(12) Patent Application Publication (10) Pub. No.: US 2009/0082338A1 Mizuno Et Al

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US 20090082338A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0082338A1 Mizuno et al. (43) Pub. Date: Mar. 26, 2009

(54) PREVENTIVE OR REMEDY FOR (86). PCT No.: PCT/UP2006/312266 GLAUCOMA S371 (c)(1), 2), (4) Date: Dec. 19, 2007 (75) Inventors: Ken Mizuno, Tokyo (JP); Jiro (2), (4) . Matsumoto, Saitama (JP) (30) Foreign Application Priority Data Jun. 21, 2005 (JP) ...... 2005-180535 Correspondence Address: Publication Classification OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, P.C. (51) Int. Cl. 194O DUKE STREET A6II 3/55 (2006.01) ALEXANDRIA, VA 22314 (US) A63/496 (2006.01) A6IP27/06 (2006.01) - 0 (52) U.S. Cl...... 514/218: 514/253.05 (73) Assignee: so Co., Ltd., Nagoya-shi, Aichi (57) ABSTRACT There is provided a preventive for glaucoma or a preventive or a remedy for ocular hypertension, with a potent ocular (21) Appl. No.:y x- - - 11A993,1019 hypotensivey effect and prolongedyp duration thereof.p A preven tive or a remedy for glaucoma comprising a Rho kinase (22) PCT Filed: Jun. 20, 2006 inhibitor and an C. blocker in combination. Patent Application Publication Mar. 26, 2009 US 2009/0082338A1

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PREVENTIVE OR REMEDY FOR nism of action (Patent Documents 1 and 2). Rho kinase GLAUCOMA inhibitors lower IOP by promoting aqueous outflow from the trabecular outflow pathway (Non-patent Document 2), and it TECHNICAL FIELD is further suggested that this action may be attributed to changes in the cytoskeleton of a trabecular meshwork cells 0001. The present invention relates to a preventive or a (Non-patent Documents 2 and 3). remedy for glaucoma or ocular hypertension. 0008. In the treatment of glaucoma and ocular hyperten Sion, drugs having an ocular hypotensive action are used in BACKGROUND ART combination to enhance the additive ocular hypotensive 0002 Glaucoma is a disease characterized by the elevation effects. For example, combination use of a prostaglandin and of intraocular pressure (IOP) due to various pathogenesis a sympathetic nerve blocker (Patent Document 3), or a com leads to damage and atrophy of the optic nerve resulting in the bination of some drugs having an ocular hypotensive action abnormal visual field, and thus visual acuity is gradually (Patent Document 4), and the like have been reported. Fur reduced. Since the optic nerve does not recover once atrophy thermore, combination use of a Rho kinase inhibitor and a B occurs, glaucoma is a refractory disease in that not only vision blocker (Patent Document 5) and a remedy for glaucoma is lost if glaucoma is untreated, but also the condition is only comprising a Rho kinase inhibitor and a prostaglandin in maintained even after Successful treatment, and recovery can combination (Patent Document 6) have also been reported. not be expected. Furthermore, ocular hypertension, which 0009. However, the above-mentioned known remedies may lead to development of glaucoma over a long time and therapies for glaucoma and ocular hypertension are far although in the absence of visual field defects, also has a from satisfactory in view of the potency of the ocular similar risk. hypotensive effect and the duration of action. In particular, it 0003 Glaucoma is classified into three types: congenital is more difficult to lower normal IOP in patients with normal (developmental) glaucoma, secondary glaucoma, and pri tension glaucoma rather than lower elevated IOP. The above mary glaucoma. Patients with congenital (developmental) mentioned existing drugs and combinations thereof have glaucoma are born with growth deficiency of the iridocorneal limitations in the treatment of normal tension glaucoma, and angle, and obstruction of the aqueous outflow causes this type enhancement of the ocular hypotensive action is needed in the of glaucoma. Secondary glaucoma arises as a result of inflam clinical setting. mation or injury and is caused by Such as uveitis or ocular 0010 Under such circumstances, there has been no report trauma as well