JP2008110981A - Ophthalmic preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sodium cromoglycate ophthalmic preparation exhibiting a prompt and enhanced antipruritic effect, with eye-ache and unpleasant irritating being alleviated. <P>SOLUTION: The ophthalmic preparation contains menthol together with sodium cromoglycate and an antihistaminic whereby unpleasant irritating eye-ache induced by the sodium cromoglycate at the time of instillation can be alleviated and further, a prompt antipruritic effect of the antihistaminic is enhanced to strongly suppress itchiness of eyes immediately after instillation. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an ophthalmic solution containing sodium cromoglycate, an antihistamine, and menthol, having no unpleasant irritation at the time of instillation and having a rapid and powerful antipruritic effect immediately after instillation.

  It is known that a typical allergic mechanism is caused by the following steps. That is, for a living body, an antigen that is a foreign substance enters the living body. When exposed to this antigen, the organism produces IgE antibodies against that antigen. The produced IgE adheres to the surface of mast cells and becomes IgE-binding mast cells. When an antigen invades into the living body where IgE-binding mast cells are formed again, an antigen-antibody reaction occurs on the surface of IgE-binding mast cells. As a result, degranulation of IgE-binding mast cells causes various chemical mediators such as histamine and leukotriene to be produced. Liberate. And allergic reaction arises by the effect | action of this chemical transmitter.

  Several drugs have been developed to suppress such allergic reactions. For example, sodium cromoglycate is an antiallergic agent that suppresses degranulation of mast cells and suppresses the release of chemical mediators such as histamine. As an excellent preventive antiallergic agent, it is clinically used as an inhalant, nasal drop, eye drop, and internal use, and in particular in the ophthalmic field, it is used as an eye drop for diseases such as allergic conjunctivitis and spring catarrh in Japan. It has been. However, since cromoglycate sodium has a mechanism of action that suppresses degranulation of mast cells, it has no effect of blocking the already released chemical transmitter, is inferior in terms of rapid action, and is 4 weeks after the onset of symptoms. It was necessary to start administration as early as possible. Furthermore, sodium cromoglycate eye drops have the disadvantage of causing eye pain (irritating pain) upon instillation (Allergy Immunological and Clinical Aspects, A Wiley Medical Publication and JP-A-61-246117). It was not satisfactory from the aspect.

  For this reason, a combination eye drop comprising an antiallergic eye drop containing sodium cromoglycate and an antihistamine that blocks released histamine in order to add a fast-acting effect has been developed. For example, in Japan, a combination ophthalmic solution of sodium cromoglycate 1.0% and an antihistamine chlorpheniramine maleate 0.015% has been clinically tested (medicine and pharmacy 34 (3) 507, 1995). Overseas, a combination of sodium cromoglycate and chlorpheniramine maleate, an antihistamine, is used (MARTINDALE The Extra Pharmacopoeia 30th Edition, The Pharmaceutical Press, 1993). In these eye drops containing sodium cromoglycate and an antihistamine, a fast-acting antipruritic effect can be obtained by adding an antihistamine to the eye drops after allergic symptoms have occurred. However, since the antipruritic effect is weak, it has not been possible to prevent the patient from crushing the eyes due to severe itching and causing inflammation of the ocular mucosa. Furthermore, since no consideration has been given to reducing eye irritation, patients have to withstand pain during use.

JP-A-61-246117 discloses that sodium cromoglycate is dissolved in a solvent containing sodium bicarbonate and boric acid to adjust the pH to neutrality in order to improve ocular pain at the time of instillation of the antiallergic eye drops. Is preferred.
However, the method disclosed in Japanese Patent Application Laid-Open No. 61-246117 has not been able to obtain a sodium cromoglycate eye drop having an antiallergic effect excellent in preventive and rapid action. Moreover, when the present inventors actually prescribed and instilled and made a follow-up examination, the eye irritation of the sodium cromoglycate eye drop was not sufficiently reduced.

