JP2004339119A - Medicinal preparation for use in local application - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal preparation for use in local application designed to prevent corneal disorders caused by exposure to rays such as ultraviolet radiation. <P>SOLUTION: The medicinal preparation for use in local application designed to prevent corneal disorders or inhibit the onset of ultraviolet ophthalmia contains a terpenoid. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【００４８】
試験例２ 紫外線照射ウサギ角膜上皮細胞に対する保護作用（コメットアッセイ法）
テルペノイドの角膜保護作用を下記に記載の方法に従い、角膜上皮細胞のアポトーシス抑制効果に基づいて検討した。
方法）ウサギ角膜上皮細胞（ＮＲＣＥ２、クラボウ（株））を無血清培地（ＲＣＧＭ２、クラボウ（株））中に８×１０^５ｃｅｌｌｓ／ｍｌに分散した細胞浮遊液と試験液を用いてＣｏｍｍｅｔＡｓｓａｙＫｉｔ（販売：Ｒ＆Ｄ社）を用いて電気泳動を行い移動距離を測定した。詳細には、細胞浮遊液２０μｌと試験液９０μｌと１％ｌｏｗ ｍｅｌｔｉｎｇ ａｇａｒｏｓｅ９０μｌを混合した液とを混和した。混和液５０μｌをコメットスライドガラスにコーティング（１０００ｃｅｌｌｓ／スライド）し、４℃で１０分間放置した。トランスルイミネーターを用いてＵＶ−Ｂ（３０２ｎｍ）を５００ｍＪ／ｃｍ^２照射した後、溶液Ａ（Ｌｙｓｉｓ ｓｏｌｕｔｉｏｎ ４０ｍｌにＤＭＳＯ ４００μｌを混合し、ｐＨ１０．０に調整した溶液）に６０分間浸漬し、溶液Ｂ（３００ｍＭ ＮａＯＨ、１ｍＭ ＥＤＴＡ、ｐＨ１３．０となるよう調整した溶液）に２０分間浸漬してＤＮＡを抽出した。この液を用いて２０分間電気泳動した後、ＤＮＡを染色した後、蛍光顕微鏡を用いて観察して、ＤＮＡの移動距離を測定した。
【００４９】
【表２】

【００５０】
表１に示すように、ｌ−メントール添加群では、ＵＶ照射によるＤＮＡ破壊が２９．４％抑制されていることが認められ、ｌ−メントールによってアポトーシスが抑制されていることが示された。
【００５１】
試験例１及び２の実験結果から、ｌ−メントールがＵＶ曝露後の角膜上皮細胞におけるアポトーシスを抑制することが確認できた。角膜上皮細胞のアポトーシスはＵＶ誘発角膜炎の第一段階である。これらの結果は、テルペノイドがＵＶ曝露後の角膜上皮細胞におけるアポトーシスを抑制することにより角膜障害をその発生初期段階で抑制する作用を有し、角膜保護剤として有用であることを示すものである。さらに、試験例１及び２の実験結果から、テルペノイドはＵＶ等による角膜上皮障害の予防的処置に有効であることが確認された。これらの結果はまた、本発明の局所適用製剤を用いると、通常ならば重篤な角膜障害を引き起こす紫外線に曝露された場合であっても、その症状をより軽微なものに抑制できることを示している。
【００５２】
実施例１−８
常法により、以下の表に記載の処方の点眼薬を調製した。
【００５３】
【表３】

【００５４】
【発明の効果】
本発明のテルペノイドを含有する局所適用製剤は、紫外線等の光線に被曝する前から被曝後、好ましくは被曝前から被曝後早期段階に適用することにより、角膜障害の発生を予防し、進行を阻止し、眼痛などの発現を抑制する作用を示す。本発明の局所適用製剤は、適用形態が簡便であるために、様々な場面で広範に利用することができ、紫外線のみならず種々の光線により惹起され得る角膜障害の迅速で適切な処置を可能にするという利点を有する。
本発明のテルペノイドを含有するアポトーシス抑制剤は、細胞組織が紫外線等の光線に被曝する前から被曝後、好ましくは被曝前から被曝後早期段階に適用することにより、組織障害の発生を予防し、進行を阻止する作用を示す。本発明のアポトーシス抑制剤は、適用形態が簡便であるために、様々な場面で広範に利用することができ、紫外線のみならず種々の光線により惹起され得る組織障害の迅速で適切な処置を可能にするという利点を有する。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a topical preparation containing a terpenoid, and more particularly to a composition for preventing corneal damage by topical application and protecting the cornea, and using the composition to protect the cornea from damage caused by light rays such as ultraviolet rays. For how to.