as hemorrhage due to diabetes, long-term use on glaucoma treatment using a Rho kinase inhibitor and a of steroid hormones for the treatment of other diseases, and selective sympathetic nerve C. receptor blocking agent in the like. Primary glaucoma is a generic name of glaucomas of combination, and there has been no description about the types with unclear causes and occurs most commonly of cooperative effect of Such a combination. glaucomas, with a high incidence among middle aged and O011 Patent Document 1 WO00/09162 elderly persons. Primary glaucoma and secondary glaucoma 0012 Patent Document 2.JP-A-11-349482 are further Subdivided into two types, open-angle glaucoma (0013 Patent Document 3 Japanese Patent No. 2726672 and angle-closure glaucoma, depending on the blockage of 0014 Patent Document 4 WO02/38158 the aqueous outflow. While many patients develop normal 00.15 Patent Document 5 JP-A-2004-182723 tension glaucoma in the absence of elevated IOP, the primary 0016 Patent Document 6.JP-A-2004-107335 aim of glaucoma treatment is to lower the IOP 0017 Non-patent Document 1 Journal of Japanese Oph 0004 For the treatment of glaucoma, laser treatment (laser thalmological Society, 94(8), 762-768 (1990) trabeculoplasty), Surgical therapy (trabeculectomy or trabe (0018 Non-patent Document 2 IOVS, 42(1), 137-144 culotomy), or the like is performed when IOP cannot be (2001) controlled with a drug or a patient with angle-closure glau 0019 Non-patent Document 3) IOVS, 42(5), 1029-1037 coma has an acute glaucoma attack, but drug therapy is used (2001) as the first line therapy. 0005 Drugs used in the drug therapy of glaucoma include DISCLOSURE OF THE INVENTION sympathetic nerve stimulants (nonselective stimulants such 0020. An object of the present invention is to provide a as epinephrine and C stimulants such as apraclonidine), sym preventive or a remedy for glaucoma or ocular hypertension pathetic nerve blockers (B blockers such as timolol. with a potent ocular hypotensive effect and a prolonged dura befunolol, carteolol, nipradillol, betaxolol, levobunolol, and tion of action. metipranolol and C. blockers such as bunaZosin hydrochlo 0021. The inventors of the present invention conducted ride), parasympathetic nerve agonists (pilocarpine, etc.), car various researches in order to achieve the foregoing object. As bonic anhydrase inhibitors (acetazolamide, etc.), prostaglan a result, we have found that a potent ocular hypotensive effect dins (isopropyl unoprostone, latanoprost, travoprost, is exerted by administering a Rho kinase inhibitor and an O. bimatoprost, etc.), and so forth. blocker in combination, and the duration of action is pro 0006. Of these, bunaZosin hydrochloride is a drug first longed. developed as an agent for selectively blocking sympathetic 0022 Specifically, the present invention relates to the fol nerve C. receptors, unlike existing remedies for glaucoma. As lowings. its mechanism of action, bunaZosinhydrochloride locally acts 0023, 1) A preventive or a remedy for glaucoma compris on the eyes by instillation and lowers IOP by promoting ing a Rho kinase inhibitor and an O. blocker in combina aqueous outflow from the uveoscleral outflow pathway (Non tion. patent Document 1). 0024. 2) A preventive or a remedy for ocular hypertension 0007 Meanwhile, Rho kinase inhibitors have been found comprising a Rho kinase inhibitor and an C. blocker in as candidate remedies for glaucoma based on a novel mecha combination. US 2009/0082338 A1 Mar. 26, 2009

0025, 3) Use of a Rho kinase inhibitor and an C. blocker in a Rhokinase inhibiting action and can be produced by known combination for production of a preventive or a remedy for methods such as, for example, the method described in glaucoma. WO99f2O62O. 0026 4) Use of a Rhokinase inhibitor and an O blocker in 0036 Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-di combination for production of a preventive or a remedy for azepine can be produced by known methods such as, for ocular hypertension. example, the method described in JP-A-61-227581 and, fur 0027 5) A method for preventing or treating glaucoma, ther, can be purchased and used as a drug (Eril.R S Injection wherein the method comprises administratinga Rhokinase nonproprietary name: fasudil hydrochloride hydrate, Asahi inhibitor and an O blocker in combination. Kasei Pharma). 