  On the other hand, a fragrance mainly composed of menthol is often blended as a cooling agent in eye drops. For example, the literature (Research Disclosure 31997) discloses that patient compliance is improved by adding a fragrance to a sodium cromoglycate solution. EP 670161 also includes 0.1-10% sodium cromoglycate, 0.005-0.2% bicyclic fragrance (camphor, eucalyptus oil, or mixtures thereof), And a pharmaceutical composition comprising an aqueous base is disclosed.

  However, an eye drop containing three elements of sodium cromoglycate, an antihistamine and menthol has not been developed so far.

  An object of the present invention is to provide a sodium cromoglycate ophthalmic solution that exhibits a rapid antipruritic effect and has improved eye pain and unpleasant irritation.

  Since the present inventors have a problem that the conventional sodium cromoglycate eye drops cause eye pain at the time of instillation, in order to find a component capable of reducing eye pain at the time of eye drops, the present inventors have earnestly I did research. As a result, the present inventors have found that menthol, which has been often used in eye drops as a refreshing agent, can reduce irritation and unpleasant eye pain that occurs when instilling sodium cromoglycate.

  In addition, the present inventors have found that a conventional ophthalmic solution composed of sodium cromoglycate and an antihistamine can obtain rapid action, but because the antipruritic effect is weak, itching does not stop immediately, and patients suffer from severe eye itchiness. We also focused on the problem of crushing the eyes and worsening the ocular mucosa. And earnestly researched about the composition of eye drops that brings about a powerful antipruritic effect immediately after instillation. As a result, the present inventors have found that menthol blended with the eye drop of the present invention not only reduces eye pain, but also further enhances the rapid antipruritic effect of the antihistamine, thereby causing severe eye itchiness immediately after the eye drop. It was found that it can be strongly suppressed.

  Further, the present invention has been completed by finding that it brings about an effect of habitually instilling the patient in combination with the refreshing feeling of the menthol and the effect of reducing the patient's refreshing feeling and eye pain at the time of instillation.

That is, the present invention
(1) an eye drop comprising sodium cromoglycate, an antihistamine, and menthol,
(2) The eye drop according to (1), wherein the antihistamine is chlorpheniramine maleate or diphenhydramine hydrochloride,
About.

  According to the present invention, an eye drop containing sodium cromoglycate, an antihistamine, and menthol was provided. If the eye drop of the present invention is used, it is possible to strongly suppress severe eye itching immediately after instillation by the enhanced antipruritic effect, and as a result, it is possible to prevent deterioration of the ocular mucosa due to the patient's crushing. It is. At the same time, it is possible to reduce eye pain, which is an unpleasant stimulus of sodium cromoglycate eye drops. Furthermore, the refreshing sensation of menthol improves the patient's feeling of use and can quickly remove various discomforts that are symptoms of ocular allergies from the patient, thus reducing eye pain during instillation. It is also possible to make the patient's eye drops habitual.

  The menthol used in the present invention is described in the literature (13th revised Japanese Pharmacopeia, D1050-1058), and a commercially available product can also be used. The menthol of the present invention may be either l-form or dl-form, and essential oil containing menthol such as peppermint oil is also included in the menthol of the present invention.

  Examples of the antihistamine used in the present invention include chlorpheniramine maleate, diphenhydramine hydrochloride, clemastine fumarate, and mequitazine, but chlorpheniramine maleate and diphenhydramine hydrochloride, which are superior in terms of safety and effect, are available. Chlorpheniramine maleate, which is preferable in terms of stability, is most preferable.

  A commercially available product can be used as the sodium cromoglycate used in the present invention. The content of sodium cromoglycate in the eye drop is usually 0.5 to 5% (w / v). Moreover, although the content of the antihistamine mix | blended changes also with the kind, it is 0.005-0.1% normally, Preferably it is 0.01-0.05%. Moreover, the content of menthol to be blended is usually 0.001 to 0.1%, preferably 0.002 to 0.05%.

  The pH of the eye drop of the present invention is not particularly limited as long as it is ophthalmically acceptable, and is usually adjusted to about 4.0 to 7.0 by a conventional method, but 4.5 to 6.0. It is more preferable to prepare it. The osmotic pressure of the eye drop of the present invention is usually adjusted to 0.5 to 5 pressure ratio by a conventional method, but more preferably 0.8 to 2 pressure ratio.

