, the branch of the ophthalmic artery from the internal carotid artery enters the optic nerve and reaches the retina, and it is divided into a number of branches in the optic nerve head. The retinal blood vessels are responsible for the inner boundary membrane force of the retina and the blood flow to the outer reticulated layer, while the inner granule layer to the pigment epithelial layer are responsible for the choroidal blood vessels coming from the ciliary vasculature. The blood vessels distributed in the retina and choroid are the branches of the central retinal arteriovenous and the short posterior ciliary arteriovenous, respectively, running the nerve fiber layer and playing a role in supplying oxygen and nutrients to the optic nerve. If the ocular circulation is impaired due to factors such as arteriosclerosis of the internal carotid artery and ophthalmic artery, blood flow disturbance due to high blood sugar, vasospasm of the retina choroid, thrombus, and obturator, supply of oxygen and nutrients to the optic nerve is closed. And presents with various symptoms.

[0003] Symptoms caused by ocular circulation disorders include retinal vascular occlusion (central retinal artery occlusion, retinal artery branch occlusion, central retinal vein occlusion, retinal vein branch occlusion, etc.), diabetic retinopathy (simple Retinopathy, preproliferative retinopathy, proliferative retinopathy, proliferative retinopathy, etc.), hypertensive fundus, arteriosclerotic retinopathy, vasospastic retinopathy, hypertensive retinopathy, renal retinopathy, hypertensive optic neuroretinopathy Central retina choroidopathy (central serous retina choroidosis, etc.), macular degeneration (age-related macular degeneration, etc.), retinitis pigmentosa, ischemic optic neuropathy, transient cataract, ocular ischemia is there. Along with these, optic nerve atrophy, retinal vasculitis, fundus hemorrhage (retinal hemorrhage, vitreous hemorrhage, etc.), retinal edema, macular edema, angiogenesis, retinal vitiligo (hard vitiligo, soft vitiligo etc.) are caused. Symptoms include decreased visual acuity and visual field impairment (dark vision, visual field constriction, visual dark spot, etc.), foggy vision, metamorphosis, central dark spot, flying mosquito disease, headache, and eye pain. In addition, various complications (hypocirculatory retinopathy, iris rubeosis, neovascular glaucoma, retinal detachment, etc.) It can also be caused. For these, treatments such as laser photocoagulation, eyeball massage, hyperbaric oxygen therapy, anterior chamber puncture, vitreous surgery, and drug administration, etc., are appropriately performed according to each symptom. However, these treatments may not be able to be treated sufficiently.

[0004] As one of drugs for treating the above-mentioned symptoms, an intravenous PGE preparation is known.

To date, intravenous liposomal PGE preparations have been administered intravenously to patients with retinal vein occlusion daily or daily 4 to 12 times (10 g / dose), and bleeding around the fundus has been reduced. However, it has been reported that sufficient effects on macular bleeding, edema, and visual acuity have not been observed (Non-patent Document 1).

In addition, patients with retinal vein occlusion received PGE preparations (40 to 80 ag / day) for 7 to; 19 days after intravenous infusion, but patients who received 60 to 80 g received hemorrhage absorption and macular edema. Although there was a decrease and recovery in visual acuity, it was reported that no effect was seen in patients receiving 40 _{§ § to} 60 〃 g. No effect on retinal vein occlusion! / (Non-patent document 2).

[0005] In addition, as a PG preparation other than PGE preparations, PGF β derivatives have a therapeutic agent for retinal diseases.

1 2

It is disclosed that it is effective! (Patent Document 1).

[0006] On the other hand, preparations containing limaprost have already been used in clinical practice as oral PGE preparations having an effect of improving peripheral circulation, and are known as safe pharmaceuticals. Limaprost Alphadex tablets, which are preparations containing Limaprost, are useful as a preventive and / or therapeutic agent for peripheral circulatory disturbances, especially symptoms such as obstructive thromboangiitis and lumbar spinal stenosis, which are chronic diseases. It is a very useful drug for improvement. Limaprost is known to have a vasodilatory action, a platelet aggregation inhibitory action, etc., and to improve peripheral circulation. However, it has not been reported that oral PGE preparations improve ocular circulatory disturbances. Specifically, oral PGE preparations are used at any dose and how to treat symptoms caused by ocular circulatory disorders. Whether it will be effective! /, It has been described and suggested! /, Nare.

[0007] Non-Patent Document 1: Clinical Ophthalmology Journal 87 (12), 2643–2647, 1993

Non-Patent Document 2: Bulletin of Japanese Ophthalmology 37 (9), 1366–1371, 1986

Patent Document 1: JP-A-8-310955 Disclosure of the invention

Problems to be solved by the invention

[0008] An object of the present invention is to provide a safe agent for improving ocular circulation disorder which can be administered orally and has excellent convenience.

Means for solving the problem

[0009] The present inventor has given limaprost to patients with ocular circulation disorder from 5; ^ to 50; ^ 2 weeks

Oral administration for 72 weeks has been shown to improve ocular circulatory disorders and to treat and / or suppress the progression of symptoms caused by ocular circulatory disorders such as retinal vascular occlusion /

Furthermore, the present inventor used an agent for improving ocular circulation disorder for orally administering 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorder. In addition, it has been found that the bleeding and edema of the macula can be improved and symptoms such as decreased visual acuity can be improved, and in addition, the disappearance period of the fundus hemorrhage associated with diseases caused by ocular circulation disorder can be shortened. The present invention has been completed by finding that it is possible to shorten the period until recovery of vision loss and / or improvement of visual field impairment.

