WO2008023784A1 - Agent pour l'amélioration d'un trouble de la circulation ophtalmique - Google Patents

Agent pour l'amélioration d'un trouble de la circulation ophtalmique Download PDF

Info

Publication number
WO2008023784A1
WO2008023784A1 PCT/JP2007/066430 JP2007066430W WO2008023784A1 WO 2008023784 A1 WO2008023784 A1 WO 2008023784A1 JP 2007066430 W JP2007066430 W JP 2007066430W WO 2008023784 A1 WO2008023784 A1 WO 2008023784A1
Authority
WO
WIPO (PCT)
Prior art keywords
limaprost
agent
weeks
agent according
ocular
Prior art date
Application number
PCT/JP2007/066430
Other languages
English (en)
Japanese (ja)
Inventor
Masahiko Ayaki
Original Assignee
Showa University
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Showa University, Ono Pharmaceutical Co., Ltd. filed Critical Showa University
Publication of WO2008023784A1 publication Critical patent/WO2008023784A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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.
  • the blood vessels of the eyeball include the retinal vasculature and the ciliary 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.
  • 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.
  • retinal vascular occlusion central retinal artery occlusion, retinal artery branch oc
  • 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.
  • various complications hypercirculatory retinopathy, iris rubeosis, neovascular glaucoma, retinal detachment, etc.
  • 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.
  • these treatments may not be able to be treated sufficiently.
  • Non-patent Document 1 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.
  • Non-patent Document 1 it has been reported that sufficient effects on macular bleeding, edema, and visual acuity have not been observed.
  • PGF ⁇ derivatives have a therapeutic agent for retinal diseases.
  • Patent Document 1 proposes a Patent Document 1
  • 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.
  • 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.
  • 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
  • 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.
  • 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 /
  • 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.
  • 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.
  • the present invention relates to an agent for improving ocular circulation disorder having the following constitutional power.
  • the agent according to 1 above which is for promoting hemorrhage absorption and / or for inhibiting angiogenesis.
  • 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.
  • agent for improving ocular circulation disorder is an agent for treating and / or preventing progression of symptoms caused by ocular circulation disorder.
  • 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.
  • ocular circulation disorder can be improved, and treatment and / or progression of symptoms caused by ocular circulation disorder can be suppressed.
  • yellow 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.
  • 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!
  • the cyclodextrin inclusion compound of limaprost includes, for example, ⁇ -cyclodextrin inclusion compound, / 3-cyclodextrin inclusion compound, and ⁇ -cyclodextrin inclusion compound of limaprost, Above all, the following formula,
  • a compound in which limaprost is clathrated with ⁇ -cyclodextrin is preferred.
  • Chemical name is ( ⁇ ) — 7— [(1R, 2R, 3R) — 3 Hydroxy 1— [(3S, 5S) — ( ⁇ ) — 3 Hydroxy 5 Methyl-1 nonenyl] 5 oxocyclopentyl] 2 Heptenoic acid ⁇ -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.
  • 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 ⁇ -cyclodextrin inclusion compound of limaprost, ie, limaprost alpha detas.
  • ocular circulation disorder means blood vessels around the eye (for example, retinal blood vessels, choroidal blood vessels).
  • 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.
  • patient with ocular circulation disorder refers to a patient with ocular circulation disorder.
  • treatment means to guide symptoms in the direction of healing
  • 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.
  • 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.
  • 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.
  • the agent of the present invention is effective for retina
  • retinal vascular occlusion is a disease in which retinal blood vessels are occluded.
  • 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).
  • 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. !
  • proliferative retinopathy refers to the stage where neovascularization occurs and proliferates to near the vitreous body
  • 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.
  • 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.
  • fundus hemorrhage associated with retinal vascular occlusion or diabetic retinopathy 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.
  • the agent of the present invention when 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))
  • circulatory improvers such as kallidinogenase
  • hemostatic agents such as sodium carbazochrome sulfonate, tranexamic acid
  • vitamin E tocopherol acetate
  • 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.
