TECHNICAL FIELD

[0001] The present invention relates to an optic nerve protecting agent containing an α ₁ receptor blocker as an active ingredient.

BACKGROUND ART

[0002] Human optic nerve is composed of about 1,000,000 optic nerve fibers. It is said that when 30% of the fibers is disordered, abnormality can be detected with a static perimeter and that just when 50% of the fibers is disordered, the influence can emerge on their visual field and be detected with a kinetic perimeter. Optic nerve fibers are composed of the axons of retinal ganglion cells and elongate to the lateral geniculate nucleus. Anatomically and physiologically, retinal ganglion cells can be classified into several types. Axons elongating from these types of retinal ganglion cells have individually different morphologies and functions. The disorder of optic nerve occurs, essentially due to a disorder of axonal transport. Axonal transport is disordered at the part of lamina cribrosa. The disorder of axonal transport means the death of optic nerve cells. It is suggested that apoptosis is involved in the death (Journal of the eye, 16(6) 833-841). When optic nerve cells are disordered, disorders of visual field and various retinal disorders occur, eventually leading to the possibility of visual loss. Therefore, the development of an optic nerve protecting agent for protecting optic nerve cells and preventing the death of the cells is desired.

[0003] Because α ₁ receptor blockers bind to the adrenalin α ₁ receptor to suppress neurotransmission, the α ₁ receptor blockers are used as hypotensive agents. Bunazosin as an α ₁ receptor blocker is commercially available as a hypotensive agent. Japanese Patent No.2610619 reports that bunazosin has an action to reduce intraocular pressure and is useful for the treatment of high intraocular pressure. Further, JP-B-7-23302 reports a formulation for applying bunazosin to eyedrops. Further, it is reported that terazosin (WO 95/31200), prazosin (U.S. Pat. No. 4,197,301) and dapiprazole (JP-A-54-157576) as an α ₁ receptor blocker have such action to reduce intraocular pressure.

[0004] Generally, it is considered that glaucoma is a disease caused by the rise of intraocular pressure, which induces organic disorders of optic nerve fibers at the site of the optic disc of optic nerve, involving the occurrence of the inversion of the optic disc and the defects of retinal nerve fibers to finally cause visual field disorders. In the field of research works over glaucoma, mainly, a method for suppressing the rise of intraocular pressure to indirectly prevent the disorders of visual field is studied.

[0005] It is expected that a drug capable of actively protecting optic nerve cells if found may directly prevent visual field disorders.

[0006] A disease involving a change of optic disc and the change of visual field has recently been drawing attention, although no rise of intraocular pressure is involved therein. The disease is called normal tension glaucoma. Normal tension glaucoma is a disease causing defects of visual field, due to the disorders of optic nerve, although the intraocular pressure is constantly within the normal range (at 21 mm Hg or lower). Even for the treatment of such normal tension glaucoma, it is needed to reduce intraocular pressure, and ocular hypotensive agents are administered. If a drug capable of protecting optic nerve can be found, the drug may be used for direct treatment or prevention of the disorders of visual field and may therefore be a more effictive drug. Therefore, the development of such drug with those effects is demanded.

[0007] For retinal diseases, additionally, retinal blood circulation disorders occupy a particularly important position among retinal diseases. The retinal blood circulation disorders cause the deficiency in the supply of oxygen and nutrients, so that retinal ganglion cells are dead. Typically, the symptoms of retinal blood circulation disorders include for example retinal blood vessel occlusion with occlusion or stenosis of retinal vein or retinal artery, diabetic retinopathy as one pathogenesis of retinal detachment, and ischemic optic neuropathy causing the occurrence of disorders of visual functions. It is suggested that the death of retinal ganglion cells is deeply involved in the onset or symptoms of macular degeneraten, retinitis pigmentosa and Leber's disease as other retinal diseases.

[0008] As has been described above, the protection of optic nerve cells enables the direct treatment or prevention of the disorders of visual field. Additionally, the protection thereof works as a useful measure for preventing or treating various retinal diseases.

[0009] As described above, α ₁ receptor blockers have been known to have an action to reduce intraocular pressure. However, not any report exists about the effect of α ₁ receptor blockers on the protection of optic nerve. Further, no report exists as to what kind of influences α ₁ receptor blockers have on retinal diseases typically including for example normal tension glaucoma, retinal blood vessel occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneraten, retinitis pigmentosa and Leber's disease.