[0010] The present invention relates to an agent for improving ocular circulation disorder having the following constitutional power.

[1] An agent for ameliorating ocular circulatory disorder by orally administering 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorders.

[2] The agent according to 1 above, which is used for treatment of symptoms caused by ocular circulation disorder and / or for progression inhibition.

[3] The agent described in 2 above, wherein the symptom caused by ocular circulation disorder is retinal vascular occlusion or diabetic retinopathy.

[4] The agent according to 1 above, wherein the administration period is 4 to 15 weeks.

[5] The agent according to 1 above, which is orally administered once to three times a day.

[6] The agent described in 5 above, wherein 5 mg or 10 mg of limaprost is orally administered 3 times a day.

[7] The agent described in 6 above, wherein 5 g or 10 g of limaprost is orally administered 3 times a day for 4 to 15 weeks. [8] The agent according to 1 above, which is a tablet, capsule or granule.

[9] For vasodilation, platelet aggregation suppression, erythrocyte deformability enhancement, active oxygen production suppression

2. The agent according to 1 above, which is for promoting hemorrhage absorption and / or for inhibiting angiogenesis.

[10] The agent described in 2 above, wherein the symptom caused by ocular circulation disorder is optic nerve atrophy, retinal vasculitis, fundus hemorrhage, retinal edema, macular edema, angiogenesis and / or retinal vitiligo.

[11] The agent according to 2 above, wherein the symptom caused by ocular circulatory disorder is visual acuity, visual field impairment, foggy vision, metamorphosis, central scotoma, flying mosquito disease, headache and / or eye pain.

[12] The agent described in 2 above, wherein the treatment is for shortening the disappearance period of fundus oculi bleeding.

[13] The agent according to 2 above, wherein the treatment is for recovery of decreased visual acuity associated with fundus hemorrhage and / or for shortening the period of visual field impairment improvement.

[14] The agent described in 1 above, which is used for treatment and / or prevention of complications associated with symptoms caused by ocular circulation disorder.

[15] The agent according to the above 14, wherein the complication is hypocirculatory retinopathy, iris rubeosis, neovascular glaucoma and / or retinal detachment.

[16] The agent according to 12 above, wherein the fundus hemorrhage is fundus hemorrhage associated with retinal vascular occlusion or diabetic retinopathy.

[17] An agent for shortening the period of disappearance of fundus bleed for oral administration of 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with retinal vascular occlusion.

[18] The agent according to 17 above, wherein 5 mg or 10 mg of limaprost is orally administered 1 to 3 times for 2 to 52 weeks.

[19] Oral administration of 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks in patients with retinal vascular occlusion for recovery of visual loss associated with fundus hemorrhage and / or reduction of visual field impairment Agent.

[20] The agent according to 19 above, wherein 5 mg or 10 mg of limaprost is orally administered 3 times a day for 2 to 52 weeks.

[21] The agent described in 18 or 20 above, wherein 5 g or 10 g of limaprost is orally administered 3 times a day for 4 to 15 weeks.

[22] Patients with diabetic retinopathy received 5; ^ to 50; ^ limaprost per day for 2 to 72 weeks An agent for shortening the disappearance period of fundus bleeds for oral administration.

[23] The agent described in 22 above, wherein 5 mg or 10 mg of limaprost is orally administered 3 times a day for 2 to 52 weeks.

[24] Period of recovery of visual loss and / or improvement of visual field impairment due to fundus hemorrhage due to oral administration of 5; ^ to 50; ^ limaprost per day for 2 to 72 weeks in patients with diabetic retinopathy Shortening agent.

[25] The agent according to 24 above, wherein 5 mg or 10 mg of limaprost is orally administered 3 times 1 to 3 times for 2 to 52 weeks.

[26] Limaprost and selected from circulation-improving drugs, thrombolytic drugs, anticoagulants, antiplatelet drugs, vasodilators, vitamin drugs, iodine drugs, _a blockers, prostaglandin preparations, low molecular weight dextran and hemostatic drugs The agent according to claim 1, for administration in combination with one or more of the above.

[27] A method for improving ophthalmic circulation, characterized by orally administering 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorders.

[28] The method described in 27 above, which is a method for treating symptoms and / or suppressing progression caused by ocular circulation disorder.

[29] An agent for ameliorating ocular circulation disorder for oral administration of 5 mg / day, 50 mg / l g of limaprost per day for 2 to 72 weeks.

[30] The agent according to 29 above, wherein the agent for improving ocular circulation disorder is an agent for treating and / or preventing progression of symptoms caused by ocular circulation disorder.

