KR20060120424A - Preventing or treating agent for glaucoma - Google Patents

Abstract

An agent for preventing or treating glaucoma is provided to reduce intraocular pressure and extend the effective time of intraocular pressure reduction. The agent for preventing or treating glaucoma or high intraocular pressure comprises (S)-(-)-1-(4-fluoro-5-isoquinolinsulfonyl)-2-methyl-1,4-homopiperazine or its salts and nipradilol as effective ingredients. A kit for preventing or treating glaucoma or high intraocular pressure contains the medicament with (S)-(-)-1-(4-fluoro-5-isoquinolinsulfonyl)-2-methyl-1,4-homopiperazine or its salts and the medicament with nipradilol.

Description

Prevention or treatment of glaucoma {PREVENTING OR TREATING AGENT FOR GLAUCOMA}

1 is a graph showing changes over time of intraocular pressure of each administration group. Intraocular pressure is expressed as a change from the initial intraocular pressure (mean ± standard error). ○: nipradiol alone administration group, □: (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine alone administration group, △: Group of combination administration of nipradiol and (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine *: p <0.05 vs. 0 time. #: p <0.05 vs. Nipradiol eye group, $: p <0.05 vs. (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine eye drop group

[Patent Document 1] International Publication WO 00/09162 Brochure

[Patent Document 2] International Publication WO 99/20620 Pamphlet

[Patent Document 3] Japanese Patent No. 2726672

[Patent Document 4] International Publication WO 02/38158 Pamphlet

[Patent Document 5] Japanese Unexamined Patent Publication No. 2004-182723

[Non-Patent Document 1] New Ophthalmology, 16 (4), 529-535

[Non-Patent Document 2] IOVS, 42 (1), 137-144 (2001)

[Non-Patent Document 3] IOVS, 42 (5), 1029-1037 (2001)

Technical Field

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

Background

Glaucoma is a disease in which intraocular pressure rises due to various etiologies, impairs and contracts the optic nerve, causes abnormal visual field, and decreases visual acuity. Once the optic nerve contracted, it will not recover, and if you leave glaucoma, it will lead to blindness, and even if the treatment is successful, it will remain in the status quo and recovery cannot be hoped for. Although visual field abnormality is not accompanied, high ocular hypertension, which is likely to develop glaucoma in the long term, also poses the same risk.

Glaucoma is divided into three types: congenital glaucoma, secondary glaucoma, and primary glaucoma. Congenital glaucoma is a glaucoma that occurs because of congenital insufficiency in right angles and impede the discharge of waterproofing. Secondary glaucoma is glaucoma caused by obvious causes such as inflammation and wounds, and may be caused by the eyes such as uveitis or wounds of the eye, and also by long-term use of steroid hormones used in the treatment of bleeding caused by diabetes or other diseases. do. Primary glaucoma is a generic term for which the cause is unclear, and appears in middle-aged 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 by the blocked form of the waterproof flow. There are also many patients who develop normal intraocular glaucoma that does not involve an increase in intraocular pressure, but eventually the primary goal of glaucoma treatment is to lower the intraocular pressure.

Treatments for glaucoma include laser therapy (laser fibroid surgery) or surgical therapy (fibrosclerosis and fibroid incision) when the intraocular pressure cannot be controlled by drugs or when patients with closed right glaucoma develop acute glaucoma attacks. Although carried out, drug therapy is used as the first choice.

Drug therapy for glaucoma includes sympathetic stimulants (non-selective stimulants such as epinephrine, α ₂ stimulants such as apraclonidine), sympathetic nerve block drugs (timolol, befnolol, carteolol, nipradiol, beta). Β blockers such as chisolol, levobunolol and metipranolol, α ₁ blockers such as benzoxacin hydrochloride, parasympathetic agents (such as pilocarpine), carbonic anhydrase inhibitors (acetazolamide And the like, and prostaglandins (isopropyl unofrost, latanoprost, traboprost, bimatoprost, etc.) are used. Among them, nipradiol is a drug having a blood flow improving action in addition to a waterproof production inhibitory action and is useful (Non-Patent Document 1).

