JP5475958B2 - Preventive or therapeutic agent for visual impairment - Google Patents

Description

  The present invention relates to a preventive or therapeutic agent for visual dysfunction.

Visual dysfunction (where visual dysfunction is a condition in which normal vision cannot be obtained, such as clinically myopia, hyperopia, and eye strain) is formed on the retina by light transmitted through the cornea It means a state where the image cannot be clearly captured. Of these, myopia is divided into axial myopia and refractive myopia depending on the cause of the occurrence. Refractive myopia occurs because the refractive index of the cornea or the lens increases, whereas axial myopia is myopia caused by the eyeball extending in the direction of the visual axis, that is, the axial direction.
The treatment is mostly by optical correction means. As optical correction means, correction by wearing glasses and correction by contact lenses are performed. Recently, myopia correction by corneal surgery has also been performed. These optical corrections and surgical operations cannot be fundamental treatments for myopia, and treatment of myopia with drugs is expected.
Furthermore, eyestrain, pseudomyopia, pseudomyopia, and accommodative myopia (also called accommodative hypertensive myopia), which temporarily show myopic-like symptoms, are caused by systemic or local eye fatigue, and ciliary muscles. Refers to a state of being affected by a kind of regulation disorder, and as the eyes become tired, the near point gradually moves away and the object cannot be recognized temporarily. However, when fatigue recovers, it returns to its original state.
As a method for treating eye strain, drugs such as vitamins (vitamin B ₁ , vitamin B _12, etc.) and ATP have been conventionally administered.
In Patent Document 1, a drug that has both SRS-A production inhibitory action and SRS-A antagonistic action, and a drug that suppresses histamine release caused by IgE-related allergies has excellent ciliary body relaxing action, and myopia. It is described that it is useful as a preventive / therapeutic agent, and amlexanox is used in the examples. Patent Document 2 includes Patent Document 1
It is described that the compounds in the described invention have effectiveness (prevention / treatment of eye strain, suppression of extension of axial length, suppression of retinal function decrease, recovery of retinal function) for diseases other than myopia. In Patent Document 3, a composition containing a factor that increases the level of cyclic-guanosine-phosphate (cyclic-GMP) improves visual function and improves optic nerve and retinal blood flow. In this example, sildenafil citrate is used.
On the other hand, ibudilast, as its action, enhances the action of prostacycline (Non-Patent Document 1) and increases the local blood flow of the brain (Non-Patent Document 2) and leukotriene antagonism (Non-Patent Documents 3 and 4). In addition, leukotriene release inhibitory action (Non-Patent Document 5), PDE inhibitory action (Non-Patent Document 6) and the like are known, and are used as a therapeutic agent for allergic conjunctivitis, bronchial asthma, and an agent for improving cerebrovascular disorder. Non-Patent Document 7 describes that ibudilast suppresses the contractile reaction of guinea pig airways and ileal smooth muscle by leukotriene D4. Non-Patent Document 8 describes that ibudilast enhances the relaxation effect of PGI2 on the contractile response of dog basilar artery by PGF2α.
However, it has not been described at all that the compound of the present invention has an excellent ciliary muscle relaxing action, and the present inventors have found for the first time.
JP 7-258083 A Japanese Patent Laid-Open No. 10-203982 Special table 2003-506394 gazette Onoue et al., Gen. Pharmacol., 23, p 1093, 1992 Kudo et al., Folia Pharmacol. Jap., 85, p 435, 1995 Sato et al., Gen. Pharmacol., 17, p 287, 1985 Ohashi et al., Int. Arch. Allergy, Immunol., 101, p 288, 1993 Tamura et al., Basic and Climical Report, 20, p 181, 1986 Souness et al., Brit. J. Pharmacol., 111, p 1081, 1994 Japan J. Pharmacol., 1983; 33: 1215-1223 Arch. Int. Phramacodym. 1986; 280; 216-229

  An object of the present invention is to provide a therapeutic or prophylactic agent having an excellent effect of improving visual dysfunction.

  In view of such a current situation, the present inventors searched for various compounds in search of an excellent preventive or therapeutic agent for visual dysfunction. As a result, it was found that ibudilast exerts a ciliary muscle relaxing action, and the present invention has been completed.