The invention's effect

The present invention discloses that ocular circulatory disorder is improved by administering orally limaprost to patients with ocular circulatory disorders 5; ^ to 50; ^ per day for 2 to 7 weeks. Convenient and safe agent for improving ophthalmic circulation, ie `` Ocular circulatory disorder for oral administration of 5 to 50,1 g of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorder The agent for improving "(hereinafter sometimes abbreviated as" the agent of the present invention ") is provided. By using the agent of the present invention, ocular circulation disorder can be improved, and treatment and / or progression of symptoms caused by ocular circulation disorder can be suppressed. In addition to the fundus periphery, yellow It improves the bleeding and edema of the macula and can improve symptoms such as decreased visual acuity, the disappearance period of the fundus hemorrhage associated with diseases caused by ocular circulation disorder, and the recovery and / or reduction of visual acuity associated therewith It is possible to shorten the period until the visual field defect is improved.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] The agent of the present invention contains limaprost as an active ingredient, and is used for oral administration of ocular circulatory disorder patient's camoprost 5; ^ force, etc. 50; ^, 2 weeks to 72 weeks per day. If so, for example, the active ingredient limaprost is included as it is or in the form of its salt or its cyclodextrin inclusion compound!

Limaprost is the following formula:

[Chemical 1

The chemical name is (E) —7— [(lR, 2R, 31¾—3—Hydroxy-2— [(3S, 5S) — (E) — 3—Hydroxy-5-methyl 1—none. Diyl] -5-oxocyclopentyl] -2 heptenoic acid (Registry No. 74397-12-9).

[0013] The cyclodextrin inclusion compound of limaprost includes, for example, α-cyclodextrin inclusion compound, / 3-cyclodextrin inclusion compound, and γ-cyclodextrin inclusion compound of limaprost, Above all, the following formula,

[Chemical 2]

A compound in which limaprost is clathrated with α-cyclodextrin is preferred. Chemical name is (Ε) — 7— [(1R, 2R, 3R) — 3 Hydroxy 1— [(3S, 5S) — (Ε) — 3 Hydroxy 5 Methyl-1 nonenyl] 5 oxocyclopentyl] 2 Heptenoic acid α -Cyclodextrin inclusion complex (Registry No. 100459-01-01-6), commonly known as Limaprost Alphadex. This is synonymous with “Limaprost Alpha Detas” listed in the 15th revision Japanese Pharmacopoeia.

[0014] In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

[Chemical 3

Indicates that it is connected to the other side of the page (ie α configuration),

[Chemical 4

No

Indicates that it is connected to the front side of the page (ie, 0 arrangement).

[0015] The salt of limaprost is a non-toxic salt, particularly a pharmaceutically acceptable salt, and examples of such a salt include sodium salt and potassium salt.

The agent of the present invention preferably contains limaprost in the form of an α-cyclodextrin inclusion compound of limaprost, ie, limaprost alpha detas.

In the present specification, “ocular circulation disorder” means blood vessels around the eye (for example, retinal blood vessels, choroidal blood vessels).

) Means that the blood circulation is impaired. The agent of the present invention has an action of improving ocular circulation disorder, and in particular, has an action of improving blood circulation disorder in the retina or choroid, that is, reticulochoroidal circulation disorder.

In the present specification, “patient with ocular circulation disorder” refers to a patient with ocular circulation disorder.

[0017] In the present invention, "treatment" means to guide symptoms in the direction of healing, and "inhibition of progression" means to suppress progression / aggravation of symptoms or to stop progression of symptoms. The agent of the present invention improves the ocular circulation disorder, and therefore treats and / or suppresses the progression of symptoms caused by the ocular circulation disorder.

[0018] In the present invention, the "symptom caused by ocular circulation disorder" means a disease caused by an ocular circulation disorder, a disease secondarily caused by the disease, and symptoms associated therewith.

[0019] As symptoms caused by ocular circulation disorders, specifically, retinal vascular occlusion (central retinal artery occlusion, retinal artery branch occlusion, central retinal vein occlusion, retinal vein occlusion, etc.), Diabetic retinopathy (simple retinopathy, preproliferative retinopathy, proliferative retinopathy, growth retinopathy, etc.), hypertensive ocular fundus, arteriosclerotic retinopathy, vasospastic retinopathy, hypertensive retinopathy, renal retinopathy , Hypertensive optic neuroretinopathy, central chorioretinopathy (central serous chorioretinopathy, etc.), macular degeneration (such as age-related macular degeneration), retinitis pigmentosa, ischemic optic neuropathy, transient cataract Powers including ocular ischemic syndrome are not limited to these. Among them, the agent of the present invention is effective for retinal vascular occlusion or diabetic retinopathy.

In the present invention, retinal vascular occlusion is a disease in which retinal blood vessels are occluded. Depending on the occlusion site, central retinal artery occlusion, retinal artery branch occlusion, central retinal vein occlusion, retinal vein occlusion Classified as branch occlusion. The agent of the present invention is effective for any retinal vascular occlusion, but is particularly effective for retinal vein occlusion (eg, central retinal vein occlusion, retinal vein branch occlusion).