On the other hand, as a candidate of the glaucoma therapeutic drug based on a new mechanism of action, the Rho kinase inhibitor is discovered (patent document 1). The Rho kinase inhibitor lowers intraocular pressure by promoting waterproof outflow from the trabecular flow path (Non Patent Literature 2), and its action is suggested to be due to a change in the cytoskeleton in the trabecular cell (Non-Patent No. 2). Document 2, Non-Patent Document 3). The present inventors also have a low molecular weight compound having a strong intraocular pressure lowering action, which is (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4 which is an isoquinoline derivative. -Homopiperazine was discovered and patent application is already carried out (patent document 2).

In glaucoma and ocular hypertension, a combination of drugs having an intraocular pressure-lowering effect is also practiced for the purpose of enhancing the intraocular pressure-lowering effect. For example, administration of a combination of prostaglandins and sympathetic blockers (Patent Document 3), or a method of treating glaucoma by administering a combination of drugs having an intraocular pressure lowering effect to the eye (Patent Document 4), and the like are reported. In addition, there are reports of a glaucoma therapeutic agent by a combination of a Rho kinase inhibitor and a β-blocking agent (Patent Document 5).

However, it is difficult to say that the therapeutic agent and treatment method for glaucoma and ocular hypertension as known above are still satisfactory in terms of the intensity of action and duration of the IOP lowering effect. In particular, in the case of normal intraocular glaucoma, lowering the normal intraocular pressure is more difficult than lowering the elevated intraocular pressure, and the above-mentioned conventional medicines and combinations thereof have limitations in the treatment of normal intraocular glaucoma, and further lower the intraocular pressure in the medical field There is a need for enhanced action.

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

Means to solve the problem

MEANS TO SOLVE THE PROBLEM The present inventors earnestly researched in order to solve the said subject, and, as a result, (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homo By combining piperazine or its salt with nipradiol, it was found that a strong intraocular pressure-lowering effect is exerted and its duration is prolonged.

That is, the present invention combines (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof with nipradiol To prevent or treat glaucoma.

Moreover, this invention combines (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or its salt, and nipradiol, It relates to an ocular hypertension prevention or treatment.

To practice the invention  Best form for

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

As a salt of (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine, for example, hydrochloric acid, sulfuric acid, nitric acid, fluoride Inorganic acid salts, such as hydrochloric acid and hydrobromic acid, or organic acid salts, such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and campasulfonic acid Phase tolerable salts are mentioned, especially hydrochloride salts.

The (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof is not only an unsolvated type but also a hydrate. Or solvates, and in the present invention, all crystalline forms and hydrates or solvates are contained.

Nipradiol used in the present invention has an excellent β-blocking effect and is known to be useful as a therapeutic agent for circulatory diseases such as hypertension and angina (Japanese Patent Publication No. 60-54317, Japanese Patent Publication No. 01-53245). It can manufacture by a well-known method, for example, the method of Unexamined-Japanese-Patent No. 60-54317. Moreover, as a preparation for eye drops, "Hypadilco and eye drops" (Kyowa Co., Ltd.) which are glaucoma and hypertension treatment agents can be used.

(S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or salts thereof in combination with nipradiol As shown in the example, the intraocular pressure lowering action with strong and prolonged duration from normal intraocular pressure is recognized. Therefore, medicines containing these are useful as prophylactic or therapeutic agents for glaucoma and ocular hypertension. Here, glaucoma includes, for example, primary open-angle glaucoma, normal-tension glaucoma, overproduction glaucoma in waterproof production, ocular hypertension, acute occluded glaucoma, chronic occluded glaucoma, plateau iris syndrome, mixed glaucoma. , Steroidal glaucoma, cystic glaucoma of the lens, pigmented glaucoma, amyloid glaucoma, angiogenic glaucoma, malignant glaucoma and the like. In addition, ocular hypertension, also referred to as chronic hypertension, refers to a symptom that exhibits very high intraocular pressure even when no clear lesion is recognized in the optic nerve, and includes many ocular pressure states such as the ocular pressure expression described below.

