Eye drops

Abstract

This eye drop contains (A) 0.02-0.15 w / w% (inclusive) of a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer in which the molar ratio of structural units represented by formula (1) is a: b: c = 100: 10-400: 2-50, (B) 0.000001-0.0001 w / w% (inclusive) of polyhexamethylene biguanide represented by formula (2) or a salt thereof, and (C) 0.02 to 2.0 w / w% (inclusive) of polyoxyethylene polyoxypropylene glycol, and the content of sodium chloride is 0.3 w / w% or less. According to the present invention, it is possible to provide an eye drop which imparts lubricity to the cornea surface, has sufficient storage efficacy, and has low eye irritation.

Description

Technical Field

[0001] The present invention relates to eye drops. Background Art

[0002] In recent years, the incidence of dry eye has increased dramatically due to contact lens wear, smartphones, and personal computer use. The main causes of dry eye include increased tear evaporation due to decreased blinking, friction between the conjunctiva and the ocular surface caused by blinking, and dry eyes caused by air leaking from masks. Therefore, eye drops for dry eye require both moisturizing properties to inhibit tear evaporation and lubricity to reduce friction during blinking.

[0003] Eye drops are typically used repeatedly for several weeks after opening, so they contain preservatives to prevent bacterial contamination within the container. Therefore, it is important that the preservatives used in eye drops fully preserve the product. For example, polyhexamethylene biguanide is often used as a preservative.

[0004] In addition, it is known that the technology of improving lubricity and moisture retention by coordinating the polymer containing phosphorylcholine group in eye drops. For example, in patent documentation 1, eye drops coordinating with the polymer containing phosphorylcholine group are disclosed. By using the eye drops described in this patent documentation 1, the lubricity of the corneal surface can be improved, and the friction between the palpebral conjunctiva and the ocular surface during blinking can be reduced. In addition, in patent documentation 2, eye drops coordinating with the polymer containing phosphorylcholine group and polyhexamethylene biguanide are disclosed. By using the eye drops described in this patent documentation 2, sufficient preservation efficacy is achieved, rapid diffusion occurs on the surface of eyes or contact lenses, and moisture retention and lubrication effects are achieved.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: International Publication No. 2016 / 140242

[0008] Patent Document 2: Japanese Patent Application Laid-Open No. 2021-20856

[0009] Non-patent literature

[0010] Non-Patent Document 1: New Ophthalmology (Atarashi Ophthalmology), Vol. 28, No. 3, Ise Nomi Kazuyuki et al., published by Medical Aoi Co., Ltd., issued on March 31, 2011, pp. 421-424. Summary of the Invention

[0011] Problems to be solved by the invention

[0012] However, Patent Document 1 reports that sufficient lubricity is imparted by adding a polymer containing a phosphorylcholine group to eye drops, but there is no clear description of preservative efficacy. Patent Document 2 discloses a method for imparting lubricity and moisturizing properties and achieving sufficient preservative efficacy by using eye drops containing a polymer containing a phosphorylcholine group, polyhexamethylene biguanide, and polyoxyethylene polyoxypropylene glycol. However, there is no clear description of the use of only a sufficient amount of a terpolymer that contributes to improved lubricity, nor is there any description of sodium chloride. In order to improve the moisturizing and lubricity of eye drops, even when a sufficient amount of the specific terpolymer described in Patent Documents 1 and 2, which significantly contributes to improved lubricity, is added, sufficient preservative efficacy may not be achieved when polyhexamethylene biguanide is used as a preservative.

[0013] Furthermore, although polyhexamethylene biguanide has sufficient preservative efficacy as described above, wearing contact lenses cleaned with a multifunctional care solution containing polyhexamethylene biguanide on a cornea with reduced tear volume, reduced barrier function, or damage due to dry eye may cause corneal disorders and corneal infections (e.g., see Non-Patent Document 1). Specifically, not limited to multifunctional care solutions, even eye drops containing preservatives with high preservative efficacy may cause irritation in some patients on corneas with reduced or damaged barrier function, depending on the circumstances. Therefore, there is a demand for eye drops with low eye irritation that can be applied even on corneas with reduced or damaged barrier function.

[0014] Specifically, in the treatment of dry eye, eye drops having high lubricity, sufficient preservative efficacy, and low eye irritation are required.

[0015] The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide an eye drop having high lubricity and preservative effectiveness and capable of reducing eye irritation.

