The posterior eye segment tissue such as vitreous body, retina, choroid, and sclera is an important domain for visual performance. If the domain is damaged, it may often cause severely-reduced visual acuity or visual loss. Typical diseases in posterior eye segment include age-related macular degeneration, diabetic retinopathy, diabetic macular edema, macular edema, myopic choroidal neovascularization, retinal vein occlusion, choroidal neovascularization, uveitis, retinitis pigmentosa, proliferative vitreoretinopathy, and central serous chorioretinopathy. In particular, age-related macular degeneration or diabetic retinopathy is main diseases causing visual loss in late-middle-aged to senile people in developed countries such as Europe, America, and Japan, which is a very problematic disease in ophthalimic clinic and also in whole society (Patent Literature 1).
In general, the drug delivery to the posterior eye segment such as retina via blood is severely limited with blood-retinal barrier (BRB) in the posterior eye segment. When a drug is administered in eyedrops, most of the drug can be quickly discharged from the eye surface by tear-turnover and then transferred to blood in general-circulation via nasolacrimal canal (Non-Patent Literature 1). Thus, if the amount of a drug in an ophthalmic formulation is 100, the amount of the delivered drug administered in eyedrops is 0.1-0.5 in cornea to which the drug is most transferred; 0.01-0.1 in anterior aqueous humor/iris and ciliary; and about 0.0001 in lens and vitreous body, i.e., it has been known that the delivered amount is too low (Non-Patent Literature 2). In addition, it is generally thought that a drug can be hardly delivered to the posterior eye segment by the administration in eyedrops because the posterior eye segment locates in further back of lens or vitreous body. And, it is generally thought that an ophthalmic suspension which is used in case of a low-water-soluble drug is more difficult to be delivered to the posterior eye segment by the administration in eyedrops than a normal ophthalmic solution, because such drug is not dissolved in water and thus it is generally hardly absorbed into intraocular site (Non-Patent Literature 3). There are some ophthalmic suspensions in clinical practice, but the use is limited in a disease in anterior eye segment such as conjunctivitis. It is thought that the means to make a drug delivered to the posterior eye segment are only an injection into vitreous body or a surgery, or a systemic administration via general circulation blood, i.e., the other means are very difficult (Patent Literature 4, Non-Patent Literature 4).
A disease in posterior eye segment is an eye disease causing a severe symptom, but there are few useful drugs for it, and furthermore the administration is limited because the targeting site is the posterior eye segment where a drug is hard to be delivered. Thus, the treatment for the disease is now done by the injection of an anti-vascular endothelial growth factor (anti-VEGF) into vitreous body, the injection of a steroid into vitreous body or Tenon capsule, the photodynamic therapy (PDT), the surgery of vitreous body, etc. However, all of these current treatments, i.e., injection into eyes, etc., are very invasive for patients, and inflict pain to patients, thus it has been desired to develop a new administration such as eyedrops.
(R)-(−)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone (ranirestat) (hereinafter, defined as “Compound A”) has a potent action inhibiting aldose reductase, and the compound is also a low-toxic compound, thus the compound are useful as a drug for treating diabetic complication (Patent Literature 2, Patent Literature 3).
