Eye drop composition containing diquafosol

Abstract

The objective is to provide a composition that delays the release of diquafosol while maintaining excellent eye drop comfort. [Solution] We have discovered an eye drop composition containing diquafosol, specifically an eye drop composition containing diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate.

Description

[Technical Field]

[0001] The present invention relates to an eye drop composition containing diquafosol, and more specifically, to an eye drop composition containing diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. [Background technology]

[0002] Diquafosol is a P2Y2 purine receptor agonist used to treat dry eye. Diquas (registered trademark) is a commercially available eye drop containing diquafosol as its active ingredient. This eye drop contains diquafosol sodium at a concentration of 3 w / v% and is administered six times a day. Considering that dry eye is a chronic disease requiring long-term medication administration for at least one month, up to several months, or even a lifetime, frequent administration can reduce patient tolerance to the medication. Therefore, there is a need to provide a diquafosol-containing composition that reduces the frequency of administration and improves medication tolerance.

[0003] On the other hand, since eye drops are administered directly to the delicate mucous membrane of the eye, they need to exhibit physicochemical properties (e.g., viscosity, pH, osmotic pressure, etc.) suitable for application to eye tissue. In particular, stability is required, such as the ability to maintain their properties, physicochemical characteristics, and active ingredient content during storage. Furthermore, since the generation of related substances may reduce drug permeability, it is also necessary to minimize the generation of related substances.

[0004] Furthermore, diquafosol has the disadvantage of poor absorption and sustained release in the eye due to its strong hydrophilicity. For this reason, commercially available diquas products are administered six times a day. To solve this problem, it is necessary to provide a composition that extends the duration of drug effect in the eye. Generally, increasing the viscosity of the product is considered as a method to achieve this, but simply increasing viscosity to improve drug delivery rate may increase patient discomfort such as burning sensation and foreign body sensation, and may actually decrease drug adaptation. Therefore, it is necessary to provide a composition that delays the release of diquafosol while maintaining a good eye drop sensation.

[0005] Therefore, there is a need to develop a new eye drop that can maintain its properties, physicochemical characteristics, and active ingredient content during storage, exhibit excellent stability by minimizing the generation of related substances, maintain a good eye drop sensation while having a delayed release effect, and reduce the number of daily doses. [Prior art documents] [Patent Documents]

[0006] [Patent Document 11] Registered Patent No. 10-1867791 of the Republic of Korea [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention provides an eye drop composition comprising diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. [Means for solving the problem]

[0008] The present invention provides an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, and polyvinyl alcohol.

[0009] The aforementioned eye drop composition retains its properties, physicochemical characteristics, and active ingredient content during storage. Furthermore, it minimizes the generation of related substances, exhibits excellent stability, maintains a pleasant eye drop sensation, and provides sustained dry eye treatment effects through the delayed release of the active ingredient, thereby improving patient convenience.

[0010] The terms "First," "Second," etc., used in this specification are used to distinguish between multiple components or steps, and do not indicate priority.

[0011] In this invention, "Diquafosol" refers to the compound represented by the following chemical formula I, which is generally useful in the treatment of dry eye.

[0012] [Chemical formula I]

[0013] [ka]

[0014] The composition of the present invention comprises diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient, and may, but is not limited to, diquafosol sodium.

[0015] In this specification, "diquafosol" may refer not only to the compound represented by the above chemical formula I, but also to all pharmaceutically acceptable salts thereof.

[0016] The aforementioned diquafosol or a pharmaceutically acceptable salt thereof may be included in the eye drop composition in a therapeutically effective amount for the prevention, improvement, or treatment of dry eye. Specifically, the diquafosol or a pharmaceutically acceptable salt thereof may be included in the total eye drop composition in a content of 0.1 w / v% to 18 w / v%, more specifically in a content of 2 w / v% to 18 w / v%, 1 w / v% to 10 w / v%, 4 w / v% to 10 w / v%, 4.5 w / v% to 10 w / v%, 3 w / v% to 6 w / v%, or 5 w / v% to 10 w / v%, and even more specifically in a content of 4.5 w / v% to 5 w / v% or 5 w / v%, but not limited thereto. The diquafosol may be present in the total eye drop composition in an amount of 0.1 w / v% or more, 1 w / v% or more, 2 w / v% or more, 3 w / v% or more, more specifically, 4 w / v% or more, and even more specifically, 4.5 w / v% or more or 5 w / v% or more. The diquafosol may also be present in the total eye drop composition in an amount of 18 w / v% or less, 10 w / v% or less, or 6 w / v% or less.

[0017] Since the composition of the present invention contains diclofenac sodium or a pharmaceutically acceptable salt thereof, it can be usefully used for the prevention, improvement or treatment of dry eye or related symptoms (e.g., corneal epithelial disorder). It can also be effectively used for the treatment of dry eye with a short tear break-up time and obstructive meibomian gland dysfunction (MGD). The dry eye or related symptoms may include, but are not limited to, symptoms such as a feeling of dryness, discomfort, fatigue, heaviness, and pain in the eyes.

[0018] In a specific embodiment of the present invention related thereto, the composition of the present invention showed a significant effect in the TBUT (Tear break-up time) and corneal fluorescein staining experiments compared with the saline solution administration group, and it was confirmed that it can be usefully used for the prevention , improvement or treatment of dry eye or related symptoms (Figure 5).