[0016] Methods for solving problems

[0017] The present inventors conducted intensive studies and, based on the novel finding that sodium chloride, a component of tear fluid incorporated into eye drops, reduces the antiseptic activity of polyhexamethylene biguanide, discovered that eye drops containing a ternary copolymer containing a phosphorylcholine group, a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer (hereinafter sometimes referred to as "copolymer (P)"), a specific preservative, and a specific surfactant in specific ratios exhibit high lubricity and preservative effectiveness and reduced eye irritation, thereby completing the present invention.

[0018] The present invention based on the above findings is as follows.

[0019] [1] An eye drop comprising 0.02 w / w% to 0.15 w / w% of a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer in which the molar ratio of the structural units represented by formula (1) is a:b:c=100:10 to 400:2 to 50, 0.000001 w / w% to 0.0001 w / w% of polyhexamethylene biguanide or a salt thereof represented by formula (2), and 0.02 w / w% to 2.0 w / w% of polyoxyethylene polyoxypropylene glycol, wherein the sodium chloride content of the eye drop is 0.3 w / w% or less.

[0020]

[0021] In formula (1), a, b, and c represent the molar ratio of each structural unit.

[0022]

[0023] In formula (2), d is a number representing a repeating unit, and is an integer of 3 or more and 40 or less.

[0024] Effects of the Invention

[0025] The eye drops of the present invention contain a phosphorylcholine group-containing terpolymer, a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer, polyhexamethylene biguanide, and polyoxyethylene polyoxypropylene glycol. Furthermore, the sodium chloride content of the eye drops is 0.3 w / w% or less. Therefore, the eye drops can impart corneal lubricity while exhibiting sufficient preservative efficacy and reducing eye irritation. Specifically, the present invention can provide an eye drop having excellent lubricity, sufficient preservative efficacy, and reduced eye irritation. DETAILED DESCRIPTION

[0026] The eye drops of the present invention contain 0.02 w / w% to 0.15 w / w% of a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer in which the molar ratio of each structural unit represented by formula (1) is a:b:c=100:10 to 400:2 to 50 as component (A), 0.000001 w / w% to 0.0001 w / w% of polyhexamethylene biguanide or a salt thereof represented by formula (2) as component (B), and 0.02 w / w% to 2.0 w / w% of polyoxyethylene polyoxypropylene glycol as component (C), and the sodium chloride content of the eye drops is 0.3 w / w% or less.

[0027]

[0028] In formula (1), a, b, and c represent the molar ratio of each structural unit.

[0029]

[0030] In formula (2), d is a number representing a repeating unit, and is an integer of 3 or more and 40 or less.

[0031] Component (A) used in the eye drops of the present invention comprises three structural units: 2-methacryloyloxyethylphosphocholine represented by formula (1), dimethylacrylamide, and stearyl methacrylate, with the molar ratio of the structural units being a:b:c = 100:10 to 400:2 to 50. The inclusion of component (A) in the eye drops improves lubricity and reduces eye irritation.

[0032] The molar number b of dimethylacrylamide, when the molar number a of 2-methacryloyloxyethylphosphocholine is 100, is b / a = 10 / 100 or more and 400 / 100 or less, preferably 30 / 100 or more and 250 / 100 or less. If the molar number of dimethylacrylamide is too high, the sterile filtration required for the production of eye drops may become difficult, while if it is too low, the lubricity-enhancing effect cannot be expected.

[0033] The molar number c of stearyl methacrylate, when the molar number a of 2-methacryloyloxyethylphosphocholine is 100, is c / a = 2 / 100 or more and 50 / 100 or less, preferably 5 / 100 or more and 25 / 100 or less. If the molar number of stearyl methacrylate is too high, the hydrophilicity of the copolymer (P) decreases, thereby reducing its solubility in water, making the production of eye drops difficult. If the molar number of stearyl methacrylate is too low, the lubricity-enhancing effect becomes insufficient.

[0034] In addition, the weight average molecular weight of the copolymer (P) is 5,000 to 2,000,000. When the weight average molecular weight is less than 5,000, the adsorption force of the polymer on the surface of the contact lens is insufficient, so it is possible that the lubricity cannot be expected to be improved. When the weight average molecular weight exceeds 2,000,000, it is possible that the required sterile filtration is difficult to perform when manufacturing eye drops. In addition, from the viewpoint of improving lubricity, the weight average molecular weight of the copolymer (P) is preferably 100,000 to 1,500,000. It should be noted that the above-mentioned weight average molecular weight refers to the value converted to polyethylene glycol (PEG) measured by gel permeation chromatography (GPC).

