JP5083502B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition that is excellent in preservative efficacy and has little irritation to the eyes even if it does not contain an irritating preservative such as benzalkonium chloride.

  Ophthalmic compositions are usually used for the purpose of preventing the decay of preparations derived from secondary contamination and the like, and usually include cationic preservatives such as benzalkonium chloride and chlorhexidine gluconate, and paraoxybenzoates such as methylparaben. Add preservatives. In particular, cationic preservatives such as benzalkonium chloride and chlorhexidine gluconate are excellent in preservative effect, and this preservative is used as a preservative in the eye drop field at a rate of about 60% (reference name “Ophthalmic drop”). How to use the medicine "Ophthalmology practice, 42, 1999). However, these preservatives are known to impart irritation to the mucosa.

  On the other hand, in recent years, with an increase in VDT work, an increase in contact lens users, and an increase in allergic patients, the number of patients having eye troubles is rapidly increasing. Soft contact lens users in particular are prone to damage to the cornea, are hypersensitive to irritating preservatives, and are susceptible. Therefore, an ophthalmic composition that does not contain or contain the irritating preservative as described above has been desired.

  In addition, as a technique for ensuring the preservation effect of the ophthalmic composition without reducing or using an irritating cationic preservative, a technique for enhancing the antiseptic effect by adding berberine to the preservative (Patent Document 1: JP 2001-64108 A), panthenol, boric acid, a technique of blending a compound having three or more hydroxyl groups in the molecule (see Patent Document 2: JP 2002-265357 A), and trometamol. Technology (see Patent Document 3: Japanese Patent Laid-Open No. 2002-316926), Technology for making an ophthalmic composition containing trometamol and boric acid at a specific ratio and having a pH of 5 to 7.5 (Patent Document 4: Japanese Patent 2004-2364), an eye drop composition containing 0.001 to 0.005% benzalkonium chloride and 8.14 mM to 0.24M borate ion (Patent Document 5). JP-A-10-130156), an ophthalmic solution composition containing a low concentration of a cationic activator, a buffering agent, a chelating agent, and a polymer polysaccharide (Patent Document 6: see JP-A-10-203960), Preservative made of a combination of boric acid, EDTA and PVP (Patent Document 7: see JP-A-2002-80314), ophthalmic preservative made of a copolymer composed of a basic amino acid and an amino acid having a hydroxyl group (Patent Document 8) : Japanese Patent Laid-Open No. 2004-203867), preservatives comprising diphenhydramine, chlorpheniramine and boric acid (Patent Document 9: see Japanese Patent Laid-Open No. 2005-330276).

JP 2001-64108 A JP 2002-265357 A JP 2002-316926 A JP 2004-2364 A JP-A-10-130156 Japanese Patent Laid-Open No. 10-203960 Japanese Patent Laid-Open No. 2002-80314 JP 2004-203867 A Japanese Patent Laying-Open No. 2005-330276 How to use eye drops, “Ophthalmology Practice”, 42, 1999

  The present invention has been made in view of the above circumstances, and even if it does not contain a preservative selected from cationic preservatives such as benzalkonium chloride and chlorhexidine gluconate, parabens, sorbic acid, and salts thereof, the storage efficacy ( An object of the present invention is to provide a new ophthalmic composition having excellent antiseptic power and low eye irritation.

  As a result of intensive investigations to achieve the above object, the present inventor has found that the pH of the composition is 3.5 to 3.9, and the buffering power of the composition is adjusted to a specific low range, so that sufficient It has been found that an ophthalmic composition having an antiseptic effect and less irritation such as squeezing or painful can be obtained. In general, it is common knowledge in the art that ophthalmic compositions have strong eye irritation in a low pH range. Usually, the pH is 5 or more even when the composition is adjusted to near neutrality to be acidic. Therefore, the ophthalmic composition with low eye irritation in the pH range of the present invention is a novel invention.

Accordingly, the present invention provides the following inventions.
[1]. Contains a buffer selected from trometamol, boric acid and borax , and has a pH of 3. An ophthalmic composition that is 6 to 3.9, has a Q of 3 to 18 mL, and does not contain a preservative selected from cationic preservatives, parabens, sorbic acid, and salts thereof.
Q = QHCl + QNaOH
(In the above formula, QHCl: 0.1 mol / L HCl amount (mL) necessary to lower 100 g of the composition to pH 3.5,
QNaOH: 0.1 mol / L NaOH amount (mL) required to raise 100 g of the composition to pH 7.5)
[2]. The ophthalmic composition according to [1], wherein the content of the buffering agent is 0.001 to 1.3 w / v% in the ophthalmic composition.
[3]. Moreover, menthol, borneol, camphor, geraniol, peppermint water, eucalyptus oil, fennel oil, bergamot oil, linalool, and containing a cooling agent selected from peppermint oil [1] or [2] Symbol ophthalmic compositions of the mounting .
[4]. The ophthalmic composition according to any one of [1] to [ 3 ], which is an eye drop or an eye wash.
[5]. The ophthalmic composition according to any one of [1] to [ 4 ], which is an eye drop for a soft contact lens, an eye wash for a soft contact lens, a soft contact lens mounting liquid, a soft contact lens removal liquid, or a contact lens care agent. .