That is, the present invention
(1) A prophylactic or therapeutic agent for visual impairment, comprising ibudilast or a salt thereof or a hydrate thereof,
(2) The preventive or therapeutic agent according to (1) above, wherein the visual dysfunction is a disease based on tension of ciliary muscles,
(3) The preventive or therapeutic agent according to (1) above, wherein the visual dysfunction is myopia or eye strain
(4) The preventive or therapeutic agent according to the above (3), wherein the myopia is refractive myopia, pseudomyopia, pseudomyopia or accommodative tension myopia,
(5) The preventive or therapeutic agent according to any one of (1) to (4) above, which is for topical ocular administration,
(6) The preventive or therapeutic agent according to (5) above, which is in the form of eye drops,
(7) The preventive or therapeutic agent according to (5) above, which is in the form of an eye ointment,
(8) The preventive or therapeutic agent according to (5) above, which is in the form of a patch.

  Since the prophylactic or therapeutic agent for visual dysfunction according to the present invention has excellent myopia, pseudomyopia, pseudomyopia, and control (hypertensive) myopia, and has a therapeutic effect, it can prevent or treat clinically applicable visual dysfunction. It can be advantageously used as an agent.

  Ibudilast, which is an active ingredient of the preventive or therapeutic agent for visual dysfunction of the present invention, has the formula:

で示される公知化合物であり(特公昭５２−２９３１８号公報、米国特許登録第３，８５０，９４１号ほか）、１９８９年１月に日本国厚生省の製造承認を受けて以来、気管支喘息用薬、また脳循環改善剤として、広く医療の場に供されている。

(Japanese Patent Publication No. 52-29318, U.S. Patent Registration No. 3,850,941, etc.), and since receiving approval from the Japanese Ministry of Health and Welfare in January 1989, bronchial asthma drugs, In addition, it is widely used in the medical field as a cerebral circulation improving agent.

  The salt of ibudilast is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, citric acid, maleic acid and the like.

  Since the preventive or therapeutic agent for visual dysfunction according to the present invention has excellent ciliary muscle relaxation action, it is particularly useful as a preventive or therapeutic agent for visual dysfunction, particularly for preventing or preventing dysfunction based on tension of the ciliary muscle. It is useful as a therapeutic agent. Here, visual impairment refers to a state in which light transmitted through the cornea does not form an image on the retina and cannot be clearly captured. Specific diseases of visual dysfunction include myopia, hyperopia and eye strain. Myopia is divided into axial myopia and refractive myopia depending on the cause of the occurrence, and refractive myopia (pseudomyopia) continues to increase the refractive power of the cornea and the tension (contraction) state of the ciliary muscle, and the refractive index of the lens It is an increased state. Furthermore, eyestrain, pseudomyopia, pseudomyopia, and accommodative tension myopia, which temporarily show myopia-like symptoms, are caused by systemic or local eye fatigue, and the ciliary muscles suffer from a type of regulation disorder. This is a state in which the muscle tension (contraction) state continues. Thus, the preventive or therapeutic agent for visual dysfunction according to the present invention is particularly useful for refractive myopia, eye strain, pseudomyopia, pseudomyopia, and accommodative myopia.

The agent for preventing or treating visual dysfunction of the present invention is useful as a prophylactic / therapeutic agent for visual dysfunction in mammals (eg, humans, rabbits, dogs, cats, cows, horses, monkeys, etc.).
The prophylactic / therapeutic agent for visual dysfunction of the present invention can be administered to a patient orally or parenterally. Examples of dosage forms suitable for oral administration include solid preparations such as powders, granules, tablets and capsules, and liquid preparations such as emulsions, syrups and suspensions. Examples of parenteral administration forms include topical ocular administration, intravenous administration, and transdermal administration. Examples of dosage forms suitable for parenteral administration include eye drops, eye ointments, injections, patches, lotions, creams and the like.

  The agent for preventing or treating visual dysfunction according to the present invention is preferably used as a preparation for topical ocular administration. Examples of the topical ocular administration form include eye drop administration, intravitreal administration, subconjunctival administration, subtenon administration and the like. Examples of the dosage form suitable for topical ocular administration include eye drops, eye ointments, gels and the like, with eye drops being preferred. The eye drops may be either aqueous or non-aqueous eye drops, and may be a solution or a suspension.

  For example, when the agent for preventing or treating visual dysfunction according to the present invention is used as an eye drop, a stabilizer (for example, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.) Solubilizer (eg, glycerin, propylene glycol, macrogol, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, polysorbate 80, etc.), buffer (eg, phosphate buffer, Acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamic acid, epsilon aminocaproic acid, etc.), thickener (eg, methylcellulose, hydroxyethyl acetate) Water-soluble cellulose derivatives such as loin, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium chondroitin sulfate, sodium hyaluronate, carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, etc.), preservatives (eg, benzalkonium chloride, benzethonium chloride) , Chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, paraoxybenzoates, sodium edetate, boric acid, etc.), isotonic agents (eg, sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boron) Acid, glucose, propylene glycol, etc.), pH adjusters (eg, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.), cooling agents ( For example, additives such as l-menthol, d-camphor, d-borneol, mint oil, etc.) can be added. The amount of these additives varies depending on the type of additive to be added, application, etc. What is necessary is just to add the density | concentration which can achieve the objective of an agent.

