Application of ipratropium bromide in preventing and improving myopia and eye drops containing ipratropium bromide

Abstract

The invention belongs to the technical field of medicine. The invention relates to the field of eye drops, in particular to application of ipratropium bromide in the aspect of preventing or improving myopia and eye drops containing ipratropium bromide. The research proves that the single drug of the ipratropium bromide can effectively inhibit the growth of the ocular axis and the deterioration of the diopter, and the brand new medicinal value of the ipratropium bromide in the aspect of preventing and improving the myopia is disclosed for the first time. More importantly, the invention finds that the combination of the ipratropium bromide and the diquafosol sodium can generate a remarkable synergistic effect, and the curative effect of the combined preparation is far better than that of a single drug and even better than that of a clinical drug atropine. The invention provides a safe, effective and long-term brand new drug choice for myopia prevention and control, and has good application prospect and value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine. More particularly, it relates to the application of ipratropium bromide in preventing and improving myopia and an eye drop containing ipratropium bromide. BACKGROUND

[0002] Myopia is a common eye disease. When the eye is in a relaxed state of accommodation, parallel light enters the eye and is focused in front of the retina, resulting in no clear image on the retina. In recent years, the incidence of myopia in China has shown an upward trend, and myopia in children and adolescents has shown a high incidence and a trend of younger age. High myopia also increases the risk of potential blinding eye diseases, such as glaucoma, cataract, retinal detachment and scleral posterior staphyloma.

[0003] There are not many drugs that can be used clinically to prevent and treat myopia. Atropine, a common drug in China, is a type of acetylcholine M receptor blocker that can slow the progression of myopia in children. However, as a cycloplegic and mydriatic drug, atropine can cause photophobia, blurred near vision, loss of accommodation and excessive pupil dilation, resulting in inconvenience in life, and the effect varies greatly among individuals.

[0004] Therefore, it is necessary to continuously explore and seek new drugs for preventing and treating myopia. SUMMARY

[0005] The present application aims to provide new drugs for preventing and treating myopia. Research shows that ipratropium bromide has value in preventing and treating myopia, and in particular, ipratropium bromide combined with dorzolamide sodium produces a significant synergistic effect in preventing and treating myopia.

[0006] The first object of the present application is to provide the use of ipratropium bromide as the only active ingredient in the preparation of a drug for preventing or improving myopia.

[0007] The second object of the present application is to provide the use of a combination of ipratropium bromide and dorzolamide sodium in the preparation of a drug for preventing or improving myopia.

[0008] The third object of the present application is to provide a composition and its use.

[0009] The fourth object of the present application is to provide a drug for preventing and improving myopia.

[0010] The fifth object of the present application is to provide an eye drop.

[0011] The above objects of the present application are achieved by the following technical solutions: Research shows that ipratropium bromide alone can effectively inhibit the growth of the eye axis and the deterioration of the refractive power. Therefore, the present application provides the use of ipratropium bromide as the only active ingredient in the preparation of a drug for preventing or improving myopia.

[0012] Further experimental results of the present application also show that ipratropium bromide and dorzolamide sodium used in combination can produce significant synergistic effect, and the combination preparation is not only far superior to single drug in myopia prevention and control, but also superior to atropine, therefore the present application also claims the following scheme: The present application provides use of ipratropium bromide and dorzolamide sodium in combination in preparation of a drug for preventing or improving myopia.

[0013] The present application provides a composition comprising ipratropium bromide and dorzolamide sodium.

[0014] As an alternative embodiment, in the composition, the mass ratio of ipratropium bromide and dorzolamide sodium is 1: (50-150).

[0015] Preferably, in the composition, the mass ratio of ipratropium bromide and dorzolamide sodium is 1: (80-120).

[0016] More preferably, in the composition, the mass ratio of ipratropium bromide and dorzolamide sodium is 1:100.

[0017] The use of the above-mentioned composition as an active ingredient in the preparation of a drug for preventing or improving myopia should also be within the protection scope of the present application.

[0018] The present application provides a drug for preventing or improving myopia, which comprises the above-mentioned composition as an active ingredient.

[0019] The present application provides an eye drop comprising the above-mentioned composition.