  ADVANTAGE OF THE INVENTION According to this invention, the ophthalmic composition which is excellent in preservative efficacy and has low irritation | stimulation to eyes can be provided, and the compounding quantity of antiseptic | preservatives, such as benzalkonium chloride, can be reduced.

  The ophthalmic composition of the present invention has a pH (20 ° C.) of 3.5 to 3.9, preferably 3.6 to 3.8. If the pH is lower than 3.5, a feeling of irritation such as blotting may be felt, and if it exceeds 3.9, the effect of the antiseptic power is insufficient. Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, hydrochloric acid and the like. These can be used individually by 1 type or in combination of 2 or more types. The pH is measured at 20 ° C. using a pH osmometer (HOSM-1), Toa DKK Corporation.

In the ophthalmic composition of the present invention, Q represented by the following formula is 18 mL or less.
Q = QHCl + QNaOH
(In the above formula, QHCl: 0.1 mol / L HCl amount (mL) necessary for lowering 100 g of the composition to pH 3.5 (20 ° C.),
QNaOH: 0.1 mol / L NaOH amount (mL) necessary to raise 100 g of the composition to pH 7.5 (20 ° C.)
The above Q indicates the buffering power of the composition, Q is 18 mL or less, and a composition having no irritation is obtained within this range. Q is preferably 3 to 18 mL, more preferably 3 to 14 mL.

  Examples of the buffer include boron-based buffers such as boric acid and borax, acetic acid-based buffers such as acetic acid, sodium acetate, and potassium acetate, and phosphorous such as sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. 1 selected from an acid buffer, a carbonate buffer such as sodium carbonate, a citric acid buffer such as citric acid and sodium citrate, epsilon aminocaproic acid, trometamol, aspartic acid and aspartate, and glutamic acid and glutamate A seed | species or 2 or more types is mentioned. Among these, trometamol, boric acid, and borax are preferable, and boric acid, trometamol, or a mixture thereof is particularly preferable from the viewpoint of antiseptic effect.

  The content of the buffer is preferably 0.001 to 1.3 w / v% (mass / volume%, g / 100 mL, the same applies hereinafter) in the ophthalmic composition, more preferably 0.05 to 1.2 w / v. %, More preferably 0.05 to 1.0 w / v%.

  The above-mentioned buffering agent is low in eye irritation in the vicinity of neutral to weakly acidic pH of 5 or higher, which is normally set in an ophthalmic composition, and the buffering power is ocular irritation in the range of the buffering agent allowed in the ophthalmic composition. There is no big impact. Therefore, it can be said that the presence or absence of eye irritation due to the buffering force is a unique phenomenon in a low pH range as in the present invention.

  It is preferable to add a refreshing agent to the ophthalmic composition of the present invention, and by adding the refreshing agent, it is possible to further mask the irritation caused by the drug. Examples of the refreshing agent include menthol, borneol, camphor, geraniol, peppermint water, eucalyptus oil, fennel oil, bergamot oil, linalool, peppermint oil and the like, which may be used alone or in combination of two or more. it can. Among these, menthol, camphor, and borneol are preferable from the viewpoint of usability.

  The content of the refreshing agent is preferably 0.0005 to 0.03 w / v% in the ophthalmic composition, more preferably 0.001 to 0.015 w / v%, and still more preferably 0.001 to 0.012 w. / V%.

  The ophthalmic composition of this invention can mix | blend the various components used for an ophthalmic composition in the range which does not impair the effect of this invention as needed. Examples of preferable ingredients include drugs, stabilizers, thickeners, tonicity agents, solubilizers, antioxidants, and the like.

Examples of the drug include the following.
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 (eg, 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 component or astringent component: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, lintiprofen sodium chloride, tiaramid hydrochloride And pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate), azulenesulfonic acid and pharmacologically acceptable salts (for example, sodium azulenesulfonate), zinc salts (for example, zinc sulfate, lactic acid) Zinc), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizic acid and pharmacologically acceptable salts (eg dipotassium glycyrrhizinate, glycyrrhizin) Ammonium phosphate, etc.), and the like.
Antihistamine component or antiallergic agent component: for example, ketotifen, acitazanolast, chlorpheniramine, diphenhydramine, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast and pharmaceutically or physiologically acceptable salts thereof .