0028 6) A method for preventing or treating ocular hyper 0037. Furthermore, Y-39983 is known to lower IOP in tension, wherein the method comprises administrating a rabbits with normal IOP from 1 hour after instillation, shows Rho kinase inhibitor and an C. blocker in combination. the maximum ocular hypotensive effect at 2 to 4 hours after 0029. According to the present invention, a preventive or a instillation, and has a potent action dependent on the concen remedy for glaucoma or ocular hypertension with a potent tration, with the maximum IOP reduction of 15 mmHg at a ocular hypotensive effect and a prolonged duration of action concentration of 0.1% (BIO Clinica, 1713), 1191-1194 can be provided. 2002: The 4th Int. Symp. Ocular Pharmacol. Pharm. Feb. 28, 2002, Seville 2002: 2: Annu. Meet. Assoc. Res. Vision BRIEF DESCRIPTION OF THE DRAWINGS Ophthalmol. May 1, 2005, Fort Lauderdale 2005: Abst. 3787/B145). 0030 FIG. 1 is a graph showing changes in IOP over time 0038 Examples of salts of (S)-(-)-1-(4-fluoro-5-iso in each treatment group. IOP is shown as a change from the quinolinesulfonyl)-2-methyl-1,4-homopiperazine and initial IOP (meantstandard error). O, bunaZosin alone group; hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine , (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1, include pharmaceutically acceptable salts such as salts of 4-homopiperazine alone group; A, bunaZosin plus (S)-(-)-1- inorganic acids Such as hydrochloric acid, Sulfuric acid, nitric (4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopip acid, hydrofluoric acid, and hydrobromic acid and salts of erazine group. organic acids such as acetic acid, tartaric acid, lactic acid, 0031 FIG. 2 is a graph showing changes in IOP over time citric acid, fumaric acid, maleic acid, Succinic acid, methane in each treatment group. IOP is shown as a change from the Sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, initial IOP (meantstandard error). O, bunaZosin alone group: toluenesulfonic acid, naphthalenesulfonic acid, and cam , hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine phorsulfonic acid, and hydrochlorides are particularly pre alone group; AbunaZosin plus hexahydro-1-(5-isoquinoline ferred. Sulfonyl)-1H-1,4-diazepine group. 0039 (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-me thyl-1,4-homopiperazine and hexahydro-1-(5-isoquinoline BEST MODE FOR CARRYING OUT THE sulfonyl)-1H-1,4-diazepine or salts thereof can exist not only INVENTION as unsolvated forms, but also as hydrates or Solvates, and the present invention includes all the crystalline forms of these 0032. In the present invention, “Rho kinase inhibitor compounds and hydrates or Solvates thereof. refers to a Substance that inhibits Rho kinase, an enzyme 0040. In the present invention, “C. blocker” refers to a phosphorylating “Rho known as one of low molecular drug that inhibits the sympathetic nervous system by binding weight GTP binding proteins. to C. receptors of the sympathetic nerve to inhibit the binding 0033 Examples of such Rhokinase inhibitors include iso of nerve transmitters. quinoline derivatives described in JP-A-11-349482 (the 0041. Examples of such an O. blocker include bunazosin, above-mentioned Patent Document 2), compounds described indole derivatives described in WO99/043652, in particular, in WO05/37198, WO05/371.97, WO05/35501, WO05/35506, (R)-3-7-carbamoyl-5-2-[2-(2-ethoxyphenoxy)ethyl WO05/35503, WO05/34866, WOO4/84813, JP-A-2004 aminopropyl)-1H-indol-1-yl)propyl hydrochloride pivalate 250410, WOO4/39796, WOO4/22541, WO03/59913, WO03/ (KRG-3332 (Kissei Pharmaceutical Co., Ltd.)), and so forth. 62227, WO01/68607, and WO01/56988, (S)-(-)-1-(4-fluoro Of these, bunaZosin is most preferred. 5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine 0042 Bunazosin is a drug first developed as an agent for (WO99/20620), hexahydro-1-(5-isoquinolinesulfonyl)-1H selectively blocking sympathetic nerve C. receptors and is 1,4-diazepine (Biochem. Biophys. Res. Commun. 