[0020] Specifically, the drug for preventing or improving myopia and the eye drop further comprise excipients required for eye drops.

[0021] Further, in the drug for preventing or improving myopia, such as eye drops, provided by the present application and containing ipratropium bromide and dorzolamide sodium, the mass concentration of ipratropium bromide is 0.005-0.015%, and the mass concentration of dorzolamide sodium is 0.5-1.5%. More preferably, the mass concentration of ipratropium bromide is 0.008-0.012%, and the mass concentration of dorzolamide sodium is 0.8-1.2%.

[0022] More preferably, the mass concentration of ipratropium bromide is 0.01%, and the mass concentration of dorzolamide sodium is 1%.

[0023] As an alternative embodiment, the excipients required for eye drops comprise any one or several of thickening agents, buffering agents, osmotic pressure adjusting agents, and bacteriostatic agents.

[0024] Optionally, the thickener is any one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinyl alcohol, polyacrylic acid, sodium hyaluronate, and sodium alginate.

[0025] Optionally, the buffer is any one or more of borate, citrate, and phosphate.

[0026] Optionally, the osmotic pressure regulator is any one or more of sodium chloride, potassium chloride, boric acid, glucose, and borax.

[0027] Optionally, the antibacterial agent is any one or more of potassium sorbate, benzalkonium bromide, and benzalkonium chloride.

[0028] As an alternative implementation, the above-mentioned eye drops contain the following components in parts by weight: ipratropium bromide 0.005~0.015 parts, diquafosol sodium 0.5~1.5 parts, thickener 0.5~1.5 parts, buffer 0.2~1 parts, osmotic pressure regulator 0.5~1.5 parts, antibacterial agent 0.01~0.05 parts, and water 90~110 parts.

[0029] As an alternative implementation, the above-mentioned eye drops contain the following components in parts by weight: ipratropium bromide 0.005~0.015 parts, diquafosol sodium 0.5~1.5 parts, hydroxypropyl methylcellulose 0.5~1.5 parts, disodium hydrogen phosphate 0.1~0.5 parts, sodium dihydrogen phosphate 0.1~0.5 parts, sodium chloride 0.5~1.5 parts, benzalkonium chloride 0.01~0.05 parts, and water 90~110 parts.

[0030] As an alternative implementation, the above-mentioned eye drops contain the following components in parts by weight: 0.01 parts ipratropium bromide, 1 part diquafosol sodium, 1 part hydroxypropyl methylcellulose, 0.35 parts disodium hydrogen phosphate, 0.15 parts sodium dihydrogen phosphate, 0.75 parts sodium chloride, 0.02 parts benzalkonium chloride, and 100 parts water.

[0031] As an alternative implementation, the above-mentioned eye drops are prepared by heating water to 40-50°C, adding antibacterial agents and buffers to dissolve them, then adding thickeners, ipratropium bromide, diquafosol sodium and osmotic pressure regulators and stirring until homogeneous. The pH value is adjusted to 6-8, and the eye drops are obtained by filtration.

[0032] The pH value of the eye drops is 6-8.

[0033] The present invention has the following beneficial effects: The results of this invention show that ipratropium bromide alone can effectively inhibit axial elongation and refractive error deterioration, with efficacy comparable to atropine in clinical use. More importantly, this invention discovers that the combination of ipratropium bromide and diquafosol sodium produces a significant synergistic effect. This combined formulation is not only far more effective than either drug alone in myopia control, but even surpasses atropine, providing a more effective and innovative solution for myopia control.

[0034] This invention reveals for the first time the novel pharmaceutical value of ipratropium bromide in preventing and improving myopia, breaking through the limitations of its understanding as a traditional respiratory medication. This invention provides a safe, effective, and long-term usable new drug option for myopia control, with excellent application prospects and value. Attached Figure Description

[0035] Figure 1 The results of measuring changes in axial length and refractive error in mice under different treatments in Experiment Example 1 are shown in Figure A (results of refractive error change; Figure B (results of axial length change)).

[0036] Figure 2 The results of measuring changes in axial length and refractive error in mice under different treatments in Experiment Example 2 are shown in Figure A (results of refractive error change; Figure B (results of axial length change)).

