A dry eye treatment agent that shortens tear film breakup time and eye drops containing the treatment agent

Abstract

Provided are a therapeutic agent for short tear breakup time (TBUT)–type dry eye, which has excellent therapeutic effect on dry eye and high safety, and eye drops containing the therapeutic agent.　The present inventors found that a therapeutic agent for short TBUT-type dry eye, said therapeutic agent comprising a copolymer which has three different structural units at a specific ratio and water, is efficacious for treating dry eye, because this therapeutic agent sufficiently moisturizes the corneal surface and retains water thereon so as to induce mucin production on the corneal surface, thereby completing the invention.

Description

[Technical Field]

[0001] The present invention relates to a dry eye treatment agent that shortens tear break-up time (TBUT) and contains a copolymer having a specific structure, and to eye drops containing the treatment agent. This application claims priority to Japanese Patent Application No. 2020-197735, as incorporated herein by reference. [Background technology]

[0002] With the widespread use of smartphones and PCs in recent years, dry eye has become prevalent among a wide range of age groups. Therefore, there is a strong demand for the development of highly effective and safe dry eye treatments.

[0003] Although we refer to it simply as dry eye, the pathology is said to be diverse, and can be classified into three types, for example: (1) tear-deficient dry eye, (2) evaporation-enhanced dry eye, and (3) shortened tear film breakup time dry eye (hereinafter also called "shortened TBUT dry eye").

[0004] For these three types of dry eye, the optimal treatment differs for each: (1) In tear-deficient dry eye, the amount of tears secreted decreases in the first place, so treatment often involves replenishing tears with artificial tears or hyaluronic acid eye drops, or preventing tear reduction with punctal plugs, etc. (Non-patent Literature 1). (2) In evaporative dry eye, the oil layer component of the mucin layer, aqueous layer, and oil layer that make up the tear film is reduced, and dry eye occurs as the evaporation of the aqueous layer is increased (Non-patent Literature 2). For this reason, artificial tears or hyaluronic acid eye drops are instilled to replenish the evaporated tears, and treatments such as warm compresses and lid hygiene aimed at improving the function of the meibomian glands that secrete the oil layer component are often used in combination. (3) In tear film breakup time-reduced dry eye, dry eye symptoms occur when the function of mucin present on the corneal surface is impaired or when the absolute amount of mucin decreases, resulting in reduced tear film spread on the corneal surface and reduced tear film retention. For this reason, eye drops that promote the production of mucin present on the corneal surface (such as Mucosta eye drops or Diquas eye drops) are often used (Non-Patent Literature 3, Non-Patent Literature 4).

[0005] Since tear film breakup time-reduced dry eye is a relatively new type of dry eye discovered through recent research, its treatments have not always proven to be sufficiently effective. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Majid Moshirfar et al., Artificial TearsPotpourri: A Literature Review, Clinical Ophthalmology, 8, 1419-1433, 2014. [Non-Patent Document 2] G.N. Foulks, A.J. Bron, Meibomian gland dysfunction: A clinical scheme for description, diagnostics, classification, and grading., Ocul. Surf., 1, 107 - 126, 2003.

Non - Patent Document 3

Non - Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0007] Regarding dry eye with shortened tear film break - up time, there is currently a demand for a dry eye treatment agent with excellent moisturizing and water - retaining effects on the corneal surface for dry eye with shortened tear film break - up time. For this reason, the present invention provides a TBUT - shortened dry eye treatment agent having an excellent dry eye treatment effect, and an eye drop containing the same.

Means for Solving the Problems

[0008] As a result of intensive research to solve the above problems, the inventors of the present invention have found that a TBUT - shortened dry eye treatment agent containing a copolymer having three different structural units in a specific ratio and water can sufficiently moisturize and retain water on the corneal surface, and thus induce the promotion of mucin production on the corneal surface and is effective for dry eye treatment, and have completed the present invention.

