JP2011011984A - Therapeutic agent for pseudomyopia - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for pseudomyopia that hardly has mydriatic action felt when tropicamide is administered as eye drops, ameliorates an unpleasant irritating sensation and has excellent sense of use.SOLUTION: The therapeutic agent for pseudomyopia comprises (A) tropicamide or its salt and (B) an α adrenoceptor antagonist in the content of the component (A) of 0.001-0.1 W/V%.

Description

  The present invention relates to a pseudomyopia therapeutic agent for preventing and treating pseudomyopia containing tropicamide. More specifically, the present invention relates to a pseudomyopia therapeutic agent that reduces side effects that occur when tropicamide is instilled and is excellent in use feeling.

  Pseudomyopia is also called pseudomyopia or accommodation tension, and the ciliary muscle that temporarily regulates visual acuity remains in tension (continuous contraction) due to eye fatigue due to long-term near work. This is a symptom in which the camera cannot return to its original state, the state of myopia continues, and the focus cannot be adjusted well. If pseudomyopia continues continuously, it leads to true myopia, and treatment with eye drops can no longer be expected, and eyesight correction devices such as glasses and contact lenses must be used to ensure vision. For this reason, it is believed that improving the sustained contraction state of the ciliary muscle and restoring it to the original state is effective for the treatment of pseudomyopia.

A dysregulation caused by the ciliary muscle can be expected to have a therapeutic effect by a drug. As a conventional pharmacotherapy, a drug that relieves tension of the ciliary muscle is used.
Up to now, the use of neostigmine methylsulfate having a ciliary muscle tone-relaxing action for eye drops (for example, see Non-patent Document 1), myopia using a compound having a ciliary muscle tone-relaxing action different from tropicamide. Prophylactic / therapeutic agents (for example, see Patent Document 1), eye drops of atropine that is a muscarinic receptor inhibitor, and methods for producing the same (for example, see Patent Document 2), and tropicamide that is a muscarinic choline inhibitor An eye drop is disclosed (for example, see Non-Patent Document 2). On the other hand, a cyanocobalamin-containing eye drop that activates the oculomotor nerve and enhances the function of the ciliary muscle is disclosed separately from the ciliary muscle tone relieving agent (see, for example, Non-Patent Document 3). In addition, an ophthalmic preparation containing phentolamine, which is a selective α1 antagonist, is disclosed in order to suppress pupil dilation due to ciliary muscle palsy (see, for example, Patent Document 3).
However, these drugs are not yet satisfactory as pseudomyopia drugs, such as those that are not sufficiently effective and those that have high effects but have side effects.

Japanese Patent No. 3066561 JP 2007-308398 A Special table 2008-502724 gazette

Pharmaceutical manufacturing standards Eye drops Midrin M ophthalmic solution 0.4% package insert Sankoba ophthalmic solution 0.02% package insert

  An object of the present invention is to provide a pseudomyopia therapeutic agent that has almost no mydriatic action when tropicamide is instilled, improves an unpleasant irritation, and is excellent in use feeling.

  As a result of intensive studies to achieve the above object, the present inventors have limited the drug concentration of tropicamide to an appropriate concentration range, and suppressed the mydriatic action by using an α-adrenergic receptor antagonist in combination. And it discovered that a pseudomyopia improvement effect was heightened by the ciliary muscle relaxation action, and came to complete this invention.

Accordingly, the present invention provides the following pseudomyopia therapeutic agent.
[1]. (A) It contains tropicamide or a salt thereof, and (B) an α-adrenergic receptor antagonist, and the content of component (A) is 0.001 W / V% to 0.1 W / V%. Pseudomyopia treatment.
[2]. The pseudomyopia therapeutic agent according to [1], further comprising a cooling agent.
[3]. The pseudomyopia remedy according to [1] or [2], which contains no preservative.
[4]. The pseudomyopia therapeutic agent according to any one of [1] to [3], which is an eye drop for contact lenses.

  According to the present invention, it is possible to provide a tropicamide-containing pseudomyopia therapeutic agent in which the mydriatic action of tropicamide is suppressed and the effect of improving pseudomyopia is enhanced by the ciliary muscle relaxing action.

Hereinafter, the present invention will be described in detail.
The pseudomyopia therapeutic agent of the present invention contains (A) tropicamide or a salt thereof, and (B) an α-adrenergic receptor antagonist, and the content of (A) component is 0.001 W / V% to 0.1 W / It is a pseudomyopia therapeutic agent that is V% (mass / volume% (g / 100 mL), the same applies hereinafter).