[0037] Figure 3 The results of measuring changes in axial length and refractive error in mice under different treatments in Experiment Example 3 are shown in Figure A (results of refractive error change; Figure B (results of axial length change)). Detailed Implementation

[0038] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0039] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0040] Ipratropium bromide, CAS No.: 22254-24-6, structural formula: .

[0041] Diquaphosphonosodium, CAS No.: 211427-08-6, structural formula: .

[0042] In the following examples, dilute hydrochloric acid or sodium hydroxide solution was used to adjust the pH value.

[0043] Placebo eye drops (NS): A buffer solution without active ingredients (containing 0.35 g disodium hydrogen phosphate, 0.15 g sodium dihydrogen phosphate, 0.75 g sodium chloride, 1 g hydroxypropyl methylcellulose, diluted with water for injection to 100 mL).

[0044] Example 1: An eye drop containing ipratropium bromide An eye drop (denoted as eye drop A) has the following composition: 0.01g of ipratropium bromide added to a placebo eye drop.

[0045] Example 2: An eye drop containing ipratropium bromide An eye drop (denoted as eye drop B) has the following composition: 1g of diquafosol sodium added to a placebo eye drop.

[0046] Example 3: An eye drop containing ipratropium bromide An eye drop (denoted as eye drop C) has the following composition: 1g of diquarfossol sodium is added to the base of eye drop A.

[0047] Comparative Example 1: An eye drop containing ipratropium bromide An eye drop (denoted as eye drop D) consists of: 0.01g of atropine added to a placebo eye drop (as a positive control).

[0048] Comparative Example 2: An eye drop containing ipratropium bromide An eye drop (denoted as eye drop E) has the following composition: 1g of diquarfossol sodium added to the base of eye drop D.

[0049] Comparative Example 3 An eye drop (denoted as eye drop F) has the following composition: 0.01g of adecyl bromide added to a placebo eye drop.

[0050] Comparative Example 4 An eye drop (denoted as eye drop G) has the following composition: 0.01g of solifenacin added to a placebo eye drop.

[0051] Comparative Example 5 An eye drop (denoted as eye drop H) has the following composition: 0.01g of oxybutynin added to a placebo eye drop.

[0052] Example 1: Pharmacodynamic evaluation of ipratropium bromide alone and in combination in a myopic mouse model. I. Experimental Methods 1. Construction of Form Deprivation Myopia Model (FDM) Three-week-old healthy C57BL / 6 mice (half male and half female) were selected. In the experimental group (n=6), the right eye of each mouse was completely covered with a specially designed opaque black eye patch to establish a form deprivation myopia (FD) model, with the left eye serving as a self-control. The blank control group (BC group, n=6) wore only a collar and did not have their eyes covered. All mice were housed in a 12-hour light / 12-hour dark environment with free access to water and food. To prevent scratching and subsequent eye patch removal, all mice wore ring-shaped plastic collars. The model was maintained for one week, during which the eye patch wearing was checked regularly to ensure stable coverage.

[0053] 2. Selection of eye drops Placebo eye drops (NS), eye drops A, eye drops B, eye drops C, eye drops D (as a positive control), eye drops E, eye drops F, eye drops G, and eye drops H.

[0054] All eye drops were prepared under sterile conditions, pH adjusted to 6.5, and stored at 4°C protected from light.

[0055] 3. Dosing regimen and grouping The model mice were randomly divided into 9 treatment groups, with 6 mice in each group, and were treated with the drug for 1 week. The specific groupings are as follows: Model group: The model mice were given 10 μL of placebo eye drops twice a day, morning and evening.

[0056] Blank control group: Mice in the blank control group were given 10 μL of placebo eye drops twice a day, morning and evening.

[0057] Group A: The model mice were given 10 μL of eye drops A twice a day, once in the morning and once in the evening.

[0058] Group B: The model mice were given 10 μL of eye drops B twice a day, once in the morning and once in the evening.

[0059] Group C: The model mice were given 10 μL of eye drops C twice a day, once in the morning and once in the evening.

[0060] Group D: The model mice were given 10 μL of eye drops D twice a day, once in the morning and once in the evening.

[0061] Group E: The model mice were given 10 μL of eye drops E twice a day, once in the morning and once in the evening.

