Eye drop composition comprising lifitegrast

Abstract

The present invention provides an eye drop composition comprising lifitegrast or a pharmaceutically acceptable salt thereof, and propylene glycol as a degradation inhibitor. The eye drop composition according to the present invention exhibits excellent stability by inhibiting decomposition of an active ingredient without side effects caused by an antioxidant.

Description

Lipitegrast-containing ophthalmic composition

[0001] The present invention relates to an ophthalmic composition containing lipitegrast, and more particularly, to an ophthalmic composition containing lipitegrast with excellent stability without side effects due to an antioxidant.

[0002] Tears act as lubricants, facilitating smooth eye movement. They consist of a mucus layer, an aqueous layer, and a lipid layer. The aqueous layer adheres the tears to the eyeball, keeping them evenly distributed. The aqueous layer removes impurities and cleanses the eye, while the lipid layer inhibits tear evaporation. When the balance of these layers is disrupted by external factors such as aging, imaging devices, medication side effects, and contact lens wear, dry eye occurs.

[0003] Dry eye syndrome is a common condition. Symptoms include eye redness, swelling, a foreign body sensation, fatigue, burning, and itching. In severe cases, it can affect vision. Artificial tears containing active ingredients such as lipitegrast, diquafosol, sodium carboxymethylcellulose, cyclosporin, and sodium hyaluronate are used as treatments for dry eye syndrome.

[0004] Lipitegrast is an integrin receptor antagonist used in the treatment of dry eye disease that reduces inflammation by binding to lymphocyte function-associated antigen-1 (LFA-1) and inhibiting the interaction between intercellular adhesion molecule-1 (ICAM-1).

[0005] Most commercially available dry eye treatments containing lifitegrast contain antioxidants to inhibit oxidative degradation of the active ingredient. However, these antioxidants can be toxic to ocular cells and cause eye discomfort and inflammation in patients with severe dry eye.

[0006] For example, Korean Patent Publication No. 10-2015-0100763 discloses the use of thiosulfate salts as antioxidants to prevent oxidative degradation of lifitegrast. However, thiosulfate salts can cause irritation, including redness, itching, and conjunctivitis, upon application.

[0007] Therefore, there is a need for the development of an ophthalmic composition containing lipitegrast with excellent stability by inhibiting the decomposition of the active ingredient without side effects due to antioxidants.

[0008] The purpose of the present invention is to provide an eye drop composition containing lipitegrast with excellent stability by inhibiting the decomposition of an active ingredient without causing side effects due to an antioxidant.

[0009] Meanwhile, the present invention provides an eye drop composition comprising lipitegrast or a pharmaceutically acceptable salt thereof, and propylene glycol as an anti-disintegrant.

[0010] In one embodiment of the present invention, the propylene glycol may be included at a concentration of 0.2 to 5% (w / v).

[0011] An eye drop composition according to one embodiment of the present invention may further include one or more additives selected from a pH adjusting agent, a buffering agent, and an isotonic agent.

[0012] In one embodiment of the present invention, the pH adjusting agent may be at least one selected from the group consisting of lactic acid, hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0013] In one embodiment of the present invention, the buffer may be at least one selected from the group consisting of phosphoric acid, phosphate, carbonate, bicarbonate, tris(hydroxymethyl)aminomethane (TRIS), lactic acid, lactate, citric acid, citrate, boric acid, borate, acetic acid, and acetate.

[0014] In one embodiment of the present invention, the isotonic agent may be at least one selected from the group consisting of glycerin, sodium chloride, potassium nitrate, potassium chloride, calcium chloride, magnesium chloride, trehalose, maltose, sucrose, mannitol, sorbitol, and boric acid.

[0015] An eye drop composition according to one embodiment of the present invention may be in the form of an aqueous solution.

[0016] The eye drop composition according to one embodiment of the present invention may have a pH in the range of 7 to 8.

[0017] An eye drop composition according to one embodiment of the present invention may not contain an antioxidant.