(A) Tropicamide or a salt thereof Tropicamide used in the present invention has a chemical name of (2RS) -N-ethyl-3-hydroxy-2-phenyl-N- (pyridin-4-ylethyl) propanamide and has a molecular formula of C ₁₇ It is a known substance represented by H ₂₀ N ₂ O ₂ and having a molecular weight of 284.35. The compound is synthesized by a known method. Tropicamide is not particularly limited as long as it is a grade used for ophthalmic agents.
The compounding amount of tropicamide or a salt thereof is preferably 0.001 to 0.1 W / V%, more preferably 0.005 to 0.05 W / V% in the pseudomyopia therapeutic agent. If the blending amount is less than 0.001 W / V%, the ciliary muscle relaxation effect of tropicamide is insufficient.

(B) α-adrenergic receptor antagonist Examples of the α-adrenergic receptor antagonist include phentolamine, phenoxybenzamine, and prazosin. Of these, phentolamine is preferable. The α-adrenergic receptor antagonist is not particularly limited as long as it is a grade used for ophthalmic agents.
The blending amount of the α-adrenergic receptor antagonist is preferably in the range of 0.001 to 1 W / V% in the pseudomyopia therapeutic agent. If the blending amount is less than 0.001 W / V%, the effect of suppressing mydriasis is insufficient, and if it exceeds 1 W / V%, redness of the eyes may be caused.

The refreshing agent is preferably blended because it has a high effect of relieving the irritation of component (A). Examples of the refreshing agent include camphor and cool mint no. 71212, geraniol, mint water, menthol, borneol, eucalyptus oil, fennel oil, bergamot oil, linalool, N-ethyl-p-menthane-carboxyamide (for example, WS-3, Takasago International Corporation), ethanol, etc. Can be mentioned.
The blending amount of the refreshing agent is preferably in the range of 0.0001 to 0.1 W / V% in the pseudomyopia therapeutic agent. If it is less than 0.0001 W / V%, the effect of alleviating the feeling of irritation is insufficient, and if it exceeds 0.1 W / V%, a feeling of irritation due to a refreshing feeling may be felt.

The preservative can be blended within a range that does not impair the effects of the present invention, but the pseudomyopia therapeutic agent of the present invention preferably contains no preservative and does not contain a preservative from the viewpoint of eye irritation. Preservatives include benzalkonium chloride, benzethonium chloride, sorbic acid or salts thereof, paraoxybenzoic acid esters (such as methylparaben, ethylparaben, propylparaben), chlorhexidine gluconate, tiromesal, polydronium, polyhexanide, phenylethyl alcohol, alkyl hydrochloride Examples include diaminoethylglycine and chlorobutanol. The content of the preservative is preferably in the range of 0.01 W / V% or less in the pseudomyopia therapeutic agent.
When the preservative is not added, the preservative power may be one or more, preferably two or more, in combination of sodium edetate, boric acid and trometamol. Moreover, it can be set as preservative-free combination by putting the pseudomyopia therapeutic agent of this invention into a unit dose container and a container with a filter.

  In the pseudomyopia therapeutic agent of the present invention, various components used in the ophthalmic composition can be blended, if necessary, within a range not impairing the effects of the present invention. Examples of preferable ingredients include drugs, buffers, stabilizers, thickeners, tonicity agents, solubilizers, antioxidants, and the like. These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix | blend suitable amount.

  Examples of the drug include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial component or bactericidal component, oligo Examples include saccharides, polysaccharides or derivatives thereof, local anesthetic components, steroid components, glaucoma treatment components, and cataract treatment components. Specific examples are shown below.

  Decongestant: α-adrenergic agonist, for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmaceutically or physiologically acceptable Salts (for example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate) and the like.

Eye muscle modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methyl sulfate and salts thereof.
Anti-inflammatory or astringent components: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, zinc thiaramide hydrochloride Salts (eg, zinc sulfate, zinc lactate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizic acid, and pharmacologically acceptable salts (eg, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc.).

  Antihistamine component or antiallergic agent component: for example, ketotifen, acitazanolast, chlorpheniramine, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast and pharmaceutically or physiologically acceptable salts thereof.

