JP2006290827A - Preventing or treating agent of glaucoma - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventing or treating agent of glaucoma, having a potent ocular pressure-decreasing activity, and having the sufficient ocular pressure-decreasing activity even from the normal ocular pressure. <P>SOLUTION: This preventing or treating agent of glaucoma contains (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methylhomopiperadine or its salt, and boric acid or its salt. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a glaucoma preventive or therapeutic agent containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof.

  Usually, the aqueous humor constantly circulates in the eyeball to maintain a constant intraocular pressure. However, if the flow rate in the trabecular meshwork, which is the exit of the aqueous humor, gradually decreases, or if the corner is narrowed and the flow of the aqueous humor is obstructed, the intraocular pressure in the eyeball increases, and as a result, the optic nerve is compressed and the visual field is compressed. Abnormal glaucoma, ocular hypertension, etc. that do not involve visual field abnormalities but are likely to develop into glaucoma in the long term develop. To treat glaucoma and ocular hypertension, it is necessary to lower the elevated intraocular pressure. In actual medical practice, sympathomimetic drugs such as epinephrine, parasympathomimetic drugs such as pilocarpine hydrochloride, and beta-blocking such as timolol. Drugs, prostaglandin drugs such as isopropyl unoprostone, and carbonic anhydrase inhibitors such as dorzolamide are used, but it cannot be said that any of the therapeutic drugs is sufficient in reducing intraocular pressure.

  In recent years, for the purpose of enhancing the intraocular pressure-reducing effect, treatment combining a β-blocker, a prostaglandin drug, and a carbonic anhydrase inhibitor (see Non-Patent Document 1), or combining an alginic acid with a β-blocker in intraocular pressure A method for maintaining the lowering action (see Patent Document 1) has also been reported. More recently, it has been reported that a compound having Rho kinase inhibitory activity is excellent in glaucoma prevention and treatment effects and has a strong intraocular pressure lowering effect (see Patent Document 2).

In addition, there are many glaucoma patients who develop glaucoma (normal tension glaucoma) without increasing intraocular pressure, and the normal intraocular pressure must be further reduced for the treatment. However, reducing normal intraocular pressure is more difficult than reducing elevated intraocular pressure, and there are limits to the treatment of normal intraocular glaucoma with the above existing drugs and combinations thereof, and further from the medical field. There is a demand for enhancement of the action of reducing intraocular pressure.
Japanese translation of PCT publication No. 2002-511430 International Patent Publication No. 00/9162 pamphlet Ophthalmology practice 4 (5): 2-6, 2001

  An object of the present invention is to provide a glaucoma preventive or therapeutic agent having a strong intraocular pressure reducing action and having a sufficient intraocular pressure reducing action even from normal intraocular pressure.

  As a result of intensive studies to solve the above problems, the present inventors have substance P antagonism, leukotriene D4 antagonism and Rho kinase inhibitory action, and are known as preventive or therapeutic agents for asthma (S )-(-)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof in combination, has a strong intraocular pressure lowering effect. As a result, the present invention has been completed.

  That is, the present invention provides a preventive or therapeutic agent for glaucoma containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof. To do.

  The present invention also provides an ocular hypertension preventive or therapeutic agent comprising (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof. Is to provide.

  The present invention also provides an eye drop containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof. It is.

  The glaucoma preventive or therapeutic agent of the present invention has a strong intraocular pressure lowering action and exhibits a sufficient effect even from normal intraocular pressure. Therefore, if this is used, a high prevention / treatment effect can be obtained for glaucoma and ocular hypertension with a small number of administrations.

  The preventive or therapeutic agent for glaucoma, the preventive or therapeutic agent for ocular hypertension and the eye drop of the present invention are (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof. And boric acid or a salt thereof.

  (S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine is a known compound having substance P antagonistic activity, leukotriene D4 antagonistic activity and Rho kinase inhibitory activity ( JP-A-11-349482), a known method, for example, a method described in International Patent Publication No. 99/20620 pamphlet.

  Examples of the salt of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid. Salts of inorganic acids 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, camphorsulfonic acid, etc. The salt of the organic acid of these is mentioned, Especially hydrochloride is preferable.

  Further, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof is not only an unsolvated type, but also as a hydrate or a solvate. In the present invention, all crystal forms and hydrates or solvates are included.

  Examples of boric acid or a salt thereof include boric acid, ammonium borate, and borax, and boric acid and borax are particularly preferable.

  In the preventive or therapeutic agent for glaucoma, the preventive or therapeutic agent for ocular hypertension and the eye drop of the present invention, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof Is preferably contained in an amount of 0.1 to 5% by weight, more preferably 0.25 to 3% by weight, particularly preferably 0.5 to 2% by weight, based on the total weight of the pharmaceutical composition. . Moreover, it is preferable to contain boric acid or its salt 0.1 to 2 weight% with respect to the pharmaceutical composition total weight, More preferably, it is 0.5 to 1.5 weight%.

  When (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof are used in combination, as shown in Test Examples described later It has an excellent intraocular pressure lowering effect even from normal intraocular pressure. Therefore, the medicine containing these is useful as a preventive or therapeutic agent for glaucoma and a preventive or therapeutic agent for ocular hypertension. Here, as glaucoma, for example, primary open angle glaucoma, normal pressure 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.