[0002]
[Prior art]
In recent years, destruction of the ozone layer due to changes in the global environment has increased the chances of exposing living bodies to strong ultraviolet rays, and has had various effects including sunburn. On the other hand, the eye is also an organ that is directly affected by light rays such as ultraviolet rays, and in particular, the cornea, which is exposed to the outside world, can be said to be suffering from some kind of obstacle by being constantly exposed to light rays such as ultraviolet rays.
[0003]
The degree of corneal damage due to exposure to light rays such as ultraviolet rays varies depending on the dose received, but it appears in the surface layer of the corneal epithelium in a relatively short time of about several hours after exposure, or in the deep part of the corneal epithelium for 12 hours or more Some occur gradually after elapse and reach a peak in about 24 hours.
Moreover, when receiving strong ultraviolet rays at one time during sports such as skiing, corneal epithelial damage occurs over a wide area. Further, this may cause serious corneal disorders such as keratitis such as ultraviolet eye inflammation (so-called snow-blindness, snow-eye inflammation, and dream) and corneal ulcer. On the other hand, corneal damage due to repeated exposure to less intense UV light cannot be ignored.
Therefore, in order to prevent the occurrence of corneal damage due to ultraviolet rays, it is of utmost importance to treat subjects who may be exposed to ultraviolet rays in an appropriate manner, regardless of the presence or absence of symptoms.
[0004]
The mechanism by which the cornea is damaged has not yet been fully elucidated, but recently, abnormal apoptosis caused by exposure of ultraviolet light (UV) to an abnormal apoptotic signal in corneal epithelial cells has been implicated. Is said to be. Apoptosis of corneal epithelial cells caused by UV exposure affects the entire cornea, and even if there is no subjective symptom, it is said that there are many voids in the corneal tissue due to the lack of cells that died by apoptosis I have. When such cell death increases, subjective symptoms such as discomfort and pain in the eyes appear, and corneal disorders such as inflammation may be caused by external stimuli such as rubbing the eyes.
[0005]
Accordingly, it is extremely important to prevent the occurrence of corneal epithelial damage beforehand and to suppress the progression of corneal epithelial damage early, with respect to corneal damage due to light rays such as ultraviolet rays, and it is suitable for such treatment. There is a strong need for the development of safe, stable and effective drugs.
[0006]
Conventionally, as a therapeutic / prophylactic agent for corneal disorders, a therapeutic agent containing lecithinated superoxide dismutase as an active ingredient has been known (Patent Document 1). However, the preparation described in Patent Document 1 uses an enzyme as an active ingredient, and it is difficult to supply the preparation as a stable preparation for topical application. Also, a therapeutic agent for corneal disorders containing a phosphoric diester compound of ascorbic acid and tocopherol has been provided (Patent Document 2). However, the preparation described in Patent Literature 2 may not be able to stably maintain its effect due to decomposition of the active ingredient or adsorption to a container.
[0007]
[Patent Document 1]
JP-A-9-124505
[0008]
[Patent Document 2]
JP-A-7-291870
[0009]
[Problems to be solved by the invention]
An object of the present invention is to provide a preparation for topical application for preventing the occurrence of corneal epithelial damage mainly due to exposure to light rays such as ultraviolet rays and suppressing the progress of corneal epithelial damage.
Another object of the present invention is to provide an apoptosis inhibitor for corneal epithelial cells.
[0010]
[Means for Solving the Problems]
The present inventors have conducted intensive studies and found that, when a composition containing a terpenoid is applied topically, damage to the corneal epithelium caused by rays such as ultraviolet rays can be prevented and the cornea can be protected. It was completed.
That is, the present invention provides a topical preparation for preventing corneal disorders, which comprises a terpenoid as an active ingredient.
The present invention also provides an apoptosis inhibitor for corneal epithelial cells containing a terpenoid as an active ingredient.
That is, the present invention
(1) a topically-applied preparation for preventing corneal disorder, comprising a terpenoid;
(2) The topical preparation according to (1), wherein the corneal disorder is caused by a light beam.
(3) a topically applied preparation containing terpenoids for suppressing the occurrence of ultraviolet ophthalmitis,
(4) The topical preparation according to (1) to (3), wherein the terpenoid is at least one selected from the group consisting of menthol, borneol, and camphor.
(5) an apoptosis inhibitor containing a terpenoid,
(6) the apoptosis inhibitor according to (5), wherein the terpenoid is at least one selected from the group consisting of menthol, borneol, and camphor;
It is about.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
For the purpose of the present invention, "prevent corneal disorder" means to prevent the occurrence of corneal epithelial disorder or to suppress the progression of corneal epithelial disorder and corneal disorder, and the disorder is a subjective symptom. It has nothing to do with presence. The degree of corneal epithelial damage when exposed to light or the like varies depending on the dose and site, and the speed of progress of the damage also varies. Symptoms of corneal disorders become more serious as the number of corneal epithelial cells that have died in a short time increases, and the burden on the patient also increases. Therefore, even when cells are exposed to a light beam corresponding to a lethal dose, a treatment for suppressing rapid cell death is effective. Therefore, the prevention of corneal disorders in the present invention includes all treatments for preventing light and the like from exerting a lethal effect on cells and reducing corneal disorders, such as prevention, reduction / decrease of symptoms, and reduction of symptoms. This includes treatments at all stages and phases, such as slowing down or stopping progress of the disease. Therefore, the preparation for topical application of the present invention has a function as a corneal protective agent.
[0012]
The prevention of corneal damage in the present invention is effective for preventing light such as ultraviolet rays from causing lethal damage to corneal epithelial cells, preventing corneal epithelial damage and corneal damage induced by cell death, and suppressing progression.
Causes of the corneal epithelial disorder according to the present invention include light such as ultraviolet rays, for example, sunlight, welding light, germicidal lamp, laser light, etc., but the topically applied preparation of the present invention is effective regardless of the cause. . The topical formulation of the present invention is particularly effective in treating disorders caused by light such as ultraviolet rays.
[0013]
The topically applied preparation of the present invention enables appropriate treatment of a corneal disorder by incorporating a terpenoid. Conventionally, terpenoids have been used as a cooling agent in topically applicable agents such as ophthalmic compositions, but it has not been known that this can be an active ingredient of topically applied preparations for treating corneal disorders.
[0014]
The topical formulation of the present invention may contain any ophthalmically acceptable terpenoid, such as menthol, borneol, camphor, geraniol, cineol, anethole, limonene, eugenol, etc., monoterpenes, farnesol, nerolidol And diterpenes such as phytol and sembrene. Among them, menthol, borneol, camphor and the like are preferable. These terpenoids may be any of d-form, l-form and dl-form, and may also be blended as essential oils containing these terpenoids.
The concentration of the terpenoid in the preparation for topical application of the present invention varies depending on the type and dosage form of the terpenoid, but is preferably in the range of 0.0005 to 1% by weight as the concentration of the terpenoid. More preferably, the amount is in the range of 0.001 to 0.5% by weight, and in the case of eyewash, 0.001 to 0.2% by weight.
The topical formulation of the present invention can be applied before and after exposure to ultraviolet light or the like. The preparation can be carried out by applying an appropriate amount of the preparation to both eyes at any number of times from about 1 hour before exposure to ultraviolet rays or the like to about 24 hours after final exposure. Preferably, it is applied between before exposure and about 24 hours after exposure. The applied amount is about 0.2 ml for both eyes in a single eye drop for eye drops, about 10 ml for both eyes for eyewash, and about 0.1 g for both eyes for eye ointment. More preferably, corneal damage due to exposure to ultraviolet rays or the like can be prevented or reduced by instilling 1 to 2 drops at a time, 5 to 6 times a day. However, the timing of application, the number of applications, and the amount of application of the topically applied preparation of the present invention should be appropriately adjusted according to the type and intensity of the exposed light beam, the intensity, and the situation (symptoms, age, etc.) of the exposed subject. However, the present invention is not limited to the above.
The topical preparation of the present invention can prevent corneal epithelial damage and prevent corneal damage such as ultraviolet blepharitis.
[0015]
The present invention also applies a topical formulation containing a terpenoid to both eyes before exposure to a subject that may be exposed to light rays such as ultraviolet rays, and within about 24 hours after exposure to an exposed subject. And a method for preventing corneal disorders.
[0016]
The topical preparation of the present invention can contain various components other than terpenoids in combination, as long as the object of the present invention is not adversely affected. Components that can be combined include, for example, decongestant components, anti-inflammatory drug components, antihistamine drug components, other astringent components, bactericide components, antitumor drug components, hormones, proteins or peptides, vitamins, Amino acids and the like can be used. Specifically, the following components can be exemplified.
[0017]
Decongestant: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof.
[0018]
Ocular 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.
[0019]
Anti-inflammatory drug components: for example, zinc sulfate, zinc lactate, celecoxib, rofecoxib, indomethacin, diclofenac, planoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, azulurinic acid, glycyrrhizin Acids, lysozyme, methyl salicylate, allantoin, and pharmacologically acceptable salts (eg, berberine chloride, berberine sulfate, diclofenac sodium, sodium azulene sulfonate, dipotassium glycyrrhizinate, lysozyme chloride, etc.) and the like.
[0020]
Antihistamine drug components: for example, diphenhydramine, chlorpheniramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, amlexanox, mequitazine, loratadine, fexofenadine, fexofenadine (fexofenadine) , Ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, hydrochloric acid Olopatadine, sodium cromoglycate, etc.).
[0021]
Fungicide components: for example, sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.); Acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), alkylpolyaminoethyl Glycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin hydrochloride, ofloxacin, norfloxacin, etc.) and the like.
[0022]
Vitamin B: Vitamin B such as, for example, vitamin A (for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmaceutically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.)) (E.g., thiamine, thiamine disulfide, dicetiamine, octiamine, sicotiamine, bisibutiamine, bisbenthamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, Cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, bread Knol, biotin, choline, inositol and their pharmacologically acceptable salts (eg, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, phosphoric acid Vitamin Cs (ascorbic acid and its derivatives, erythorbic acid and its derivatives and its pharmacologically acceptable), such as pyridoxal, calcium pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, and sodium pantothenate). Vitamins (eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol) such as salts (eg, sodium ascorbate, sodium erythorbate, etc.) , Dihydroxycholecalciferol, dihydrotaxerol and pharmacologically acceptable salts thereof, and the like, and vitamin Es (eg, tocopherol and its derivatives, ubiquinone derivatives and its pharmacologically acceptable salts (tocopherol acetate, And other vitamins (e.g., carnitine, ferulic acid, γ-oryzanol, orotic acid, cyanocobalamin, rutin, eriocitrin, hesperidin, and its pharmacological properties), such as tocopherol nicotinate, tocopherol succinate, and calcium tocopherol succinate. Acceptable salts (such as carnitine chloride).
[0023]
Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxy Lysine, glycylglycine, aminoethylsulfonic acid (taurine) and pharmacologically acceptable salts thereof (eg, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.);
Saccharides: monosaccharides (eg, glucose, etc.), disaccharides (eg, trehalose, lactose, fructose, etc.), oligosaccharides (eg, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (eg, methylcellulose, ethylcellulose, hydroxyethylcellulose) , Hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, etc.), high molecular sugars (eg, chondroitin sulfate, hyaluronic acid) and pharmaceutically acceptable salts thereof (eg, chondroitin sulfate, sodium hyaluronate, etc.) ), Sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.), antipruritic components (crotamiton, itctamole, moctamole, thymol acid, etc.), etc.
[0024]
Other components: polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone and the like.
[0025]
The content of these components can be selected according to the type of the preparation, the type of the active ingredient, and the like. For example, the content is in the range of about 0.0001 to 30%, preferably about 0.001 to 10% based on the whole preparation. You can choose. More specifically, each component can be contained in the topical preparation of the present invention in the amounts exemplified below.
[0026]
Ocular muscle modulator component: for example, 0.0001 to 0.5%, preferably 0.0002 to 0.1%.
Anti-inflammatory component or astringent component: for example, 0.001 to 10%, preferably 0.002 to 3%.
Antihistamine component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Fungicide component: for example, 0.001 to 10%, preferably 0.01 to 5%
Vitamins: for example, 0.0001 to 1%, preferably 0.001 to 0.3%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.
[0027]
The topically-applied preparation of the present invention is optionally formulated with various components and additives used in pharmaceuticals, quasi-drugs and the like, as long as the effects of the present invention are not impaired. It is possible. Specific examples are described below, but the present invention is not limited to these examples.
[0028]
Saccharides: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like, and pharmacological properties thereof Salts and the like that are acceptable for
[0029]
Thickeners: For example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac fat, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc., ceramide, cellulose derivative (methyl cellulose) , Ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, Ruboxylethyl cellulose, cellulose, etc.), polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethylene imine, ribonucleic acid, deoxyribonucleic acid, etc., and drugs thereof Physically acceptable salts and the like.
[0030]
Saccharides: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like, and pharmacological properties thereof And the salts that are acceptable.
[0031]
Surfactant: For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.), polyoxyethylene-polyoxypropylene block copolymer adduct of ethylenediamine (for example, POE (20) sorbitan (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), POE sorbitan fatty acid esters such as POE (60) hydrogenated castor oil, etc. POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE (10) nonylphen Nonionic surfactants such as POE alkyl phenyl ethers such as phenyl ether; glycine type such as alkyldiaminoethyl glycine; betaine type such as lauryl dimethylaminoacetic acid betaine; and amphoteric surfactants such as imidazoline type; POE (10) POE alkyl ether phosphoric acid such as sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurine, tetradecene Sulfonates such as sodium sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefin sulfonate Any anionic surfactants such as alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.) and alkylpyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.) No. The numbers in parentheses indicate the number of moles added.
[0032]
Preservatives, bactericides or antibacterials: for example, sorbic acid or a salt thereof (sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate, etc.), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, Propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine or a salt thereof, polyhexamethylene biguanide, alkylpolyaminoethyl glycine, benzyl Carriers such as alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, silver zirconium phosphate, thimerosal, Hydroacetic acid, chlorxylenol, chlorophen, resorcin, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, halocarban, thiabendazole, polymyxin B, 5- Chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polydronium chloride, Glokill (for example, Glokill PQ, manufactured by Rhodia), polydiallyl Dimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethlenechloride], polyethylenepolyamine / dimethylamine epichlorohydrin Compound (trade name, for example Busan1157, manufactured by Buckman Co., Ltd.), and the like.
[0033]
pH adjusters: For example, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid) , Propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, hydroxide) Calcium, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof.
[0034]
Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate and the like.
[0035]
pH adjusters: for example, hydrochloric acid, sulfuric acid, lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethyl Sulfonic acid, phosphoric acid, polyphosphoric acid, boric acid, gluconolactone, ammonium acetate, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, Diisopropanolamine, triisopropanolamine, lysine, borax and the like, and pharmacologically acceptable salts thereof.
[0036]
Isotonizing agents: for example, polyhydric alcohols such as glycerin and propylene glycol, and sugars such as glucose, mannitol and sorbitol.
[0037]
Chelating agents: for example, edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and the like Pharmacologically acceptable salts and the like.
[0038]
Water-soluble polymer substances: for example, gelatin, polyacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, methylvinylether / anhydrous Maleic acid copolymer, sodium alginate, polyethylene oxide, gum arabic, xanthan gum, tragacanth gum and the like.
[0039]
Polyhydric alcohols: for example, glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethylene glycol and the like.
[0040]
Further, a fragrance, a cooling agent, a local anesthetic or the like can be added as needed.
[0041]
According to the topical preparation of the present invention, unlike systemic administration such as oral administration, corneal damage can be promptly and effectively prevented without affecting other circulations. The preparation of the present invention can be formulated into any dosage form used in ophthalmic topical preparations, and can be in the form of eye drops, eyewashes, eye ointments, contact lens mounting solutions, and contact lens preparations. May be. Here, the “agent for contact lenses” is a composition for preserving, cleaning, and disinfecting contact lenses. The preparation of the present invention is particularly preferably an eye drop or an eyewash. By adopting such a dosage form, the user himself / herself can apply the preparation of the present invention to the cornea in a case where there is a risk of exposure to ultraviolet rays or early after the exposure, and the prevention of corneal disorders can be more effectively prevented. And prevent the onset of symptoms and prevent progression.
[0042]
The topical formulation of the present invention is adjusted to a pH and / or osmotic pressure within a range acceptable for a living body, if necessary. The acceptable pH is usually pH 4.0 to 9.0, preferably 4.5 to 8.5, and particularly preferably 4.5 to 8.0. The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600, particularly preferably about 150 to 400, and the osmotic pressure ratio to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.6. Adjustment of pH and osmotic pressure can be performed by a method known in the art using the above-mentioned pH adjuster, isotonic agent, salts and the like.
[0043]
Eye drops and eyewashes are prepared by mixing terpenoids and optional ingredients in an appropriate diluent such as distilled water or purified water, adjusting the osmotic pressure and pH as described above, and sterilizing by filtration under an aseptic environment. It can be manufactured by aseptically filling a container that has been washed and sterilized. An ophthalmic ointment can be prepared aseptically by mixing a terpenoid and any compounding ingredients into a commonly used ophthalmic ointment base, and according to a conventional method. Examples of bases for eye ointments include petrolatum, xylene 50, plastibase, macrogol and the like, and a surfactant can be added for the purpose of further enhancing hydrophilicity.
[0044]
The present invention also relates to an apoptosis inhibitor containing a terpenoid as an active ingredient. The kind, proportion and the like of the terpenoid to be added to the apoptosis inhibitor can be determined in accordance with the description of the topical preparation of the present invention. Such an apoptosis inhibitor can be applied to not only corneal epithelial cells but also cells and tissues in contact with the outside world.
[0045]
【Example】
Hereinafter, the present invention will be described in detail with reference to Test Examples and Examples, but the present invention is not limited thereto.
Test Example 1 UV-irradiated protective effect on rabbit corneal epithelial cells (DNA staining method)
The corneal protective action of terpenoids was examined based on the apoptosis-suppressing effect of corneal epithelial cells according to the method described below.
Method) Rabbit corneal epithelial cells (NRCE2, Kurabo Industries, Ltd.) were inoculated into a 96-well microplate (2500 cells / well), and 37 ° C., 5% CO 2 ₂ For 5 days in a serum-free medium (RCGM2, Kurabo Industries, Ltd.). L-Menthol serially diluted with the above serum-free medium was added to the cells that had become 90% confluent (treatment group). The control group received only serum-free medium. Immediately 1000mJ / cm ² Was irradiated for 20 minutes, and apoptosis Dye (APOPentagedye, Biocolor, Ltd.) was added to the cells and reacted for 1 hour. One hour later, a dye that was specifically taken up by apoptotic cells was extracted with an alkaline solution (APOPentage dye release reagent, Biocolor, Ltd.), and the absorbance at 540 nm was measured, and the value was used as an index of apoptosis.
[0046]
(Results) In Table 1, the vertical axis indicates the ratio (%) of the apoptosis index in the treatment group when the apoptosis index in the control group was set to 100. As shown in Table 1, the l-menthol-added group showed a concentration-dependent tendency to suppress apoptosis at 0.001% or more compared to the control group.