  When the agent for preventing or treating visual dysfunction according to the present invention is used as an eye ointment, for example, an ointment base (white petrolatum, purified lanolin, liquid paraffin, vegetable oil (such as olive oil, camellia oil, peanut oil), etc.) and the like are additives. Can be added as.

  When the preventive or therapeutic agent for visual dysfunction according to the present invention is an eye drop or an eye ointment, it may be produced according to a method commonly used in the field of preparations. It can be manufactured based on the method described in the section of the preparation and the section of the eye ointment.

When the preventive or therapeutic agent for visual dysfunction according to the present invention is used as a patch, for example, as the base matrix of the patch, an acrylic adhesive, a silicone elastomer or a styrene-isoprene-styrene copolymer is preferable. It is composed of a combination, and may be appropriately selected from these. In addition, the matrix is used by holding it on one side of a support usually used for a preparation to be applied to the skin such as a tape preparation, a patch or a patch, or a support made of a material that is not inconvenient for use in the present invention. It's okay.
A conventionally known percutaneous absorption enhancer may be supplementarily added to the patch. The patch for preventing or treating visual dysfunction according to the present invention can be used after being applied to a desired site of the body. In particular, it may be applied to the eyelid skin, the corners of the eyes, other areas around the eyes, or temples close to the eyes.

  The dose of the preventive or therapeutic agent for visual dysfunction according to the present invention varies depending on the administration route, the type of disease, symptoms, the age of the patient, the body weight, etc. Alternatively, when used as an eye drop for a myopic patient, an ophthalmic solution containing 0.001 to 1.0 (W / V)%, preferably 0.005 to 0.5 (W / V)%, of ibudilast as an active ingredient As an agent, it is desirable to administer 1 to several drops at a time, once to several times a day, preferably about 2 to 5 times depending on the symptoms. When used as an ophthalmic ointment, 0.001 to 1.0 (W / V)%, preferably 0.005 to 0.5 (W / V) of ibudilast, which is an active ingredient, per eye per patient. V) As an eye ointment containing about%, it is desirable to administer 1 to several times a day, preferably about 2 to 5 times a day depending on the symptoms. When used as a patch, the drug concentration contained in the base matrix is, for example, 0.05 to 10 (W / V)%, preferably 0.1 to 10 (W / V)% of the drug-containing layer. It can be appropriately selected depending on the type and degree of the target disease.

  The present invention will be described in more detail with reference to the following examples. However, these are merely examples and do not limit the scope of the present invention.

Inhibitory effect of ibudilast on contraction of white rabbit ciliary muscle by carbamylcholine chloride Method Anesthetized white rabbit with 4% sodium pentobarbital at 30 mg / mL / kg from the auricular vein, amputated the carotid artery and lethal After removing the eyeball, a mixed gas (95% O ₂ , 5% CO ₂ ) saturated ice-cold Krebs-Henseleit solution (118.0 mmol / L NaCl, 4.70 mmol / L KCl, 2.50 mmol / L CaCl ₂ , 1.20 mmol / L MgSO ₄ , 1.20 mmol / L KH ₂ PO ₄ , 25.0 mmol / L NaHCO ₃ , 10.0 mmol / L glucose), and the cornea was removed along the eyeball conjunctiva. The sclera was cut along the corneal ring leaving about 5 mm outside. The lens and the surrounding deposits were removed, the ciliary body was peeled into a ring shape, and the ciliary body was divided into two to prepare 4 ciliary smooth muscle specimens per animal. The prepared specimen was suspended in a Krebs-Henseleit solution (37 ° C., 10 mL) in a Magnus tube (10 mL) aerated with a mixed gas with a load of about 0.3 g.
After the specimen was stabilized for 1 hour or more after suspension, the maximum contraction reaction was observed with 3 × 10 ⁻⁵ mol / L carbamylcholine chloride (CCh). After washing with Krebs buffer, the reaction with CCh was observed again, and after the maximum contraction reaction was stabilized, the effect of ibudilast was examined.