  The preventive or therapeutic agent for glaucoma or ocular hypertension of the present invention is preferably used as an ophthalmic preparation, particularly as an eye drop. Such an eye drop is an aqueous eye drop, non-aqueous eye drop, suspension eye drop, milk. Any of turbid eye drops, eye ointments and the like may be used.

  The pH and osmotic pressure of the eye drop of the present invention are not particularly limited, but the pH is usually 5 to 9, preferably 5 to 8, particularly preferably 5 to 7, and the osmotic pressure is usually 200 to 700 mOsm. / Kg, preferably 200 to 600 mOsm / Kg, and the osmotic pressure ratio with respect to physiological saline is preferably 0.6 to 3, particularly preferably 0.6 to 2. By setting the pH and osmotic pressure within these ranges, a preparation that does not irritate the eyes during application can be obtained.

  The eye drop of the present invention includes (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof, and boric acid or a salt thereof, which are essential components. If necessary, an isotonic agent, a chelating agent, a stabilizer, a pH adjuster, an antiseptic, an antioxidant, a solubilizing agent, a thickening agent, other medicinal ingredients, and the like can be blended.

  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 adjuster include acids such as hydrochloric acid, carbonic acid, acetic acid and citric acid, and further alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, Examples include alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, and the like, and the blending amount is preferably 0 to 20% by weight based on the total amount of the composition.

  As preservatives, sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate propyl, paraoxybenzoate butyl ester, 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.

  As other medicinal ingredients, for example, receptor non-selective sympathomimetic drugs, sympathomimetic drugs such as α2 receptor selective sympathomimetic drugs, non-selective β receptor blockers, β1 receptor blockers, αβ receptor blockers, α1 receptor blockers and other sympathetic blockers, parasympathomimetics, prostaglandins, carbonic anhydrase inhibitors, hypertonic osmotic agents, muscarinic agonists, cholinesterase inhibitors, glutamate antagonists Examples include drugs.

  The eye drop of the present invention can be prepared, for example, by dissolving or suspending the desired components in an aqueous solvent such as sterile 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. It can be performed by turbidity, adjusting to a predetermined osmotic pressure, and performing sterilization treatment 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 agent for preventing or treating glaucoma or the agent for preventing or treating ocular hypertension of the present invention is administered, the dosage is adjusted in consideration of the patient's condition such as age and weight, administration route, nature and degree of disease, etc. However, it is usually 0.1 to 10 mg, preferably 0.5 to 5 mg per day as an active ingredient amount for an adult, and is administered once a day or divided into 2 to several times a day. In the case of liquid eye drops, one drop or a few drops may be applied at a time.

  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-methylhomopiperazine hydrochloride 0.825 g, boric acid (manufactured by Kanto Chemical) 1.19 g, potassium chloride 0.32 g 50 g of purified water was added and stirred to completely dissolve, and borax (manufactured by Nikko Pharmaceutical) dissolved in purified water was added to adjust the pH to 6.7, and further purified water was added to make the total amount 100 g. The osmotic pressure was 340 mOsm / Kg.

Comparative Example 1
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine hydrochloride (0.825 g) and potassium chloride (1 g) were added with 50 g of purified water and stirred until completely dissolved. Sodium hydroxide dissolved in purified water was added to adjust the pH to 6.7, and purified water was added to make the total amount 100 g. The osmotic pressure was 366 mOsm / Kg.

Comparative Example 2
(S)-(-)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine hydrochloride 0.825 g, potassium chloride 0.9 g, alginic acid (Duck Acid A. Kibun Food Chemifa Corporation )) 50 g of purified water was added to 0.1 g and stirred to dissolve completely, sodium hydroxide dissolved in purified water was added to adjust the pH to 6.7, and purified water was added to make the total amount 100 g. The osmotic pressure was 353 mOsm / Kg.

Comparative Example 3
A 0.5% timolol maleate ophthalmic solution (trade name: Timoptol (registered trademark) 0.5%, manufacturer: Manyu Pharmaceutical, distributor: Santen Pharmaceutical: serial number: 9AC19P) was used. The pH was 6.9, and the osmotic pressure was 270 mOsm / Kg.

Test example 1
Male Japanese white rabbits (2.0-2.5 Kg) with normal intraocular pressure were fixed to a rabbit fixator without anesthesia, and local ocular anesthesia with 1 drop of Benokiseal (Santen Pharmaceutical) was performed on both eyes. Thereafter, the intraocular pressure of both eyes was measured with a pneumatic applanation tonometer (Alcon Applanation PneumatonographTM, Nippon Alcon), and the value was set to 0 hour. Immediately after measurement of the 0 hour value, 50 μl of the eye drops of Example 1 and Comparative Examples 1 to 3 were administered to the left eye of the rabbit, and after 1 hour, 2 hours, 3 hours, and 4 hours after the instillation, both eyes The pressure was measured. The results are shown in Table 1.

  From Table 1, the preparation of the present invention (Example 1) is a preparation containing no boric acid (Comparative Example 1), a preparation containing alginic acid instead of boric acid (Comparative Example 2), and timolol which is widely used as a commercially available drug. Compared with eye drops (Comparative Example 3), it can be seen that they have an excellent intraocular pressure lowering effect even from normal intraocular pressure.

Claims (3)

  A glaucoma preventive or therapeutic agent comprising (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof.   (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof for preventing or treating ocular hypertension.   An ophthalmic solution containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methylhomopiperazine or a salt thereof and boric acid or a salt thereof.