[0010] As described above, the action of α ₁ receptor blockers to protect optic nerve has not yet been known. Therefore, studies concerning the action of α ₁ receptor blockers to protect the nerve have been a subject of much interest.

DISCLOSURE OF THE INVENTION

[0011] Therefore, the present inventors have made studies about the relation between α ₁ receptor blockers and an optic nerve protecting action. Consequently, the inventors have found that α ₁ receptor blockers have a great action to protect optic nerve cells.

[0012] The invention relates to an optic nerve protecting agent containing an α ₁ receptor blocker as the active ingredient.

[0013] Additionally, the invention relates to a method for treating or preventing a disease due to the disorders of optic nerve cells, comprising administering an effective amount of an α ₁ receptor blocker to a patient in need thereof, as well as use of an α ₁ receptor blocker in the manufacture of a medicament to treat or prevent a disease due to disorders of optic nerve cells.

[0014] In the prevent invention, compounds with an action to block α ₁ receptors include for example bunazosin, prazosin, terazosin, naftopidil, doxazosin, trimazosin, dapiprazole, alfuzosin, tamslosin, and KRG-3332.

[0015] Among the α ₁ receptor blockers, α ₁ receptor blockers having a basic heterocyclic ring in each chemical structure are preferable. The basic heterocyclic ring means a heterocyclic ring which has at least one nitrogen atom in the ring and which is basic. Saturated heterocyclic rings having two nitrogen atoms are more preferable among such basic heterocyclic rings. example imidazolidine, piperazine, and homopiperazine. The α ₁ receptor blockers having a basic heterocyclic ring in each chemical structure include bunazosin, prazosin, terazosin, naftopidil, doxazosin, trimazosin and dapiprazole.

[0016] These drugs may take salt forms with inorganic acids and organic acids. Examples of the salts include for example hydrochlorides, sulfates, phosphates and oxalates.

[0017] In the course of the development and research of α ₁ receptor blockers as therapeutic agents of glaucoma, unexpectedly, the inventors found that α ₁ receptor blockers had an action to protect optic nerve cells. Thus, the prevent invention has been achieved. According to the method of Kashii et al. (IOVS. 1994, vol.35, no.2 685-695), the inventors had been studying their action on the death of rat fetal retinal nerve cells in culture as induced by glutamate addition and their action on the death of rat fetal retinal nerve cells in culture as induced by serum elimination. (The details are described in the following section of a pharmacological test.) The inventors consequently found that α ₁ receptor blockers effectively suppressed the death of such nerve cells and would potentially be great drugs for protecting optic nerve.

[0018] In accordance with the invention, the a, receptor blockers may be administered orally or parenterally. The dosage forms thereof include for example tablets, capsules, granules, powders, eye drops and injections. Particularly, eye drops and injections are preferable. These can be formulated, using routine techniques.

[0019] Specifically, formulations described in for example JP-B-7-23302 and WO 95/31200 and commercially available formulations can be used.

[0020] Taking an example by eyedrops, formulation methods are described in detail. Using isotonic agents such as sodium chloride and concentrated glycerin, buffers such as boric acid, borax, sodium phosphate, and sodium acetate, surfactants such as polyoxyethylene sorbitan monooleate, stearate polyoxyl 40 and polyoxyethylene hardened castor oil, stabilizers such as sodium citrate and sodium edetate, and preservatives such as benzalkonium chloride and paraben depending on the necessity, such eyedrops can be prepared. The pH may be within a range acceptable for ophthalmic formulations. Preferred pH is within the range of 4 to 8. Eye ointment can be prepared, using usual base such as white Vaseline and fluid paraffin.

[0021] The dose may appropriately be selected, depending on the symptoms, the age and the like of patients. For oral administraten, the dose of 0.1 to 100 mg per day can be administered in one time or in several times. Eyedrops at 0.0001 to 1 w/v %, preferably 0.001 to 0.1 w/v % are instilled into eyes in one time or in several times per day.

[0022] The α ₁ receptor blocker of the invention may be used in combination with other intraocular pressure reducing agents.

[0023] As an example, the results of a pharmacological test are shown below. The example is for higher understanding of the invention but never limits the scope of the invention.

BEST MODE FOR CARRYING OUT THE INVENTION