JP5530483B2 - Glaucoma preventive or therapeutic agent - Google Patents

Description

  The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension.

  Glaucoma is a disease in which intraocular pressure increases due to various etiologies, the optic nerve is damaged and atrophy occurs, visual field abnormalities occur, and visual acuity decreases. Since the optic nerve that has once atrophy does not recover, if the glaucoma is left unattended, it leads to blindness, and even if the treatment is successful, the current state is maintained, and it is an intractable disease that cannot be recovered. In addition, ocular hypertension, which is not accompanied by visual field abnormalities but is likely to develop into glaucoma in the long term, entails similar risks.

  Glaucoma can be divided into three types: congenital glaucoma, secondary glaucoma, and primary glaucoma. Congenital glaucoma is a glaucoma that occurs due to a lack of growth in the corner and obstruction of aqueous humor discharge. Secondary glaucoma is a glaucoma caused by obvious causes such as inflammation and injury, which may be caused by eyes such as uveitis or eye injury, bleeding due to diabetes, long-term use of steroid hormones used for treatment of other diseases, etc. Develops. Primary glaucoma is a collective term, although the cause is not clear. It is common among middle-aged and older people and is the most common type of glaucoma. Primary glaucoma and secondary glaucoma are further divided into two types, open-angle glaucoma and closed-angle glaucoma, depending on how the aqueous humor flows. In addition, there are many patients who develop normal-tension glaucoma without increasing intraocular pressure, but in any case, the primary goal of glaucoma treatment is to decrease intraocular pressure.

Treatment methods for glaucoma include laser therapy (laser trabeculoplasty) and surgical treatment (trabeculectomy) when intraocular pressure cannot be controlled with drugs or when acute glaucoma attacks occur in patients with angle-closure glaucoma. Surgery and trabeculotomy) etc. are performed, but pharmacotherapy is used as the first choice.
For glaucoma drug therapy, sympathomimetic drugs (non-selective stimulants such as epinephrine, α ₂ stimulants such as apraclonidine), sympathetic nerve blockers (timolol, befunolol, carteolol, nipradilol, betataxol, levobunolol, metipranol) (Metipranolol) beta blockers, such as, alpha ₁ blockers such as bunazosin hydrochloride), parasympathetic agonists (pilocarpine, etc.)
Carbonic anhydrase inhibitors (such as acetazolamide) and prostaglandins (such as isopropyl unoprostone, latanoprost, travoprost, and bimatoprost) are used. Among these, nipradilol is a drug having both an aqueous humor production inhibitory effect and a blood flow improving effect (Non-Patent Document 1).

On the other hand, a Rho kinase inhibitor has been found as a candidate for a glaucoma therapeutic drug based on a new mechanism of action (Patent Document 1). Rho kinase inhibitors decrease intraocular pressure by promoting aqueous humor outflow from the trabecular meshwork outflow pathway (Non-Patent Document 2), and further suggest that the action is due to changes in cytoskeleton in trabecular meshwork cells. (Non-Patent Document 2, Non-Patent Document 3). The present inventors also have (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1, which is an isoquinoline derivative, as a low molecular compound having a strong intraocular pressure lowering effect. 4-homopiperazine has been found and a patent application has already been filed (Patent Document 2).

  Furthermore, in glaucoma and ocular hypertension, a drug having an intraocular pressure lowering action is also used in combination for the purpose of enhancing the intraocular pressure lowering action. For example, administration of a combination of a prostaglandin and a sympatholytic agent (Patent Document 3) or a method for treating glaucoma by administering a combination of several drugs having a lowering effect on intraocular pressure to the eye (Patent Document 4) In addition, there is also a report of a glaucoma therapeutic agent using a combination of a Rho kinase inhibitor and a β-blocker (Patent Document 5).

  However, the therapeutic agents and treatment methods for glaucoma and ocular hypertension as described above are still unsatisfactory in terms of the strength and duration of the intraocular pressure lowering effect. In particular, for normal-tension glaucoma, lowering normal intraocular pressure is more difficult than lowering elevated intraocular pressure, and there is a limit to the treatment of normal-tension glaucoma with the existing drugs and their combinations. From the medical field, further enhancement of the intraocular pressure lowering action is demanded.

International Publication WO00 / 09162 Pamphlet International Publication WO99 / 20620 Pamphlet Japanese Patent No. 2726672 International Publication WO02 / 38158 Pamphlet JP 2004-182723 A

New Ophthalmology, 16 (4), 529-535 IOVS, 42 (1), 137-144 (2001) IOVS, 42 (5), 1029-1037 (2001)

  An object of the present invention is to provide a preventive or therapeutic agent for glaucoma or ocular hypertension, which has a strong intraocular pressure lowering action and an extended duration.