[0062] Group F: The model mice were given 10 μL of eye drops F twice a day, once in the morning and once in the evening.

[0063] Group G: The model mice were given 10 μL of eye drops G twice a day, once in the morning and once in the evening.

[0064] Group H: The model mice were given 10 μL of eye drops H twice a day, once in the morning and once in the evening.

[0065] 4. Detection indicators Before administration (4 weeks of age) and at the end of administration (5 weeks of age), the refractive power of both eyes of the mice was measured using an infrared autorefractor, and the axial length of both eyes was measured using an optical coherence tomography (OCT) scanner. To ensure sufficient pupil dilation for easy detection, the refractive measurements were performed in a dark room.

[0066] The formula for calculating the axial length increase in mice is: the difference in cumulative axial length increase between the two eyes = (right eye axial length - left eye axial length) at the end of administration - (right eye axial length - left eye axial length) before administration.

[0067] The formula for calculating the change in refractive power in mice is: the difference in refractive power between the two eyes = (right eye refractive power - left eye refractive power) at the end of administration - (right eye refractive power - left eye refractive power) before administration.

[0068] II. Experimental Results The experimental results for each group are shown in Table 1 and Figure 1 As shown, the results indicated that the axial length of the model group mice significantly increased and the refractive error significantly decreased, indicating that the FDM myopia model was successfully established. Compared with the model group, the refractive error of group A was significantly restored, indicating that ipratropium bromide treatment has a controlling effect on myopia. However, treatment in group B did not reduce the refractive error, indicating that diquafosol sodium alone has no significant intervention effect on the progression of myopia in FDM model mice.

[0069] Notably, group C (ipratropium bromide combined with diquarfossol sodium) exhibited the best therapeutic effect, with the smallest axial elongation and the slightest change in refractive error. Its efficacy was significantly superior to other treatment groups, even surpassing the positive control group D (0.01% atropine). This result demonstrates that the combined use of ipratropium bromide and diquarfossol sodium produces a significant synergistic effect, more effectively inhibiting myopia progression, indicating that this combination has significant application value in myopia prevention and control.

[0070] The group E (atropine combined with diquafosol sodium) showed no significant difference from the group D, indicating that the combination of atropine and diquafosol sodium could not enhance the efficacy.

[0071] Furthermore, we compared various muscarinic receptor antagonists. The adecanoate (F) group, solifenacin (G) group, and oxybutynin (H) group showed no statistically significant differences in any indicators compared to the model group (P>0.05), indicating that adecanoate, solifenacin, and oxybutynin have limited regulatory effects on myopia progression. This suggests that not all muscarinic receptor antagonists possess pharmacological activity to inhibit myopia progression, and their effects may exhibit drug specificity.

[0072] Table 1. Effects of different treatment groups on axial elongation and refractive error in mice (n=6, mean ± standard error)

[0073] Note: Different lowercase letters in the table indicate significant differences. P <0.05) Experimental Example 2: Pharmacodynamic Evaluation of Ipratropium Bromide Alone and in Combinations in the Prevention of Myopia I. Experimental Methods 1. Selection of medicated eye drops The following eye drops were used in this experiment: placebo eye drops (NS), eye drops A, eye drops B, eye drops C, eye drops D (as a positive control), eye drops E, eye drops F, eye drops G, and eye drops H.

[0074] All eye drops were prepared under sterile conditions, pH adjusted to 6.5, and stored at 4°C protected from light.

[0075] 2. Dosing regimen and grouping A myopia model was constructed following the method described in Example 1. Three-week-old healthy male C57BL / 6 mice were selected and divided into nine treatment groups and one control group (n=6 in each group). In the treatment groups, mice had their right eye completely covered by a specially designed opaque black eye patch to establish a form-deprivation myopia (FD) model. During the modeling period, mice were given 10 μL of the corresponding eye drops (eye drops A–H or placebo) twice daily, morning and evening, and the eye patch was immediately reapplied after each application. The model was maintained for one week, with regular checks to ensure stable coverage.

[0076] The specific groups are as follows: Model group: The model mice were given 10 μL of placebo eye drops twice a day, morning and evening.