[0035] The copolymer (P) represented by formula (1) comprises structural units derived from 2-methacryloyloxyethylphosphocholine, dimethylacrylamide and stearyl methacrylate. The arrangement of the structural units in the copolymer (P) is not particularly limited and may be random or block.

[0036] The copolymer (P) of component (A) can be manufactured as follows, for example. 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate can be manufactured by free radical polymerization in the presence of a free radical polymerization initiator and under an inert gas replacement or atmosphere such as nitrogen, carbon dioxide, argon, or helium. The polymerization method can be carried out by known methods such as bulk polymerization, suspension polymerization, emulsion polymerization, and solution polymerization. The copolymer (P) can be purified by known methods such as reprecipitation, dialysis, and ultrafiltration.

[0037] The amount of component (A) in the eye drops of the present invention is 0.02 w / w% to 0.15 w / w%. If it is less than 0.02 w / w%, lubricity may not be fully exerted, while if it is greater than 0.15 w / w%, the preservative effect of the preservative may be impaired. From the perspective of exerting both the preservative effect and lubricity of the preservative, the amount of component (A) is preferably 0.075 w / w% to 0.125 w / w%.

[0038] Component (B) is a compound represented by the above formula (2), which is called polyhexamethylene biguanide. Alternatively, it may be a salt thereof. In the above formula (2), d is a number representing a repeating unit, which is an integer of 3 or more and 40 or less. If the value of d is less than 3 or greater than 40, it may not be possible to fully exert the preservation effect as an eye drop. From the viewpoint of exerting a more sufficient preservation effect, the value of d is preferably 10 or more and 18 or less.

[0039] Examples of salts of polyhexamethylene biguanide include hydrochloride, borate, acetate, gluconate, sulfonate, tartrate, and citrate. Specific examples include commercially available products such as Cosmocil CQ (registered trademark) or Vantcil IB (registered trademark) manufactured by Arch UK Biocides and BG-1 manufactured by Sanyo Chemical Industries, Ltd. These salts may be used singly or in combination of two or more.

[0040] The amount of component (B) in the eye drops of the present invention is from 0.000001 w / w% to 0.0001 w / w%. If it is less than 0.000001 w / w%, the eye drops may not exhibit sufficient preservative efficacy. Even if it exceeds 0.0001 w / w%, the preservative efficacy may not be improved commensurate with the amount, and cell viability may decrease. To achieve an improvement in preservative efficacy commensurate with the amount of the ingredient and to avoid a decrease in cell viability, the amount of polyhexamethylene biguanide or a salt thereof is preferably from 0.00001 w / w% to 0.00002 w / w%.

[0041] The polyoxyethylene polyoxypropylene glycol as component (C) may be any substance commonly used in pharmaceuticals, and for example, a substance listed in the Japanese Pharmacopoeia may be used. Specific examples thereof include commercially available products such as UNILUBE (registered trademark) 70DP-950B manufactured by NOF Corporation, PLONON (registered trademark) 188P manufactured by NOF Corporation, and NEWPOL (registered trademark) PE-68 manufactured by Sanyo Chemical Industries, Ltd.

[0042] The amount of component (C) in the eye drops of the present invention is 0.02 w / w% to 2.0 w / w%. If the amount of component (C) is less than 0.02 w / w%, the preservation efficacy may be reduced. Even if it is greater than 2.0 w / w%, the preservation efficacy may also be reduced, and the cell survival rate may be reduced. To avoid reducing the preservation efficacy and cell survival rate, the amount of polyoxyethylene polyoxypropylene glycol is preferably 0.1 w / w% to 1.0 w / w%.

[0043] The sodium chloride content in the eye drops of the present invention is 0.3 w / w% or less. A sodium chloride content exceeding 0.3 w / w% may reduce the preservative efficacy. It should be noted that the eye drops of the present invention do not necessarily contain sodium chloride, but a sodium chloride content of 0.1 w / w% to 0.3 w / w% further reduces eye irritation.

[0044] The eye drops of the present invention may contain other ingredients in addition to the above-mentioned components (A) to (C). Examples of other ingredients include polyols, cooling agents, inorganic salts, salts of organic acids, acids, bases, and antioxidants.

[0045] Examples of the polyol include propylene glycol, glycerin, glucose, mannitol, sorbitol, xylitol, and trehalose.

[0046] Examples of the cooling agent include menthol and camphor.