  • the agent of the present invention when 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.
  • 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.
  • various complications hypercirculatory retinopathy, iris rubeosis, neovascular glaucoma, retinal detachment, etc.
  • 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.
  • 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.
  • 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.
  • Symptoms resulting from ocular circulation disorder may be accompanied by bleeding, causing fundus hemorrhage and retinal edema.
  • 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.
  • 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.
  • 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.
  • OCT optical coherence tomography
  • retinal temperature measurement estimate of blood flow on the eyeball surface
  • 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! /.
  • the agent of the present invention is applied to patients with ocular circulation disorder.
  • 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.
  • 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.
  • 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.
  • 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.
  • the route of administration of the agent of the present invention is oral administration
  • the dosage form for oral administration is preferably a solid preparation (eg, tablet, granule, capsule, etc.).
  • 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.
  • 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.
  • 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.
  • 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.
  • tablets containing limaprost are limaprost. Limaprost alphadex tablets contained as huadetas are preferred.
  • 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.
  • 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.
  • the agent of the present invention may be used in combination with a drug usually used for improving ocular circulation.
  • Anvilin Crested DNA Fravin Adenine Dinucleotide Somum
  • vitamin B for example, cobamamide, cyanocobalami
  • n Nolamin, Hyd, Loxo: ⁇ -Noramine (hydroxocobalamin), Me: ⁇ Noramine ( me cobalamin, etc.), Vitamin E (tocopherol acetate))), iodine drugs (for example, Iodine lecithin, etc.), ⁇ -blockers (Tolazoline Hydrochloride, etc.), prostaglandin preparations, low molecular weight dextrans and hemostatic agents (eg, carbazochrome sodium sulfonate, tranexamic acid, etc.).
  • iodine drugs for example, Iodine lecithin, etc.
  • ⁇ -blockers Tolazoline Hydrochloride, etc.
  • prostaglandin preparations low molecular weight dextrans and hemostatic agents (eg, carbazochrome sodium sulfonate, tranexamic acid, etc.).
  • thrombolytic drugs include: Eight kinds? 8. Alteplase (alt-marked lase), Tisokinase (tisokinase), Naaphuase (nateplase), Noapaphuuse (pamiteplase, Monapplase), Wasmoaphu (desmoteplase, etc., urokinase) ), Nasanoplase, Streptokinase, etc.
  • t-PAs are t-PA and t-PA modified (eg, genetically 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 ⁇ rin, nadroparin), be: emirin (bemiparin), levino ⁇ 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, Idraparin
  • 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.
  • 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.
  • 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.
  • therapies laser photocoagulation, eyeball massage, hyperbaric oxygen therapy, anterior chamber puncture, vitrectomy, etc.
  • 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.
  • 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.
  • excipients include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritonor, manoletithonole, xylitolore, noratinose, trenosucrose, recbitole, 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.
  • dextran e.g., dextran, dextran 4 0, dextran 70, etc.
  • the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like.
  • disintegrant examples 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a solvent for example, water, an organic solvent (for example, ethanol, acetone, etc.), or a mixed solvent thereof
  • Limaprost Alphadex tablets (trade names: Opalmon Tablets, Rimaprost 5) per day for patients with retinal vascular occlusion 1 ⁇ 20-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent pour améliorer un trouble de la circulation ophtalmique pour une administration orale de limaprost à un patient, ayant un trouble de la circulation ophtalmique, en quantité de 5 à 50 µg par jour, pendant une période de 2 à 72 semaines. L'agent peut être administré par voie orale pour améliorer le trouble de la circulation ophtalmique, et traiter un symptôme induit par le trouble de la circulation ophtalmique et/ou prévenir la progression du symptôme. En outre, l'agent peut raccourcir la période requise pour la disparition de l'hémorragie du fond de l'œil associée au trouble de la circulation ophtalmique, et également raccourcir la période nécessaire pour le rétablissement de l'acuité visuelle diminuée et/ou l'amélioration d'un trouble du champ visuel.
PCT/JP2007/066430 2006-08-25 2007-08-24 Agent pour l'amélioration d'un trouble de la circulation ophtalmique WO2008023784A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006228590 2006-08-25
JP2006-228590 2006-08-25