[0019] The composition of the present invention contains xanthan gum.

[0020] The xanthan gum is included for the viscosity of the composition, the stability of the composition, and the delay of the release of the active ingredient. Specifically, the xanthan gum may be included in a content of 0.15 w / v% to 0.6 w / v% in the total eyedrop composition, and more specifically, 0.15 w / v% to 0.4 w / v%, 0.2 w / v% to 0.4 w / v%, 0.2 w / v% to 0.3 w / v%, 0.2 w / v% to 0.25 w / v%, or 0.22 w / v% to 0.25 w / v%, and even more specifically, it may be included in a content of 0.225 w / v% to 0.24 w / v% Although it may be rare, it is not limited to this. The xanthan gum may be contained in the total eye drop composition at a content of 0.15 w / v% or more, 0.2 w / v% or more, 0.22 w / v% or more, 0.225 w / v% or more, 0.23 w / v% or more, 0.24 w / v% or more. The xanthan gum may be contained in the total eye drop composition at a content of 0.6 w / v% or less, 0.4 w / v% or less, 0.3 w / v% or less, 0.25 w / v% or less, 0.24 w / v% or less. The xanthan gum may be contained in the total eye drop composition at a content of 0.22 w / v%, 0.225 w / v%, 0.23 w / v%, or 0.24 w / v%.

[0021] The composition of the present invention contains polyvinyl alcohol (Polyvinyl Alcohol; P VA).

[0022] The polyvinyl alcohol is contained for the viscosity of the composition and the delay of the release of the active ingredient. Specifically, the polyvinyl alcohol may be contained in the total eye drop composition at a content of 0.01 w / v% to 1.8 w / v%, more specifically, 0.03 w / v% to 1.4 w / v%, 0.01 w / v% to 1 w / v%, 0.03 w / v% to 1 w / v%, 0.05 w / v % to 1 w / v%, or 0.03 w / v% to 0.28 w / v%, and more specifically, it may be contained at a content of 0.1 w / v% to 1 w / v%, but is not limited thereto. The polyvinyl alcohol may be contained in the total eye drop composition at a content of 0.01 w / v% or more, 0.03 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more. The polyvinyl alcohol may be contained in the total eye drop composition at a content of 1.8 w / v% or less, 1.4 w / v% or less, 1 w / v% or less, 0.5 w / v% or less, 0.3 w / v% or less, 0.28 w / v% or less, 0.1 w / v% or less.

[0023] Polyvinyl alcohol can decompose over time, producing substances such as acetaldehyde and acetic acid, which can result in a sour taste and unpleasant odor. This can cause undesirable problems in terms of taste and smell when used as eye drops. Furthermore, if the polyvinyl alcohol content is too high, it can cause problems in the manufacturing process, such as difficulty dissolving the active ingredient, and reduce stability.

[0024] In order to produce an eye drop composition that is easy to manufacture and has excellent instillation feel and stability, the polyvinyl alcohol may be contained in the total eye drop composition at a concentration of 1 w / v% or less, specifically 0.1 w / v% to 1 w / v%.

[0025] The composition of the present invention comprises diquafosol, xanthan gum, and polyvinyl alcohol, and delays the release of diquafosol, resulting in excellent eye instillation comfort and stability.

[0026] The composition of the present invention may be a stable composition comprising diquafosol, xanthan gum, and polyvinyl alcohol, with a viscosity of 20 mPa·s or higher.

[0027] The composition of the present invention comprises diquafosol, xanthan gum, and polyvinyl alcohol. It can be a stable composition with a viscosity of 20 mPa·s to 450 mPa·s.

[0028] The composition of the present invention comprises diquafosol, xanthan gum, and polyvinyl alcohol, and can be a stable composition that delays the release of diquafosol and has a viscosity of 20 mPa·s to 450 mPa·s.

[0029] The composition of the present invention comprises diquafosol, xanthan gum, and polyvinyl alcohol, and delays the release of diquafosol, allowing for administration in fewer doses.

[0030] The present invention can provide a composition comprising diquafosol, 0.15 w / v% to 0.4 w / v% xanthan gum, and 0.1 w / v% to 1 w / v% polyvinyl alcohol, with a viscosity of 20 mPa·s to 450 mPa·s. The present invention can provide a composition comprising 0.1 w / v% to 18 w / v% diquafosol, 0.15 w / v% to 0.4 w / v% xanthan gum, and 0.1 w / v% to 1 w / v% polyvinyl alcohol, with a viscosity of 20 mPa·s to 450 mPa·s. The present invention can provide a composition comprising 0.1 w / v% to 10 w / v% diquafosol, 0.15 w / v% to 0.4 w / v% xanthan gum, and 0.1 w / v% to 1 w / v% polyvinyl alcohol, with a viscosity of 20 mPa·s to 450 mPa·s.

[0031] The composition of the present invention is excellent in stability and ease of instillation, is easy to manufacture, has an appropriate viscosity, and has the effect of delaying the release of diquafosol.

[0032] In this regard, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention has excellent stability (Figures 1-3, Tables 6-9, Tables 11-14) and that it delays the release of diquafosol (Figures 4, 6-8). Furthermore, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention maintains a constant viscosity at shear rates such as blinking and exhibits high viscosity (Figures 9 and 10).

