KR102548710B1 - Pharmaceutical composition for prevention or treatment of dry eye syndrome comprising diquafosol or pharmaceutically acceptable salts thereof and tocopherol - Google Patents

Abstract

A pharmaceutical composition for preventing or treating dry eye syndrome is provided. The active ingredient of the pharmaceutical composition for preventing or treating dry eye syndrome according to the present invention is diquafosol or a pharmaceutically acceptable salt thereof, and the ingredient improving the diffusion and durability of eye drops is tocopherol or a derivative thereof. The pharmaceutical composition according to the present invention can reduce damage and inflammation of the ocular surface by reinforcing the lipid layer of the tear film, and has excellent storage stability. The pharmaceutical composition according to the present invention has a fast diffusion rate in the corneal conjunctiva when instilled, so it is more effective in treating dry eye syndrome.

Description

Pharmaceutical composition for preventing or treating dry eye containing diquafosol or a pharmaceutically acceptable salt thereof and tocopherol

The present invention relates to a pharmaceutical composition for preventing or treating dry eye syndrome. Specifically, it relates to a pharmaceutical composition for preventing or treating dry eye syndrome comprising diquafosol or a pharmaceutically acceptable salt thereof and tocopherol or a derivative thereof. More specifically, the present invention relates to a pharmaceutical composition capable of reducing damage and inflammation of the ocular surface by reinforcing the lipid layer of the tear film. Tocopherol or a derivative thereof included in the pharmaceutical composition of the present invention is a component that improves the diffusion and durability of eye drops, and exhibits a synergistic effect related to the prevention or treatment of dry eye syndrome and simultaneously achieves an effect of increasing storage stability. In particular, since the pharmaceutical composition of the present invention has a rapid diffusion rate in the cornea and conjunctiva when instilled, it has an excellent therapeutic effect on dry eye syndrome.

Tears are composed of three layers: a mucous layer, an aqueous layer, and a lipid layer. The mucus layer is produced by the goblet cells of the conjunctiva, the aqueous layer is produced by the lacrimal gland, and the outermost lipid layer is the meibomian gland. is created from The maintenance of moisture in the eye is maintained by three factors: production of the tear layer by the secretion of tears in the lacrimal gland, loss of tears by discharge through the nasolacrimal duct toward the nose, and self-evaporation from the eye. If these factors are not properly balanced with each other, dry eye occurs.

Dry eye syndrome, also called dry eye syndrome or dry eye syndrome, refers to a disease state in which abnormalities occur in the tear layer due to a decrease or change in the quantity and quality of the tear layer that moistens the eyes and maintains a soft and comfortable eye condition.

Japanese Patent Registration No. 3652707 discloses diquafosol as a substance capable of preventing or treating dry eye syndrome. Diquafosol is a purinergic receptor agonist, also called P ¹ , P ⁴ -di(uridine-5′)tetraphosphate or Up ₄ U, and has been reported to have a tear secretion promoting action in the conjunctiva. An eye drop containing diquafosol sodium salt is marketed under the product name Diquas ^® and is reported to be effective in dry eye syndrome in which tear film break-up time (TBUT) is reduced.

Republic of Korea Patent Registration No. 1536885 discloses that storage stability is improved by suppressing the generation of insoluble precipitates by adding a chelating agent to Diquafosol eye drops.

Korean Registered Patent No. 1867791 states that benzalkonium chloride, a preservative commonly used in eye drops, may cause corneal disorders when used in high concentrations, and that preservation stability was secured by using chlorhexidines instead of benzalkonium chloride in Diquafosol eye drops. has been initiated.

In the case of eye drops, additives such as preservatives may be included to secure storage stability, but there is a risk of irritation to the cornea due to these additives, and as a result, there is a problem that the therapeutic effect is not sufficiently exhibited. Since eye drops are used directly on the eyeball, which is a sensitive part of the body, it is necessary to maintain stable physical and chemical properties during the manufacturing and distribution process as well as during use by patients, and corneal irritation due to ingredients contained in eye drops should not occur Can not be done.