[0021] In the present invention, diabetic retinopathy includes all diabetic retinopathy as long as the retina is damaged. For example, it may be classified into any stage such as simple retinopathy, preproliferative retinopathy, proliferative retinopathy, and growth arrested retinopathy. Simple retinopathy is the stage of abnormal retinal blood vessels only, and pre-proliferative retinopathy is an ischemic part (blood reaches V, TE! /, NA! /, Part), but new blood vessels are generated. ! /, !!, stage, proliferative retinopathy refers to the stage where neovascularization occurs and proliferates to near the vitreous body, and growth arrested retinopathy refers to the stage where the condition is stabilized by treatment. The agent of the present invention is effective for any diabetic retinopathy, but is particularly effective for simple retinopathy.

[0022] In addition, the agent of the present invention includes optic nerve atrophy associated with the above symptoms, retinal vasculitis, fundus hemorrhage (retinal hemorrhage, vitreous hemorrhage, etc.) retinal edema, macular edema, angiogenesis, retinal vitiligo (hard vitiligo, Soft white spot etc.), and especially effective for fundus hemorrhage including bleeding in the macular region as well as the periphery of the fundus, and retinal vitiligo. In particular, it is effective for fundus hemorrhage associated with retinal vascular occlusion or diabetic retinopathy. In addition, it improves symptoms such as visual loss and visual field impairment (dark vision, visual field stenosis, visual dark spot, etc.), foggy vision, metamorphosis, central focus, flying mosquito disease, headache, and eye pain.

In particular, when the agent of the present invention is administered to patients with ocular circulatory disorders, particularly those with fundus bleeds, there is a tendency to shorten the period until fundus bleeds disappear. The degree of shortening of the period is standard 20-30% reduction compared to traditional treatments (for example, administration of circulatory improvers (such as kallidinogenase), hemostatic agents (such as sodium carbazochrome sulfonate, tranexamic acid), vitamin E (tocopherol acetate)) For example, in a patient whose bleeding from the fundus is expected to be about 3 months, it was shortened to about 2 months by administering the agent of the present invention. In addition, with the disappearance of blood from the fundus, the period until recovery of visual acuity and improvement of visual field impairment was also reduced by about 20 to 30% compared to standard treatment. For example, when the agent of the present invention was administered for 5 days to 2 weeks, symptoms such as fundus hemorrhage, visual acuity recovery and visual field impairment were improved, and further effects were observed when administered for 4 to 15 weeks.

[0023] Further, the agent of the present invention can treat and / or prevent various complications (hypocirculatory retinopathy, iris rubeosis, neovascular glaucoma, retinal detachment, etc.) associated with the above-mentioned symptoms.

[0024] The above-described excellent effects of the agent of the present invention may be due to any mechanism of action, but vasodilatory action, platelet aggregation inhibitory action, and erythrocyte deformability enhancing action of limaprost, which is an active ingredient. This is largely due to the action of inhibiting the production of active oxygen, the action of promoting bleeding absorption and / or the action of inhibiting angiogenesis.

Limaprost has a vasodilatory effect, an inhibitory effect on platelet aggregation, etc., and it has been known to improve peripheral circulation, but there has been no suggestion or report regarding improvement of ocular circulation disorder. It is a finding for the first time in the present invention that the ocular circulation is improved by the vasodilatory action, the platelet aggregation inhibitory action and the like of the agent of the present invention.

[0025] Red blood cells are narrower than themselves! / And have the ability to pass through capillaries by deforming their shape when passing through capillaries. This is called “red blood cell deformability”. When the deformability of red blood cells is reduced, blood vessels tend to become clogged and blood circulation becomes worse. The agent of the present invention has an action of enhancing erythrocyte deformability and can improve blood circulation, especially capillary circulation.

[0026] Further, since the agent of the present invention also has an active oxygen production inhibitory action, it is controlled by the ability to suppress cell oxidation and protect cells.

[0027] Symptoms resulting from ocular circulation disorder may be accompanied by bleeding, causing fundus hemorrhage and retinal edema. When the agent of the present invention is administered to a patient with bleeding, ocular blood circulation is improved and absorption of bleeding can be promoted. [0028] Furthermore, if the ocular ischemia continues due to ocular circulation disorder, new blood vessels appear to compensate for oxygen deficiency. Since the new blood vessels are brittle and easily bleed, they can cause complications such as vitreous hemorrhage, retinal detachment, and neovascular glaucoma. The agent of the present invention can suppress angiogenesis due to ocular ischemia by improving ocular circulation.

[0029] Whether or not the agent of the present invention has an effect of improving ocular circulation disorder can be determined by a known method. For example, visual field measurement, visual acuity measurement, fundus photo evaluation (evaluation of bleeding degree), retinal structure evaluation by OCT (optical coherence tomography), retinal temperature measurement (estimation of blood flow on the eyeball surface), etc. In addition, it is possible to measure the effect of improving ocular circulation disorder and the treatment of various symptoms associated with ocular circulation disorder and the effect of suppressing progression.

[0030] In addition, any method can be used as long as it can determine the effect of improving ocular circulation disorder and the degree of symptoms caused by ocular circulation disorder! /.

[0031] The agent of the present invention is applied to patients with ocular circulation disorder. In particular, it is preferable to administer to a patient having symptoms caused by ocular circulation disorder, and particularly to a patient with retinal vascular occlusion or a patient with diabetic retinopathy.