[0033] The composition of the present invention contains povidone (PVP), polyethylene glycol (PEG), or for delaying the release of the active ingredient. These mixtures may further include:

[0034] The povidone may be included in a content of 0.01 w / v% to 4 w / v%, specifically in a content of 0.01 w / v% to 1.8 w / v%, 0.04 w / v% to 0.6 w / v%, or 0.04 w / v% to 0.12 w / v%, and more specifically in a content of 0.12 w / v%, but is not limited thereto. The povidone may be included in a content of 0.01 w / v% or more, 0.04 w / v% or more, 0.1 w / v% or more, or 0.12 w / v% or more. The povidone may be included in a content of 4 w / v% or less, 1.8 w / v% or less, 0.6 w / v% or less, or 0.12 w / v% or less.

[0035] The polyethylene glycol may be included in a content of 0.01 w / v% to 2 w / v%, specifically in a content of 0.1 w / v% to 2 w / v% or 1 w / v% to 2 w / v%, and more specifically in a content of 1 w / v%, but is not limited thereto. The polyethylene glycol may be included in a content of 0.01 w / v% or more, 0.1 w / v% or more, or 1 w / v% or more. The polyethylene glycol may be included in a content of 2 w / v% or less, or 1 w / v% or less.

[0036] The composition of the present invention contains polysorbates such as polysorbate 20 and polysorbate 80, polyoxyl castor oil, and dexpanthenol to increase the permeability of the active ingredients. It may further contain (nol) or a mixture thereof.

[0037] The composition of the present invention may further contain additives.

[0038] The composition of the present invention may further contain one or more additives selected from pH adjusters, buffers, isotonic agents, viscosity modifiers, solubilizers, stabilizers, and preservatives.

[0039] As the pH adjusting agent, sodium hydroxide, hydrochloric acid, etc., may be used, and the necessary amount can be added by a method known to those skilled in the art to obtain an appropriate pH.

[0040] The buffering agent may include acetic acid and / or its salts, citric acid and / or its salts, phosphoric acid and / or its salts (e.g., sodium hydrogen phosphate and / or its hydrate, sodium dihydrogen phosphate and / or its hydrate), boric acid and / or its salts, and more specifically, phosphates, citric acid and / or its salts, or mixtures thereof may be used, but are not limited thereto.

[0041] The isotonic agent may be glycerol, mannitol, sorbitol, sodium chloride, potassium chloride, boric acid, etc.

[0042] The viscosity modifier may be alginic acid or its salts, carbomer, bentonite, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, etc., and can be used by adding the necessary amount in a manner known to those skilled in the art in order to obtain an appropriate viscosity.

[0043] As the solubilizing agent, benzalkonium chloride, sodium lauryl sulfate, sorbitan monopalmitate, non-oxynol 10, oxynol 9, tyroxapol, poloxamers, diethylene glycol monoethyl ether, polyethylene glycols, polyoxyl 15 hydrogenated stearic acid, etc. may be used.

[0044] The stabilizers may include sodium edetate, aminocaproic acid, carnitine, vitamin E and / or derivatives (e.g., tocopherol acetate), sorbitol, ascorbic acid, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, poloxamer, polypropylene glycol, guar gum, carbomer, alginic acid and its salts, gellan gum, carrageenan, chitosan, and the like.

[0045] The preservatives may include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetalkonium chloride, and polyquaternium-1 (e.g., Polyquad); guanidine compounds such as PHMB and chlorohexidine; chlorobutanol; mercury preservatives such as thimerosal, phenylmercury acetate, and phenylmercury nitrate; and antioxidants such as stabilized oxychloro complexes (e.g., Purite) and alkyl parahydroxybenzoates (e.g., methyl parahydroxybenzoate (PM)).

[0046] The composition of the present invention contains a high concentration of diquafosol, delays its release, and exhibits excellent instillation comfort and stability.

[0047] The composition of the present invention is a stable composition containing a high concentration of diquafosol, which delays its release and has a viscosity of 20 mPa·s to 450 mPa·s.

[0048] The composition of the present invention contains a high concentration of diquafosol, and by delaying its release, the number of administrations can be reduced.

[0049] The composition of the present invention may be administered four times or less per day, more specifically, three times or less per day, two times or less per day, more specifically, two to four times per day, and even more specifically, three times or less per day, but is not limited thereto.

[0050] In this invention, one administration may mean one intravenous infusion.

[0051] The composition of the present invention can improve drug adaptation by reducing the number of administrations.

[0052] The present invention provides an eye drop composition comprising 4 w / v% to 18 w / v% diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w / v% to 0.4 w / v% xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate.

[0053] The present invention provides an eye drop composition comprising 4 w / v% to 10 w / v% diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w / v% to 0.4 w / v% xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate.

[0054] The composition may further contain dexpanthenol.

[0055] The composition may further contain povidone or polyoxyl castor oil.

[0056] The composition may further contain one or more additives selected from pH adjusters, buffers, isotonic agents, viscosity modifiers, solubilizers, stabilizers, and preservatives.

[0057] The present invention can provide a composition comprising 5 w / v% diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 5 w / v% diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, administered three times daily. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.22 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.25 w / v%. The xanthan gum in the composition may be present in an amount of 0.22 to 0.25 w / v%. The composition may further contain dexpanthenol. The dexpanthenol in the composition may be present in an amount of 0.0001 to 1 w / v%.