262(1), known to have an ocular hypotensive effect by promoting 211-215 (1999)), Y-39983 (BIO Clinica, 1713), 1191-1194 aqueous outflow from the uveoscleral outflow pathway (J. 2002: The 4th Int. Symp. Ocular Pharmacol. Pharm. Feb. Ocular Pharmacol. Ther. 143: 217 1998). BunaZosin can 28, 2002, Seville 2002: 2: Annu. Meet. Assoc. Res. Vision be produced by known methods such as, for example, the Ophthalmol. May 1, 2005, Fort Lauderdale 2005: Abst. method described in JP-A-49-066690. Furthermore, “Detan 3787/B145), and so forth. tol(R) 0.01% Ophthalmic Solution' (Santen Pharmaceutical 0034. Of these, (S)-(-)-1-(4-fluoro-5-isoquinolinesulfo Co., Ltd.), a remedy for glaucoma and ocular hypertension, nyl)-2-methyl-1,4-homopiperazine or salts thereof, hexahy can be used as a preparation for instillation. dro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine or salts 0043. When a Rho kinase inhibitor and an C. blocker are thereof, and Y-39983 are more preferred, and salts of (S)-(-)- used in combination, a potent and prolonged ocular hypoten 1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopip sive effect is exhibited even from normal IOP as shown in the erazine are particularly preferred. examples described later. Therefore, a medicament contain 0035 (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-me ing these compounds is useful as a preventive or a remedy for thyl-1,4-homopiperazine is a compound having antagonistic glaucoma or ocular hypertension. Here, examples of glauco actions against Substance P and leukotriene D4 in addition to mas include primary open-angle glaucoma, normal tension US 2009/0082338 A1 Mar. 26, 2009 glaucoma, glaucoma with hypersecretory form, ocular hyper Zoate, chlorhexidine gluconate, quaternary ammonium salts tension, acute angle-closure glaucoma, chronic angle-closure Such as benzalkonium chloride, benzethonium chloride, and glaucoma, plateau iris Syndrome, combined-mechanism cetylpyridinium chloride, alkylpolyaminoethylglycine, chlo glaucoma, Steroid glaucoma, pseudoexfoliation glaucoma, robutanol, Polycuad, polyhexamethylene biguanide, chlo pigmentary glaucoma, amyloid glaucoma, neovascular glau rhexidine, and so forth, and the blending quantity thereof is coma, malignant glaucoma, and so forth. Furthermore, ocular preferably 0 to 0.2% by weight based on the total amount of hypertension is also called “high blood pressure of the eye’ the composition. and refers to a symptom with abnormally high IOP even in the 0051 Examples of antioxidants include sodium hydrogen absence of any clear lesion in the optic nerve. Many high IOP Sulfite, dry sodium sulfite, Sodium pyrosulfite, concentrated conditions such as postoperative high IOP fall within the mixed tocopherol, and so forth, and the blending quantity Scope of the present invention. thereof is preferably 0 to 0.4% by weight based on the total 0044) The preventive or the remedy for glaucoma or ocular amount of the composition. hypertension comprising a Rho kinase inhibitor and an O. 0.052 Examples of solubilizing agents include sodium blocker in combination of the present invention may be pre benzoate, glycerine, D-Sorbitol, glucose, propylene glycol, pared in one dosage form comprising effective amounts of the hydroxypropylmethylcellulose, polyvinylpyrrolidone, mac respective drugs at a suitable mixing ratio as a combination rogol, D-mannitol, and so forth, and the blending quantity drug or a kit used by administering preparations each com thereof is preferably 0 to 3% by weight based on the total prising an effective amount of drug either simultaneously or amount of the composition. separately at an interval. 