Vitamins: for example, flavin adenine dinucleotide sodium (active vitamin B ₂ ), cyanocobalamin (vitamin B ₁₂ ), pyridoxine hydrochloride (vitamin B ₆ ), vitamin E acetate, panthenol, calcium pantothenate, sodium pantothenate, retinol acetate , Amino acids such as retinol palmitate (vitamin A palmitate): for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, Hydroxylysine, glycylglycine, aminoethylsulfonic acid (taurine) and its salts (for example, cysteine hydrochloride, etc.) and the like.

Antibacterial component or bactericidal component: This is blended as an active ingredient, not as a preservative. Sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), acrinol, alkylpolyaminoethylglycine , New quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin, etc.), berberine and its salts (eg, berberine sulfate), β-lactam antibacterials (sulbenicillin, cefmenoxime, etc.), aminoglycosides Antibacterials (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), tetracycline antibacterials (eg, ocitetracycline), macro Id antibacterials (such as erythromycin), chloramphenicol antibacterials (such as chloramphenicol), polypeptide antibacterials (such as colistin), etc. In addition, antiviral drugs (doxuridine, acyclovir, adenine arabinoside, Ganciclovir, foscalnet, valacyclovir, trifluorothymidine, cidophobia, carbocyclic oxetanocin G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B, etc.).

Oligosaccharides: lactulose, raffinose, pullulan, cyclodextrin, 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 (alginate), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate and salts thereof (sodium alginate, sodium hyaluronate, chondroitin) Sodium sulfate).
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) and the like.
Mydriatic components: cyclopentrate hydrochloride, tropicamide, etc.

  The effective content of each drug can be selected as the content of the drug. From the viewpoint of irritation to the eye, stability of the composition, etc., 0.001 to 5 w / v% in the ophthalmic composition The range of is preferable.

  Examples of the stabilizer include sodium edetate and edetic acid. Edetic acids have the effect of maintaining system stability. The content of the stabilizer is preferably in the range of 0.001 to 2 w / v% in the ophthalmic composition.

  Examples of the thickening agent include cellulose polymer compounds such as methyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose, polyvinyl polymer compounds such as polyvinyl pyrrolidone and polyvinyl alcohol, liquid paraffin, carboxyvinyl polymer, and polyethylene glycol. The content of the thickening agent is preferably in the range of 0.005 to 3 w / v% in the ophthalmic composition.

  Examples of the isotonic agent include potassium chloride, sodium chloride, glycerin and the like. The content of the tonicity agent is preferably in the range of 0.001 to 3 w / v% in the ophthalmic composition.

  Examples of solubilizers include polyhydric alcohols such as propylene glycol, polyethylene glycol and sorbitol, polysorbate 80, poloxamers, POE sorbitan fatty acid esters such as POE (20) sorbitan monooleate, POE (60) hydrogenated castor oil, etc. Surfactants such as POE hydrogenated castor oil are listed. The content of the solubilizer is preferably in the range of 0.001 to 3 w / v% in the ophthalmic composition.

  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 ophthalmic composition.

  The ophthalmic composition of the present invention comprises cationic preservatives such as benzalkonium chloride and chlorhexidine gluconate, parabens (paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl paraoxybenzoate), sorbic acid, and salts thereof. Even if it does not contain the selected preservative, it has a preservative effect (preservative power), so the content of the preservative is 0.001 w / v% or less in the ophthalmic composition, or an ophthalmology that does not contain the preservative. It can also be set as a composition for use.

  The ophthalmic composition of the present invention can be produced by, for example, a known production method with the balance being water. Specifically, after each of the above components is dissolved in water such as sterilized purified water, ion-exchanged water, or a mixed solvent with alcohol such as ethanol, the pH is adjusted to 3.5 to 3.9, and If necessary, it can be obtained by appropriately adjusting the osmotic pressure or the like with a pH adjusting agent or tonicity agent. The obtained ophthalmic composition is filled in a known eye drop container (a composition containing an ultraviolet ray prevention agent or a dye is preferable in terms of stability of the compounding ingredients), and is packaged such as a film package, so that the storage stability is good. Can be provided as a unique ophthalmic composition.