  As a result of intensive studies to solve the above problems, the present inventors have obtained (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine. Alternatively, it has been found that administration of a salt thereof and nipradilol in combination exerts a strong intraocular pressure lowering action and extends its duration.

  That is, the present invention provides (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradilol for prevention or treatment of glaucoma. It concerns the agent.

  The present invention also relates to prevention of ocular hypertension comprising a combination of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradilol. Or it concerns a therapeutic agent.

  According to the present invention, it is possible to provide a preventive or therapeutic agent for glaucoma or ocular hypertension having a strong intraocular pressure lowering action and an extended duration.

It is a graph which shows a time-dependent change of the intraocular pressure of each administration group. The intraocular pressure is indicated by a change from the initial intraocular pressure (average value ± standard error). ○: nipradilol single administration group, □: (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine single administration group, Δ: nipradilol (S )-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine administration group, *: p <0.05 vs. 0 hours, #: p <0.05 vs Nipradilol ophthalmic group, $: p <0.05 vs. (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine ophthalmic group.

  (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine used in the present invention is substance P antagonistic activity, leukotriene D4 antagonistic activity and Rho kinase inhibition. It is a known compound having an action (Japanese Patent Laid-Open No. 11-349482), and can be produced by a known method, for example, the method described in International Patent Publication No. 99/20620 pamphlet.

  Examples of the salt of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine include hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, bromide. Salts of inorganic acids such as hydrogen acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfone Examples include pharmaceutically acceptable salts such as salts of organic acids such as acids, and hydrochlorides are particularly preferable.

  The (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof is not only unsolvated but also hydrated or solvated. In the present invention, all crystal forms and hydrates or solvates are included.

  The nipradilol used in the present invention has an excellent β-blocking action and is known to be useful as a therapeutic agent for circulatory diseases such as hypertension and angina (Japanese Examined Patent Publication No. 60-54317, Japanese Patent Publication No. Hokuhei). 01-53245), and a known method, for example, a method described in Japanese Patent Publication No. 60-54317. Moreover, as a preparation for eye drops, “Hypazil Kowa ophthalmic solution” (Kowa Co., Ltd.), which is a therapeutic agent for glaucoma and ocular hypertension, can be used.

  When (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradilol are used in combination, as shown in Examples below. Even from normal intraocular pressure, an intraocular pressure lowering action with a strong and prolonged duration is observed. Therefore, the medicine containing these is useful as a preventive or therapeutic agent for glaucoma and ocular hypertension. Here, as glaucoma, for example, primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma, Examples include steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma. Ocular hypertension, also called ocular hypertension, refers to symptoms that show abnormally high intraocular pressure despite the absence of clear lesions in the optic nerve. High ocular pressure conditions are included.

  (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine of the present invention or a salt thereof and nipradilol in combination with glaucoma or ocular hypertension The prophylactic or therapeutic agent is a combination drug prepared by formulating each effective amount into a single dosage form at an appropriate mixing ratio, or a combination of drugs containing each effective amount separately or simultaneously. It may be a kit that can be used separately at intervals.

  The above preparation is preferably used for ophthalmic preparations, particularly for eye drops. Such eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments, etc. Good. Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, for example, an isotonic agent, a chelating agent, a stabilizer, a pH adjusting agent, a preservative, an antioxidant. , A solubilizing agent, a thickening agent, and the like, and can be produced by a method known to those skilled in the art.

  Isotonic agents include glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and other sugars, glycerin, polyethylene glycol, propylene glycol and other polyhydric alcohols, sodium chloride, potassium chloride, calcium chloride and other inorganic salts The blending amount is preferably 0 to 5% by weight with respect to the total amount of the composition.

  Examples of chelating agents include edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like, and the blending amount is preferably 0 to 0.2% by weight based on the total amount of the composition.

  Examples of the stabilizer include sodium bisulfite and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.

  Examples of the pH regulator include acids such as hydrochloric acid, carbonic acid, acetic acid, citric acid, phosphoric acid, and boric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate. Examples include salts or bicarbonates, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, etc. The blending amount is 0 to 20 wt. % Is preferred.

  Examples of preservatives include sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate propyl, paraoxybenzoate butyl ester, etc., chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, Examples include quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine, and the blending amount is 0 to 0.2% by weight based on the total amount of the composition. Is preferred.

  Examples of the antioxidant include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount is preferably 0 to 0.4% by weight with respect to the total amount of the composition.