Glaucoma formed by combining (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradiol of the present invention Alternatively, the prophylactic or therapeutic agent for ocular hypertension may be a compounding agent, each of which may be formulated in a single dosage form at an appropriate blending ratio, and at the same time or at an interval of formulating a drug containing each effective amount alone. It may be a kit so that it can be used separately.

It is preferable to use the said formulation for ophthalmic preparations, especially eyedrops, and such eyedrops may be any of an aqueous eye drop, a non-aqueous eye drop, a suspension eye drop, an emulsion eye drop, an ointment. Such a formulation is a composition suitable for a dosage form, and a pharmaceutically acceptable carrier, for example, isotonic agents, chelating agents, stabilizers, pH adjusting agents, preservatives, antioxidants, dissolution aids, thickening agents, and the like, as necessary, are formulated. Thus, a person skilled in the art can manufacture by a well-known preparation method.

Isotonic agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol, polyhydric alcohols such as glycerin, polyethylene glycol, propylene glycol, inorganic salts such as sodium chloride, potassium chloride, calcium chloride, and the like. The compounding quantity is 0-5 weight% with respect to composition whole quantity.

Examples of the chelating agent include edetic acid salts such as sodium edetic acid dibasic, sodium edetic acid dibasic, sodium edetic acid trisodium, edetic acid tetrasodium, and calcium edetate, ethylenediamine tetraacetic acid, nitriloacetic acid or its salts, and hexameta. Sodium phosphate, citric acid, etc. are mentioned, The compounding quantity is 0-0.2 weight% with respect to composition whole quantity.

As a stabilizer, sodium hydrogen sulfite etc. are mentioned, As for the compounding quantity, 0-1 weight% is preferable with respect to composition whole quantity.

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 carbonates such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, hydrogen carbonate, sodium acetate, and the like. Alkali metal citrate, such as alkali metal acetate, sodium citrate, and bases, such as tromethamol, etc. are mentioned, The compounding quantity is 0-20 weight% with respect to composition whole quantity.

Examples of the preservative include paraoxybenzoic acid esters such as sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoic acid and butyl paraoxybenzoate, chlorohexidine gluconate, benzalkonium chloride, and benzyl chloride. Quaternary ammonium salts such as tonium and cetylpyridinium chloride, alkylpolyaminoethylglycines, chlorobutanol, polyquads, polyhexamethylene biguanides, and chlorhexidine; and the compounding amount thereof relative to the total amount of the composition. 0 to 0.2% by weight is preferred.

Examples of the antioxidant include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the compounding amount thereof is preferably 0 to 0.4% by weight based on the total amount of the composition.

Examples of the dissolution aid include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, and D-mannitol. 0 to 3% by weight is preferred.

Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, sodium carmellose, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. The compounding quantity is 0-70 weight% is preferable with respect to composition whole quantity.

When preparing eye drops, for example, the desired components are dissolved or suspended in sterile purified water, aqueous solvents such as physiological saline, or non-aqueous solvents such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, and peanut oil. It can be used by adjusting to a predetermined penetration pressure and performing sterilization treatment such as filtration sterilization. In addition, when preparing ophthalmic ointment, the ointment base may be contained in addition to the said various components. Although it does not specifically limit as said ointment base, Oil bases, such as petroleum jelly, a liquid paraffin, polyethylene; Emulsion bases obtained by emulsifying the oil phase and the water phase with a surfactant or the like; The water-soluble base which consists of hydroxypropyl methylcellulose, carboxymethylcellulose, polyethyleneglycol, etc. are mentioned preferably.

 In the case of using the kit for preventing or treating glaucoma or ocular hypertension of the present invention, (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl Drugs containing -1,4-homopiperazine or salts thereof and drugs containing nipradiol are packaged separately, and each drug formulation can be designed to be taken out of each package and used for administration. Can be. Moreover, each pharmaceutical formulation can also be packaged in the form suitable for combined administration once.