  Examples of the ophthalmic composition include eye drops, eye wash and the like, which are suitable for contact lenses, particularly for soft contact lenses. More specifically, eyedrops for soft contact lenses to be used while wearing soft contact lenses, eyewashes for soft contact lenses to be used after removing soft contact lenses, soft contact lens mounting liquids to be used when wearing soft contact lenses, It can be used for a soft contact lens removing liquid used when removing a soft contact lens, or a contact lens care agent (cleaning, rinsing, disinfection and storage). The type of soft contact lens to which the ophthalmic composition of the present invention can be applied is not particularly limited. In addition to a soft contact lens that is used repeatedly, a one-day disposable soft contact lens, a one-week disposable soft contact lens, 2 Can be used for any of the weekly disposable soft contact lenses.

EXAMPLES Hereinafter, although an Example , a reference example, and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 10, Reference Examples 1 to 14 , Comparative Examples 1 to 17]
Each composition component (composition unit w / v%) shown in Tables 1 to 7 was dissolved in sterilized purified water according to a conventional method, and then each solution was sterile filtered to prepare an ophthalmic composition (test solution). did. About each obtained ophthalmic composition, pH (20 degreeC) was measured and the following test was implemented. The results are also shown in the table.

[Test Example 1]
Preservation Efficacy Test Fifteenth revision Japanese Pharmacopoeia ・ It was carried out according to the preservative efficacy test of reference information. That is, after adding the following bacteria and fungi to the test solution so as to be 10 ⁵ to 10 ⁶ per mL, and allowing to stand at 25 ° C., culturing each 1 mL of the solution inoculated with the bacteria after 14 and 28 days. The number of viable bacteria was measured, and the survival rate (%) relative to the number of inoculated bacteria was calculated.
Bacteria Pseudomonas aeruginosa ATCC 9027
Escherichia coli ATCC 8739
Staphylococcus aureus ATCC 6538
The fungus Candida albicans ATCC 10231
Aspergillus niger ATCC 16404
The criteria for preserving efficacy are: the survival rate after 14 days is less than 0.1% of the number of inoculated bacteria, the same level or less than the number of inoculated bacteria, and the survival rate after 28 days is the same level after 14 days in bacteria Or less than that, in fungi, the same or less than the number of inoculated bacteria. Those satisfying this criterion were marked with ◯, and those not satisfying even one were marked with ×. The same level means ± 10%.
In addition, the culture is SCDLP agar medium (manufactured by Nippon Pharmaceutical Co., Ltd.) for bacteria, and the GPLP agar medium (Glucose Peptone Agar with 80%). ))).

[Test Example 2]
Irritation test after instillation The following evaluation criteria are the irritation feeling when the test solution is instilled with a soft contact lens attached to a panel of OA equipment operators suffering from dry eyes of 3 men and women (total 6 people) Based on the evaluation. Based on the total score of all the panelists, the total score was 0 to 2 points, ◯ 3 to 5 points, and 6 points or more to × points.
<Evaluation criteria>
3: Smear very much 2: Smear 1: Slightly look 0: No stain

[Test Example 3]
Titration test (Q value)
100 g of the test solution was weighed and titrated with 0.1 mol / LHCl, the pH was lowered to 3.5 (20 ° C.), and the necessary 0.1 mol / LHCl amount (QHCl) was measured.
Separately, 100 g of the test solution was weighed and titrated with 0.1 mol / L NaOH, the pH was raised to 7.5 (20 ° C.), and the necessary 0.1 mol / L NaOH amount (QNaOH) was measured.
From the obtained value, Q = QHCl + QNaOH was calculated.

Claims (5)

Contains a buffer selected from trometamol, boric acid and borax , and has a pH of 3. An ophthalmic composition that is 6 to 3.9, has a Q of 3 to 18 mL, and does not contain a preservative selected from cationic preservatives, parabens, sorbic acid, and salts thereof.
Q = QHCl + QNaOH
(In the above formula, QHCl: 0.1 mol / L HCl amount (mL) necessary to lower 100 g of the composition to pH 3.5,
QNaOH: 0.1 mol / L NaOH amount (mL) required to raise 100 g of the composition to pH 7.5) The ophthalmic composition according to claim 1, wherein the content of the buffer is 0.001 to 1.3 w / v% in the ophthalmic composition. Moreover, menthol, borneol, camphor, geraniol, peppermint water, eucalyptus oil, fennel oil, bergamot oil, linalool, and claim 1 or 2 Symbol ophthalmic composition of the mounting comprising a freshening agent selected from peppermint oil. The ophthalmic composition according to any one of claims 1 to 3 , which is an eye drop or an eye wash. The ophthalmic composition according to any one of claims 1 to 4 , which is an eye drop for a soft contact lens, an eye wash for a soft contact lens, a soft contact lens mounting liquid, a soft contact lens removal liquid, or a contact lens care agent.