[0047] Examples of the inorganic salt include potassium chloride, borax, sodium hydrogen carbonate, disodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate.

[0048] Examples of the salt of an organic acid include sodium citrate and sodium acetate.

[0049] Examples of the acid include boric acid, phosphoric acid, citric acid, sulfuric acid, acetic acid, and hydrochloric acid.

[0050] Examples of the base include sodium hydroxide, potassium hydroxide, tromethamine, and monoethanolamine.

[0051] Examples of the antioxidant include tocopherol acetate and dibutylhydroxytoluene.

[0052] Example

[0053] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the scope of the following examples.

[0054] The copolymers and homopolymers used in the following Examples and Comparative Examples are as follows.

[0055] Copolymer (P)

[0056] Polymer 1: Copolymer of 2-methacryloyloxyethylphosphocholine (MPC), dimethylacrylamide, and stearyl methacrylate (copolymer composition ratio of MPC, dimethylacrylamide, and stearyl methacrylate (MPC / dimethylacrylamide / stearyl methacrylate (molar ratio) = 10 / 9 / 1), weight-average molecular weight: 100,000)

[0057] Polymer 2: Copolymer of 2-methacryloyloxyethylphosphocholine (MPC), dimethylacrylamide, and stearyl methacrylate (copolymer composition ratio of MPC, dimethylacrylamide, and stearyl methacrylate (MPC / dimethylacrylamide / stearyl methacrylate (molar ratio) = 5 / 4 / 1), weight-average molecular weight: 100,000)

[0058] Copolymer (Q): Copolymer of 2-methacryloyloxyethyl phosphorylcholine (MPC) and butyl methacrylate (copolymer composition ratio of MPC and butyl methacrylate (MPC / butyl methacrylate (molar ratio) = 4 / 1), weight average molecular weight: 600,000)

[0059] [Preparation of eye drops]

[0060] (Example 1)

[0061] Approximately 50 g of purified water was heated to 45°C, and 0.1 g of potassium chloride, 0.4 g of boric acid, 0.04 g of borax, 0.00008 g of Cosmocil CQ (registered trademark) as component (B) (since it is a 20% aqueous solution, it contains 0.000016 g of polyhexamethylene biguanide hydrochloride (polyhexamethylene biguanide hydrochloride)), 1.8 g of concentrated glycerin, 0.2 g of UNILUBE 70DP-950B as component (C), and 10 g of copolymer (P) as component (A) (since it is a 1% aqueous solution, it contains 0.1 g of 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer) were added in this order and stirred. Purified water was then added to bring the total amount to 100 g. The mixture was then sterilized by filtration to prepare a sterile eye drop.

[0062] It should be noted that the above-mentioned CosmocilCQ (registered trademark) is a compound represented by formula (2), where d=14.

[0063] (Examples 2 to 10)

[0064] The same procedures as in Example 1 were followed using the components in the types and amounts shown in Table 1.

[0065] (Comparative Examples 1 to 11)

[0066] The same procedures as in Example 1 were followed using the components in the types and amounts shown in Table 2. Hyaluronic acid was prepared using Bio-Sodium Hyaluronate Powder (MMW) (manufactured by HYUNDAI BIOLAND).

[0067] [Table 1]

[0068]

[0069] [Table 2]

[0070]

[0071] [evaluate]

[0072] The above-mentioned Examples and Comparative Examples were evaluated as follows.

[0073] (1) Evaluation of lubricity

[0074] The slip properties of the gel sheets impregnated with the eye drops of Examples 1 to 10 and Comparative Examples 1 to 11 were evaluated by sensory evaluation when rubbed with fingers.

[0075] (Gel Plate Preparation)

[0076] (1) 19.8166 g of 2-hydroxyethyl methacrylate (HEMA) (manufactured by Mitsubishi Chemical Corporation), 0.2011 g of methacrylic acid (MAA) (manufactured by Tokyo Chemical Industry Co., Ltd.), 0.1429 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), and 0.1005 g of 2,2-azobis(isobutyronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a brown screw tube and stirred and mixed for 1 hour using a wave rotor.

[0077] (2) Use a pipette to dispense into the plate making unit.

[0078] (3) Curing was performed at 100°C for 1 hour.

[0079] (4) The solidified gel was immersed in ISO saline to obtain HEMA-MAA gel.

[0080] After immersing the gel sheet in approximately 50 mL of the eye drops of Examples 1 to 10 and Comparative Examples 1 to 11, the gel sheet was removed and its slipperiness when rubbed with a finger was evaluated according to the following evaluation criteria. The average score of the seven panelists was calculated, and the lubricity was evaluated according to the following evaluation criteria.