[0058] The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, administered four times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.2 to 0.4 w / v%. Tan gum may be present in an amount of 0.2 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in an amount of 4.5 to 18 w / v%, 4.5 to 10 w / v%, 4.5 to 9 w / v%, 4.5 to 8 w / v%, 4.5 to 7 w / v%, or 4.5 to 6 w / v%. The composition may further contain dexpanthenol. The dexpanthenol in the composition may be present in an amount of 0.0001 to 1 w / v%.

[0059] The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, which is administered four times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.25 w / v%. The composition may contain diquafosol and its pharmaceutically acceptable salts in amounts of 4.5-18 w / v%, 4.5-10 w / v%, 4.5-9 w / v%, 4.5-8 w / v%, 4.5-7 w / v%, or 4.5-6 w / v%. The composition may further contain dexpanthenol. The composition may contain dexpanthenol in amounts of 0.0001-1 w / v%.

[0060] The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, which is administered three times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.2 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.2 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in amounts of 5-18 w / v%, 5-10 w / v%, 5-9 w / v%, 5-8 w / v%, 5-7 w / v%, or 5-6 w / v%. The composition may further contain The composition may contain expanthenol. The amount of dexpanthenol in the composition may be 0.0001 to 1 w / v%.

[0061] The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, which is administered three times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.4 w / v%. The xanthan gum in the above composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.25 w / v%. The xanthan gum in the above composition may be present in an amount of 0.22~0.4 w / v% or 0.22~0.25 w / It may contain v%. The diquafosol of the composition and its pharmaceutically acceptable salts may be 5-18 w / v%, 5-10 w / v%, 5-9 w / v%, 5-8 w / v%, and 5-7 w / v%. Alternatively, it may contain 5-6 w / v%. The composition may further contain dexpanthenol. The dexpanthenol in the composition may be present in an amount of 0.0001-1 w / v%.

[0062] The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 4.5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w / v% of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, which is administered three times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.4 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v% and less than or equal to 0.25 w / v%. The xanthan gum in the composition may be present in an amount of 0.22 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.22 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in an amount of 4.5 to 18 w / v%, 4.5 to 10 w / v%, 4.5 to 9 w / v%, 4.5 to 8 w / v%, 4.5 to 7 w / v%, or 4.5 to 6 w / v%. The composition may further contain dexpanthenol. The dexpanthenol in the composition may be present in an amount of 0.0001 to 1 w / v%.

[0063] The present invention can provide a composition comprising 4 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate. The present invention can provide a composition comprising 4 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w / v% or more of xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate, which is administered four times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in amounts of 4-18 w / v%, 4-10 w / v%, 4-9 w / v%, 4-8 w / v%, 4-7 w / v%, or 4-6 w / v%. The composition may also contain dexpanthenol. The dexpanthenol in the composition may be present in an amount of 0.0001 to 1 w / v.

[0064] The present invention can provide a composition comprising 4 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof; 0.15 w / v% or more of xanthan gum; polyvinyl alcohol and / or polyethylene glycol; and polysorbate and / or dexpanthenol. The present invention can provide a composition comprising 4 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof; 0.15 w / v% or more of xanthan gum; polyvinyl alcohol and / or polyethylene glycol; and polysorbate and / or dexpanthenol, administered four times or less per day. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.15 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in an amount of 4 to 18 w / v%, 4 to 10 w / v%, 4 to 9 w / v%, 4 to 8 w / v%, 4 to 7 w / v%, or 4 to 6 w / v%. Expanthenol may be present in a concentration of 0.0001 to 1 w / v%.

[0065] The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof; 0.2 w / v% or more of xanthan gum; polyvinyl alcohol and / or polyethylene glycol; and polysorbate and / or dexpanthenol. The present invention can provide a composition comprising 5 w / v% or more of diquafosol or a pharmaceutically acceptable salt thereof; 0.2 w / v% or more of xanthan gum; polyvinyl alcohol and / or polyethylene glycol; and polysorbate and / or dexpanthenol, administered three times a day or less. The polyvinyl alcohol in the composition may be present in an amount of 0.1 to 1 w / v%. The polyethylene glycol in the composition may be present in an amount of 0.01 to 2 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 5 w / v%. The polysorbate in the composition may be present in an amount of 0.01 to 1 w / v%. The xanthan gum in the composition may be present in an amount of 0.2 to 0.4 w / v%. The xanthan gum in the composition may be present in an amount of 0.2 to 0.25 w / v%. The xanthan gum in the composition may be present in an amount greater than 0.2 w / v%, 0.4 w / v% or less, 0.22 to 0.4 w / v%, or 0.22 to 0.25 w / v%. The diquafosol and its pharmaceutically acceptable salts in the composition may be present in an amount of 5 to 18 w / v%, 5 to 10 w / v%, 5 to 9 w / v%, 5 to 8 w / v%, 5 to 7 w / v%, or 5 to 6 w / v%. The dexpanthenol in the composition may be present in an amount of 0.0001 to 1 w / v%.

[0066] The components and effects of the aforementioned composition are as described above.

[0067] In this regard, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits a sustained dry eye treatment effect even with fewer administrations compared to commercially available products (Figure 5).

[0068] The compositions of the present invention exhibit physicochemical properties (e.g., viscosity, pH, osmotic pressure, etc.) suitable for application to ocular tissue.