[0018] In one embodiment of the present invention, the antioxidant may be one or more of dibutylhydroxytoluene, ascorbic acid, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetyl cysteine, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbyl palmitate, alpha-thioglycerol, erythorbic acid, cysteine ​​hydrochloride, citric acid, tocopherol, tocopherol acetate, soy lecithin, sodium thioglycolate, butylhydroxyanisole, propyl gallate, uric acid, melatonin, and thiourea.

[0019] An eye drop composition according to one embodiment of the present invention may be used for treating dry eye.

[0020] The ophthalmic composition according to the present invention contains propylene glycol as a decomposition inhibitor and does not contain an antioxidant, thereby inhibiting the decomposition of the active ingredient without side effects caused by the antioxidant, thereby exhibiting excellent stability.

[0021] Figure 1 is a graph showing the total amount of decomposition products generated after storing the eye drop compositions of Example 1 and Comparative Examples 1 to 9 at 40°C for 8 weeks.

[0022] Figure 2 is a graph showing the total amount of decomposition products generated after storing the eye drop compositions of Example 1 and Comparative Examples 1 to 9 at 60°C for 4 weeks.

[0023] Figure 3 is a photograph showing the properties of the eye drop compositions of Examples 2 to 4 and Comparative Example 1 after storage for 24 weeks under conditions of 40±2°C and 25% RH.

[0024] Figure 4 is a graph showing the total amount of decomposition products generated after storing the eye drop compositions of Examples 1 to 4 and Comparative Examples 1, 8, and 9 for 24 weeks under conditions of 40±2°C and 25% RH.

[0025] Figure 5 is a graph showing the total amount of decomposition products generated after storing the eye drop compositions of Examples 1 to 4 and Comparative Examples 1, 8, and 9 for 4 weeks under conditions of 50±2°C and 20% RH.

[0026] Hereinafter, the present invention will be described in more detail.

[0027]

[0028] One embodiment of the present invention relates to an eye drop composition comprising lipitegrast or a pharmaceutically acceptable salt thereof, and propylene glycol as an anti-disintegrant.

[0029] In one embodiment of the present invention, the lipitegrast is a compound represented by the following chemical formula 1, and is a dry eye treatment agent, Xiidra ® ) is the active pharmaceutical ingredient (API).

[0030] [Chemical Formula 1]

[0031]

[0032] In one embodiment of the present invention, the pharmaceutically acceptable salt of lifitegrast may be any salt commonly used in the art without limitation, and includes, for example, both non-toxic inorganic salts and organic salts, and may be a base addition salt. The base addition salts include alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonium salts and quaternary ammonium salts such as tetramethylammonium; Amine salts such as methylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylamine, isopropylamine, methanolamine, ethanolamine, dimethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and meglumine; polyamine resins, etc.

[0033] The content of the above-mentioned lipitegrast or a pharmaceutically acceptable salt thereof may be appropriately selected within a therapeutically effective content range, and specifically may be 0.01 to 10% (w / v) based on the entire ophthalmic composition.

[0034] In one embodiment of the present invention, the propylene glycol acts as a decomposition inhibitor of the ophthalmic composition, minimizing the generation of decomposition products of the active ingredient, thereby maintaining the properties of the ophthalmic composition and ensuring stability.

[0035] The above propylene glycol may be included at a concentration of 0.2 to 5% (w / v), preferably 0.5 to 3% (w / v). If the concentration of the propylene glycol is below the above range, the decomposition prevention effect may be reduced, and if it exceeds the above range, it may cause contact dermatitis or cause irritation.

[0036] An eye drop composition according to one embodiment of the present invention may further include one or more additives selected from a pH adjusting agent, a buffering agent, and an isotonic agent.

[0037] The pH adjusting agent may be at least one selected from the group consisting of lactic acid, hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, and in particular, from the viewpoint of stability of the eye drop composition, may be hydrochloric acid, sodium hydroxide or a combination thereof.