[0047]
[Table 1]

[0048]
Test Example 2 Protective Effect on Rabbit Corneal Epithelial Cells Irradiated with Ultraviolet Light (Comet Assay)
The corneal protective action of terpenoids was examined based on the apoptosis-suppressing effect of corneal epithelial cells according to the method described below.
Method) Rabbit corneal epithelial cells (NRCE2, Kurabo Industries, Ltd.) were placed in a serum-free medium (RCGM2, Kurabo Industries, Ltd.) at 8 × 10 5 ⁵ Using a cell suspension dispersed in cells / ml and a test solution, electrophoresis was performed using a Commet Assay Kit (available from R & D) to measure a moving distance. Specifically, a liquid obtained by mixing 20 μl of the cell suspension, 90 μl of the test liquid, and 90 μl of 1% low melting agarose was mixed. 50 μl of the mixed solution was coated on a comet slide glass (1000 cells / slide) and left at 4 ° C. for 10 minutes. UV-B (302 nm) was measured at 500 mJ / cm using a transluminator. ² After irradiation, it was immersed in a solution A (a solution in which 400 μl of DMSO was mixed with 40 ml of Lysis solution and adjusted to pH 10.0) for 60 minutes, and a solution B (a solution adjusted to be 300 mM NaOH, 1 mM EDTA, and pH 13.0). For 20 minutes to extract DNA. After electrophoresis using this solution for 20 minutes, the DNA was stained, and then observed using a fluorescence microscope to measure the moving distance of the DNA.
[0049]
[Table 2]

[0050]
As shown in Table 1, in the l-menthol-added group, it was found that DNA destruction by UV irradiation was suppressed by 29.4%, indicating that apoptosis was suppressed by l-menthol.
[0051]
From the experimental results of Test Examples 1 and 2, it was confirmed that l-menthol suppressed apoptosis in corneal epithelial cells after UV exposure. Apoptosis of corneal epithelial cells is the first step in UV-induced keratitis. These results indicate that terpenoids have an action of suppressing corneal damage at an early stage of development by suppressing apoptosis in corneal epithelial cells after UV exposure, and are useful as corneal protective agents. Furthermore, from the experimental results of Test Examples 1 and 2, it was confirmed that terpenoids were effective for preventive treatment of corneal epithelial damage caused by UV and the like. These results also show that the topical formulation of the present invention can reduce the symptoms even more subtle, even when exposed to ultraviolet light that would normally cause severe corneal damage. I have.
[0052]
Example 1-8
Eye drops having the formulations shown in the following table were prepared by a conventional method.
[0053]
[Table 3]

[0054]
【The invention's effect】
The topically applied preparation containing the terpenoid of the present invention can prevent the occurrence of corneal damage and prevent the progression by applying it from before exposure to light such as ultraviolet rays to after exposure, preferably before exposure to early stage after exposure. And has the effect of suppressing the development of eye pain and the like. The topically applied preparation of the present invention can be widely used in various situations due to its simple application form, and enables rapid and appropriate treatment of corneal disorders that can be caused by various rays as well as ultraviolet rays. Has the advantage of
The apoptosis inhibitor containing the terpenoid of the present invention prevents the occurrence of tissue damage by being applied before or after exposure of the cell tissue to light such as ultraviolet rays, preferably at an early stage after the exposure. It has the effect of inhibiting progress. The apoptosis inhibitor of the present invention can be widely used in various situations due to its simple form of application, and enables rapid and appropriate treatment of tissue disorders that can be caused by various rays as well as ultraviolet rays. Has the advantage of

Claims (6)

A topically-applied preparation for preventing corneal damage, comprising a terpenoid. The topical preparation according to claim 1, wherein the corneal disorder is caused by a light beam. A topically applied preparation containing a terpenoid for suppressing the occurrence of ultraviolet ophthalmitis. The topical preparation according to any one of claims 1 to 3, wherein the terpenoid is at least one selected from the group consisting of menthol, borneol, and camphor. An apoptosis inhibitor containing a terpenoid. The apoptosis inhibitor according to claim 5, wherein the terpenoid is at least one selected from the group consisting of menthol, borneol, and camphor.