[0032] In the present invention, the amount of limaprost contained in the agent of the present invention may be any amount as long as it is effective, but the daily dose for adults is 5 _§ as the amount of limaprost. Mosquitoes, etc. 50 _§ coconut, 15 g or 30 ^ g force is more preferred. The dose per dose is preferably 5 g or 10 g. When limaprost is administered as a cyclodextrin inclusion compound of limaprost (eg, limaprost alpha detus), the limaprost contained in the cyclodextrin inclusion compound of limaprost is 5 to 50 Hg per day, preferably 15 g or 30 Hg should be administered in terms of dose. As a method of administration, it is preferable to administer 1 to 3 times a day, particularly 3 times a day in the morning, noon, and preferably after meals. The administration period may be any period as long as it is effective, and may vary depending on the type and severity of symptoms. For example, it is preferably 2 to 72 weeks. More preferably, it is 2 weeks to 52 weeks, more preferably 4 weeks to 28 weeks, still more preferably 4 weeks to 15 weeks, and particularly preferably 6 weeks to 15 weeks. [0033] In the present invention, the route of administration of the agent of the present invention is oral administration, and the dosage form for oral administration is preferably a solid preparation (eg, tablet, granule, capsule, etc.). Yes. In the solid preparation, limaprost may be contained as limaprost alphadex. More preferable are tablets (for example, uncoated tablets, dry-coated tablets, coated tablets, three-layer tablets, etc.). The tablet may be a sustained-release preparation such as an intraoral rapidly disintegrating tablet. Tablets containing Limaprost include, for example, Opalmon Tablets (trade name), Prolenal Tablets (trade name), Opaprosmon Tablets (trade name), Optilan Tablets (trade name), Zeflobut Tablet (trade name), Limarmon Tablets (product) Name), Rimaprost Alphadex tablets 5 g “F” (trade name), Olfalumin Tablets (trade name), Fadermon Tablets (trade name), etc., and Rimaprost Alphadex tablets containing Rimaprost as Rimaprost Alphaadetas. Furthermore, the tablets containing limaprost may be other than the above-mentioned tablets as long as they contain limaprost. Further, tablets described in JP-A-2005-272458, JP-A-2005-314413, JP-A-2006-045218 or JP-A-3646310 may be used. The amount of limaprost in the tablet is preferably 5 g or 10 g per tablet. In the tablet, when limaprost is contained as a cyclodextrin inclusion compound of limaprost (eg, limaprost alpha detas), the limaprost contained in the cyclodextrin inclusion compound of limaprost is 5 ^ g or 1 tablet. It is preferable that it is included so as to be 10 ^ g.

[0034] The administration of the agent of the present invention is performed by combining the above-mentioned preferable dose, administration method, administration period, administration route, dosage form and the like. Specifically, oral administration of 5 to 50 g of limaprost per day for 2 to 72 weeks is particularly effective in improving ocular circulatory disturbance, and 5 or 10 g of limaprost is administered once. Orally administered 3 times a day, 2 weeks to 72 weeks, preferably 2 weeks to 52 weeks, more preferably 4 weeks to 28 weeks, more preferably 4 weeks to 15 weeks, particularly preferably 6 weeks to 15 weeks More specifically, or tablets containing 10 g of limaprost, 1 tablet or 2 tablets 3 times a day, 2 weeks to 72 weeks, preferably 2 weeks to 52 It is preferable to administer to a patient with ocular circulation disorder for a week, more preferably 4 to 28 weeks, further preferably 4 to 15 weeks, particularly preferably 6 to 15 weeks. In addition, tablets containing limaprost are limaprost. Limaprost alphadex tablets contained as huadetas are preferred.

[0035] Limaprost or limaprost alphadex used in the agent of the present invention can be produced by a known method, for example, the method described in JP-A-55-100360.

[0036] The toxicity of limaprost and limaprost alpha detas used in the agent of the present invention is very low, and is sufficiently safe for use as a medicine.

[0037] The agent of the present invention may be used in combination with a drug usually used for improving ocular circulation.

Other drugs that may be combined with the agent of the present invention include, for example, circulation improving drugs (eg, Kallidinogenase, alprostadil, etc.), thrombolytic drugs, anticoagulants, antiplatelet drugs, blood vessels Extenders (eg, nitrite (nitroglycerin, amyl nitrite, etc.)), vitamins (vitamin C (ascorbic acid)), vitamin A (eg, retinol palmitate), Vitamin B (for example, flavin

2

Anvilin Crested DNA (Flavin Adenine Dinucleotide Somum)

6

(Pyridoxine, pyridoxal, pyridoxamine, etc.), vitamin B (for example, cobamamide, cyanocobalami)

12

n), Nolamin, Hyd, Loxo: π-Noramine (hydroxocobalamin), Me: ^ Noramine ( _me cobalamin, etc.), Vitamin E (tocopherol acetate))), iodine drugs (for example, Iodine lecithin, etc.), α-blockers (Tolazoline Hydrochloride, etc.), prostaglandin preparations, low molecular weight dextrans and hemostatic agents (eg, carbazochrome sodium sulfonate, tranexamic acid, etc.).