  Examples of solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, macrogol, D-mannitol, and the blending amount thereof is based on the total amount of the composition. 0 to 3% by weight is preferred.

  Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like. 0 to 70% by weight is desirable based on the total amount of the composition.

  When preparing eye drops, for example, the desired components described above are dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil. The osmotic pressure can be adjusted to a predetermined osmotic pressure and subjected to sterilization such as filtration sterilization. In addition, when preparing an eye ointment, an ointment base can be included in addition to the various components described above. The ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant; hydroxypropyl methylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.

  When the preventive or therapeutic agent for glaucoma or ocular hypertension of the present invention is used as a kit, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl formulated as described above -Designed so that drugs containing 1,4-homopiperazine or a salt thereof and drugs containing nipradilol are packaged separately, and each pharmaceutical preparation is taken out from each package at the time of administration. can do. Each pharmaceutical preparation can also be packaged in a form suitable for each combined administration.

When the preventive or therapeutic agent for glaucoma or ocular hypertension of the present invention is administered, the dosage varies depending on the patient's body weight, age, sex, symptoms, dosage form, number of administrations, etc. (S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, 0.025 to 2000 μg per day, preferably 0.1 to Examples of 1000 μg and nipradilol include a range of 10 to 1250 μg, preferably 50 to 250 μg per day.
The number of administrations is not particularly limited, but it is preferable to administer once or several times. In the case of liquid eye drops, one to several drops may be instilled at a time. In the case of a kit, each single preparation may be administered simultaneously, or may be administered at intervals of 5 minutes to 24 hours.

  Hereinafter, the present invention will be described in more detail, but the present invention is not limited thereto.

Example 1
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradilol were examined for their usefulness in order to study both drugs alone. Alternatively, the effect of lowering intraocular pressure when administered in combination was compared.

1. Preparation of test compound solution Preparation of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution (S)-(−)-1- (4-fluoro-5 -Isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine monohydrochloride dihydrate was dissolved in physiological saline, and then sodium dihydrogen phosphate and sodium hydroxide were added to neutralize the solution ( (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution having a desired concentration was prepared.

B. Preparation of nipradilol solution A commercially available nipradilol ophthalmic solution was used as it was.

2. Test Method (S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradilol were examined for the effect of decreasing intraocular pressure. As a comparative control, the effect of decreasing intraocular pressure when nipradilol was administered alone or (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine was administered alone. We also examined.

A. Drugs and animals used in the test (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution: 1% solution (eye drop amount: 50 μl)
Nipradilol solution: nipradilol ophthalmic solution (trade name: HIPAJIRKOWA 0.25%, ophthalmic volume: 50 μl)
Experimental animal: Japanese white rabbit (strain: JW, gender: male, 6-8 animals per group)

B. Administration method and measurement method (1) Combined administration of both drugs 1) One drop of 4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benokiseal 0.4% solution) was instilled into both eyes of experimental animals and local anesthesia was performed (data) Is the eye drop side only).
2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
3) The nipradilol solution is instilled into one eye of an experimental animal, and then (S)-(-)-1- (
4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution was instilled into the same eye.
4) One hour, two hours, three hours, four hours, and five hours after instillation of both drugs, 0.4% oxybuprocaine hydrochloride ophthalmic solution was instilled into both eyes, and after local anesthesia, intraocular pressure was measured.
(2) Single administration of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (S)-(−)-1- (4- Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine alone was instilled, and the test was performed at the same measurement time as the above combined administration test.

(3) Single administration of nipradilol The test solution for the single administration of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine is replaced with a nipradilol solution. The others were tested in the same manner as the above single administration test.

3. Results and Discussion The test results are shown in FIG. The intraocular pressure indicates a change value from the initial intraocular pressure.
As is clear from FIG. 1, the combination group of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradilol is a drug single administration group That is, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine administration group or nipradilol administration group shows a superior intraocular pressure lowering effect. And also showed an improvement in the duration of its action.
From the above, by combining nipradilol with (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine, stronger intraocular pressure lowering effect as well as lasting It turned out that the improvement of an effect is acquired.

Claims (6)

  (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradilol in combination for preventing or treating glaucoma.   The agent for preventing or treating glaucoma according to claim 1, which is a combination drug.   (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and a drug containing nipradilol The agent for preventing or treating glaucoma according to claim 1, which is a kit.   (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradilol is used for the prevention or treatment of ocular hypertension.   The ocular hypertension preventive or therapeutic agent according to claim 4, which is a combination drug.   (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and a drug containing nipradilol The agent for preventing or treating ocular hypertension according to claim 4, which is a kit.

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