[0038] The above buffer may be at least one selected from the group consisting of phosphoric acid, phosphate, carbonate, bicarbonate, tris(hydroxymethyl)aminomethane (TRIS), lactic acid, lactate, citric acid, citrate, boric acid, borate, acetic acid, and acetate, and may be a phosphate, particularly in terms of the stability of the ophthalmic composition. As the phosphate, disodium hydrogen phosphate or a hydrate thereof, sodium dihydrogen phosphate or a hydrate thereof, etc. may be used.

[0039] The above-mentioned emollient may be at least one selected from the group consisting of glycerin, sodium chloride, potassium nitrate, potassium chloride, calcium chloride, magnesium chloride, trehalose, maltose, sucrose, mannitol, sorbitol and boric acid, and may be sodium chloride in particular from the viewpoint of stability of the eye drop composition.

[0040] An ophthalmic composition according to one embodiment of the present invention may be in the form of an aqueous solution. In this case, the aqueous medium may be water for injection, sterile purified water, physiological saline solution, etc.

[0041] An eye drop composition according to one embodiment of the present invention may have a pH range of 7 to 8. When the pH is adjusted to the above range, the stability of the eye drop composition is excellent and irritation upon application can be reduced.

[0042] An eye drop composition according to one embodiment of the present invention may not contain an antioxidant that is commonly used for the purpose of inhibiting decomposition of an active substance and preventing oxidation.

[0043] If the ophthalmic composition according to one embodiment of the present invention includes an antioxidant, stability may be reduced.

[0044] The eye drop composition according to one embodiment of the present invention does not contain an antioxidant, and thus can prevent side effects such as redness, itching, and conjunctivitis that may be caused by an antioxidant when instilled into the eye.

[0045] Specifically, examples of the antioxidant include dibutylhydroxytoluene, ascorbic acid, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetyl cysteine, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbyl palmitate, alpha-thioglycerol, erythorbic acid, cysteine ​​hydrochloride, citric acid, tocopherol, tocopherol acetate, soy lecithin, sodium thioglycolate, butylhydroxyanisole, propyl gallate, uric acid, melatonin, thiourea, or salts or combinations thereof.

[0046] Additionally, the eye drop composition according to one embodiment of the present invention may substantially not contain a preservative.

[0047] An eye drop composition according to one embodiment of the present invention does not contain a preservative, thereby preventing side effects such as irritation, inflammation, and cytotoxicity that may be caused by a preservative.

[0048] Specifically, examples of the preservative include quaternary ammonium salts including benzalkonium chloride, benzethonium chloride, cetalkonium chloride, polyquaternium-1 (e.g., polyquad), etc.; guanidine compounds including PHMB, chlorohexidine, etc.; alcohol compounds including chlorobutanol, benzyl alcohol, etc.; mercury compounds including thimerosal, phenylmercuric acetate, and phenylmercuric nitrate, etc.; parahydroxybenzoic acid ester compounds including methylparaben and propylparaben, etc.; sorbic acid compounds including potassium sorbate, etc.

[0049] An eye drop composition according to one embodiment of the present invention comprises propylene glycol as a decomposition inhibitor and substantially does not comprise an antioxidant and / or a preservative, thereby maintaining the properties of the eye drop composition even after long-term storage without side effects caused by the antioxidant and / or preservative and minimizing the generation of decomposition products.

[0050] An ophthalmic composition according to one embodiment of the present invention can be used for treating dry eye by containing lifitegrast or a pharmaceutically acceptable salt thereof as an active ingredient.

[0051]

[0052] Hereinafter, the present invention will be described in more detail through examples, comparative examples, and experimental examples. These examples, comparative examples, and experimental examples are intended solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited thereto.

[0053]

[0054] Example 1 and Comparative Examples 1 to 9: Preparation of eye drop compositions according to the type of anti-disintegrant

[0055] An eye drop composition was prepared according to the following method with the compositions shown in Tables 1 and 2 below (unit: %, w / v).

[0056] While stirring the injection water, the isotonic agent, buffer, and the active ingredient, lipitegrast, were added and dissolved, and then each anti-disintegrant was added and dissolved, and the pH was adjusted to 7 to 8 using a pH adjuster. Thereafter, the composition was filtered through a sterilizing filter of 0.2 μm or less to prepare an ophthalmic composition.