[0038] Examples of thrombolytic drugs include: Eight kinds? 8. Alteplase (alt-marked lase), Tisokinase (tisokinase), Naaphuase (nateplase), Noapaphuuse (pamiteplase, Monapplase), Wasmoaphu (desmoteplase, etc., urokinase) ), Nasanoplase, Streptokinase, etc. Here, t-PAs are t-PA and t-PA modified (eg, genetically modified t-PA). , Modified t-PA) Anticoagulants include, for example, heparins (heparin sodium (h-marked arin sodium), heparin calcium (h-marked arin calcium), heparinoids, low molecular weight heparins (parna parin, tanorthenoline) (dalteparin), tanaroid (danaparoid), enoxanoline, enoxap arin), nadrono ヽ rin, nadroparin), be: emirin (bemiparin), levino ヽ rin (reviparin, tenzaparin, etc.)), activity Blood coagulation factor X inhibitor (fondano linutatus, DX— 9065a, DU— 176b, CS— 3030, JTV— 803, BMS— 56 1389, BAY— 59— 7939, YM150, LY— 517717, KFA — 1982, KFA-182 9, Idraparinux, DPC—423, DPC—602, DPC—A52350, Otamixaban, HMR2096, FXV—673, RPR—130673, MCM16, MCM17, TC—10, RPR—256580, RPR—225430, RPR—247978, RPR—231352, RPR 209685, RPR—208944, RPR—208815, RPR—208707, RPR—208 566, RPR—200095, RPR—130338, RPR—130737, RPR—132747, RPR—128515, RPR—120844, M—55113, M—55190 , M— 55555, M— 5552 9, MLN— 1021, EGR— Xa, CI— 1031, ZD— 5227, AX— 1826, ZK- 8130 39, DE— 00684, BIBT— 986, BIBT—Dish 1, BM— 141248, PD—198961, PD—0313052, PD—313052, PMD—3112, PMD—3833, PMD—3805, PMD—3829, PMD—2612, PMD—2837, PMD—2566, SEL-2711, SSR—122497A, SSR—126517, SSR—128428, SSR—128429, SSR—80670 A, SSR—121903A, SSR—122429A, SSR—122574A, Org—42675, etc., activated blood coagulation factor IX inhibitor (TTP—889, 224AE3 Etc.), vitamin K antagonists (ヮ nofarfalin etc.), antithrombin drugs (argatroban, gabexate mesilate, nafamos mesinolate) Tufa (nafamostat mesilate), ximelagatran, melagatran, dabigatran, davinigatran, bivalirudin, lepirudin, hirudin, dennoresin 182, SSR — 123781A, S— 18326, AZD— 0837, LB— 308 70, L 375378, MCC— 977, AT— 1362, etc.), activated protein C preparation (dried human activated protein C) , Antithrombin III preparation, pair Tissue factor pathway inhibitor, thrombomodulin preparation (ART-123, MR-33, etc.), carboxypeptidase U inmbitor (thrombin-activatable fibnnoly sis inhibitor (TAFI)) (sodium taenoate, AZD- 9684 Etc.).

[0040] Antiplatelet drugs include, for example, aspirin, ticlopidine, clopidogrel, dipyridamole, ciiostazol, ozagrel, prasgrerel, prasugrel, Ethicosapentate (ethyl icosap entate), beraprost, sanogrepogrelate, sarpogrelate, GPIIb / IIIa receptor antagonist (abciximab, tirofiban, teptifibatide, etc.) AZD6140 etc. are mentioned.

[0041] Further, other drugs to be combined with the agent of the present invention include not only those that have been found so far, but also those that will be found in the future based on the mechanism described above.

[0042] Further, the drug treatment with the agent of the present invention and / or other agents is used in combination with other therapies (laser photocoagulation, eyeball massage, hyperbaric oxygen therapy, anterior chamber puncture, vitrectomy, etc.). May be.

[0043] In the agent of the present invention, the solid preparation containing limaprost is added with pharmaceutically acceptable additives as necessary to limaprost, and a technique widely used as a single preparation or a combined preparation is used. Can be manufactured. In formulating, Limaprost may be used as Limaprostanolefadetas.

[0044] In the case of producing a solid preparation containing limaprost, in addition to limaprost, an additive caloric agent may be further contained. Any additive that is generally used in the production of solid preparations may be used, for example, excipients, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, A fragrance, a colorant, an antioxidant, a masking agent, an antistatic agent, a fluidizing agent, a wetting agent, and the like can be appropriately used in one or more kinds.

[0045] Examples of excipients include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritonor, manoletithonole, xylitolore, noratinose, trenosucrose, sonorebitole, corn starch , Potato starch, wheat starch, rice starch, crystalline cellulose, talc, anhydrous carboxylic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, dextran (e.g., dextran, dextran 4 0, dextran 70, etc.), pullulan, dextrin, alpha-unified starch, etc. Norelose, povidone, polyvinylinolepyrrolidone, methinoresenorelose, polyvinylinole noreconole, carboxymethylcellulose, partially alpha-unified starch, alpha Examples thereof include monolized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like, and one or more of these may be used in appropriate combination. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, canolemellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, and corn starch. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citrate, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, sodium monoinosinate, Examples include 5'-sodium guanylate. Examples of the flavoring agent include trehalose, phosphoric acid, maltose, potassium darconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like. Examples of the surfactant include polysorbate (polysorbate 80, etc.), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. Examples of the fragrances include lemon oil, orange oil, menthol and brackish oil. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. As the fluidizing agent, for example, light anhydrous caustic acid, talc, hydrous diacid oxide and the like can be mentioned. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, macrogol, and hydroxypropyl cellulose (HP C). These additives are generally blended at a ratio usually used for oral preparations. In addition to the above, well-known documents such as Yakuji Nippo 2000 Such additives may be used as described in the “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association).