Publications (1)

Publication Number Publication Date
WO2008023784A1 true WO2008023784A1 (fr) 2008-02-28

Family

ID=39106866

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/066430 WO2008023784A1 (fr) 2006-08-25 2007-08-24 Agent pour l'amélioration d'un trouble de la circulation ophtalmique

Country Status (1)

Country Link
WO (1) WO2008023784A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012137987A1 (fr) * 2011-04-07 2012-10-11 Sucampo Ag Procédé de traitement de l'asthénopie
JP2012229209A (ja) * 2011-04-13 2012-11-22 Ono Pharmaceut Co Ltd 耳管開放症治療剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029135A1 (fr) * 1996-12-26 1998-07-09 Kirin Beer Kabushiki Kaisha Medicaments pour soigner les troubles de la circulation ophtalmiques
WO2000010605A2 (fr) * 1998-08-20 2000-03-02 Senju Pharmaceutical Co., Ltd. Prophylaxie ou remedes pour la perturbation circulatoire de l'oeil
JP2005314413A (ja) * 2004-04-02 2005-11-10 Ono Pharmaceut Co Ltd 経口投与用医薬組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029135A1 (fr) * 1996-12-26 1998-07-09 Kirin Beer Kabushiki Kaisha Medicaments pour soigner les troubles de la circulation ophtalmiques
WO2000010605A2 (fr) * 1998-08-20 2000-03-02 Senju Pharmaceutical Co., Ltd. Prophylaxie ou remedes pour la perturbation circulatoire de l'oeil
JP2005314413A (ja) * 2004-04-02 2005-11-10 Ono Pharmaceut Co Ltd 経口投与用医薬組成物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
FUKUSHIMA M.: "Merck Manual, Japanese language edition", vol. 17TH ED., 10 December 1999, NIKKEI BUSINESS PUBLICATIONS, INC., pages: 728 - 736, XP003020292 *
HATA N. ET AL.: "Jiko Men'eki Momakusho ga Utagawareta 2 Rei", JAPANESE JOURNAL OF CLINICAL OPHTHALMOLOGY, vol. 52, no. 12, 2005, pages 1837 - 1842, XP003020290 *
HINOHARA S. ET AL.: "1997 Kyo no Chiryo Shishin,", IGAKU-SHOIN LTD., 15 January 1997 (1997-01-15), pages 816 - 818, XP003020293 *
KOMABA J. ET AL.: "Kenko Seijin Dansei o Taisho to shita Opalmon-jo (Limaprost Afladex-jo) no Rinsho Yakubutsu Dotai Shiken", THE JOURNAL OF MEDICINE, vol. 53, no. 2, 25 February 2005 (2005-02-25), pages 265 - 271, XP003020291 *
SEKIYA N. ET AL.: "Opalmon-jo no Kashitsuka deno Anteisei Kaizen I - Dextran Matawa Dextrin no Tenka ni yoru Anteika -", JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, JAPAN, vol. 66, no. 2, 1 March 2006 (2006-03-01), pages 160 - 166, XP003020294 *
WAKUSAWA R. ET AL.: "Shinkosei no Gimomaku Shikiso Hensei o Teishita white dot syndrome no 1 Rei", JAPANESE JOURNAL OF CLINICAL OPHTHALMOLOGY, vol. 60, no. 5, 2006, pages 775 - 780, XP003020289 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012137987A1 (fr) * 2011-04-07 2012-10-11 Sucampo Ag Procédé de traitement de l'asthénopie
CN103561748A (zh) * 2011-04-07 2014-02-05 苏坎波公司 治疗眼疲劳的方法
US8889735B2 (en) 2011-04-07 2014-11-18 Sucampo Ag Method for treating asthenopia
JP2012229209A (ja) * 2011-04-13 2012-11-22 Ono Pharmaceut Co Ltd 耳管開放症治療剤

Similar Documents

Publication Publication Date Title
JP5696121B2 (ja) α−２アドレナリン受容体アゴニスト含有生分解性眼内インプラント
WO2010113753A1 (fr) Agent prophylactique ou thérapeutique des rétinopathies comprenant un peptide inhibiteur de jnk (c-jun n-terminal kinase), méthode de prévention ou de traitement des rétinopathies, et utilisation du peptide
US12083128B2 (en) Use of medications with neuroprotective properties to prevent or reduce the risk of ischemia-reperfusion injury in a subject
Klais et al. Intraocular recombinant tissue-plasminogen activator fibrinolysis of fibrin formation after cataract surgery in children
BR112021006132A2 (pt) compostos bifenil sulfonamida para o tratamento de doenças de colágeno tipo iv
US4407801A (en) Anti-ischemic pharmaceutic compositions
JP6820658B2 (ja) ジピリダモールを用いる眼疾患の治療において使用するための組成物
JP2967523B2 (ja) 眼病用製薬組成物
WO2008023784A1 (fr) Agent pour l'amélioration d'un trouble de la circulation ophtalmique
WO2010117077A1 (fr) Agent thérapeutique pour des maladies choriorétiniennes comprenant un dérivé de sirolimus comme principe actif
ES2324200T3 (es) Medicamentos oftalmologicos retino-protectores, que comprenden ramipril o ramiprilato.
JPH09278653A (ja) 網膜疾患治療剤
KR20220166203A (ko) 퇴행성 안질환의 예방 또는 치료용 약학적 조성물
WO2000021531A1 (fr) Medicaments pour maladies oculaires
CN116829168A (zh) 环孢菌素类似物作为抗血栓形成剂的用途
JP4921165B2 (ja) 視覚器官の神経変性疾患及び真性糖尿病の治療用フルピルチン製剤
CN110496130B (zh) 一种防治糖尿病性视网膜病变的药物组合物
JPH027293B2 (fr)
WO2024177104A1 (fr) Produit pharmaceutique pour le traitement ou la prévention d'une neuropathie périphérique
JPS63502270A (ja) 散瞳作用を有する眼科用医薬組成物
CA2451475A1 (fr) Agent de protection des neurones retiniennes
JP4393863B2 (ja) 視神経細胞保護剤
JP2006076956A (ja) 胃炎の治療・予防用配合剤
CN112618701A (zh) 一种抗血小板溶栓素在制备治疗视网膜静脉阻塞性疾病的药物中的应用
KR20240115650A (ko) 티로신 키나아제 억제제의 무정형 나노 분자회합체와 이를 포함하는 조성물 및 그의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07792959

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07792959

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP