JP2005187407A - Ophthalmic composition for allergic eye disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an ophthalmic composition for allergic eye diseases excellent in symptom-improving effect and lasting effect of amelioration on allergic eye diseases and having little irritation. <P>SOLUTION: This ophthalmic composition for allergic eye diseases comprises cromoglycic acid and/or its salt, an antihistamic agent and an acid mucopolysaccharide. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an ophthalmic composition for allergic eye diseases that has a high symptom-improving effect and a long-lasting effect and has suppressed eye irritation.

  Conventionally, many drugs have been used to suppress allergic reactions. Among them, cromoglycate sodium suppresses degranulation of mast cells associated with antigen-antibody reaction and suppresses release of chemical mediators such as histamine. As a result, influx of antigen into the blood and immune complex Inhibits formation and suppresses allergic reactions. Therefore, while cromoglycate sodium is effective as a prophylactic antiallergic agent, it does not suppress the symptoms caused by the already released chemical transmitter, is inferior in terms of rapid action, and has been available for several weeks before the onset of symptoms. Had to be used. Furthermore, eye drops containing sodium cromoglycate have the drawback of causing eye pain when instilled, and are not satisfactory from the viewpoint of eye irritation.

  In order to impart rapid action to an antiallergic ophthalmic composition containing sodium cromoglycate, a preparation containing sodium cromoglycate and chlorpheniramine maleate, which is an antihistamine, has been proposed (Patent Document 1: Special). (Kaihei 4-9339). In practice, eye drops containing these are used for treatment. On the other hand, an antiallergic agent containing sodium cromoglycate and gyrometazoline which is a vasoconstrictor is also marketed overseas. Further, a preparation comprising an antihistamine and a vasoconstrictor combined with sodium cromoglycate (Patent Document 2: JP-A-6-336429), an eye drop containing an antiallergic agent, an antihistamine and glycyrrhizinate (Patent Document 3: Special) JP 2002-114686), an ophthalmic composition containing an antiallergic agent, an antihistamine, a vasoconstrictor, and a terpenoid (Patent Document 4: JP 2001-187728 A) has been proposed.

  Although the use of these preparations has improved the effects such as quick stagnation improvement effect and anti-hyperemia effect even if instilled after the onset of allergic symptoms, it is still not satisfactory. In particular, it is not satisfactory in terms of sustained effect, and there is a concern that eye drops may occur due to repeated administration and eye irritation due to overdose.

  In addition, as a measure for reducing eye irritation, a preparation containing sodium cromoglycate, an antihistamine, and menthol has been proposed (Patent Document 5: International Publication No. 98/13040 pamphlet), but the effect is satisfactory. It wasn't. As described above, an ophthalmic composition for allergic eye diseases that has a high symptom-improving effect and a long-lasting effect and has suppressed eye irritation has been desired.

Japanese Patent Laid-Open No. 4-9339 JP-A-6-336429 JP 2002-114686 A JP 2001-187728 A International Publication No. 98/13040 Pamphlet JP 2001-97861 A JP 2002-154989 A JP 2003-183157 A

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an ophthalmic composition for allergic eye diseases which is excellent in symptom improving effect and improvement sustaining effect for allergic eye diseases and has little irritation.

  As a result of diligent studies to achieve the above object, the present inventor further blends acidic mucopolysaccharides such as sodium chondroitin sulfate with an ophthalmic composition for allergic eye diseases containing cromoglycic acid and / or a salt thereof and an antihistamine. As a result, it has been found that an ophthalmic composition for allergy treatment can be obtained which has an allergic symptom improving effect, in particular, a long-lasting effect and less irritation, and has led to the present invention.

Therefore, the present invention
[1]. An ophthalmic composition for allergic eye diseases comprising cromoglycic acid and / or a salt thereof, an antihistamine and an acidic mucopolysaccharide;
[2]. The ophthalmic composition for allergic eye diseases according to [1], wherein the acidic mucopolysaccharide is one or more selected from chondroitin sulfate, chondroitin sulfate and heparin,
[3]. The ophthalmic composition for allergic eye disease according to [1] or [2], wherein the content of acidic mucopolysaccharide is 0.01 to 0.5 W / V% in the ophthalmic composition for allergic eye disease,
[4]. Furthermore, the ophthalmic composition for allergic eye diseases according to any one of [1] to [3], containing 0.01 to 2 W / V% of cellulose or a derivative thereof,
[5]. Furthermore, the ophthalmic composition for allergic eye diseases according to any one of [1] to [4], which contains one or more selected from boric acid, borate and trometamol.

  ADVANTAGE OF THE INVENTION According to this invention, the ophthalmic composition for allergy treatment which is excellent in the allergy symptom improvement effect, especially the sustainability of the effect, and there is little irritation can be obtained.

Hereinafter, the present invention will be described in more detail.
Examples of cromoglycic acid and / or a salt thereof used in the present invention include sodium cromoglycate and potassium cromoglycate, and these may be used alone or in combination of two or more. Of these, sodium cromoglycate is preferable.

  The lower limit of the content of cromoglycic acid and / or a salt thereof is preferably 0.1 W / V% (mass / volume%, the same applies hereinafter) or more, more preferably 0.5 W / V% in the ophthalmic composition for allergic eye diseases. That's it. The upper limit is preferably 5 W / V% or less, more preferably 3 W / V% or less. When the amount falls within this range, an ophthalmic composition having particularly excellent antiallergic action and low irritation to the eyes can be obtained.

  Examples of the antihistamine used in the present invention include chlorpheniramine maleate, diphenhydramine hydrochloride, clemastine fumarate, mequitazine, etc., but chlorpheniramine maleate and diphenhydramine hydrochloride are preferred and stable in terms of allergy improvement effect. More preferred is chlorpheniramine maleate, which is excellent in terms of properties. These can be used individually by 1 type or in combination of 2 or more types as appropriate.

  The lower limit of the content of the antihistamine is preferably 0.005 W / V% or more, more preferably 0.01 W / V% or more in the ophthalmic composition for allergic eye diseases. The upper limit is preferably 0.1 W / V% or less, more preferably 0.05 W / V% or less. Within this range, the onset of allergic symptoms such as itching of the eyes in particular is rapid and there is little irritation to the eyes.

  By blending acidic mucopolysaccharides in an ophthalmic composition for allergic eye diseases, an allergic ophthalmic composition for allergic treatment can be obtained which is excellent in allergic symptom improvement effect, in particular, the sustainability of the effect and less irritation. Examples of the acidic mucopolysaccharide used in the present invention include hyaluronic acid, chondroitin sulfate, chondroitin polysulfate, keratosulfuric acid, keratopolysulfuric acid, heparin, heparitin sulfate, teicuronic acid, and salts thereof. Or two or more can be used in appropriate combination. In the present invention, among these, particularly preferred acidic mucopolysaccharides include chondroitin sulfate, chondroitin sulfate and heparin.

  Examples of chondroitin sulfate and chondroitin sulfate used in the present invention include chondroitin sulfate and sodium chondroitin sulfate. Examples of commercially available products include sodium chondroitin sulfate “Biochemical” for injection manufactured by Seikagaku Corporation and external standard sodium chondroitin sulfate manufactured by Maruha Corporation.

  When chondroitin sulfate and chondroitin sulfate are blended, the lower limit of the content is preferably 0.01 W / V% or more, more preferably 0.02 W / V% or more in the ophthalmic composition for allergic eye diseases, Preferably it is 0.05 W / V% or more. The upper limit is preferably 1.0 W / V% or less, more preferably 0.5 W / V% or less, and particularly preferably 0.3 W / V% or less. When blending chondroitin sulfate and chondroitin sulfate, a particularly excellent feeling of use can be obtained by combining with chondroitin sulfate and cellulose or a derivative thereof described later.

  In addition to the above essential components, the ophthalmic composition of the present invention further includes one or two selected from cellulose or a derivative thereof, polyvinyl alcohol, and polyvinylpyrrolidone from the viewpoint of improving the retention of the drug in the ocular mucosa. It is preferable to blend more than one kind of water-soluble polymer compound, and cellulose or a derivative thereof is particularly preferable.

  The lower limit of the content of the water-soluble polymer compound (excluding chondroitin sulfate (salt)) is preferably 0.02 W / V% or more, more preferably 0.05 W / V% or more, and particularly preferably 0.1 W. / V% or more. The upper limit is preferably 20 W / V% or less, more preferably 10 W / V% or less.

Examples of cellulose or derivatives thereof include crystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and hydroxyethyl methyl cellulose. These can be used individually by 1 type or in combination of 2 or more types as appropriate. The molecular weight of preferable cellulose or a derivative thereof is 5 × 10 ⁴ or more, more preferably 5 × 10 ⁴ to 1 × 10 ⁶ , and 5 × 10 ^{4 to} 5 × 10 ⁵ . This molecular weight is a value obtained by measurement by gel permeation chromatographic analysis (GPC).

  When cellulose or a derivative thereof is blended, the content thereof is in the range of 0.01 to 2 W / V%, particularly preferably 0.05 to 1 W / V% in the ophthalmic composition for allergic eye diseases.

  The polyvinyl alcohol preferably has a saponification degree of 78 mol% or more, more preferably 78 to 96 mol%, particularly preferably 85 to 90 mol%. The molecular weight of polyvinyl alcohol is preferably 1 to 200,000, more preferably 2 to 150,000. This molecular weight is a value obtained by measurement by gel permeation chromatography (GPC).

  When mix | blending polyvinyl alcohol, 0.02 W / V% or more is preferable, as for the minimum of the content, More preferably, it is 0.05 W / V% or more, Most preferably, it is 0.1 W / V% or more. The upper limit is preferably 20 W / V% or less, more preferably 10 W / V% or less.

  In addition, the ophthalmic composition for allergic eye diseases of the present invention includes other drugs, buffers, pH adjusters, solubilizers, isotonic agents, stabilizers, cooling agents, preservatives as necessary. Etc. can be mix | blended in the range which does not impair the effect of this invention. Each of the various components can be used alone or in combination of two or more.

Other drugs include, for example, decongestants (naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate, etc.), anti-inflammatory / astringent agents (methyl sulfate) Neostigmine, allantoin, zinc sulfate, zinc lactate, lysozyme chloride, methyl salicylate, tranexamic acid, sodium azulenesulfonate, glycyrrhizic acid and / or its salt, glycyrrhetinic acid and / or its derivative, etc. Water-soluble vitamins (flavin adenine di) Nucleotide sodium, pyridoxine hydrochloride, cyanocobalamin), vitamins (vitamins A (for example, retinol acetate, retinol palmitate), vitamins E (tocopherol acetate ( Eg to acetic d-alpha-tocopherol), activated vitamin B _2, vitamin B _6, vitamin B _12), amino acids (potassium L- aspartate, magnesium L- aspartic acid, aminoethyl sulfonic acid, etc.), sulfa drugs, Bactericides (sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidine, isopropylmethylphenol, hinokitiol, sulfur, etc.), local anesthetics (lidocaine, lidocaine hydrochloride, procaine hydrochloride) , Dibucaine hydrochloride, etc.), terpenoid compounds and (menthol, camphor, borneol, geraniol, cineol, linalool).

  As an ophthalmic composition for allergic eye diseases, it is preferable to add a decongestant, an anti-inflammatory / astringent agent, a local anesthetic, and a terpenoid compound because a higher effect can be obtained. The effective amount of each of the other drugs can be appropriately blended, but is usually in the range of 0.001 to 5 W / V% in the ophthalmic composition for allergic eye diseases.

  Examples of the buffer include boric acid or a salt thereof (such as borax), citric acid or a salt thereof (such as sodium citrate), phosphoric acid or a salt thereof (such as sodium monohydrogen phosphate), tartaric acid or a salt thereof (tartaric acid) Sodium, etc.), acetic acid or a salt thereof (sodium acetate, etc.), carbonic acid or a salt thereof (sodium bicarbonate, etc.), ε-aminocaproic acid, trometamol, ethanolamine, or a combination thereof. Preferred buffering agents are boric acid or a salt thereof (such as borax), phosphoric acid or a salt thereof (such as sodium monohydrogen phosphate), ε-aminocaproic acid, or trometamol. Particularly preferably, boric acid or a salt thereof, trometamol is used. By combining boric acid (salt) and trometamol, the antiseptic effect of the composition is improved, and it is possible to reduce or eliminate the formulation of stimulating preservatives such as benzalkonium chloride. It is particularly useful as an agent.