As a method of providing a physicochemically stable eye drop, a method is known in which an isotonic agent, a chelating agent, a pH adjusting agent, a preservative, a solubilizing agent, a viscosity increasing agent, and the like are mixed as necessary in addition to the active ingredient. Japanese Patent Laid-Open No. 1996-231403 discloses a method of mixing sugar alcohols, sugars, and polyhydric alcohols, and Japanese Patent Laid-Open No. 2007-182438 discloses a method of adding glycerin. Depending on the type of additive, it should be applied differently.

However, the literatures listed above are only based on the technical idea that diquafosol promotes tear production and secretion by stimulating purinergic receptors expressed in the lacrimal gland and conjunctiva, the role of a purinergic receptor agonist. A pharmaceutical composition capable of treating dry eye syndrome by simultaneously acting on the three layers of the mucous layer, aqueous layer and lipid layer has not been disclosed. Furthermore, there is no recognition of the diffusion rate when eye drops are applied in relation to the treatment of dry eye syndrome.

The inventors of the present invention, when applying a means capable of supplementing all of the three component layers constituting tears, significantly improves eye dryness and eye fatigue, and at the same time increases the holding power and holding time of the tear layer or tear film, thereby improving the eye It was found that xerostomia can be effectively prevented or treated, and in particular, when the diffusion rate in the cornea and conjunctiva is increased, the present invention is based on the fact that the therapeutic effect can be more excellent.

Japanese Patent Registration No. 3652707 Republic of Korea Patent No. 1536885 Republic of Korea Patent No. 1867791 Japanese Patent Laid-Open No. 1996-231403 Japanese Patent Laid-Open No. 2007-182438

Effectiveness of Combined Tear Film Therapy in Patients with Evaporative Dry Eye with Short Tear Film Breakup Time (Journal of Ocular Pharmacology and Therapeutics Vol. 33, No. 8)

The problem to be solved by the present invention is a new method for preventing or treating dry eye syndrome, which can more effectively improve symptoms of dry eye syndrome compared to existing dry eye treatment eye drops (commercial product Diquas ^® ) containing diquafosol as a main component. To provide a pharmaceutical composition. Furthermore, providing a pharmaceutical composition for treating and preventing dry eye syndrome with increased storage stability without using a separate chelating agent is also included in the object to be solved by the present invention. The present inventors found that dry eye syndrome can be effectively prevented or cured by significantly improving eye dryness and eye fatigue by acting on the three layers of the mucous layer, aqueous layer and lipid layer constituting tears, and increasing tear stability at the same time. As obtained, this becomes the problem solving principle of the present invention. In particular, the principle of solving the problems of the present invention is to provide a novel technical idea that the diffusion rate of eye drops in the corneal conjunctiva can be increased by including tocopherol or a derivative thereof as a component that improves the diffusion and persistence of eye drops. am.

The above problems are solved by providing a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient and tocopherol or a derivative thereof as a component improving the diffusion and durability of eye drops.

The pharmaceutical composition according to the present invention achieves the effect of increasing the tear film breakup time and the tear film lipid layer grade, and the corneal fluorochrome staining score when compared to conventional eye drops for the treatment of dry eye syndrome containing diquafosol as an active ingredient. , showing a reducing effect on inflammatory T cells and active oxygen concentrations. The pharmaceutical composition according to the present invention can reduce damage and inflammation of the ocular surface by acting on the three layers of mucous layer, aqueous layer and lipid layer.

1 shows a photograph taken during an experiment to measure the diffusion rate of a pharmaceutical composition according to the present invention.
Figure 2 is a graph showing the results of measuring the diffusion rate of the pharmaceutical composition according to the present invention.

Diquafosol refers to P ¹ ,P ⁴ -di(uridine-5')tetraphosphate represented by the following chemical formula, and is a potent agonist of purinergic receptors expressed in the lacrimal gland and conjunctiva. It is a substance known to have the effect of promoting corneal epithelial elongation.