[0057] In Example 1, dibutylhydroxytoluene, an antioxidant, and polysorbate 80, a surfactant, were further added to dissolve the antioxidant.

[0058] ClassificationIngredient nameComparative example 1Comparative example 2Comparative example 3Comparative example 4Comparative example 5Active ingredientLifitegrast5.05.05.05.05.0Anti-decomposition agentSodium bisulfite0.2TPGS0.5Ascorbic acid0.3Sodium metabisulfite0.4Isostatic agentSodium chloride0.3050.3050.3050.3050.3050.305Buffering agentAnhydrous disodium hydrogen phosphate0.3550.3550.3550.3550.3550.355pH regulatorSodium hydroxideAmountAmountAmountAmountAmountAmountHydroxychloric acidAmountAmountAmountAmountAmountWater for injectionRemaining amountRemaining amountRemaining amount

[0059]

[0060] Ingredient nameComparative example 6Comparative example 7Comparative example 8Comparative example 9Example 1Active ingredientLifitegrast5.05.05.05.05.0Anti-decomposition agentPhosphoric acid0.228Sodium sulfite0.2Potassium sorbate0.47Hyaluronic acid0.3Propylene glycol3AntioxidantDibutylhydroxytoluene0.005SurfactantPolysorbate800.25Isostatic agentSodium chloride0.3050.3050.3050.3050.305Buffering agentAnhydrous disodium hydrogen phosphate0.3550.3550.3550.3550.3550.355pH regulatorSodium hydroxideAmountAmountAmountAmountAmountAmountHydroxyacidAmountAmountAmountAmountAmountWater for injectionRemaining amountRemaining amountRemaining amount

[0061]

[0062] Experimental Example 1: Stability of eye drop compositions according to the type of anti-disintegrant

[0063] The ophthalmic compositions of the above examples and comparative examples were placed in glass bottles, tightly sealed, and stored at 40°C for 8 weeks and at 60°C for 4 weeks.

[0064] Afterwards, the amount of decomposition products generated was measured using liquid chromatography.

[0065] The results are shown in Tables 3 and 4 below and Figures 1 and 2.

[0066] FIG. 1 is a graph showing the amount of total decomposition products generated after the ophthalmic compositions of Example 1 and Comparative Examples 1 to 9 were stored at 40°C for 8 weeks, and FIG. 2 is a graph showing the amount of total decomposition products generated after the ophthalmic compositions of Example 1 and Comparative Examples 1 to 9 were stored at 60°C for 4 weeks.

[0067]

[0068] Storage Conditions Item Initial (%) 8 weeks (%) Comparative Example 140℃ Individual decomposition product not detected 0.17 Total decomposition product not detected 0.23 Comparative Example 240℃ Individual decomposition product 0.14 2.56 Total decomposition product 0.19 4.43 Comparative Example 340℃ Individual decomposition product not detected 0.22 Total decomposition product not detected 0.39 Comparative Example 440℃ Individual decomposition product 0.06 0.56 Total decomposition product 0.06 1.78 Comparative Example 540℃ Individual decomposition product 0.18 2.59 Total decomposition product 0.23 4.94 Comparative Example 640℃ Individual decomposition product not detected 0.07 Total decomposition product not detected 0.07 Comparative Example 740℃ Individual decomposition product 0.10 1.99 Total Decomposition products 0.103.29 Comparative example 840℃ Individual decomposition products not detected 0.07 Total decomposition products not detected 0.07 Comparative example 940℃ Individual decomposition products not detected 0.08 Total decomposition products not detected 0.08 Example 140℃ Individual decomposition products not detected Not detected Total decomposition products not detected Not detected

[0069]