[0009] In other words, the TBUT-shortening type dry eye treatment agent of the present invention, and the eye drops containing the same, are as follows. 1. A dry eye treatment agent that shortens tear film breakup time, comprising a copolymer (P) having constituent units represented by the following general formulas (1a) to (1c) and having a weight-average molecular weight of 5,000 to 2,000,000, wherein the concentration of the copolymer (P) is 0.001 to 1.0 w / v%, and the molar ratio of the constituent units in the copolymer (P) [(1a) / (1b) / (1c)] is 100 / 10 to 400 / 2 to 50. [ka] (In general formula (1a), R 1 (This represents a hydrogen atom or a methyl group.) [ka] (In general formula (1b), R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other. [ka] (In general formula (1c), R 5 R represents a hydrogen atom or a methyl group. 6 (This represents a hydrocarbon group with 12 to 24 carbon atoms.) 2. The tear film breakdown time shortening type dry eye treatment agent according to item 1, wherein the copolymer (P) consists of a constituent unit represented by the general formula (1a), a constituent unit represented by (1b), and a constituent unit represented by (1c). 3. A tear film breakup time shortening type dry eye treatment according to item 1 or 2 above, wherein the constituent unit represented by (1b) is N,N-dimethylacrylamide and the constituent unit represented by (1c) is stearyl methacrylate. 4. An eye drop containing a dry eye treatment agent that shortens the tear film breakup time, as described in any one of items 1 to 3 above. 5. A dry eye treatment method that shortens tear film breakup time, including the following steps: A step of administering a copolymer (P) having a structural unit represented by the following general formulas (1a) to (1c), having a weight average molecular weight of 5,000 to 2,000,000, and having a molar ratio [(1a) / (1b) / (1c)] of the structural units of 100 / 10 to 400 / 2 to 50, or a composition having a concentration of the copolymer (P) of 0.001 to 1.0 w / v% to mammals including humans.

Chemical formula

Chemical formula

Chemical formula

[0010] The present invention's TBUT-shortening dry eye treatment agent has been confirmed to adequately moisturize and retain moisture on the corneal surface and induce the promotion of mucin production on the corneal surface. Furthermore, eye drops containing the TBUT-shortening dry eye treatment agent of the present invention can provide eye drops with excellent therapeutic effects for TBUT-shortening dry eye. [Brief explanation of the drawing]

[0011] [Figure 1]This figure shows the effects of instillation of copolymer (P) on tear volume (A) and TBUT (B) in normal rabbits. In the figure, "Normal" represents the group of normal rabbits without eye instillation (no instillation), "Vehicle" represents the group of normal rabbits without dry eye that received saline eye instillation, and "MPC" represents the group of normal rabbits without dry eye that received MPC polymer (solution containing 0.1 w / v% copolymer (P)) eye instillation. The experiment was conducted on 8 eyes (n=8) of normal rabbits, and samples were collected 2 hours after instillation. [Figure 2] This figure shows the effect of copolymer (P) treatment on the moisture retention time of excised rabbit corneas. A shows the results of observation of the appearance of excised rabbit corneas, and B shows the change in weight of excised rabbit corneas over time. In the figure, "Vehicle" refers to the group of normal rabbits without dry eye treated with physiological saline eye drops, and "MPC" refers to the group of normal rabbits without dry eye treated with MPC polymer (solution containing 0.1 w / v% copolymer (P)) eye drops. [Figure 3] This figure shows the effects of copolymer (P) treatment on tear volume (A), mucin content (B), and tear film disruption (C and D) in a dry eye rabbit model. In the figure, "None" represents the group of rabbits with dry eye that received no eye drops, "Vehicle" represents the group of rabbits with dry eye that received saline eye drops, and "MPC" represents the group of rabbits with dry eye that received MPC polymer (a solution containing 0.1 w / v% copolymer (P)) eye drops. The scale bar size is 1 mm. C shows a magnified image of the rabbit cornea. The black areas in the figure are dry eye spots, indicating areas where tear film disruption and rupture have occurred. The dry eye model was tested with 9 eyes (n=9), eye drops were administered once a day (at 2 PM), and tears were collected using Schirmer test strips at 6 PM, 5 days after the start of the experiment. [Modes for carrying out the invention]

[0012] The present invention will be described in more detail below. The TBUT-shortening type dry eye treatment agent of the present invention contains a copolymer (P) having constituent units represented by the following general formulas (1a) to (1c) and having a weight-average molecular weight of 5,000 to 2,000,000, and water. Furthermore, the concentration of the copolymer (P) is 0.001 to 1.0 w / v%. In addition, the molar ratio of the constituent units in the copolymer (P) [(1a) / (1b) / (1c)] is 100 / 10 to 400 / 2 to 50.

[0013] [ka] (In general formula (1a), R 1 (This represents a hydrogen atom or a methyl group.)

[0014] [ka] (In general formula (1b), R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.

[0015] [ka] (In general formula (1c), R 5 R represents a hydrogen atom or a methyl group. 6 (This represents a hydrocarbon group with 12 to 24 carbon atoms.)

[0016] The configuration of the present invention will be described below. In this specification, "(meth)acrylate" means "acrylate or methacrylate," and the same applies to other similar terms. Furthermore, when preferred numerical ranges (e.g., ranges for concentration or weight-average molecular weight) are described in steps in this specification, each lower and upper limit can be combined independently. For example, in the description "preferably 10 or more, more preferably 20 or more, and preferably 100 or less, and more preferably 90 or less," the "preferred lower limit: 10" and the "more preferred upper limit: 90" can be combined to get "10 or more and 90 or less." Similarly, in the description "preferably 10 to 100, more preferably 20 to 90," the range can be changed to "10 to 90."

[0017] <Copolymer (P)> The copolymer (P) used (included) in the TBUT shortening type dry eye treatment agent of the present invention is a copolymer having general formulas (1a) to (1c) as constituent units and a weight-average molecular weight of 5,000 to 2,000,000.

[0018] [Constituent units represented by general formula (1a)] The copolymer (P) used in the present invention has a constituent unit represented by the following general formula (1a), that is, a constituent unit having a phosphorylcholine structure (hereinafter also referred to as "PC constituent unit"). By having PC constituent units, the copolymer (P) is given hydrophilicity, and can exhibit excellent moisturizing and water-retaining effects on the corneal surface.

[0019] [ka] (In general formula (1a), R 1 (This represents a hydrogen atom or a methyl group.)

[0020] The PC constituent units can be obtained by copolymerizing monomers represented by the following general formula (1a') (hereinafter also referred to as "PC monomers"). From the viewpoint of availability, the PC monomer is preferably 2-((meth)acryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate, and more preferably 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate represented by the following (1a') (hereinafter also referred to as "2-methacryloyloxyethyl phosphorylcholine").

[0021] [ka]

[0022] The content of PC constituent units in the copolymer (P) is preferably 10 mol% or more, more preferably 20 mol% or more, even more preferably 25 mol% or more, and preferably 80 mol% or less, more preferably 75 mol% or less, and even more preferably 70 mol% or less, from the viewpoint of exhibiting excellent moisturizing and water-retaining effects on the corneal surface.

[0023] [Constituent units represented by general formula (1b)] The copolymer (P) used in the present invention has a constituent unit represented by the following general formula (1b) (hereinafter also referred to as "amide constituent unit"). By increasing the molecular weight of the copolymer (P) with the amide constituent unit, the retention of the copolymer (P) on the corneal surface can be improved.

[0024] [ka] (In general formula (1b), R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other.

[0025] The amide constituent units can be obtained by copolymerizing (meth)acrylamide or (meth)acrylamide derivatives, which are monomers represented by the following general formula (1b') (hereinafter also referred to as "amide monomers").

[0026] [ka] (R in general formula (1b') 2 , R 3 , and R 4 These are equivalent to those in general formula (1b).

[0027] Specific examples of monomers represented by formula (1b') include N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, and N-acryloylmorpholine.

[0028] In copolymer (P), the ratio of the number of PC constituent units (1a) to the number of amide constituent units (1b) [(1a) / (1b)] is 100 / 10 to 400, with the number of PC constituent units being 100, preferably 100 / 30 to 250, more preferably 100 / 50 to 150, even more preferably 100 / 70 to 120, even more preferably 100 / 80 to 110, and even more preferably 100 / 80 to 100. If the ratio of the number of amide constituent units to the number of PC constituent units is too large, sterile filtration performed when producing the solution of the present invention may become difficult. On the other hand, if the ratio is too small, the molecular weight of copolymer (P) may not be sufficiently increased, and the retention effect of copolymer (P) on the corneal surface may be insufficient.