  As long as the subject of the present invention is solved, the eye drop of the present invention further includes various agents such as a buffer, an isotonic agent, a solubilizing agent, a preservative, a thickener, a chelating agent, and a pH adjuster. Additives may be added.

  Examples of the preservative to be added include chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, paraoxybenzoates, benzethonium chloride, and the like. Examples of the buffer include a borate buffer, a phosphate buffer, a carbonate buffer, and an acetate buffer. Examples of the thickener include methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, chondroitin sulfate, and salts thereof. Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate and the like. Examples of the chelating agent include sodium edetate and citric acid. Examples of the stabilizer include sodium edetate and sodium bisulfite. Furthermore, examples of the pH adjuster include sodium hydroxide, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid, acetic acid, hydrochloric acid and the like.

  The usage and dosage of the eye drop of the present invention varies depending on the patient's symptoms, age, etc., but usually 1 to 6 times a day, and 1 to 2 drops are instilled per time.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to this.
[Example 1] Eye drops
1000ml sodium cromoglycate in 100ml
Chlorpheniramine maleate 15mg
1-menthol 6mg
Benzalkonium chloride 2mg
Borax 10mg
Boric acid 1800mg
Sterilized purified water
Total volume 100ml
Sterile purified water is added to make the total volume 100 ml, and an eye drop is obtained by a conventional method.

[Example 2] Eye drops
1000ml sodium cromoglycate in 100ml
Diphenhydramine hydrochloride 20mg
1-menthol 6mg
Benzalkonium chloride 2mg
Borax 10mg
Boric acid 1800mg
Sterilized purified water
Total volume 100ml
Sterile purified water is added to make the total volume 100 ml, and an eye drop is obtained by a conventional method.

[Test Example] Effects of menthol in eye drops The eye drops of Example 1 and eye drops lacking l-menthol from Example 1 were prepared. The subjects were 10 adult men and women with a history of allergies. When an allergic symptom (itching) of the eye occurred, one ophthalmic solution lacking l-menthol in the left eye and one ophthalmic solution containing l-menthol in the right eye. ˜2 drops were instilled, and the degree of itching was self-determined before instillation (after 0 seconds) and at a specific time after instillation, and the change from the itching score before instillation was measured over time. FIG. 1 shows an average value of 10 subjects of “values subtracted from the itch score before instillation from the itch score at each time”. Table 1 shows judgment criteria for itch. At the same time, both preparations were compared in terms of eye irritation at the time of instillation.

  As a result, it was confirmed that the preparation of the present invention containing l-menthol strongly suppressed itching immediately after instillation compared to the control (FIG. 1). Regarding eye irritation, it was determined that 8 out of 10 had unpleasant eye pain after instilling the control, but the preparation of the present invention did not feel pain.

  In addition, when the same experiment was performed using 20 mg of diphenhydramine hydrochloride instead of 15 mg of chlorpheniramine maleate as an antihistamine, the same result as that obtained when chlorpheniramine maleate was used was obtained.

FIG. 1 is a diagram showing the effect of suppressing itching in the eye of the eye drop of the present invention.

Claims (8)

An eye drop comprising sodium cromoglycate, an antihistamine, and menthol. The eye drop according to claim 1, wherein the antihistamine is chlorpheniramine maleate or diphenhydramine hydrochloride. The eye drop according to any one of claims 1 to 2, wherein the content of sodium cromoglycate is 0.5 to 5%. An eye drop comprising sodium cromoglycate, an antihistamine, and menthol, wherein the content of sodium cromoglycate is 1%. A method for enhancing the antipruritic effect of an eye drop by adding menthol to an eye drop containing sodium cromoglycate and an antihistamine. A method for reducing the eye pain action of an eye drop by adding menthol to an eye drop containing sodium cromoglycate. The eye drop according to claim 1, wherein the antipruritic effect is enhanced. The eye drop according to claim 1, wherein the eye pain action is reduced.

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