[0081] (Evaluation Criteria)

[0082] Good sliding properties of the gel plate: 3 points

[0083] The gel plate has slightly better sliding properties: 2 points

[0084] The gel plate has slightly poor sliding properties: 1 point

[0085] Poor sliding properties of the gel plate: 0 points

[0086] (Judgment Criteria)

[0087] If the average evaluation score is 2 points or more and less than 3 points, it is recorded as good "A", if it is 1.5 points or more and less than 2 points, it is recorded as passing "B", and if it is 0 points or more and less than 1.5 points, it is recorded as unsatisfactory "C".

[0088] The test results are shown in Table 3. The gel sheets of Examples 1 to 10 containing the copolymer (P) exhibited better slip properties than those of Comparative Example 9 in which the copolymer (P) was not contained.

[0089] [Table 3]

[0090] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Rating (points) 2.4 2.3 2.1 2.3 2.3 2.2 2.8 1.8 2.5 1.6 determination A A A A A A A B A B

[0091] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Rating (points) 2.0 2.3 2.4 1.4 3.0 2.4 0.9 2.6 1.2 2.7 1.3 determination A A A C A A C A C A C

[0092] (2) Preservation efficacy test

[0093] The preservation efficacy test was conducted according to the "18th Edition Japanese Pharmacopoeia Reference Information Preservative Efficacy Test Method." Three bacteria species were used: Escherichia coli (hereinafter referred to as Ec) (NBRC3972), Pseudomonas aeruginosa (hereinafter referred to as Pa) (NBRC13275), and Staphylococcus aureus (hereinafter referred to as Sa) (NBRC13276). Two fungi species were used: Candida albicans (hereinafter referred to as Ca) (NBRC1594) and Aspergillus brasiliensis (hereinafter referred to as Ab) (NBRC9455).

[0094] The above-mentioned BIOBALL (registered trademark) (manufactured by BIOMERIEUX Japan Co., Ltd.) containing Ec, Pa, Sa, Ca, and Ab was re-dissolved to prepare 10 8 CFU (Colony Forming Unit, the number of units with the ability to form colonies) was used as the test bacterial solution. This test bacterial solution was added to Examples 1 to 10 and Comparative Examples 1 to 11 in a manner of 1 v / v %, and the inoculated bacterial count was adjusted to 10 per 1 mL. 6 CFU and stored at 25°C.

[0095] Samples were collected 14 and 28 days after inoculation, cultured, and the viable bacterial count was determined. No colonies were observed after 28 days, indicating a good score (A). Colonies were observed after 28 days, but the bacterial count did not increase from the 14-day count, indicating a passing score (B). An increase in the bacterial count after 28 days was considered a failing score (C).

[0096] In addition, in the comprehensive evaluation, the case where no bacterial species produced colonies after 28 days was judged as good "A", the case where at least two or more bacterial species produced colonies after 28 days but the number of colonies was less than that after 14 days was judged as qualified "B", and the case where the number of colonies of at least one bacterial species after 28 days was higher than that after 14 days was judged as unqualified "C".

[0097] The results are shown in Table 4. In Examples 1 to 10, all bacteria and fungi met the criteria. In summary, the eye drops of the present invention have sufficient preservative efficacy.

[0098] [Table 4]

[0099]

[0100] (3) Evaluation of cell survival rate

[0101] Rabbit corneal epithelial cells (SIRC cells) were used to evaluate cell viability. SIRC cells pre-cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10 v / v% FBS (fetal bovine serum) were trypsinized and 1.0 × 10 5 cells / mL of cell suspension. The cell suspension was inoculated into a 96-well plate at 0.1 mL / well and cultured for 24 hours to allow the cells to adhere. Then, 0.1 mL / well of each of Examples 1 to 10 and Comparative Examples 1 to 11 was added and cultured for another 24 hours. The culture medium was removed and 50 μg / mL of neutral red solution was added to allow the neutral red to enter the living cells. After 3 hours, the cells were washed with PBS (phosphate buffered saline), the neutral red was extracted with 1 v / v% acetic acid / 50 v / v% ethanol aqueous solution, and the absorbance at 540 nm was measured. The absorbance when no sample solution was added was set as 100% cell survival rate, and the cell survival rate of those added with Examples 1 to 10 and Comparative Examples 1 to 11 was calculated, and the 50% inhibitory concentration (IC 50 ). In IC 50 When the cell viability is 50% or more and less than 100%, it is judged as "A" because the cell viability is high. 50 When the cell viability is 40% or more and less than 50%, the cell viability is judged as medium and is rated as "B". 50 When the cell viability is greater than 0% and less than 40%, it is judged as "C" because the cell viability is low.