[0029] [Constituent units represented by general formula (1c)] The copolymer (P) used in the present invention has a constituent unit represented by the following general formula (1c) (hereinafter also referred to as the "hydrophobic constituent unit"). By having a hydrophobic constituent unit in the copolymer (P), the adhesion of the copolymer (P) to the corneal surface can be improved, and the ability to form a physically crosslinked gel through hydrophobic interactions can be enhanced, further improving the water retention and moisturizing effects of the copolymer (P).

[0030] [ka] (In general formula (1c), R 5 R represents a hydrogen atom or a methyl group. 6 (This represents a hydrocarbon group with 12 to 24 carbon atoms.)

[0031] R in general formula (1c) 6 The group is a hydrocarbon group having 12 to 24 carbon atoms, and may be linear or branched, but linear is preferred. Examples of hydrocarbon groups having 12 to 24 carbon atoms include lauryl, myristyl, cetyl, stearyl, oleyl, and behenyl groups. R 6 Among these, from the viewpoint of improving the adhesion of the copolymer (P) to the corneal surface, it is preferably a hydrocarbon group having 12 to 20 carbon atoms, more preferably a hydrocarbon group having 12 to 18 carbon atoms, and specifically, preferably a lauryl group and a stearyl group.

[0032] Hydrophobic constituent units can be obtained by copolymerizing monomers represented by the following formula (1c') (hereinafter also referred to as "hydrophobic monomers").

[0033] [ka] (R in general formula (1c') 5 and R 6 These are equivalent to those in general formula (1c).

[0034] Specific examples of hydrophobic monomers represented by general formula (1c') include linear alkyl(meth)acrylates such as lauryl(meth)acrylate, myristyl(meth)acrylate, cetyl(meth)acrylate, stearyl(meth)acrylate, oleyl(meth)acrylate, and behenyl(meth)acrylate. Among these, the hydrophobic monomer represented by general formula (1c') is preferably lauryl (meth)acrylate, myristyl (meth)acrylate, and stearyl (meth)acrylate, more preferably lauryl methacrylate and stearyl methacrylate, and more preferably stearyl methacrylate, from the viewpoint of improving the adhesion of the copolymer (P) to the corneal surface.

[0035] In copolymer (P), the ratio of the number of PC constituent units (1a) to the number of hydrophobic constituent units (1c) [(1a) / (1c)] is 100 / 2 to 50, preferably 100 / 5 to 25, more preferably 100 / 7 to 20, and even more preferably 100 / 8 to 15, with the number of PC constituent units being 100. If the ratio of hydrophobic constituent units to the number of PC constituent units is too small, the adhesion of copolymer (P) to the corneal surface may be insufficient. On the other hand, if the ratio is too large, the hydrophilicity of copolymer (P) decreases, reducing its solubility in aqueous solutions, which may make it difficult to manufacture a TBUT-shortening type dry eye treatment agent.

[0036] From the above, the molar ratio of the constituent units in copolymer (P) [(1a) / (1b) / (1c)] is 100 / 10 to 400 / 2 to 50, preferably 100 / 30 to 250 / 5 to 25, more preferably 100 / 50 to 150 / 5 to 25, even more preferably 100 / 70 to 120 / 5 to 25, even more preferably 100 / 80 to 110 / 7 to 20, and even more preferably 100 / 80 to 100 / 8 to 15.

[0037] The copolymer (P) used in the present invention only needs to have at least one PC constituent unit, an amide constituent unit, and a hydrophobic constituent unit, and may, for example, contain multiple types of PC constituent units.

[0038] [Weight-average molecular weight of copolymer (P)] The weight-average molecular weight of copolymer (P) is 5,000 to 2,000,000, preferably 10,000 or more, more preferably 20,000 or more, even more preferably 50,000 or more, and even more preferably 700,000 or more, and preferably 1,800,000 or less, more preferably 1,600,000 or less, even more preferably 1,500,000 or less, even more preferably 1,300,000 or less, and even more preferably 1,100,000 or less. If the weight-average molecular weight is less than 5,000, the copolymer (P) may not adhere well to the corneal surface, potentially resulting in ineffective treatment of TBUT-shortened dry eye. If the weight-average molecular weight exceeds 2,000,000, the viscosity may increase, making handling difficult.