[0069] The viscosity of the composition of the present invention, when measured using a single cylindrical rotational viscometer and spindle S61, may be between 1 mPa·s and 450 mPa·s, more specifically between 10 mPa·s and 450 mPa·s, 20 mPa·s and 450 mPa·s, 10 mPa·s and 200 mPa·s, and more specifically between 20 mPa·s and 70 mPa·s, but is not limited thereto. The viscosity of the composition of the present invention may be 1 mPa·s or more, 10 mPa·s or more, and more specifically, 20 mPa·s or more. The viscosity of the composition of the present invention may be 450 mPa·s or less, 200 mPa·s or less, and more specifically, 70 mPa·s or less.

[0070] The pH of the composition of the present invention may be 5 to 9, and more specifically, it may be 6 to 8, but is not limited thereto.

[0071] The osmotic pressure of the composition of the present invention may be 250 mOsmol / kg to 500 mOsmol / kg, and more specifically, 270 mOsmol / kg to 330 mOsmol / kg, but is not limited thereto.

[0072] The composition of the present invention can maintain its properties, physicochemical characteristics, and active ingredient content during storage, and exhibits excellent stability while minimizing the generation of related substances.

[0073] In this regard, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention can maintain stable pH, osmotic pressure, viscosity, and active ingredient content during storage, exhibiting excellent stability (Figure 3, Tables 6-9, Tables 11-14), and that it generates a small amount of related substances, exhibiting excellent stability (Figure 2).

[0074] Furthermore, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention did not change in properties during storage, and that its property stability was improved (Figure 1).

[0075] The composition of the present invention can exhibit excellent sustained effect and delayed release while maintaining a pleasant eye drop sensation.

[0076] In this regard, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits excellent eye drop sensation (Table 20).

[0077] Furthermore, in one specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits excellent persistence (Figures 9 and 10) and shows a delayed release effect (Figures 4, 6-8).

[0078] The compositions of the present invention are specially formulated for topical application and may be administered topically in dosage forms such as liquids, emulsions, suspensions, gels, or ointments.

[0079] The present invention provides an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, and polyethylene glycol.

[0080] The components contained in the aforementioned composition, the amount of each component, and their effects are as described above.

[0081] The present invention provides an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polysorbate, and dexpanthenol.

[0082] The components contained in the aforementioned composition, the amount of each component, and their effects are as described above.

[0083] The present invention provides an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, povidone, polyethylene glycol, polysorbate, and dexpanthenol.

[0084] The components contained in the aforementioned composition, the amount of each component, and their effects are as described above.

[0085] The present invention can provide a method for producing an eye drop composition comprising mixing diquafosol, xanthan gum, and polyvinyl alcohol.

[0086] The above manufacturing method may further include adding additives or carriers such as polyethylene glycol, povidone, polysorbate, and dexpanthenol.

[0087] The present invention provides a method for preventing or treating dry eye, which includes administering the aforementioned eye drop composition to an individual.

[0088] For example, the present invention provides a method for preventing or treating dry eye, comprising administering an eye drop composition containing diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate to an individual.

[0089] The present invention also provides the use of the aforementioned eye drop composition for the manufacture of agents for the prevention or treatment of dry eye.

[0090] For example, the present invention provides uses for eye drop compositions comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate for the manufacture of agents for the prevention or treatment of dry eye.

[0091] The present invention also provides the aforementioned use of the eye drop composition for the prevention or treatment of dry eye.

[0092] For example, the present invention provides uses for eye drop compositions comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate for the prevention or treatment of dry eye.

[0093] In the present invention, the term "individual" may mean any animal, including humans, that has been diagnosed with or may be diagnosed with dry eye. The animal may be, but is not limited to, humans, mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms.

[0094] In the present invention, "administration" means introducing the eye drop composition of the present invention to a patient by any appropriate method, and the route of administration of the present invention may be local administration to the eyeball, since the composition is an eye drop. The method for treating dry eye of the present invention includes administering the eye drop composition of the present invention in a therapeutically effective amount.

[0095] The composition of the present invention can be administered in a pharmaceutically effective amount. The pharmaceutically effective amount is sufficient to treat the disease with a reasonable benefit / risk ratio applicable to medical treatment, and This refers to an amount that does not cause side effects, and the level of the effective dose can be determined according to the patient's health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the timing of administration, the route of administration and elimination rate, the duration of treatment, factors including drugs that are combined or used simultaneously, and other factors that are well known in the medical field. Specifically, it may be administered once to several times a day at regular intervals, at the discretion of the physician or pharmacist, and each dose may be 0.01 ml to 0.1 ml, but is not limited to these.