[0046] A solid preparation containing limaprost can be produced by a known method, for example, a rolling granulator, a stirring granulator, a fluidized granulator, a centrifugal tumbling granulator, a dry granulator, etc. Can be used to produce granules by granulating.

[0047] For the solid preparation, for example, the granules obtained by the above method can be used as a granule as it is. The solid preparation also includes a capsule containing the granule. Capsenoles can be produced by a known method. For example, the above-mentioned granules, and those to which additives are added as necessary, are hard capsules (for example, gelatin capsules, hydroxypropylmethylenocellulose (HPMC) capsules, pullulan). Capsules, polybulal alcohol (PVA) capsules, etc.) can be filled by using a capsule filling machine. The solid preparation includes a tablet containing the granule. Tablets can be manufactured by known methods. For example, the above granule and additives as necessary may be mixed evenly, and compression-molded with a rotary tableting machine or the like to obtain an uncoated tablet, and the uncoated tablet may be used as a tablet as it is. Furthermore, even if it is coated with a coating base, it does not work. It is also possible to prepare a mixed powder containing a drug or the like without granulation and tablet it with a rotary tableting machine or the like. Furthermore, a lyophilized product obtained by dissolving limaprost and excipients in a solvent (for example, water, an organic solvent (for example, ethanol, acetone, etc.), or a mixed solvent thereof) instead of the above granules, and lyophilizing according to a conventional method. You can make tablets using That is, after freeze-dried products containing limaprost are pulverized, additives may be added and mixed as necessary, and tablets may be formed into tablets.

Example

[0048] Hereinafter, the present invention is described in detail by clinical pharmacological test examples and formulation examples, but the present invention is not limited thereto. Naturally, various conditions may be changed without departing from the scope of the present invention. In the following clinical cases, the power to administer 6 tablets of Rimaprostal Adades (2 tablets at a time, 3 times a day) as well as 3 tablets of Rimaprost alfadex (1 tablet once a day) It is effective even when administered 1 tablet 3 times a day.

[0049] [Clinical pharmacological study example] L

Limaprost Alphadex tablets (trade names: Opalmon Tablets, Rimaprost 5) per day for patients with retinal vascular occlusion ½0-year-old male with left visual acuity observed for 1 week before a general or ophthalmic history g / tablet) 6 tablets (2 tablets at a time, 3 times a day) were orally administered for 11 months. In addition, 20 mg of prednisolone (trade name: predonin) was administered for 6 days per day, and 9 g of saireito (trade name: TSUMURA Sairei extract granule) was administered for 5 months per day. At the first visit of the treated patient, the left-eye correction visual acuity was 0.4, and the left fundus showed marked dilation of blood vessels, retinal bleeding and retinal vitiligo. The fundus findings began to improve 1 month after the start of treatment, and visual acuity recovered to 0.9 after 5 days, and then recovered to 1.0 after 3 months without further decline. Fundus hemorrhage and vascular abnormalities almost disappeared 45 days after administration.

In the figure, photographs of the left eye fundus before treatment with rimaprost (Fig. 1), after administration for 1 week (Fig. 2), after administration for 3 months (Fig. 3) and after administration for 9 months (Fig. 4) are shown.

As is apparent from the above study, administration of limaprost improved symptoms caused by ocular circulation disorders. Short-term prednisolone administration was used to suppress acute vasculitis, and Sairei-to was administered for the purpose of reducing retinal edema. These single administrations have no therapeutic effect on ocular circulation disorders.

[Formulation example]

The typical formulation example used for this invention is shown below.

Row 1

350 g of dextran 40 was weighed and dissolved in 1875 g of purified water. 50 g of Limaprost alphadex was dissolved in this, and then lyophilized according to a conventional method. 4 g of the obtained powder was mixed with 26 g of dextrin, 252.9 g of lactose, 15 g of corn starch, 0 · 6 g of light anhydrous anhydrous and 1 · 5 g of stearic acid, and using a rotary tableting machine, Tablets containing 5 g of limaprost per tablet (100 mg, 6.5 mm φ) by tableting at a tableting pressure of 800 kg / cm ² and drying under the conditions of 60 ° C, 0.1 kPa or less, 2 hours 2000 I got a tablet. Table 1 shows the composition of one tablet (lOOmg).

[table 1] table 1

Industrial applicability

[0051] If an ophthalmic circulatory disorder improving agent for oral administration of 5; ^ to 50; ^ limaprost per day for 2 to 72 weeks is used in patients with ocular circulatory disturbance, Treatment and / or progression of symptoms caused by ocular circulation disorders can be suppressed. In addition to improving the bleeding and edema of the macular region in addition to the periphery of the fundus, it can improve symptoms such as decreased visual acuity, and the period of disappearance of fundus hemorrhage associated with diseases caused by ocular circulation disorders, and The power S can be used to recover the loss of visual acuity and / or shorten the period until visual field impairment is improved.