  The lower limit of the content of the buffering agent is preferably 0.001 W / V% or more, more preferably 0.005 W / V% or more in the ophthalmic composition for allergic eye diseases. The upper limit is preferably 10 W / V% or less, more preferably 5 W / V% or less.

  Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, dilute hydrochloric acid and the like. The pH of the composition is preferably 4-9, more preferably 4.5-8.

  Examples of solubilizing agents include polyoxyethylene higher fatty acid esters such as polyoxyethylene (p = 60) hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters such as polyoxyethylene (p = 20) sorbitan monooleate, and the like. Is mentioned.

  The lower limit of the content of the solubilizing agent is preferably 0.001 W / V% or more in the ophthalmic composition for allergic eye diseases, and the upper limit is preferably 0.5 W / V% or less, more preferably 0.3 W / V%. It is as follows.

  Examples of the isotonic agent include sodium chloride and potassium chloride. The osmotic pressure is preferably 0.1 to 5 pressure ratio, more preferably 0.2 to 2 pressure ratio.

  Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, citric acid or a salt thereof, and dibutylhydroxytoluene.

  When sodium edetate is added, the content thereof is 0.001 to 0.5 W / V%, preferably 0.01 to 0.2 W / V% in the ophthalmic composition for allergic eye diseases. . Moreover, when mix | blending dibutylhydroxytoluene, the content is 0.001-0.1 W / V% in the ophthalmic composition for allergic eye diseases normally, Preferably it is 0.005-0.1 W / V%. It is a range.

  Examples of the refreshing agent include menthol, borneol, camphor, geraniol, limonene, eugenol, mint oil, eucalyptus oil, N-substituted-P-menthane-3-carboxamide and the like.

  Examples of the preservative include chlorobutanol, benzalkonium chloride, sodium dehydroacetate, cetylpyridinium chloride, phenethyl alcohol, paraoxybenzoates, benzethonium chloride and the like. A preservative is normally mix | blended in the range of 0.001-0.5 W / V% in the ophthalmic composition for allergic eye diseases. When allergic symptoms are serious, these may become irritation, so it is preferable to reduce the preservative as much as possible.

  The ophthalmic composition for allergic eye diseases of the present invention can be produced according to a conventional method. For example, when a water-soluble polymer compound is blended, it is first sufficiently dissolved in sterilized purified water to obtain a water-soluble polymer compound solution. Separately, each compounding component (including other components such as drugs) excluding a cationic substance such as benzalkonium chloride is dissolved in sterilized purified water, and mixed well with a water-soluble polymer compound solution. Then, after adding a cationic substance and adjusting the pH, a method of aseptic filtration and filling into an ophthalmic container (15 mL) made of polyethylene terephthalate can be mentioned.

  The usage amount and frequency of use of the ophthalmic composition for allergic eye diseases of the present invention are in accordance with a standard method.

  EXAMPLES Hereinafter, although an 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 16, Comparative Examples 1 and 2]
The ophthalmic compositions (eye drops) having the compositions shown in Tables 1 to 3 were prepared (blending amount: g / 100 mL), filled in containers, and then evaluated as follows. The results are shown in Tables 1-3.