Vitamins: For example, flavin adenine dinucleotide sodium (active vitamin B2), cyanocobalamin (vitamin B12), pyridoxine hydrochloride (vitamin B6), vitamin E acetate, panthenol, calcium pantothenate, sodium pantothenate, retinol acetate, palmitic acid Retinol (vitamin A palmitate) etc. Amino acids: For example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, Glycylglycine, aminoethylsulfonic acid (taurine) or a salt thereof (for example, cysteine hydrochloride, etc.) and the like.

  Antibacterial component or bactericidal component: Sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), Acrinol, alkylpolyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin, etc.), berberine or a salt thereof (for example, berberine sulfate), β-lactam antibacterial agent (Sulbenicillin, cefmenoxime, etc.), aminoglycoside antibiotics (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), tetracycline antibiotics (Ocite) Rascycline), macrolide antibacterials (erythromycin, etc.), chloramphenicol antibacterials (chloramphenicol, etc.), polypeptide antibacterials (colistin, etc.), etc. Antiviral drugs (docoxuridine, acyclovir, etc.) , Adenine arabinoside, gancyclovir, foscarnet, valacyclovir, trifluorothymidine, cidophobia, carbocyclic oxetanocin G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B, etc.).

Oligosaccharides: lactulose, raffinose, pullulan, etc.
Polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, hyaluronic acid, chondroitin sulfate or salts thereof (sodium alginate, sodium chondroitin sulfate, etc.) and the like.

Local anesthetic ingredients: lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine and their salts (such as lidocaine hydrochloride, oxybuprocaine hydrochloride).
Steroid component: hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone and salts thereof.
Glaucoma treatment components: distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropyl unoprostone, dipivefrin hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide, and salts thereof.
Cataract treatment component: pirenoxine, glutathione, salivary gland hormone, thiopronin, Dihydro azapentacene disulfonate and salts thereof (for example, Sodium 5, 12-dihydro azapentene disulfonate etc.) and the like.

  The effective content of each drug can be selected as the content of the drug. From the viewpoint of eye irritation, composition stability, etc., 0.001 to 5 W / V% in the pseudomyopia therapeutic drug It is preferable that it is the range of these.

  As the buffer, for example, citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, and sodium hydrogen carbonate are preferably used. Among these, boric acid, borax, and trometamol are preferable. When trometamol is blended, it is preferable because it is less irritating and the antiseptic effect of the composition is obtained. Furthermore, when boric acid and borax are used in combination, a particularly high antiseptic effect is obtained, which is preferable. The content of the buffering agent is preferably in the range of 0.003 to 5 W / V% in the pseudomyopia therapeutic agent.

  Examples of the stabilizer include sodium edetate, edetic acid, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. Edetic acids have the effect of maintaining the stability of the system, and cyclodextrins have the effect of suppressing the adsorption of components that are easily adsorbed to soft contact lenses (for example, benzalkonium chloride). The content of the stabilizer is preferably in the range of 0.003 to 2 W / V% in the pseudomyopia therapeutic agent.

  Examples of the thickening agent include cellulose polymer compounds such as methyl cellulose, hypromellose and hydroxyethyl cellulose, polyvinyl polymer compounds such as povidone and polyvinyl alcohol, liquid paraffin, carboxyvinyl polymer and polyethylene glycol. The content of the thickening agent is preferably in the range of 0.003 to 3 W / V% in the pseudomyopia therapeutic agent.

  Examples of the isotonic agent include potassium chloride, sodium chloride, glycerin, mannitol and the like. The content of the tonicity agent is preferably in the range of 0.001 to 3 W / V% in the pseudomyopia therapeutic agent.

  Examples of solubilizers include surfactants such as polyhydric alcohols such as propylene glycol, butylene glycol, polyethylene glycol, and sorbitol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, and proxamers. As polyoxyethylene hydrogenated castor oil, besides polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 100, and the like can be used. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene (20) sorbitan (polysorbate 80) monooleate, polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), and polyoxyethylene sorbitan monostearate (polysorbate 20). Polysorbate 60), polyoxyethylene sorbitan tristearate (polysorbate 65) and the like can be used. The content of the solubilizing agent is preferably in the range of 0.001 to 3 W / V% in the pseudomyopia therapeutic agent.

  Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), hydroquinone, propyl gallate, sodium bisulfite and the like. The content of the antioxidant is preferably in the range of 0.001 to 1 W / V% in the pseudomyopia therapeutic agent.