[0039] The weight-average molecular weight of copolymer (P) refers to the value obtained by gel permeation chromatography (GPC). Specifically, it refers to the molecular weight in terms of polyethylene glycol, measured using one of the following as the eluent: chloroform, dimethylformamide, tetrahydrofuran, methanol, or a solution of these solvents.

[0040] [Method for producing copolymer (P)] The copolymer (P) can be prepared, for example, by copolymerizing the monomers according to the method described in International Publication No. 2013 / 128633. In addition, although it is usually a random copolymer, it may also be an alternating copolymer or a block copolymer in which each constituent unit is regularly arranged, and may have a graft structure in part.

[0041] [Concentration of copolymer (P)] The TBUT-shortening type dry eye treatment agent of the present invention has a copolymer (P) concentration of 0.001 w / v% or more, preferably 0.002 w / v% or more, more preferably 0.003 w / v% or more, even more preferably 0.005 w / v% or more, and 1.0 w / v% or less, preferably 0.8 w / v% or less, more preferably 0.6 w / v% or less, and even more preferably 0.5 w / v% or less. If the copolymer (P) concentration is less than 0.001 w / v%, a sufficient TBUT-shortening type dry eye treatment effect cannot be obtained. If it exceeds 1.0 w / v%, it is economically disadvantageous because the effect commensurate with the amount added cannot be obtained. In this invention, "w / v%" represents the mass of a certain component in 100 ml of solution, expressed in grams (g). For example, "the solution of this invention contains 1.0 w / v% copolymer (P)" means that 100 ml of the solution contains 1.0 g of copolymer (P).

[0042] 〔solvent〕 The TBUT-shortening type dry eye treatment agent of the present invention can use water as a solvent. The water used in the TBUT-shortening type dry eye treatment agent of the present invention can be water that is normally used in the manufacture of pharmaceuticals and medical devices. Specifically, ion-exchanged water, purified water, sterile purified water, distilled water, and water for injection can be used.

[0043] [Other ingredients] The TBUT-shortening type dry eye treatment agent of the present invention may further contain the following additives as needed, in addition to the copolymer (P).

[0044] Examples of additives include those conventionally used in eye drops, such as vitamins, amino acids, sugars, cooling agents, inorganic salts, organic acid salts, acids, bases, antioxidants, stabilizers, and preservatives.

[0045] Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, retinyl acetate, retinyl palmitate, pyridoxine hydrochloride, panthenol, sodium pantothenate, and calcium pantothenate.

[0046] Examples of amino acids include aspartic acid and its salts, and aminoethylsulfonic acid.

[0047] Examples of sugars include glucose, mannitol, sorbitol, xylitol, and trehalose.

[0048] Examples of cooling agents include menthol and camphor.

[0049] Examples of inorganic salts include sodium chloride and potassium chloride.

[0050] Examples of organic salts include sodium citrate.

[0051] Examples of acids include phosphoric acid, citric acid, sulfuric acid, and acetic acid.

[0052] Examples of bases include trishydroxymethylaminomethane and monoethanolamine.

[0053] Examples of antioxidants include tocopherol acetate and dibutylhydroxytoluene.

[0054] Examples of stabilizers include sodium edetate and glycine.

[0055] Examples of preservatives include benzalkonium chloride, chlorhexidine gluconate, potassium sorbate, and polyhexanide hydrochloride.

[0056] [Method for manufacturing eye drop solution] The eye drops containing the TBUT-shortening type dry eye treatment agent of the present invention can be manufactured by a general eye drop manufacturing method, which involves mixing and stirring a copolymer (P), water, and other components as needed. The obtained eye drops may be subjected to sterile filtration or other operations as needed.

[0057] [Dry eye treatment method that shortens tear film breakup time] The present invention also includes a method for treating dry eye that shortens tear film breakdown time, comprising the following steps. A step of administering to a mammal, including a human, a copolymer (P) having constituent units represented by the following general formulas (1a) to (1c), having a weight-average molecular weight of 5,000 to 2,000,000, and having a molar ratio of the constituent units [(1a) / (1b) / (1c)] of 100 / 10 to 400 / 2 to 50, or a composition having a concentration of 0.001 to 1.0 w / v% of the copolymer (P). [ka] (In general formula (1a), R 1 (This represents a hydrogen atom or a methyl group.) [ka] (In general formula (1b), R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other. [ka] (In general formula (1c), R 5 R represents a hydrogen atom or a methyl group. 6 (This represents a hydrocarbon group with 12 to 24 carbon atoms.)