[0096] The matters mentioned in the eye drop compositions, uses, and therapeutic methods of the present invention shall apply equally to each other, insofar as they do not contradict each other. [Effects of the Invention]

[0097] The composition of the present invention can maintain its properties, physicochemical characteristics, and active ingredient content during storage, exhibits excellent stability with minimal generation of related substances, and can provide sustained effects through delayed release of the active ingredient. The composition of the present invention can maintain excellent eye drop comfort and exhibit excellent sustained effect. The composition of the present invention can improve medication adaptation by reducing the number of administrations. Therefore, the composition of the present invention can be usefully used for the prevention or treatment of dry eye or related symptoms. [Brief explanation of the drawing]

[0098] [Figure 1] Figure 1 is a photograph showing the results (properties evaluation) of the stability evaluation (1) for Experimental Example 1. [Figure 2] Figure 2 is a graph showing the results of the stability evaluation (1) for Experimental Example 1 (evaluation of the amount of related substances generated). [Figure 3] Figure 3 is a graph showing the results of the stability evaluation (2) for Experimental Example 2. [Figure 4] Figure 4 is a graph showing the results of the delayed release evaluation (1) for Experimental Example 3. [Figure 5] Figure 5 is a graph showing the results of the evaluation of the treatment effect for dry eye in Experimental Example 4. [Figure 6] Figure 6 is a graph showing the results of the delayed release evaluation (2) for Experimental Example 7. [Figure 7] Figure 7 is a graph showing the results of the delayed release evaluation (3) for experimental example 8. [Figure 8] Figure 8 is a graph showing the results of the delayed release evaluation (4) for experimental example 9. [Figure 9] Figure 9 is a graph showing the results of the endurance evaluation (i) for Experiment Example 11. [Figure 10] Figure 10 is a graph showing the results of the endurance evaluation (b) for Experiment Example 11. [Modes for carrying out the invention]

[0099] The present invention will be described in more detail below with reference to experimental examples. These experimental examples are merely illustrative of the present invention, and it will be obvious to those with ordinary skill in the art that the scope of the present invention is not limited by these examples. [Examples]

[0100] <Experimental Example 1> Stability Evaluation (1) - Property Stability and Amount of Related Substances Generated

[0101] The compositions of Example 1 and Comparative Example 1 were prepared according to the compositions shown in Table 1 below.

[0102] Example 1: Sterile purified water was hydrated with polyvinyl alcohol and xanthan gum at a high temperature (60-70°C or higher), and then sterilized at high temperature and high pressure to produce the first solution. Diquafosol sodium and disodium hydrogen phosphate dihydrate were added to another sterile purified water and dissolved, and then filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce the composition of Example 1 with a pH of approximately 7.2 ± 0.2.

[0103] Comparative Example 1: A composition of Comparative Example 1 with a pH of approximately 7.2 ± 0.2 was prepared in the same manner as in Example 1, except that the addition of xanthan gum was omitted.

[0104] [Table 1]

[0105] As described above, Example 1 and Comparative Example 1 were stored at 70°C (55% humidity) for 4 weeks. After storage, their properties were observed, and the content of related substances was measured. The results are shown in Figures 1 and 2.

[0106] As can be seen from the results in Figure 1, Comparative Example 1 showed a change in properties to yellow (right photo), while Example 1 showed no change in properties (left photo). This indicates that the composition of the present invention has improved property stability.

[0107] As can be seen from the results in Figure 2, Comparative Example 1 generated a relatively large amount of related substances, while Example 1 according to the present invention generated a relatively small amount of related substances.

[0108] This revealed that the composition of the present invention reduces the amount of related substances generated.

[0109] <Experimental Example 2> Stability Evaluation (2) - Changes in pH, osmotic pressure, and viscosity

[0110] The composition of Example 2 was prepared according to the composition shown in Table 2 below.

[0111] Example 2: Sterile purified water was hydrated with xanthan gum and povidone at high temperature (60-70°C or higher), polyethylene glycol was added and dissolved, and then the mixture was sterilized at high temperature and high pressure to produce the first solution. Polyvinyl alcohol was added to another sterile purified water and dissolved at high temperature (60-70°C or higher), and then dexpanthenol, disodium hydrogen phosphate dihydrate, polysorbate, sodium diquafosol and an isotonic agent were added and dissolved, and then a 0.2 μm membrane was prepared. The first solution was filtered to prepare the second solution. The first and second solutions were mixed to prepare the composition of Example 2.

[0112] [Table 2]

[0113] The pH, osmotic pressure, and viscosity of the prepared Example 2 were measured while it was stored at 55°C (75% humidity) for 14 days, and the results are shown in Figure 3. As can be seen from Figure 3, the pH, osmotic pressure, and viscosity of Example 2 according to the present invention were confirmed to be stably maintained. This indicates that the composition of the present invention exhibits excellent physicochemical stability.

[0114] <Experimental Example 3> Delayed Emission (1)

[0115] The compositions of Example 3 and Comparative Example 2 were prepared according to the compositions shown in Table 3 below.

[0116] Example 3: Sterile purified water was hydrated with polyvinyl alcohol and xanthan gum at a high temperature (60-70°C or higher), and then sterilized at high temperature and high pressure to produce the first solution. Diquafosol sodium and a buffer were added to another sterile purified water and dissolved, and then filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce the composition of Example 3 with a pH of approximately 7.2 ± 0.2.

[0117] Comparative Example 2: Diquafosol sodium and a buffer were dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to produce a composition with a pH of approximately 7.2 ± 0.2.

[0118] [Table 3]

[0119] The compositions of Example 3 and Comparative Example 2, manufactured as described above, were used in a semipermeable membrane (Float-A-Lyzer) and an eluter (SOTAX) TM The release pattern of the active ingredient over time was observed using a liquid chromatogram. Specifically, the composition was placed in a semipermeable membrane and then placed in an elutor containing an STF (Simulated Tear Fluid) solution, and the amount of active ingredient released was measured using a liquid chromatogram.