[0070] Storage Conditions Item Initial (%) 4 weeks (%) Comparative Example 160℃ Individual decomposition product not detected 0.22 Total decomposition product not detected 0.33 Comparative Example 260℃ Individual decomposition product 0.14 2.79 Total decomposition product 0.19 5.42 Comparative Example 360℃ Individual decomposition product not detected 0.77 Total decomposition product not detected 1.71 Comparative Example 460℃ Individual decomposition product 0.06 0.60 Total decomposition product 0.06 1.65 Comparative Example 560℃ Individual decomposition product 0.18 2.27 Total decomposition product 0.23 4.67 Comparative Example 660℃ Individual decomposition product not detected 0.27 Total decomposition product not detected 0.48 Comparative Example 760℃ Individual decomposition product 0.10 1.58 Total Decomposition products 0.10 3.20 Comparative example 860℃ Individual decomposition products not detected 0.17 Total decomposition products not detected 0.23 Comparative example 960℃ Individual decomposition products not detected 0.18 Total decomposition products not detected 0.30 Example 160℃ Individual decomposition products not detected 0.08 Total decomposition products not detected 0.08

[0071]

[0072] Through the above Tables 3 and 4 and FIGS. 1 and 2, it can be seen that the ophthalmic composition of Example 1 containing propylene glycol as a decomposition inhibitor produces less decomposition products than the ophthalmic compositions of Comparative Examples 1 to 9 containing no decomposition inhibitor or containing another decomposition inhibitor instead of propylene glycol.

[0073]

[0074] Examples 2 to 4: Preparation of antioxidant-free eye drop compositions

[0075] An eye drop composition was prepared according to the method of Example 1 with the composition shown in Table 5 below (unit: %, w / v).

[0076] Classification Ingredient name Example 2 Example 3 Example 4 Active ingredient Lifitegrast 5.0 5.0 5.0 Anti-degradant Propylene glycol 30.75 3 Surfactant Polysorbate 80 0.25 Tonicity agent Sodium chloride 0.30 50.30 50.30 5 Buffer Anhydrous disodium hydrogen phosphate 0.35 50.35 50.35 5 pH adjuster Sodium hydroxide Amount Amount Amount Amount Hydrochloric acid Amount Amount Amount Amount Water for injection Remaining amount Remaining amount

[0077]

[0078] Experimental Example 2: Stability of eye drop compositions depending on the presence or absence of antioxidants.

[0079] The ophthalmic composition of the above example was packaged in a disposable ophthalmic solution container (single dose LDPE) and stored for 24 weeks at 40±2°C and 25% RH and for 4 weeks at 50±2°C and 20% RH, respectively.

[0080] Afterwards, the properties of the eye drop composition were observed with the naked eye, and the amount of decomposition products generated was measured using liquid chromatography.

[0081] The results are shown in Tables 6 and 7 below and Figures 3 to 5.

[0082] Figure 3 is a photograph showing the properties of the eye drop compositions of Examples 2 to 4 and Comparative Example 1 after storage for 24 weeks under conditions of 40±2°C and 25% RH.

[0083] FIG. 4 is a graph showing the total amount of decomposition products generated after the ophthalmic compositions of Examples 1 to 4 and Comparative Examples 1, 8, and 9 were stored for 24 weeks under conditions of 40±2°C and 25% RH, and FIG. 5 is a graph showing the total amount of decomposition products generated after the ophthalmic compositions of Examples 1 to 4 and Comparative Examples 1, 8, and 9 were stored for 4 weeks under conditions of 50±2°C and 20% RH.

[0084] Storage Conditions Item Initial (%) 24 weeks (%) Comparative Example 140±2℃, 25% RH Individual Decomposition Product Not Detected 0.29 Total Decomposition Product Not Detected 0.49 Comparative Example 840±2℃, 25% RH Individual Decomposition Product Not Detected 0.25 Total Decomposition Product Not Detected 0.33 Comparative Example 940±2℃, 25% RH Individual Decomposition Product Not Detected 0.33 Total Decomposition Product Not Detected 0.54 Example 140±2℃, 25% RH Individual Decomposition Product Not Detected 0.06 Total Decomposition Product Not Detected 0.06 Example 240±2℃, 25% RH Individual Decomposition Product Not Detected Not Detected Total Decomposition Product Not Detected Not Detected Example 340±2℃, 25% RH Individual Decomposition products not detected, not detected, total decomposition products not detected, not detected, example 440±2℃, 25% RH, individual decomposition products not detected, 0.08, total decomposition products not detected, 0.08