(1) Action on Tonic Contraction After the Tonic contraction by CCh was almost stabilized, ibudilast was applied cumulatively in order from the lowest dose at 1 × 10 ⁻⁸ to 1 × 10 ⁻⁴ mol / L (common ratio: 10). The inhibition rate was calculated with the contraction height immediately before the start of ibudilast application as 100%, and the IC ₅₀ was calculated.
(2) Action on phasic contraction CCh was applied cumulatively from low dose to high dose in order, and the contractile response was observed. After washing, CCh was cumulatively applied again, and after a stable contraction reaction was obtained, ibudilast (final concentration: 1 × 10 ⁻⁷ , 1 × 10 ⁻⁶ or 1 × 10 ⁻⁵ mol / L) or control substance ( Dimethyl sulfoxide, final concentration: 0.1%) was applied, and CCh (final concentration: 1 × 10 ⁻⁶ to 1 × 10 ⁻⁴ mol / L) was applied cumulatively. The treatment time for ibudilast or the control substance was 5 minutes before the start of cumulative application of CCh.
In addition, the tension change of a sample is perceived and amplified by a strain pressure amplifier (AP-601G, Nihon Koden Kogyo Co., Ltd.) via an isometric transducer (TB-612T, Nihon Koden Kogyo Co., Ltd.) Recorded on data collection system (Power Lab, MacLab / 4S, AD Instruments).

Results The results are shown in FIG. 1 and FIG.
Effect on Phasic Contraction Ibudilast showed a dose-dependent relaxation effect on Tonic contraction by CCh. _{IC 50} of ibudilast was 4.76 × ¹⁰ -7 mol / L (see FIG. 1).
Effect on Tonic Contraction Ibudilast showed a concentration-dependent contraction-inhibiting effect. Moreover, it was suggested that 1 * 10 < ^-6 > mol / L and 1 * 10 < ^-5 > mol / L show a clear contraction inhibitory action (refer FIG. 2).

Formulation examples are shown below.
Eye drops 1
According to the following prescription, an eye drop is produced by a conventional method.
Ibudilast 0.1g
Polysorbate 80 0.1g
Sodium dihydrogen phosphate 0.1g
Sodium chloride 0.9g
Benzalkonium chloride 0.005g
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
Total volume 100mL
(PH 6.5)

Eye drops 2
According to the following prescription, an eye drop is produced by a conventional method.
Ibudilast 0.01g
Hydroxyethylcellulose 0.1g
Sodium dihydrogen phosphate 0.1g
Sodium chloride 0.9g
Benzalkonium chloride 0.005g
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
Total volume 100mL
(PH 7.0)

Eye drops 3
According to the following prescription, an eye drop is produced by a conventional method.
Ibudilast 0.1g
Sodium dihydrogen phosphate 0.1g
Sodium chloride 0.9g
Benzalkonium chloride 0.005g
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
Total volume 100mL
(PH 6.0)

Eye drops 4
According to the following prescription, an eye drop is produced by a conventional method.
Ibudilast 0.01g
Hydroxyethylcellulose 0.1g
Sodium dihydrogen phosphate 0.1g
Sodium chloride 0.9g
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
Total volume 100mL
(PH 7.0)

Eye ointment 1
According to the following prescription, an ointment is produced by a conventional method.
Ibudilast 0.1g
10g of purified lanolin
100g white petrolatum

Eye ointment 2
According to the following prescription, an ointment is produced by a conventional method.
Ibudilast 0.1g
Liquid paraffin 10g
100g white petrolatum

Patch The patch is produced by the conventional method according to the following prescription.
Ibudilast 1g
Polyoxyethylene oleyl ether 0.9g
Acrylic adhesive "Nissetsu PE-300" made by Nippon Carbide Industry 1.5g
Cross-linking agent Nippon Carbide Industries "Nissetsu CK-401" 0.0015g
Isopropyl myristate 0.6g

  As described above, according to the present invention, a prophylactic or therapeutic agent for visual dysfunction having excellent ciliary muscle relaxation action can be provided, particularly for the prevention or treatment of dysfunction based on tension of the ciliary muscle. Useful.

2 is a graph showing an effect on phasic contraction in Example 1. The numerical value in the figure is an average value ± standard deviation (n = 3). 2 is a graph showing an effect on Tonic contraction in Example 1. FIG. The numerical value in the figure is an average value ± standard deviation (n = 3).

Claims (4)

A prophylactic or therapeutic agent for visual dysfunction, comprising ibudilast or a salt thereof or a hydrate thereof, for local ocular administration ,
Containing 0.005 to 0.5 (W / V)% of ibudilast,
A prophylactic or therapeutic agent in the form of eye drops .   The preventive or therapeutic agent according to claim 1, wherein the visual dysfunction is a disease based on tension of the ciliary muscle.   The preventive or therapeutic agent according to claim 1, wherein the visual dysfunction is myopia or eye strain.   The prophylactic or therapeutic agent according to claim 3, wherein the myopia is refractive myopia, pseudomyopia, pseudomyopia or accommodative tension myopia.

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