[0120] As can be seen from Figure 4, it was confirmed that the release of the active ingredient in Example 3 according to the present invention was delayed compared to Comparative Example 2 (Figure 4).

[0121] <Experimental Example 4> Treatment effect of dry eye

[0122] The compositions of Examples 4-1 and 4-2 were prepared according to the compositions shown in Table 4 below.

[0123] Examples 4-1 and 4-2: Sterile purified water was hydrated with xanthan gum and povidone at high temperature (60-70°C or higher), polyethylene glycol was added and dissolved, and then the mixture was sterilized at high temperature and high pressure to produce the first solution. Polyvinyl alcohol was added to another sterile purified water and dissolved at high temperature (60-70°C or higher), and the mixture was filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce a mixture. Diquafosol sodium, a buffer, dexpanthenol, polysorbate, and an isotonic agent were added to another sterile purified water and dissolved, and then the mixture was filtered through a 0.2 μm membrane filter to produce the third solution. The mixture produced above and the third solution were mixed to produce the compositions of Examples 4-1 and 4-2 with a pH of approximately 7.2 ± 0.2.

[0124] [Table 4]

[0125] In a New Zealand White Rabbit dry eye animal model, the therapeutic effects of commercially available products, DIQUAS® ophthalmic solution 3%, saline solution, and Examples 4-1 and 4-2, on dry eye were confirmed, and the results are shown in Figure 5. DIQUAS ophthalmic solution (G1) was administered six times by intravenous drip, while Examples 4-1 (G2), 4-2 (G3), and saline solution were each administered three times by intravenous drip.

[0126] As can be seen in Figure 5, the administration groups of Diquas eye drops and Examples 4-1 and 4-2 according to the present invention all showed significant effects compared to the saline solution administration group in terms of TBUT (Tear break-up time) and corneal fluorescent dye staining experiments.

[0127] This revealed that the composition of the present invention exhibits a sustained dry eye treatment effect even with fewer administrations compared to commercially available products.

[0128] <Experimental Example 5> Stability Evaluation (3)

[0129] The compositions of Examples 5 to 7 were prepared according to the ingredients and content shown in Table 5 below.

[0130] Examples 5-7: Sterile purified water was hydrated with polyvinyl alcohol and xanthan gum at high temperature (60-70°C or higher) and sterilized under high temperature and pressure to produce the first solution. Diquafosol sodium and a buffer were dissolved in another sterile purified water to produce a solvent, which was then filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce the compositions of Examples 5-7 with a pH of approximately 7.2 ± 0.2.

[0131] [Table 5]

[0132] The prepared samples from Examples 5-7 were stored at 55°C (75% humidity) for 28 days and at 70°C (55% humidity) for 14 days. Their properties, pH, osmotic pressure, viscosity, and diquafosol content were then evaluated, and the results are shown in Tables 6-9 below. Viscosity was measured using a single-cylinder rotational viscometer and spindle S61 at 25°C and with a torque value of 80% or higher.

[0133] As a result, even after storage at 55°C and 70°C, Examples 5 to 7 all remained transparent and clear without any change in properties, confirming their excellent property stability.

[0134] As can be seen from the results in Tables 6-9 below, Examples 5-7 of the present invention showed excellent stability, with no significant changes in pH, osmotic pressure, or viscosity even after storage under the above conditions (Tables 6-8), and the change in diquafosol content was also very small, confirming its stability (Table 9).

[0135] [Table 6]

[0136] [Table 7]

[0137] [Table 8]

[0138] [Table 9]

[0139] <Experimental Example 6> Stability Evaluation (4)

[0140] The compositions of Examples 8 to 10 were prepared according to the compositions shown in Table 10 below.

[0141] Examples 8-10: Add polyvinyl alcohol and xanthan gum to sterile purified water and heat at high temperature. The first solution was prepared by hydrating at 60-70°C or higher and sterilizing under high temperature and pressure. Diquafosol sodium and a buffer were dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare the second solution. The first and second solutions were mixed to prepare the compositions of Examples 8-10, which had a pH of approximately 7.2 ± 0.2.

[0142] [Table 10]

[0143] Examples 8-10 were stored at 55°C (75% humidity) for 28 days and at 70°C (55% humidity) for 14 days. Their properties, pH, osmotic pressure, viscosity, and diquafosol content were then evaluated, and the results are shown in Tables 11-14 below. Viscosity was measured using the same method as in Experimental Example 5.

[0144] As a result, even after storage at 55°C and 70°C, Examples 8-10 all remained transparent and clear without any change in properties, confirming their excellent property stability.

[0145] Examples 8-10 showed excellent stability, with no significant changes in pH, osmotic pressure, or viscosity after storage under the above conditions (Tables 11-13), and the change in the active ingredient content was also very small, confirming their stability (Table 14). Compared to Example 10, Examples 8-9 showed improved stability with smaller fluctuations in osmotic pressure and pH, and maintained a high viscosity, making them more preferable.

[0146] [Table 11]

[0147] [Table 12]

[0148] [Table 13]

[0149] [Table 14]

[0150] <Experimental Example 7> Delayed Release Evaluation (2)

[0151] The compositions of Comparative Example 3 and Examples 11-12 were prepared according to the compositions shown in Table 15 below.