Further, since the agent of the present invention can be administered orally, it can be a safe and effective agent for improving ocular circulation disorder with excellent convenience.

Brief Description of Drawings

[0052] FIG. 1 shows a photograph of the left fundus before treatment with the agent of the present invention.

FIG. 2 shows a photograph of the left fundus 1 week after administration of the agent of the present invention.

FIG. 3 shows a left fundus photograph 3 months after administration of the agent of the present invention.

FIG. 4 shows a left fundus photograph 9 months after administration of the agent of the present invention.

Claims

The scope of the claims

[I] An agent for ameliorating ocular circulatory disorder by administering 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorders.

[2] The agent according to claim 1, which is used for the treatment of symptoms caused by ocular circulation disorder and / or for the suppression of progression.

[3] The agent according to claim 2, wherein the symptom caused by ocular circulation disorder is retinal vascular occlusion or diabetic retinopathy.

[4] The agent according to claim 1, wherein the administration period is 4 to 15 weeks.

[5] The agent according to claim 1, for oral administration once to three times a day.

[6] The agent according to claim 5, for oral administration of 5 mg or 10 mg g of limaprost 3 times a day.

[7] The agent according to claim 6, for oral administration of 5 g or 10 g of limaprost 3 times a day for 4 to 15 weeks.

[8] The agent according to claim 1, which is a tablet, capsule or granule.

[9] The agent according to claim 1, which is used for vasodilation, platelet aggregation inhibition, erythrocyte deformability enhancement, active oxygen production inhibition, hemorrhage absorption promotion and / or angiogenesis inhibition.

[10] The agent according to claim 2, wherein the symptom caused by ocular circulation disorder is optic nerve atrophy, retinal vasculitis, fundus hemorrhage, retinal edema, macular edema, angiogenesis and / or retinal vitiligo.

[I I] The agent according to claim 2, wherein the symptom caused by ocular circulation disorder is decreased visual acuity, visual field impairment, foggy vision, metamorphosis, central scotoma, flying mosquito disease, headache and / or eye pain.

12. The agent according to claim 2, wherein the treatment is for shortening the disappearance period of fundus oculi bleeding.

[13] The agent according to claim 2, wherein the treatment is for recovery of visual acuity associated with fundus bleeding and / or for shortening the period of visual field impairment improvement.

[14] The agent according to claim 1, which is used for treatment and / or prevention of complications associated with symptoms caused by ocular circulation disorder.

[15] The agent according to claim 14, wherein the complication is hypocirculatory retinopathy, iris rubeosis, neovascular glaucoma and / or retinal detachment.

[16] The fundus hemorrhage is fundus hemorrhage associated with retinal vascular occlusion or diabetic retinopathy. 2. The agent according to 2.

[17] An agent for shortening the disappearance period of fundus bleed for oral administration of 5; ^ to 50; ^ limaprost per day for 2 to 72 weeks to patients with retinal vascular occlusion.

[18] The agent according to claim 17, for oral administration of 5 g or 10 g of limaprost 3 times a day for 2 to 52 weeks.

[19] In patients with retinal vascular occlusion, oral administration of 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks results in recovery of vision loss associated with fundus hemorrhage and / or improvement of visual field impairment An agent for shortening the period.

[20] The agent according to claim 19, for oral administration of 5 g or 10 g of limaprost 3 times a day for 2 to 52 weeks.

[21] The agent according to claim 18 or 20, for oral administration of 5 g or 10 g of limaprost 3 times a day for 4 to 15 weeks.

[22] An agent for shortening the period of disappearance of fundus bleed for oral administration of 5; ^ to 50; ^ limaprost per day for 2 to 72 weeks in patients with diabetic retinopathy.

[23] The agent according to claim 22, for oral administration of 5 g or 10 g of limaprost 3 times a day for 2 to 52 weeks.

[24] For patients with diabetic retinopathy, oral administration of 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks for recovery of vision loss associated with fundus hemorrhage and / or shortening of visual field impairment Agent.

[25] The agent according to claim 24, wherein 5 g or 10 g of limaprost is orally administered 3 times a day for 2 to 52 weeks.

[26] From limaprost and circulatory improvers, thrombolytics, anticoagulants, antiplatelets, vasodilators, vitamins, iodines, _a blockers, prostaglandins, low molecular weight dextrans and hemostatics The agent according to claim 1, for administration in combination with one or more selected.

[27] A method for ameliorating ophthalmic circulation, characterized by orally administering 5; ^ to 50; ^ of limaprost per day for 2 to 72 weeks to patients with ocular circulation disorders.

[28] The method according to claim 27, which is a method for treating and / or suppressing the progression of symptoms caused by ocular circulation disorder. The method described.

[29] An agent for ameliorating ocular circulation disorder by orally administering 5 to 50 mg / day of limaprost for 2 to 72 weeks.

[30] The agent according to claim 29, wherein the ocular circulatory disorder improving agent is a therapeutic agent for symptoms caused by ocular circulatory disorder and / or a progression inhibitor.