Diquafosol may be included in the eye drop composition in the form of a salt, and there is no particular limitation as long as the salt is approved for use in pharmaceuticals. For example, salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium; salts with ammonia or organic amines such as diethylamine and triethanolamine; salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; It can be included in pharmaceuticals in the form of salts with organic acids such as lactic acid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid. Diquafosol or a pharmaceutically included salt thereof according to the present invention is a concept including all of the salts listed above as well as salts commonly used in the pharmaceutical field even though not listed above. Diquafosol or a pharmaceutically acceptable salt thereof may have optical isomers or diastereomers, and these isomers are also included in the present invention. In addition, it may exist in the form of a solvate such as a form of a hydrate. In the pharmaceutical composition according to the present invention, diquafosol tetrasodium salt (hereinafter, simply referred to as "diquafosol sodium") is preferred. The pharmaceutical composition according to the present invention may include diquafosol or a pharmaceutically acceptable salt thereof at a concentration of 0.1 to 10% (w/v) as diquafosol. Preferably, diquafosol may be included at a concentration of 1 to 10% (w/v), more preferably at a concentration of 3% (w/v).

It is reported that the preventive or therapeutic effect of Diquafosol or a pharmaceutically acceptable salt thereof on dry eye syndrome is expressed through an action that promotes tear secretion in the lacrimal tissue and/or lacrimal gland tissue, that is, through P2Y receptor agonism. However, according to the study of the present inventors, it was found that there is a limit to effective dry eye treatment only by the action of promoting tear secretion by acting on the P2Y receptor. In particular, in the case of dry eye syndrome in which the tear film breakup time is shortened, the focus is on the function of replenishing the aqueous layer in the tear layer simply by promoting tear secretion, but the finding that effective dry eye treatment cannot be achieved only by supplementing the aqueous layer got

Therefore, the inventors of the present invention based on the idea that a more effective pharmaceutical composition for preventing or treating dry eye syndrome can be provided by applying an additional means capable of replenishing the lipid layer simultaneously with Diquafosol or a pharmaceutically acceptable salt thereof. led to the invention. In the present invention, tocopherol or a derivative thereof is adopted as the additional means.

Tocopherol or derivatives thereof referred to in the present invention include tocopherol (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc.), and as derivatives thereof, for example, tocopherol acetate, tocopherol succinate, tocopherol nicotine Derivatives of organic acid esters such as nates and salts thereof are meant, but are not limited thereto. Since tocopherol is easily oxidized and unstable when used alone, it is commonly used in the form of derivatives of organic acid esters. Considering that the derivative needs to be converted into active tocopherol by hydrolysis and that there are various types of tocopherol derivatives, the meaning of the tocopherol derivative referred to in the present invention can be clearly recognized by those skilled in the art. In the pharmaceutical composition according to the present invention, the concentration of tocopherol or a derivative thereof may be included as tocopherol in the range of 0.001% (w/v) or more and 0.1% (w/v) or less, preferably 0.005% (w/v) or more and 0.01% (w/v) or more. % (w / v) or less may be included.

The active ingredient of the pharmaceutical composition according to the present invention is diquafosol or a pharmaceutically acceptable salt thereof, and tocopherol or a derivative thereof is included as a component that improves the diffusion and durability of eye drops. Although there was no significant change in tear film breakup time when tocopherol or its derivatives, especially low-dose tocopherol was administered alone, the pharmaceutical composition of the present invention contains the above two components, thereby diquafosol or its pharmaceutically acceptable salt alone. Significantly increases tear film breakup time compared to administration. Furthermore, when compared with conventional eye drops for the treatment of dry eye syndrome containing only diquafosol or a pharmaceutically acceptable salt thereof as a main component, the pharmaceutical composition according to the present invention has an increased diffusion rate and thus has a more effective dry eye treatment effect. become excellent

Another aspect of the present invention is increased stability. According to the study of the present inventors, it was found that the stability of Diquafosol ophthalmic solution is increased by adding tocopherol or a derivative thereof. Regarding the stability of eye drops, stability evaluation such as changes in osmotic pressure or pH that may cause eye irritation, generation of related substances, sterility, and precipitation of insoluble foreign substances is very important. In the case of the pharmaceutical composition according to the present invention, excellent effects are achieved in all items related to the above stability evaluation, which constitutes one of the technical features of the present invention.

The pharmaceutical composition according to the present invention may include additives commonly used in eye drops, but may not include a separate chelating agent. In the case of eye drops containing diquafosol, it has been reported in prior literature that the use of a chelating agent such as EDTA is essential for preservation stability, but in the case of the present invention containing tocopherol or a derivative thereof, it is excellent Stability is achieved, which also constitutes a further technical feature of the invention.

The pharmaceutical composition of the present invention may or may not further contain a preservative. In the case of using a preservative, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, paraben, sorbic acid, chlorobutanol, boric acid, chlorite, etc. may be mentioned, but is not limited thereto. When a preservative is used, it is not particularly limited as long as it is at a concentration that exhibits a predetermined preservative effect, but in the case of benzalkonium chloride, it is preferably 0.0001 to 0.1% (w/v), and more preferably 0.0005 to 0.01% (w/v). It is preferred, and 0.001 to 0.005% (w/v) is particularly preferred.

Pharmaceutically acceptable additives may be added to the pharmaceutical composition of the present invention according to conventional methods, if necessary. buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, epsilon-aminocaproic acid; isotonic agents such as sodium chloride, potassium chloride, and concentrated glycerin; Surfactants such as polyoxyethylene sorbitan monooleate (polysorbate), polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil may be selected and added as necessary. Polysorbate 80 may be used as a preferred surfactant, and in this case, it may be used at a concentration of 0.01 to 0.1% (w/v).

The pharmaceutical composition of the present invention may be subjected to filtration sterilization or other sterilization treatment, and the sterilized eye drop solution is also included in the scope of the present invention.

As efficacy tests, tear secretion, tear film breakdown time, corneal fluorochrome staining, tear film lipid layer grade, number of inflammatory T cells, DCF-DA assay, as well as diffusion test and stability test results are shown below. However, these preparation examples and test examples are for better understanding of the present invention and do not limit the scope of the present invention.

Preparation Example 1: Preparation of Examples 1 and 2 and Comparative Examples 1 to 3

According to the prescription shown in Table 1 below, polysorbate 80 and Dl-alpha-tocopherol acetate were dissolved in water for injection, and separately diquafosol sodium was dissolved in water for injection, and then mixed and stirred to obtain Example 1, 2 and Comparative Examples 1 to 3 were prepared.

raw material name Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Diquafosol Sodium (mg) 30.000 - - 30.000 30.000 Polysorbate 80 (mg) - 0.100 0.200 0.100 0.200 Dl-alpha-tocopherolacetate (mg) - 0.05 0.1 0.05 0.1 water for injection Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount gross weight 1mL 1mL 1mL 1mL 1mL

Animal tests were conducted with Examples 1 and 2 and Comparative Examples 1 to 3 prepared as above. The trial design is as follows.

- Animal model: mouse (C57BL/6, 7-8 weeks old)

- Number of animals: 6 per group

- Number of drops: 4 times a day (7:00, 11:00, 15:00, 19:00), 2uL each time

- Test period: 15 days in total (After inducing EDE for 5 days, observe on the 5th and 10th days after instillation of the test sample)

The test was conducted on a group without any treatment (Comparative Group 1) and a group exposed to a dry environment for 5 days (for 18 hours a day) to experimentally induce dry eyes (Comparative Group 2 and Comparative Group 3). Comparative Example 1 to 3, Example 1 or Example 2 was administered. BSS (balanced salt solution) described in Table 2 is a balanced salt solution, a solution prepared in consideration of the pH and osmotic pressure of the human body, and was administered to comparative group 3 as a control set to confirm the efficacy of tocopherol alone administration. Details are shown in Table 2 below.

division military setting comparator group 1 Untreated(UT) comparison group 2 Experimental Dry Eye (EDE) comparator group 3 EDE + balanced salt solution (BSS) Comparative Example 1 EDE + 3% diquafosol sodium (DQS) Comparative Example 2 EDE + 0.005% Tocopherol + 0.01% Polysorbate Comparative Example 3 EDE + 0.01% Tocopherol + 0.02% Polysorbate Example 1 EDE + DQS + 0.005% Tocopherol + 0.01% Polysorbate Example 2 EDE + DQS + 0.01% Tocopherol + 0.02% Polysorbate

Test Example 1: Measurement of tear film breakup time

The tear film destruction time was determined by instilling 1 μL of 1% fluorescent dye (Fluorescein) into the lower conjunctival sac of the rat, blinking the eyes 3 times, gently opening them, and then staining through a slit lamp microscope equipped with a Cobalt blue filter. The time (seconds) until the first defect was formed in the tear film was measured. This was repeated 3 times and the average value was obtained. The results are shown in Table 3 below.

division Day 5 (seconds) Day 10 (seconds) comparator group 1 2.82 2.57 comparison group 2 1.72 1.10 Comparative Example 1 1.83 1.42 Example 1 1.96 1.74 Example 2 2.09 1.91

From the results of the increase in tear film breakup time shown in Examples 1 and 2 of Table 3 above, it was found that the pharmaceutical composition of the present invention can improve tear film stability.

Comparative Test Example 1: Measurement of tear film breakup time

The same tests as in Test Example 1 were performed on Comparative Groups 2 and 3 and Comparative Examples 2 and 3.

The results are shown in Table 4 below.

division Day 5 (seconds) Day 10 (seconds) comparison group 2 1.76 1.25 comparator group 3 1.76 1.29 Comparative Example 2 1.72 1.19 Comparative Example 3 1.77 1.32

As can be seen from Table 4 above, the tear film breaking time of Comparative Example 3 was not significantly different from that of Comparative Groups 2 and 3, and the tear film breaking time of Comparative Example 2 was also reduced compared to Comparative Groups 2 and 3, making it more inferior. It was found to be effective.

Test Example 2: Tear secretion test

For the amount of tear secretion, phenol-red impregnated cotton threads were brought into contact with the conjunctival sac on the lateral canthal side of the rat for 20 seconds, and the length of the wet cotton threads turned red by tears was measured using SMZ microscopy, and then the volume was measured. converted to The results are shown in Table 5 below.

division Day 5 (uL) Day 10 (uL) comparator group 1 0.041 0.040 comparison group 2 0.026 0.023 Comparative Example 1 0.028 0.030 Example 1 0.029 0.033 Example 2 0.031 0.034

As can be seen from Table 5 above, in Examples 1 and 2 in which the pharmaceutical composition according to the present invention was administered, it was found that the increase in tear secretion prevented the promotion of dry eye.

Test Example 3: Corneal fluorochrome staining score

The corneal fluorochrome staining score was evaluated by instilling 1 μL of 1% fluorescent staining solution, washing with saline, and then observing the mouse cornea under a slit lamp microscope to score the degree of epithelial damage (degree of fluorescence staining). To this end, the cornea was divided into 4 zones, and each segment was evaluated on a scale of 0 - 4 as follows, and then summed (0 - 16 points in total).

1) 0: Absent

2) 1 : Slightly punctuate staining < 30 spots

3) 2: Punctate staining > 30 spots, but not diffuse

4) 3: Severe diffuse staining but no positive plaque

5) 4: Severe diffuse staining with positive fluorescein plaque.

The results are shown in Table 6 below.

division Day 5 (point) Day 10 (point) comparator group 1 2.75 3.00 comparison group 2 10.75 13.08 Comparative Example 1 9.42 9.33 Example 1 8.67 8.00 Example 2 7.08 4.92

From the results of the decrease in the corneal fluorochrome staining score shown in Examples 1 and 2 of Table 6 above, it was found that the pharmaceutical composition of the present invention can improve corneal epithelial damage.

Test Example 4: Tear film lipid layer grade

The tear film lipid layer grade was evaluated by the color and shape of the lipid layer reflected on the tear film by the reflector by observing the mouse tear film with a slit lamp microscope. (Total 1 - 6 points)

1) Grade 1 : Gray appearance of low reflectivity and meshwork pattern faintly visible.

2) Grade 2 : More compact meshwork pattern with gray appearance of average reflectivity.

3) Grade 3 : Vertical and horizontal gray waves of good visibility.

4) Grade 4: Yellow-gray and yellow spread lipid layer interference fringes superimposed on a background.

5) Grade 5: Brown-yellow and brown spread lipid layer interference fringes superimposed on a background.

6) Grade 6: Blue and brown spread lipid layer interference fringes superimposed on a background.

The results are shown in Table 7 below.

division Day 5 Day 10 comparator group 1 5.25 5.08 comparison group 2 2.67 2.17 Comparative Example 1 3.33 3.58 Example 1 3.67 4.17 Example 2 3.75 4.58

From the results of the increase in the grade of the tear film lipid layer shown in Examples 1 and 2 in Table 7 above, it was found that the pharmaceutical composition of the present invention can reinforce the tear film lipid layer.

Test Example 5: Flow cytometry

The number of inflammatory T cells and DCF-DA cells were measured as follows. The conjunctiva was excised from 6 eyes of 3 animals per group, which is the amount required for histological analysis, and the conjunctiva was cut with scissors and shaken at 37°C for 60 minutes with 0.5 mg/ml collagenase type D. After grinding the tissue, it was passed through a cell strainer and then centrifuged. Flow cytometry was performed using Fluorescein-conjugated anti-CD4 antibody and Phycoerythrinconjugated anti-IFN-γ antibody, and the number of CD4+ IFN-γ+ T cells and the number of DCF-DA cells were calculated using CM-H2DCFDA kit. The results are shown in Tables 8 and 9 below.

1. Measurement of the number of inflammatory T cells

division CD4+IFN-γ+ T cells cornea(%) conjunctiva(%) comparator group 1 1.89 1.86 comparison group 2 8.47 8.35 Comparative Example 1 5.56 5.25 Example 1 5.20 4.82 Example 2 3.17 3.18

From the results of reducing the ratio of inflammatory T cells of the cornea and conjunctiva shown in Examples 1 and 2 of Table 8 above, it was found that the pharmaceutical composition of the present invention can reduce inflammation of the cornea and conjunctiva.

2. DCF-DA analysis

division DCF-DA fluorescein intensity (%) cornea(%) conjunctiva(%) comparator group 1 100.00 100.00 comparison group 2 2,122.79 1,486.58 Comparative Example 1 1,191.15 741.72 Example 1 568.16 408.69 Example 2 319.32 194.31

(The above % is a relative value when the untreated group (comparative group 1) is 100%) From the results of the decrease in DCF-DA fluoresein intensity in the cornea and conjunctiva shown in Examples 1 and 2 of Table 9 above It was found that the pharmaceutical composition of the present invention can reduce the concentration of active oxygen in the cornea and conjunctiva.

Preparation Example 2: Preparation of Examples 3 to 5 and Comparative Example 4

According to the composition shown in Table 10 below, polysorbate 80 and Dl-alpha-tocopherol acetate were dissolved in water for injection, and separately diquafosol sodium, sodium hydrogen phosphate hydrate, sodium chloride, and potassium chloride were dissolved in water for injection, and then both Examples 3 to 5 and Comparative Example 4 were prepared by mixing and stirring.

raw material name Comparative Example 4 Example 3
(0.0025%) Example 4
(0.005%) Example 5
(0.01%) Diquafosol Sodium (mg) 30.000 30.000 30.000 30.000 Sodium hydrogen phosphate monohydrate (mg) 2.000 2.000 2.000 2.000 sodium chloride (mg) 3.900 3.900 3.900 3.900 Potassium Chloride (mg) 1.500 1.500 1.500 1.500 Polysorbate 80 (mg) 0.200 0.200 0.200 0.200 Dl-alpha-tocopherolacetate (mg) - 0.025 0.050 0.100 water for injection Appropriate amount Appropriate amount Appropriate amount Appropriate amount gross weight 1mL 1mL 1mL 1mL

Test Example 6: Diffusion test

For Examples 3 to 5 and Comparative Example 4, a diffusion test was performed according to the following test method.