0053 Examples of thickening agents include polyethyl 0045. The above-described preparation is preferably used ene glycol, methylcellulose, ethylcellulose, carmellose as an ophthalmological preparation, particularly preferably Sodium, Xanthan gum, Sodium chondroitin Sulfate, hydroxy as a preparation for instillation, and Such an ophthalmic ethylcellulose, hydroxypropylcellulose, hydroxypropylm preparation may be aqueous eye drop, nonaqueous eye drop, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and Suspension eye drop, emulsion eye drop, eye ointment, and so forth, and the blending quantity thereof is preferably 0 to the like. Such a preparation can be produced by preparation 70% by weight based on the total amount of the composition. methods known to those skilled in the art as a composition 0054 An ophthalmic preparation can be prepared by, for Suitable for the dosage form by adding pharmacologically example, dissolving or Suspending desired ingredients of the acceptable carriers such as, for example, tonicity agents, above-mentioned compounds in an aqueous solvent such as chelating agents, stabilizers, pH modifiers, preservatives, sterilized purified water or physiological saline or a nonaque antioxidants, Solubilizing agents, and thickening agents, if ous solvent such as Vegetable oil such as cottonseed oil, necessary. Soybean oil, sesame oil, or peanut oil at a predetermined 0046 Examples of tonicity agents include saccharides osmotic pressure and Subjecting the Solution or Suspension to Such as glucose, trehalose, lactose, fructose, mannitol. Xyli sterilization such as sterilization by filtration. When an eye tol, and Sorbitol, polyhydric alcohols such as glycerine, poly ointment is prepared, an ointment base can be added in addi ethylene glycol, and propylene glycol, inorganic salts such as tion to the above-mentioned various ingredients. The above Sodium chloride, potassium chloride, and calcium chloride, mentioned ointment base is not particularly limited, but pre and so forth, and the addition amount thereof is preferably 0 ferred examples thereof include oily bases such as Vaseline, to 5% by weight based on the total amount of the composi liquid paraffin, and polyethylene, emulsion bases obtained by tion. emulsifying the oil phase and the aqueous phase with a Sur 0047. Examples of chelating agents include edetates such factant or the like, water-soluble bases comprising hydrox as disodium edetate, calcium disodium edetate, trisodium ypropylmethylcellulose, carboxymethylcellulose, polyethyl edetate, tetrasodium edetate, and calcium edetate, ethylene ene glycol or the like, and so forth. diamine tetraacetate, nitrilotriacetic acid or salts thereof, 0055 When the preventive or the remedy for glaucoma or Sodium hexametaphosphate, citric acid, and so forth, and the ocular hypertension of the present invention is provided as a addition amount thereof is preferably 0 to 0.2% by weight kit, it can be designed so that drugs each comprising a Rho based on the total amount of the composition. kinase inhibitor oran C. blocker prepared as described above 0048 Examples of stabilizers include sodium hydrogen should be separately packaged, and each drug preparation is sulfite and so forth, and the blending quantity thereof is pref removed from each package before use. Furthermore, both erably 0 to 1% by weight based on the total amount of the the drug preparations can be packaged in a form Suitable for composition. combination use for each dose. 0049. Examples of pH modifiers include acids such as 0056. When the preventive or the remedy for glaucoma or hydrochloric acid, carbonic acid, acetic acid, citric acid, ocular hypertension of the present invention is administered, phosphoric acid, and boric acid, further alkali metal hydrox the dose varies depending on the patient's body weight, age, ides such as sodium hydroxide and potassium hydroxide, sex, symptom, dose form, number of dosages, and the like, alkali metal carbonates Such as Sodium carbonate or hydro but the usual adult daily dose is in the range of 0.025 to 2000 gen carbonates, alkali metal acetates such as Sodium acetate, ug, preferably 0.1 to 1000 ug of a Rho kinase inhibitor, and 10 alkali metal citrates Such as Sodium citrate, bases such as to 1250 ug, preferably 50 to 250 ug of an C. blocker. trometamol, and so forth, and the blending quantity thereof is 0057 The number of dosage is not particularly limited, but preferably 0 to 20% by weight based on the total amount of it is preferable to administer the dose once daily or divide the the composition. dose into several times. One to several drops of a liquid eye 0050 Examples of preservatives include sorbic acid, drop can be instilled as one dose. When the preparations are potassium Sorbate, parahydroxybenzoate esters such as packaged as a kit, the individual preparations may be admin methyl parahydroxybenzoate, ethyl parahydroxybenzoate, istered simultaneously or at an interval of 5 minutes to 24 propyl parahydroxybenzoate, and butyl parahydroxyben hours. US 2009/0082338 A1 Mar. 26, 2009