[0085]

[0086] Storage Conditions Item Initial (%) 4 weeks (%) Comparative Example 150±2℃, 20% RH Individual Decomposition Product Not Detected 0.15 Total Decomposition Product Not Detected 0.20 Comparative Example 850±2℃, 20% RH Individual Decomposition Product Not Detected 0.09 Total Decomposition Product Not Detected 0.09 Comparative Example 950±2℃, 20% RH Individual Decomposition Product Not Detected 0.15 Total Decomposition Product Not Detected 0.21 Example 150±2℃, 20% RH Individual Decomposition Product Not Detected Not Detected Total Decomposition Product Not Detected Not Detected Example 250±2℃, 20% RH Individual Decomposition Product Not Detected Not Detected Total Decomposition Product Not Detected Not Detected Example 350±2℃, 20% RH Individual Decomposition products not detected, not detected, total decomposition products not detected, not detected, example 450±2℃, 20% RH, individual decomposition products not detected, not detected, total decomposition products not detected, not detected

[0087]

[0088] Through the above Tables 6 and 7 and FIGS. 4 and 5, it can be confirmed that the ophthalmic compositions of Examples 2 and 3, which include propylene glycol as a decomposition inhibitor but do not include an antioxidant, have better stability than the ophthalmic compositions of Comparative Examples 1, 8, and 9, which do not include propylene glycol as a decomposition inhibitor, as well as Example 1, which includes an antioxidant together with propylene glycol as a decomposition inhibitor.

[0089] In addition, it can be seen through Example 4 that stability is reduced when polysorbate 80, a surfactant, is further included together with propylene glycol as a decomposition inhibitor.

[0090] In addition, through Fig. 3, it can be confirmed that the ophthalmic compositions of Examples 2 to 4 show no change in properties after being stored for 24 weeks under conditions of 40±2°C and 25% RH.

[0091]

[0092] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Those skilled in the art will be able to make various applications and modifications within the scope of the present invention based on the above description.

[0093] Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. An ophthalmic composition comprising lipitegrast or a pharmaceutically acceptable salt thereof, and propylene glycol as a disintegration inhibitor.

2. An eye drop composition according to claim 1, wherein the propylene glycol is contained in a concentration of 0.2 to 5% (w / v).

3. An eye drop composition according to claim 1, further comprising at least one additive selected from a pH adjuster, a buffer, and an isotonic agent.

4. An eye drop composition in the third paragraph, wherein the pH adjusting agent is at least one selected from the group consisting of lactic acid, hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

5. In the third paragraph, the buffer is at least one selected from the group consisting of phosphoric acid, phosphate, carbonate, bicarbonate, tris(hydroxymethyl)aminomethane (TRIS), lactic acid, lactate, citric acid, citrate, boric acid, borate, acetic acid, and acetate.

6. An eye drop composition in the third paragraph, wherein the isostatic agent is at least one selected from the group consisting of glycerin, sodium chloride, potassium nitrate, potassium chloride, calcium chloride, magnesium chloride, trehalose, maltose, sucrose, mannitol, sorbitol, and boric acid.

7. An eye drop composition in the form of an aqueous solution according to claim 1.

8. An eye drop composition according to claim 1, wherein the pH is in the range of 7 to 8.

9. An eye drop composition according to claim 1, which does not contain an antioxidant.

10. An eye drop composition according to claim 9, wherein the antioxidant is at least one of dibutylhydroxytoluene, ascorbic acid, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetyl cysteine, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbyl palmitate, alpha-thioglycerol, erythorbic acid, cysteine ​​hydrochloride, citric acid, tocopherol, tocopherol acetate, soy lecithin, sodium thioglycolate, butylhydroxyanisole, propyl gallate, uric acid, melatonin, and thiourea.

11. An eye drop composition for treating dry eye syndrome according to claim 1.

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