The pseudomyopia therapeutic agent of the present invention may be used as it is, or may be prepared as a suspension or gel. Examples of the pseudomyopia therapeutic agent include eye drops, which are suitable for contact lenses. Note that “for contact lenses” refers to those used while wearing contact lenses. More specifically, eye drops (including eye drops for contact lenses that can be applied while wearing contact lenses) are included, and eye drops for contact lenses are preferred. The contact lens is not particularly limited, and examples thereof include a hard contact lens, an oxygen permeable hard contact lens, a soft contact lens, a disposable contact lens, and a silicon hydrogel contact lens. The pseudomyopia therapeutic agent of the present invention is particularly effective for reducing the tension of the ciliary muscles when wearing a contact lens, and is also suitable for use while wearing a contact lens because stimulation is suppressed.

  Although pH (20 degreeC) of the pseudomyopia therapeutic agent of this invention is not specifically limited, It is desirable to adjust to pH of the range accept | permitted by a biological body. Preferably it is 4.0-9.0, More preferably, it is 5.0-8.0. If the pH is too low or too high, the feeling of irritation can be strong. The pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK). As the pH adjuster, sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.

The pseudomyopia therapeutic agent of the present invention can be produced by, for example, a known production method with the balance being water. For example, each of the above components is dissolved in sterilized purified water, water such as ion exchange water, or a mixed solvent with alcohol such as ethanol, and then pH is adjusted. It can obtain by adjusting suitably by.
A preferred production method is, for example, adding purified water to tropicamide to dissolve, then adding phentolamine while stirring well, adding a metal sequestering agent, buffering agent, trometamol, and further dissolving various drugs, water After dissolving by adding a functional polymer, an isotonic agent, etc., the pH can be adjusted with hydrochloric acid or an aqueous sodium hydroxide solution to obtain the pseudomyopia therapeutic agent of the present invention.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated further in detail, this invention is not limited to the following Example.

[Examples 1-5, Comparative Examples 1-3]
As shown in Table 1, each compounding component in the table was dissolved in sterilized purified water according to a conventional method, and then each solution was aseptically filtered to prepare a pseudomyopia therapeutic agent. The following tests and evaluations were performed on each of the obtained preparations. Moreover, the eye irritation after instillation was evaluated by the following method. The results are also shown in the table.

[Mydriatic inhibition test]
The formulation shown in the table was instilled into 5 rabbits (NZW). The pupils before and 15 minutes after instillation were photographed with a digital camera, and the pupil diameters of the photographed images before and after the instillation were measured and compared.
It is preferable that the diameter of the pupil does not change (does not increase) after the instillation of the preparation, or is a very small change even if it changes.
Judgment was made according to the following evaluation criteria.
◎: Unchanged to less than 3% change ○: Change from 3% to less than 5% △: Change from 5% to less than 10% ×: Change from 10% or more

[Pseudomyopia improvement test]
For 5 patients with pseudomyopia, 2 drops of the preparations shown in the table were instilled before going to bed and continued for 1 month. After one month, the accommodation power before and after one month of instillation was measured and compared with the accommodation power before the start of instillation.
Measurement of adjusting force: Refractive value (unit D: diopter) was measured using an autorefractometer.
Pseudomyopia is a state in which the adjustment power is reduced, and it is preferable that the adjustment power is improved by instilling the preparation.
Based on the following evaluation criteria, it was determined that an improvement in the adjusting power including Δ was recognized.
A: Improvement of 1.0D or more B: Improvement of 0.5D or more to less than 1.0D Δ: Improvement of 0 <less than 0.5D ×: No change, decrease

[Evaluation of eye irritation]
For 5 panelists, one drop of the preparation was instilled, and the eye irritation feeling 3 minutes after the instillation was evaluated based on the following evaluation criteria.
◎: No irritation ○: Slight irritation △: Slight irritation ×: Irritation

Claims (4)

  (A) It contains tropicamide or a salt thereof, and (B) an α-adrenergic receptor antagonist, and the content of component (A) is 0.001 W / V% to 0.1 W / V%. Pseudomyopia treatment.   Furthermore, the pseudomyopia therapeutic agent of Claim 1 containing a cooling agent.   The pseudomyopia therapeutic agent according to claim 1 or 2, which contains no preservative. The pseudomyopia therapeutic agent according to claim 1, 2, or 3, which is an eye drop for a contact lens.