[0102] The results are shown in Table 5. Examples 1 to 10 containing copolymer (P) showed higher cell viability than Comparative Example 9 without copolymer (P) and Comparative Example 11 with a small amount of copolymer (P).

[0103] [Table 5]

[0104] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 <![CDATA[IC 50 (%)]]> 58 55 56 42 60 61 64 45 46 48 determination A A A B A A A B B B

[0105] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 <![CDATA[IC 50 (%)]]> 59 39 59 50 68 61 43 39 30 36 34 determination A C A A A A B C C C C

[0106] (4) Evaluation of cell survival rate after eye drops

[0107] In order to evaluate the cell survival rate after eye drops, the state after eye drops of the present invention mixed with tear fluid was simulated, and the cell survival rate was evaluated using a human double-layered corneal epithelium model (cornea model) (manufactured by Japan Tissue Engineering Co., Ltd.) with 0.55 g of sodium chloride added to the eye drops of Examples 1 to 10 and Comparative Examples 1 to 11. 0.1 mL of each sample solution was added to the cornea model that had been cultured in advance with a measurement culture medium (manufactured by Japan Tissue Engineering Co., Ltd.) and cultured for 24 hours. Then, the reaction solution of the LDH cytotoxicity detection kit (manufactured by TakaraBio Co., Ltd.) was added. After 30 minutes, the reaction termination solution was added and the 490 nm Absorbance. LDH activity, an indicator of the number of affected cells, was calculated from the absorbance to evaluate cell survival after eye instillation. LDH activity values ​​less than 500 units / L indicated high cell survival after eye instillation, designated "A." LDH activity values ​​between 500 units / L and less than 1,000 units / L indicated moderate cell survival after eye instillation, designated "B." LDH activity values ​​greater than 1,000 units / L indicated low cell survival after eye instillation, designated "C."

[0108] The results are shown in Table 6. In Examples 1 to 10, the LDH activity values ​​were low. The result of Example 1 was similar to that of Comparative Example 6, which did not contain polyhexamethylene biguanide hydrochloride. As described above, the eye drops of the present invention further reduce eye irritation by mixing with tear fluid.

[0109] [Table 6]

[0110] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 LDH activity value (unit / L) 320 360 330 490 310 300 290 780 650 550 determination A A A A A A A B B B

[0111] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 LDH activity value (unit / L) 320 495 450 380 250 300 890 1200 1300 1100 950 determination A A A A A A B C C C B

[0112] The results of all test items are shown in Table 7. From the above results, it can be seen that the eye drops of the present invention impart lubricity to the corneal surface, have sufficient preservative efficacy, and have low eye irritation.

[0113] [Table 7]

[0114] pilot projects Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Lubricity test A A A A A A A B A B Preservation efficacy test A A B A A B B A A B Evaluation of cell viability A A A B A A A B B B Cell survival rate after eye drops A A A A A A A B B B

[0115] pilot projects Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 1 Lubricity test A A A C A A C A C A C Preservation efficacy test C A C A C C A A A C C Evaluation of cell viability A C A A A A B C C C C Cell survival rate after eye drops A A A A A A B C C C B

[0116] Industrial Application Possibilities

[0117] According to the present invention, it is possible to obtain an eye drop that imparts lubricity to the corneal surface, has sufficient preservative efficacy, and has low eye irritation.

Claims

1. An eye drop comprising: (A) 0.02 w / w% to 0.15 w / w% of a 2-methacryloyloxyethyl phosphorylcholine-dimethylacrylamide-stearyl methacrylate copolymer having a molar ratio of a:b:c = 100:10 to 400:2 to 50 for each structural unit represented by formula (1); (B) 0.000001 w / w% to 0.0001 w / w% of polyhexamethylene biguanide represented by formula (2) or a salt thereof, and (C) polyoxyethylene polyoxypropylene glycol 0.02 w / w% or more and 2.0 w / w% or less, and The content of sodium chloride in the eye drops is 0.3w / w% or less, In formula (1), a, b, and c represent the molar ratio of each structural unit. In formula (2), d is a number representing a repeating unit, and is an integer of 3 or more and 40 or less.

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