0058. The present invention will be explained more spe 0069 Laboratory animals: Japanese white rabbits (male cifically with reference to the following examples. However, JW rabbits, 5 to 10 animals per group) the scope of the present invention is not limited to these examples. B. Administration and Measurement (1) Administration of Drugs in Combination EXAMPLES (0070 1) One drop of 4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benoxil Ophthalmic Solu Example 1 tion 0.4%) was instilled in both eyes of the laboratory animals for local anesthesia (only data for the instilled eyes are 0059. To examine usefulness of combination use of a Rho shown). kinase inhibitor and an C. blocker, the ocular hypotensive 0.071) 2) IOP was measured immediately before adminis effects were compared by administering either of these drugs tration of the test compound solution as the initial IOP. alone or both in combination to laboratory animals. 0072 3) The bunaZosin solution was instilled in one eye of the laboratory animals, followed by the instillation of (S)-(-)- 1. Preparation of Test Compound Solutions 1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopip erazine solution in the same eye. 0060 A. Preparation of (S)-(-)-1-(4-fluoro-5-isoquino 0073 4) At 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours linesulfonyl)-2-methyl-1,4-homopiperazine solution after the instillation of both drugs, one drop each of 0.4% 0061 (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-me oxybuprocaine hydrochloride ophthalmic Solution was thyl-1,4-homopiperazine-hydrochloride dihydrate was dis instilled in both eyes for local anesthesia, and IOP was mea Solved in physiological saline, and the Solution was neutral Sured. ized (pH 6.0) by adding sodium dihydrogenphosphate and sodium hydroxide to prepare a (S)-(-)-1-(4-fluoro-5-iso (2) Administration of Single Drug Alone quinolinesulfonyl)-2-methyl-1,4-homopiperazine solution at 0074 The (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2- a desired concentration. methyl-1,4-homopiperazine Solution alone or the bunaZosin B. Preparation of Hexahydro-1-(5-isoquinolinesulfonyl)-1H Solution alone was instilled, and then tests were performed at 1,4-diazepine Solution the same measuring times as in the above-described combi 0062. The commercially available “Eril.R S Injection” nation use test. (Asahi Kasei Pharma) was used as it was. 0075. The hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4- diazepine Solution and the bunaZosin solution were adminis C. Preparation of BunaZosin Solution tered in combination or either of them alone in the same 0063. The commercially available “Detantol 0.01% Oph manner as in the above (1) and (2). thalmic Solution' (Santen Pharmaceutical Co., Ltd.) was 3. Results and Discussion used as it was. 0076. The test results are shown in FIGS. 1 and 2. IOP are 2. Test Method shown as changes (meanistandard error) from the initial IOP. 0077. As shown in FIG. 1, a superior ocular hypotensive 0064. The ocular hypotensive effect was examined after effect was observed in the (S)-(-)-1-(4-fluoro-5-isoquino the combination use of (S)-(-)-1-(4-fluoro-5-isoquinoline linesulfonyl)-2-methyl-1,4-homopiperazine plus bunaZosin Sulfonyl)-2-methyl-1,4-homopiperazine and bunaZosin. As a group to those in the single drug treatment groups, i.e., the control, the ocular hypotensive effect was also examined after (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4- the use ofbunaZosin alone or (S)-(-)-1-(4-fluoro-5-isoquino homopiperazine alone group and the bunaZosin