[0077] Blank control group: Mice in the blank control group were given 10 μL of placebo eye drops twice a day, morning and evening.

[0078] Group A: The model mice were given 10 μL of eye drops A twice a day, once in the morning and once in the evening.

[0079] Group B: The model mice were given 10 μL of eye drops B twice a day, once in the morning and once in the evening.

[0080] Group C: The model mice were given 10 μL of eye drops C twice a day, once in the morning and once in the evening.

[0081] Group d: The model mice were given 10 μL of eye drops D twice a day, once in the morning and once in the evening.

[0082] Group e: The model mice were given 10 μL of eye drops E twice a day, once in the morning and once in the evening.

[0083] Group F: The model mice were given 10 μL of eye drops F twice a day, once in the morning and once in the evening.

[0084] Group G: The model mice were given 10 μL of eye drops G twice a day, once in the morning and once in the evening.

[0085] Group H: The model mice were given 10 μL of eye drops H twice a day, once in the morning and once in the evening.

[0086] 3. Detection indicators Before and after modeling, the refractive power of both eyes of the mice was measured using an infrared autorefractor, and the axial length of both eyes was measured using an optical coherence tomography (OCT) scanner. To ensure sufficient pupil dilation for easy detection, refractive measurements were performed in a dark room. The formulas for calculating mouse axial length growth and mouse refractive power change are provided in Experimental Example 1.

[0087] II. Experimental Results The experimental results are shown in Table 2 and Figure 2 As shown, the results indicate that eye drops A significantly inhibited axial elongation and refractive shift, with better efficacy than most control drugs, suggesting that ipratropium bromide has a clear effect in preventing myopia, and its effect is superior to the positive control atropine. Eye drops C exhibited the strongest efficacy, significantly better than eye drops A and the positive control, and was the best among all treatment groups, suggesting that ipratropium bromide and diquafosol sodium have a significant synergistic effect. Eye drops F, G, and H failed to effectively prevent myopia progression, indicating that not all muscarinic M3 receptor antagonists have a myopia-preventing effect, and their efficacy may be related to receptor subtype selectivity, corneal penetration, or intraocular distribution.

[0088] In summary, ipratropium bromide alone can effectively inhibit the development of form deprivation myopia, and its effect is better than that of 0.01% atropine; diquafosol sodium alone has no significant anti-myopia effect, but its efficacy is significantly enhanced when used in combination with ipratropium bromide, suggesting a synergistic mechanism; eye drops C (ipratropium bromide + diquafosol sodium) is the optimal combination, showing the most outstanding performance in controlling axial elongation and refractive changes, and has good development prospects.

[0089] Table 2 Effects of different treatment groups on axial elongation and refractive error in mice (n=6, mean ± standard error)

[0090] Note: Different lowercase letters in the table indicate significant differences. P <0.05) Experimental Example 3: Investigation into the Dosage of Ipratropium Bromide and its Combinations This experiment prepared six types of eye drops containing ipratropium bromide (groups I to N) and systematically investigated the intervention effect of ipratropium bromide at a fixed dose (0.01%) combined with different concentrations of diquafosol sodium on myopia progression, in order to determine the optimal ratio of the two for synergistic effect.

[0091] I. Animal Model Construction A form deprivation myopia (FDM) model mouse and a blank control group mouse were constructed according to the method in Experiment Example 1.

[0092] II. Preparation of Eye Drops All eye drops were prepared under sterile conditions, with the final pH adjusted to 6.5, and stored at 4°C protected from light. The specific formula is as follows (per 100 g): Eye Drops I: Ipratropium bromide 0.01 g, hydroxypropyl methylcellulose 1 g, disodium hydrogen phosphate 0.35 g, sodium dihydrogen phosphate 0.15 g, sodium chloride 0.75 g, benzalkonium chloride 0.02 g, with water for injection to a final volume of 100 g.

[0093] Eye Drops J: Ipratropium bromide 0.01 g, diquafosol sodium 0.01 g, hydroxypropyl methylcellulose 1 g, disodium hydrogen phosphate 0.35 g, sodium dihydrogen phosphate 0.15 g, sodium chloride 0.75 g, benzalkonium chloride 0.02 g, with water for injection to a final volume of 100 g.