In the case of administering the prophylactic or therapeutic agent for glaucoma or ocular hypertension of the present invention, the dosage varies depending on the weight, age, sex, symptoms, dosage form, and the number of administrations of the patient. )-(-)-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 As 1000 micrograms and nipradiol, the range of 10-1250 micrograms per day, Preferably 50-250 micrograms is mentioned.

Although the administration frequency is not specifically limited, It is preferable to divide and administer once or several times, and in the case of a liquid eye drop, what is necessary is just to drop 1 to several drops at a time. When using a kit, you may administer each individual formulation simultaneously, and you may administer at intervals of 5 minutes-24 hours.

Hereinafter, although this invention is demonstrated in detail, this invention is not limited to these.

Example

Example  One

In order to investigate the usefulness by the combination of (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradiol, experiment The effect of intraocular pressure lowering when animals were administered alone or in combination was examined.

1. Preparation of Test Compound Solution

A. Preparation of (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution

After dissolving (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine monohydrochloride and dihydrate in physiological saline, dihydrogen phosphate The solution was neutralized by adding sodium and sodium hydroxide to pH (pH6.0) to give (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl- at a desired concentration. A 1,4-homopiperazine solution was prepared.

B. Preparation of Nipradiol Solution

Commercial nipradiol eye drops were used as they are.

2. Test method

Examine the effect of intraocular pressure drop when (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradiol are administered in combination It was. As a comparative control, nipradiol may be administered alone or (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine alone. Also examined was the effect of intraocular pressure drop at the time.

A. Drugs and Animals Used in Testing

(S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine solution: 1% solution (eye drops: 50 μl)

Nipradiol solution: Nipradiol eye drops (trade name: Hyfadilco and 0.25%, eye drops: 50 μl)

Test animal: Japanese white rabbit (line: JW, gender: male, 6 to 8 groups)

B. Methods of Administration and Methods of Measurement

(1) Concomitant administration of both drugs

1) 4% hydrochloric acid oxybuprocaine eye drops (trade name: Benokisyl 0.4% solution) were topically anesthetized by dropping one drop into both eyes of the experimental animals (data only on the eye side).

2) The intraocular pressure was measured immediately before administration of the test compound solution, and the initial intraocular pressure was taken.

3) A nipradiol solution was applied to one eye of a test animal, and then (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4- Homopiperazine solution was applied to the same eye.

4) After 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours after instilling both drugs, 0.4% hydrochloric acid oxybuprocaine eye drops were applied dropwise to both eyes, and intraocular pressure was measured after local anesthesia.

(2) Administration of (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine alone

(S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine alone was administered in the same eye, and at the same measurement time as the above-mentioned combined administration test. Try it.

(3) administration of nipradiol alone

The test solution of the above-mentioned (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopyreradin mono-administration was replaced with nipradiol solution, Otherwise, the test was conducted in the same manner as the single dose test.

3. Results and Discussion

The result of the test is shown in FIG. Intraocular pressure represents a change from initial intraocular pressure.

As can be seen from Fig. 1, the combination group of (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine and nipradiol is Superior to the drug-only group, that is, (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine group or nipradiol group An intraocular pressure-lowering effect was shown, and the persistence improvement of the action was shown.

From the above, a stronger intraocular pressure drop is achieved by combining nipradiol and (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine. It turned out that the improvement of an effect and a continuous effect is obtained.

According to the present invention, it is possible to provide an agent for preventing or treating glaucoma or ocular hypertension, in which the effect of lowering intraocular pressure is strong and its duration is extended.

Claims (6)

(S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and a preparation for glaucoma prevention or treatment . The method of claim 1, A preventive or therapeutic agent for glaucoma in combination. The method of claim 1, Containing (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradiol A prophylactic or therapeutic agent for glaucoma, which is a kit consisting of drugs.  Prevention of ocular hypertension by combining (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof with nipradiol Or therapeutic agent. The method of claim 4, wherein Prophylaxis or treatment of ocular hypertension, a combination. The method of claim 4, wherein Containing (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and nipradiol Antihypertensive prevention or treatment agent which is a kit which consists of a pharmaceutical agent which consists of.

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