[Evaluation of interaction of ophthalmic composition with mucin]
Two types of evaluation solutions were prepared: A solution in which the test solution was mixed with an equal amount of 3% by weight mucin solution, and B solution in which the test solution was mixed with an equal amount of water, and their viscosity behaviors were compared. The measurement was performed at 35 ° C. according to the environment in which the ophthalmic composition acts on the ocular mucosa (E-type viscometer: an appropriate rotation speed is selected from 10, 20, 50, and 100 rpm depending on the sample to be measured). The viscosity ratio of the A liquid to the B liquid was used as an index of specific interaction with the mucin, that is, the local thickening effect at the target biological site. A score was calculated according to the following criteria for the score value calculated by the following formula.
Score value = (viscosity of liquid A) / (viscosity of liquid B)
<Score standard>
5 points: Score value 2.00 or more 4 points: Score value 1.75 to less than 2.00 3 points: Score value 1.50 to less than 1.75 2 points: Score value 1.25 to 1.50 Less than 1 point: Score value less than 1.25

[Evaluation of the degree of improvement of itching, continuous evaluation of improvement of itching]
The composition for ophthalmology (eye drops) is a panel of 10 adult males with a history of allergies, and the degree of improvement in itch and the sustainability of the effects when each eye drop is instilled at the onset of allergy. Evaluation was performed according to the following evaluation criteria. About the improvement degree of itching, it shows by the average value of 10 panelists, and about the continuation of itching improvement shows the most evaluation in 10 panelists.
<Evaluation criteria for itch improvement at 1 minute after instillation>
5 points: Itching was greatly reduced 4 points: Itching was considerably reduced 3 points: Itching was slightly reduced 2 points: Itching did not change 1 point: Itching became severe

<Sustainability evaluation criteria for itching improvement>
◎: lasted for 60 minutes or more ○: lasted for 30 minutes or more and less than 60 minutes △: sustained for 10 minutes or more and less than 30 minutes ×: sustained for less than 10 minutes −: no improvement in itching or worsening

[Evaluation of irritation]
With regard to the ophthalmic composition (eye drops), 10 adult males with a history of allergy were used as panelists, and the irritation from immediately after instillation to 3 minutes later was evaluated according to the following evaluation criteria. The result shows the highest evaluation among 10 panelists.
<Irritation criteria>
◎: No sense of stimulation ○: Little sense of stimulation △: A sense of stimulation was felt ×: A strong sense of stimulation was felt

  From the results of the continuous evaluation of the degree of itch improvement in Table 1, it was confirmed that the composition of the present invention improves the mucosal retention of the drug. In addition, there was a correlation between the viscosity behavior by mixing with the mucin solution by the above evaluation method and the continuous evaluation of itch improvement. In the following examples, only the duration of improvement in itch is shown as a simple evaluation of retention.

The following are listed in the table.
Glycerin: JP / Dense Glycerin
HPMC 60SH-50: Hydroxypropyl methylcellulose Metrows 65SH-50 (manufactured by Shin-Etsu Chemical Co., Ltd.)
HPMC 60SH-4000: Hydroxypropyl methylcellulose Metrolose 60SH-4000 (manufactured by Shin-Etsu Chemical Co., Ltd.)
HEC CF-W: Hydroxyethyl cellulose
MC SM-15: Methylcellulose Metroz SM-15 (manufactured by Shin-Etsu Chemical Co., Ltd.)
MC SM-25: Methyl cellulose Metros SM-25 (manufactured by Shin-Etsu Chemical Co., Ltd.)
PVA Gohsenol EG-05: Polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.)
PVP Kollidon 90F: Polyvinylpyrrolidone (manufactured by BASF Corporation)

Claims (5)

  An ophthalmic composition for allergic eye diseases comprising cromoglycic acid and / or a salt thereof, an antihistamine, and an acidic mucopolysaccharide.   The ophthalmic composition for allergic eye diseases according to claim 1, wherein the acidic mucopolysaccharide is one or more selected from chondroitin sulfate, chondroitin sulfate and heparin.   The ophthalmic composition for allergic eye diseases according to claim 1 or 2, wherein the content of the acidic mucopolysaccharide is 0.01 to 0.5 W / V% in the ophthalmic composition for allergic eye diseases.   The ophthalmic composition for allergic eye diseases according to any one of claims 1 to 3, further comprising 0.01 to 2 W / V% of cellulose or a derivative thereof. Furthermore, the ophthalmic composition for allergic eye diseases of any one of Claims 1-4 containing 1 type, or 2 or more types chosen from boric acid, a borate, and trometamol.