[0058] The tear film breakup time-reducing dry eye treatment method of the present invention is not particularly limited, but for example, 0.01 to 0.2 mL of the tear film breakup time-reducing dry eye treatment agent of the present invention can be dropped into the eye (eyeball) from any angle 1 to 10 times, 1 to 8 times, 1 to 6 times, 1 to 4 times, or 1 to 3 times per day (preferably in the morning, noon, and evening). The target population for treatment is not particularly limited, but includes mammals, including humans, and preferably patients who require prevention, relief, improvement, or treatment of tear film breakup time-reduced dry eye.

[0059] [Use of copolymer (P) in the manufacture of a dry eye treatment agent that shortens tear film breakup time] The present invention also includes the use of copolymer (P) as a dry eye treatment agent that shortens tear film breakdown time. Use of a copolymer (P) or a composition having constituent units represented by the following general formulas (1a) to (1c), having a weight-average molecular weight of 5,000 to 2,000,000, and having a molar ratio of the constituent units [(1a) / (1b) / (1c)] of 100 / 10 to 400 / 2 to 50, or a composition having a concentration of 0.001 to 1.0 w / v%, as a dry eye treatment agent for shortening tear film breakup time. [ka] (In general formula (1a), R 1 (This represents a hydrogen atom or a methyl group.) [ka] (In general formula (1b), R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other. [ka] (In general formula (1c), R 5 R represents a hydrogen atom or a methyl group. 6 (This represents a hydrocarbon group with 12 to 24 carbon atoms.)

[0060] The copolymer (P) used in the tear film breakup time-reducing dry eye treatment agent or tear film breakup time-reducing dry eye treatment method of the present invention can be exemplified by the following. 1) The constituent unit represented by (1a) is 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate, the constituent unit represented by (1b) is N,N-dimethylacrylamide, and the constituent unit represented by (1c) is stearyl methacrylate. 2) The constituent unit represented by (1a) is 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate, the constituent unit represented by (1b) is N,N-dimethylacrylamide, and the constituent unit represented by (1c) is lauryl methacrylate. 3) The constituent unit represented by (1a) is 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate, the constituent unit represented by (1b) is N,N-dimethylacrylamide, and the constituent unit represented by (1c) is myristyl methacrylate. [Examples]

[0061] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited thereto.

[0062] [Copolymer (P)] Copolymer (P) used was copolymer (1) shown below. Copolymer (1) was prepared by the method described in the examples of International Publication No. 2013 / 128633.

[0063] [Copolymer (1)] A copolymer using 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (2-methacryloyloxyethyl phosphorylcholine), represented by general formula (1a'), as the PC monomer, N,N-dimethylacrylamide as the amide monomer, and stearyl methacrylate as the hydrophobic monomer. Mole ratio of constituent units [(1a) / (1b) / (1c)] = 100 / 90 / 10 Weight average molecular weight: 1,000,000

[0064] In this example, the weight-average molecular weight of copolymer (P) was measured by dissolving 5 mg of each copolymer obtained in methanol / chloroform mixture (80 / 20) to prepare a sample solution, under the following analytical conditions. Column: PLgel-mixed-C Standard substance: polyethylene glycol Detector: Differential refractometer RI-8020 (manufactured by Tosoh Corporation) Method for calculating weight-average molecular weight: Molecular weight calculation program (GCP program for SC-8020) Flow rate: 1 mL per minute Injection volume: 100μL Column oven: Maintains a constant temperature of around 40°C.

[0065] [Efficacy measurement test for dry eye treatment that shortens tear film breakup time] Various measurements were performed to confirm the therapeutic effect of the tear film breakup time-reducing dry eye treatment, following the procedure outlined below (Reference: Pharmaceutics 2020, 12, 155).