① Put test solution and pigment in a glass tube and mix (0.5% w/v)

② Place the diffusion paper on the graph paper and inject 100uL of the test solution into the center of the filter (n = 3)

③ Measurement of diffusion photos at each analysis time (5, 10, 15, 20, 25, 30, 40, 60, 90, 120, 150, 180, 240, 300 seconds)

④ Area analysis of the test solution using Image J software

For area analysis, the area of one grid paper and the diffusion area of the test solution were measured, and the diffused unit area was calculated by dividing the total spread area by the area of one grid paper. (FIG. 1)

The results are shown in Table 11 and FIG. 2 below.

5 seconds 10 seconds 15 seconds 20 seconds 25 seconds 30 seconds Comparative Example 4 12.9 14.1 17.0 18.2 22.1 23.6 Example 3 13.3 14.3 17.3 18.4 22.1 23.2 Example 4 15.0 17.5 17.7 20.5 24.1 25.3 Example 5 14.7 17.2 17.2 19.4 22.9 25.0

As can be seen from Table 11 and FIG. 2, it was confirmed that the diffusion rate of Examples 3 to 5 according to the present invention was faster than that of Comparative Example 4 within the range of 5 seconds to 30 seconds. In particular, in the case of Examples 4 and 5, the diffusion rate was faster by 10% or more at 5 seconds and by 20% or more at 10 seconds.

Test Example 7: Stability test results

A stability test was conducted according to the prescription of Example 4, and the results are shown in Table 12 below.

Test Items standard first time Acceleration long time 3 months 6 months 3 months 6 months pH 7.2~7.8 7.38 7.35 7.48 7.34 7.51 softness
matter UDP:
0.6% or less 0.00 0.00 0.05 0.00 0.03 Other individual: Less than 0.2% 0.04 0.04 0.06 0.04 0.04 Total Flexibility: Less than 2.0% 0.11 0.11 0.18 0.11 0.14 Diquafosol
content 90.0~
110.0% 98.0 99.9 100.5 99.3 99.5 Judgment fitness fitness fitness fitness fitness

As can be seen from the above table, it was confirmed that the pharmaceutical composition according to the present invention has excellent stability even without using a separate chelating agent such as EDTA.

That is, the pharmaceutical composition of the present invention increases the tear film breakdown time, increases the amount of tear secretion, and reduces the corneal fluorochrome staining score, thereby improving corneal epithelial damage, and increasing the lipid layer grade of the tear film. It reinforces the lipid layer, reduces inflammatory T cells in the cornea and conjunctiva, and reduces DCF-DA fluoresein intensity, thereby reducing the concentration of active oxygen in the cornea and conjunctiva. In addition, it was confirmed that the diffusion rate in the cornea and conjunctiva was fast, and stability was secured without using a chelating agent.

The pharmaceutical composition according to the present invention has a fast diffusion rate in the cornea and conjunctiva, and can be used as a pharmaceutical for preventing or treating dry eye syndrome, which can reduce damage and inflammation of the ocular surface by reinforcing the lipid layer of the tear film.

Claims (7)

Diquafosol or a pharmaceutically acceptable salt thereof; and
tocopherol or tocopherol acetate;
A pharmaceutical composition for preventing or treating dry eye syndrome comprising a. The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 1, wherein the concentration of tocopherol or tocopherol acetate in the pharmaceutical composition is 0.001 to 0.1% (w/v) as tocopherol. The dry eye syndrome according to claim 1 or 2, wherein the concentration of diquafosol or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.1 to 10% (w/v) as diquafosol. A pharmaceutical composition for prevention or treatment. The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 1 or 2, further comprising a surfactant. The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 4, wherein the surfactant is polysorbate. The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 1 or 2, wherein the pharmaceutically acceptable salt of diquafosol is diquafosol sodium. The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 1 or 2, wherein the pharmaceutical composition does not contain a chelating agent.

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