[0094] Eye Drops K: The dosage of diquafosol sodium is 0.1 g, and the other components are the same as those in Eye Drops J.

[0095] Eye Drops L: The dosage of diquafosol sodium is 0.5 g, and the other components are the same as those in Eye Drops J.

[0096] Eye drops M: The dosage of diquafosol sodium is 1 g, and the other components are the same as those in eye drops J.

[0097] Eye Drops N: The dosage of diquafosol sodium is 1.5 g, and the other components are the same as those in Eye Drops J.

[0098] 2. Preparation method Take water for injection, heat it to 40-50℃, add benzalkonium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate and stir to dissolve. Then, under stirring, slowly add hydroxypropyl methylcellulose, then add ipratropium bromide, diquafosol sodium (not added to eye drops I) and sodium chloride and stir until completely dissolved. Adjust the pH to 6.5, and finally add water for injection to make up to 100 mL. Stir thoroughly to mix evenly and filter to obtain eye drops.

[0099] III. Grouping and Dosing Regimen FDM model mice were randomly divided into 6 treatment groups, designated as group I, group J, group K, group L, group M, and group N, and were given the corresponding eye drops, 10 μL per eye twice daily (morning and evening), for 7 consecutive days. The model group and the blank control group were given an equal volume of placebo eye drops.

[0100] IV. Detection Indicators Before administration (4 weeks old) and at the end of administration (5 weeks old), the refractive power of each group of mice was measured using an infrared autorefractor, and the axial length of each eye was measured using an optical coherence tomography (OCT) scanner. The calculation methods for axial length increase and refractive power change were the same as in Experiment 1.

[0101] V. Experimental Results The experimental results for each group are shown in Table 3 and Figure 3 As shown in the figure, the right eye of the model group mice showed significant axial elongation and a negative refractive error shift, indicating that the FDM model was successfully established. Compared with the model group, the axial elongation of group I (containing only ipratropium bromide) was significantly slowed, confirming that ipratropium bromide alone has a clear myopia control effect.

[0102] The efficacy of group J (0.01 g, i.e., 0.01%) and group K (0.10 g, i.e., 0.1%) was not significantly different from that of group I (P>0.05), and the degree of improvement in axial length and refractive error was similar, indicating that diquafosol sodium did not produce a synergistic effect with ipratropium bromide within this low dose range.

[0103] Group L (0.5% diquafosol sodium), Group M (1.0%) and Group N (1.5%) showed significant synergistic effects, with Group M showing the best effect.

[0104] In summary, the synergistic effect of ipratropium bromide and diquafosol sodium is significantly dose-dependent, exhibiting a significant synergistic effect within a mass ratio of ipratropium bromide to diquafosol sodium of 1:(50~150).

[0105] Table 3 Effects of different treatment groups on axial elongation and refractive error in mice (n=6, mean ± standard error)

[0106] Note: Different lowercase letters in the table indicate significant differences. P <0.05) The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The application of ipratropium bromide as the sole active ingredient in the preparation of drugs for the prevention or improvement of myopia.

2. Application of the combination of ipratropium bromide and diquafosol sodium in the preparation of drugs for the prevention or improvement of myopia.

3. A composition, characterized in that, Including ipratropium bromide and diquafosol sodium.

4. The composition according to claim 3, characterized in that, The mass ratio of ipratropium bromide to diquafosol sodium is 1:(50~150).

5. The composition according to claim 4, characterized in that, The mass ratio of ipratropium bromide to diquafosol sodium is 1:(80~120).

6. The composition according to claim 5, characterized in that, The mass ratio of ipratropium bromide to diquafosol sodium is 1:

100.

7. The use of the composition according to any one of claims 3 to 6 as an active ingredient in the preparation of a medicament for preventing or improving myopia.

8. A drug for preventing or improving myopia, characterized in that, The composition according to any one of claims 3 to 6 is used as the active ingredient.

9. An eye drop, characterized in that, Contains the composition according to any one of claims 3 to 6.

10. The eye drops according to claim 9, characterized in that, The composition according to any one of claims 3 to 6 is used as the active ingredient and also contains excipients required for eye drops.

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