[0066] [Measuring tear film breakup time] (1) N-acetylcysteine ​​was dissolved in physiological saline (sodium chloride: 0.9%, water: remainder) to prepare a 10 w / v% solution. (2) Using the solution prepared in (1), 50 μL was administered as eye drops to male Japanese white rabbits at 2-hour intervals for a total of 6 times. (3) After administering eye drops, the dry eye condition of male Japanese white rabbits was checked the following day, and these were used as a dry eye model that developed dry eye with shortened tear film breakup time. (4) The dry eye model was observed using a dry eye measuring device (DR-1α, Kowa) and its dry eye condition was measured (TBUT was measured). (5) The solutions of the examples or comparative examples shown below were administered as eye drops at a dose of 50 μL once daily for two days. (6) After this, the dry eye condition was measured again using the procedure shown in (4) (2 days). (7) The solution of the example or comparative example was administered as eye drops at a dose of 50 μL once daily for 3 days. (8) After this, the dry eye condition was measured again using the procedure shown in (4) (5 days).

[0067] [Measurement of tear volume] Tear volume was measured using Schirmer test strips.

[0068] [Mucin content measurement test] The mucin content measurement test was conducted according to the following procedure. (1) N-acetylcysteine ​​was dissolved in physiological saline (sodium chloride: 0.9%, water: remainder) to prepare a 10 w / v% solution. (2) Tear fluid was collected for 5 minutes using a Silmel test strip, and the amount of mucin contained in the tear fluid was measured using a tear fluid mucin measurement kit (manufactured by Cosmo Bio) and used as the initial value. (3) Using the solution prepared in (1), 50 μL was administered as eye drops to male Japanese white rabbits at 2-hour intervals for a total of 6 times. (4) The day after administering eye drops, the dry eye condition of male Japanese white rabbits was checked, and these were used as a dry eye model that developed dry eye with shortened tear film breakup time. (5) Mucin levels were measured in dry eye model rabbits or normal rabbits according to the procedure shown in (2). (6) The solution of the example or comparative example was administered as eye drops at a dose of 50 μL once a day for a total of 5 days. (7) After this, the amount of mucin was measured again using the procedure shown in (2). We compared the initial value with the value after 5 days, converted this to a percentage, and calculated the Mucin level (%).

[0069] [Calculation of tear film breakup level] After creating a dry eye model (rabbit), the TBUT was measured and images were acquired. These acquired images were imported into the image processing software ImageJ, and the area of ​​tear film rupture was calculated (initial value). The dry eye model was subjected to repeated cycles of Vehicle eye drops, MPC eye drops, or no eye drops for 5 days. After 5 days, the TBUT was measured again and images were acquired. These acquired images were imported into ImageJ, and the area of ​​tear film rupture was calculated (after 5 days). The area of ​​tear film breakage on the first day was compared with the area of ​​tear film breakage on the fifth day, and this was converted to a percentage to calculate the tearfilm breakup level (%).

[0070] [Corneal surface moisture retention time measurement test] Corneas extracted from rabbits used for measuring tear film breakup time were immersed in the solutions of the examples shown below or the physiological saline solution (sodium chloride: 0.9%, water: remainder) of the comparative example. After removal, they were left to stand for 150 minutes, and their weight was measured at multiple points in time to investigate the change in weight over time. Images of the appearance immediately after removal (0 minutes) and at 60 minutes were also taken with a digital camera.

[0071] <Examples> An aqueous solution containing 1 w / v% copolymer (P) was prepared in advance. A solution containing 0.1 w / v% copolymer (P) was prepared using 0.1 mL of this aqueous solution and physiological saline solution (sodium chloride: 0.9%, water: remainder), and this was used as the solution for the example. For the comparative example, physiological saline solution (sodium chloride: 0.9%, water: remainder) was used.

[0072] [Evaluation of eye drop treatment in healthy rabbits (those without dry eye)] The solution used in the example (labeled "MPC" in Figure 1) or physiological saline solution (sodium chloride: 0.9%, water: remainder, labeled "Vehicle (Comparative Example)" in Figure 1) was administered as eye drops to normal rabbits, and tear volume and TBUT were measured. As a reference example, TBUT was also measured in a group of normal rabbits that did not develop dry eye and received no eye drops. The results are shown in Figure 1.