alone group. linesulfonyl)-2-methyl-1,4-homopiperazine alone. Furthermore, the action remained in the combination treat 0065. Similarly, the ocular hypotensive effect was exam ment group even after 3 or 4 hours, when the ocular hypoten ined after the combination use of hexahydro-1-(5-isoquino sive effect disappeared in the single drug treatment groups, linesulfonyl)-1H-1,4-diazepine and bunaZosin. As a control, showing improvement of the prolonged action. the ocular hypotensive effect was also examined after the use 0078 Similarly in FIG. 2, a superior ocular hypotensive ofbunaZosin alone or hexahydro-1-(5-isoquinolinesulfonyl)- effect was observed in the hexahydro-1-(5-isoquinolinesulfo 1H-1,4-diazepine alone. nyl)-1H-1,4-diazepine plus bunaZosin group than in the single drug treatment groups, i.e., the hexahydro-1-(5-iso A. Drugs and Animals Used in Test quinolinesulfonyl)-1H-1,4-diazepine alone group and the bunaZosin alone group. Furthermore, since the action 0066 (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-me remained in the combination treatment group even after 5 thyl-1,4-homopiperazine solution: 0.5% solution (instillation hours, when the ocular hypotensive effect disappeared in the volume, 50 LL) single drug treatment groups, showing improvement of pro 0067 Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-di longation of the action. azepine solution: fasudil hydrochloride hydrate injection 007.9 The above results revealed that a potent ocular (1.5% solution trade name: Eril(R) S Injection; instillation hypotensive effect and improvement of the prolonged action volume, 50 LL) could be obtained by using bunaZosin and (S)-(-)-1-(4- 0068 BunaZosin solution: bunaZosin ophthalmic solution fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopipera (trade name: Detantol 0.01% Ophthalmic Solution; instil zine or hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diaz lation volume, 50 L) epine in combination. US 2009/0082338 A1 Mar. 26, 2009

1. A preventive or a remedy for glaucoma comprising a Rho 8. The preventive or the remedy for ocular hypertension kinase inhibitor and an O. blocker in combination. according to claim 6 or 7, wherein the C blocker is bunazosin hydrochloride. 2. The preventive or the remedy for glaucoma according to 9. The preventive or the remedy for ocular hypertension claim 1, wherein the Rho kinase inhibitor is (S)-(-)-1-(4- according to any one of claims 6 to 8, which is a combination fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopipera drug. Zine or a salt thereof, or a solvate thereof. 10. The preventive or the remedy for ocular hypertension 3. The preventive or the remedy for glaucoma according to according to any one of claims 6 to 8, which is a kit compris claim 1 or 2, wherein the C. blocker is bunaZosin hydrochlo ing a drug comprising a Rho kinase inhibitor and a drug ride. comprising an O. blocker. 4. The preventive or the remedy for glaucoma according to 11. Use of a Rho kinase inhibitor and an O. blocker in any one of claims 1 to 3, which is a combination drug. combination for production of a preventive or a remedy for 5. The preventive or the remedy for glaucoma according to glaucoma. 12. Use of a Rho kinase inhibitor and an O. blocker in any one of claims 1 to 3, which is a kit comprising a drug combination for production of a preventive or a remedy for comprising a Rho kinase inhibitor and a drug comprising an ocular hypertension. C. blocker. 13. A method for preventing or treating glaucoma, wherein 6. A preventive or a remedy for ocular hypertension com the method comprises administrating a Rho kinase inhibitor prising a Rho kinase inhibitor and an O blocker in combina and an C. blocker in combination. tion. 14. A method for preventing or treating ocular hyperten 7. The preventive or the remedy for ocular hypertension Sion, wherein the method comprises administrating a Rho according to claim 6, wherein the Rho kinase inhibitor is kinase inhibitor and an O. blocker in combination. (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4- homopiperazine or a salt thereof, or a Solvate thereof. c c c c c