[0073] [Evaluation of eye drop treatment in a rabbit model with reduced tear film breakup time and dry eye] The solution from the example (labeled "MPC" in Figure 3) or physiological saline solution (sodium chloride: 0.9%, water: remainder, labeled "Vehicle (Comparative Example)" in Figure 3) was administered as eye drops to a dry-eye rabbit model, and tear volume, mucin levels, and tear film breakup were measured. As a reference example, tear volume, mucin levels, and tear film breakup were also measured in a group of rabbits with dry eye that did not receive eye drops. The results are shown in Figure 3.

[0074] [Evaluation of eye drop treatment for extracted rabbit corneas] In normal rabbits after the above evaluation, the solution from the example (labeled "MPC" in Figure 2) or physiological saline solution (sodium chloride: 0.9%, water: remainder, labeled "Vehicle (Comparative Example)" in Figure 2) was instilled into the corneas of excised rabbits, and the corneal water retention time was measured. The results are shown in Figure 2.

[0075] <Result> Regarding the evaluation of eye drop treatment in normal rabbits, an increase in tear volume (Figure 1A) and an increase in TBUT (Figure 1B) were observed when eye drops were administered to normal rabbits. Regarding the evaluation results of eye drop treatment for dry-eyed rabbits, the dry-eyed rabbit model in Figure 3A showed reduced tear volume retention compared to the normal rabbit in Figure 1A, but higher moisture retention was confirmed with the application of the solution in the examples (Figure 3A). Furthermore, improvement in corneal mucin levels due to dry eye was confirmed (Figure 3B). In addition, early repair of tear film damage was also confirmed (Figures 3C and D). Regarding the evaluation of eye drop treatment on excised rabbit corneas, when excised rabbit corneas were treated with the solution from the example, the amount of water adhering to the corneas was higher than that of the comparative example solution (Figures 2A and 2B). Furthermore, an extension of the time until evaporation was confirmed (Figures 2A and 2B).

[0076] Based on the above results, the tear film breakup time-reducing dry eye model treated with the solution of the example showed moisturizing and water-retaining effects on the corneal surface at 2 days and 5 days, confirming the therapeutic effect of the tear film breakup time-reducing dry eye treatment (Figure 3C). Specifically, it was confirmed that the symptoms of tear film breakup time-reducing dry eye completely resolved after 2 days, and this condition was maintained even after 5 days. In other words, early repair of tear film breakup was confirmed. On the other hand, in the comparative and reference examples, the therapeutic effect of shortening tear film breakup time on dry eye was poor even at 2-day and 5-day measurements, and a sufficient therapeutic effect of shortening tear film breakup time on dry eye was not observed (Figure 3C). [Industrial applicability]

[0077] The TBUT-shortening type dry eye treatment agent of the present invention can provide sufficient moisture and water retention on the corneal surface and induce mucin production, thereby exhibiting an excellent TBUT-shortening type dry eye treatment effect.

Claims

1. A dry eye treatment agent that shortens tear film breakup time, comprising a copolymer (P) having constituent units represented by the following general formulas (1a) to (1c) and having a weight-average molecular weight of 5,000 to 2,000,000, wherein the concentration of the copolymer (P) is 0.001 to 1.0 w / v%, and the molar ratio of the constituent units in the copolymer (P) [(1a) / (1b) / (1c)] is 100 / 10 to 400 / 2 to 50. 【Chemistry 1】 (In general formula (1a), R １ (This represents a hydrogen atom or a methyl group.) 【Chemistry 2】 (In general formula (1b), R ２ R represents a hydrogen atom or a methyl group. ３ and R ４ Each of these independently represents a hydrogen atom, a methyl group, an ethyl group, or a morpholino group bonded to each other. 【Transformation 3】 (In general formula (1c), R ５ R represents a hydrogen atom or a methyl group. ６ (This represents a hydrocarbon group with 12 to 24 carbon atoms.)

2. The tear film breakdown time shortening type dry eye treatment agent according to claim 1, wherein the copolymer (P) consists of a constituent unit represented by the general formula (1a), a constituent unit represented by (1b), and a constituent unit represented by (1c).

3. A tear film breakup time shortening dry eye treatment agent according to claim 1 or 2, wherein the constituent unit represented by (1b) is N,N-dimethylacrylamide and the constituent unit represented by (1c) is stearyl methacrylate.

4. An eye drop for treating dry eye that shortens the tear film breakup time, containing the tear film breakup time shortening dry eye treatment agent according to any one of claims 1 to 3.

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