[0152] Comparative Example 3: Diquafosol sodium and a buffer were dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to produce the composition of Comparative Example 3, which had a pH of approximately 7.2 ± 0.2.

[0153] Examples 11 and 12: Add polyvinyl alcohol and xanthan gum to sterile purified water. The first solution was prepared by hydrating at a high temperature (60-70°C or higher) and sterilizing at high temperature and high pressure. Diquafosol sodium and a buffer were dissolved in another sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare the second solution. The first and second solutions were mixed to prepare the compositions of Examples 11 and 12, which had a pH of approximately 7.2 ± 0.2.

[0154] [Table 15]

[0155] Semi-permeable membrane (Float-A-Lyzer) and eluator (SOTAX) TM The release patterns of the active ingredients in Comparative Example 3 and Examples 11-12 were observed over time using the following method. Specifically, the compositions were placed in a semipermeable membrane and then in an elutor containing an STF (Simulated Tear Fluid) solution. The amount of active ingredient released was evaluated using a liquid chromatogram, and the results are shown in Figure 6.

[0156] As can be seen from Figure 6, it was confirmed that Examples 11 and 12 according to the present invention effectively delayed the release of the active ingredient compared to Comparative Example 3, which did not contain any xanthan gum or polyvinyl alcohol.

[0157] <Experimental Example 8> Delayed Release Evaluation (3)

[0158] The compositions of Comparative Example 4 and Example 13 were prepared according to the compositions shown in Table 16 below. Comparative Example 4 was prepared in the same manner as Comparative Example 3, and Example 13 was prepared in the same manner as Example 11. The pH of the prepared compositions was approximately 7.2 ± 0.2.

[0159] [Table 16]

[0160] A semipermeable membrane (Float-A-Lyzer) and an elutor (SOTAX) were constructed using the same method as in Experimental Example 7. TMUsing [a specific method], the time-dependent release patterns of the active ingredients in Comparative Example 4 and Example 13 were observed, and the results are shown in Figure 7.

[0161] As can be seen from Figure 7, Example 13 of the present invention uses xanthan gum and polyvinyl alcohol. We confirmed that the release of the active ingredient was more effectively delayed than in Comparative Example 4, which contained no ethanol at all.

[0162] <Experimental Example 9> Delayed Release Evaluation (4)

[0163] The compositions of Comparative Example 5 and Examples 14-15 were prepared according to the compositions shown in Table 17 below. Comparative Example 5 and Example 15 were prepared in the same manner as Comparative Example 3 and Example 11, respectively, and the pH of the prepared compositions was approximately 7.2 ± 0.2.

[0164] Example 14: Sterile purified water was hydrated with xanthan gum and povidone at high temperature (60-70°C or higher), polyethylene glycol was added and dissolved, and then the mixture was sterilized at high temperature and high pressure to produce the first solution. Polyvinyl alcohol was added to another sterile purified water and dissolved at high temperature (60-70°C or higher), then a buffer and diquafosol sodium were dissolved, the mixture was filtered through a 0.2 μm membrane filter, and the mixture was mixed with the previously produced solution to produce the composition of Example 14 with a pH of approximately 7.2 ± 0.2.

[0165] [Table 17]

[0166] The prepared samples from Examples 14-15 and Comparative Example 5 were placed in a semipermeable membrane (Float-A-Lyzer) and eluted in an elutor (SOTAX) containing STF (Simulated Tear Fluid) solution. TM The samples were placed in a container, and the amount of active ingredient released was evaluated using a liquid chromatogram. The results are shown in Figure 8.

[0167] As can be seen from Figure 8, it was confirmed that Examples 14 and 15 according to the present invention effectively delayed the release of the active ingredient compared to Comparative Example 5.

[0168] <Experimental Example 10> Evaluation of eye drop sensation - irritation

[0169] The composition of Example 16 was prepared according to the composition shown in Table 18 below.

[0170] Example 16: Sterile purified water was hydrated with xanthan gum and povidone at high temperature (60-70°C or higher), polyethylene glycol was added and dissolved, and then the mixture was sterilized at high temperature and high pressure to produce the first solution. Polyvinyl alcohol was added to another sterile purified water and dissolved at high temperature (60-70°C or higher), then dexpanthenol, polysorbate, buffer, and diquafosol sodium were dissolved, and the mixture was filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce the composition of Example 16 with a pH of approximately 7.2 ± 0.2. did.

[0171] [Table 18]

[0172] The irritant properties were evaluated using the prepared Example 16. 30 μL of the composition of Example 16 was administered to each eye of 23 healthy adults, and the burning sensation, foreign body sensation, blurred vision, and residual sensation felt after 3 minutes were evaluated according to the criteria in Table 19.

[0173] [Table 19]

[0174] [Table 20]

[0175] Table 20 shows the average evaluation scores. The evaluation results showed that burning sensation, foreign body sensation, blurred vision, and residual sensation were either absent or present at a very low level, indicating that the eye drop composition of the present invention has excellent eye drop comfort (Table 20).

[0176] <Experimental Example 11> Endurance Evaluation

[0177] The composition of Example 17 was prepared according to the composition shown in Table 21 below.

[0178] Example 17: Xanthan gum was added to sterile purified water and hydrated at high temperature (60-70°C or higher). Polyethylene glycol was added and dissolved, and then the mixture was sterilized at high temperature and high pressure to produce the first solution. Polyvinyl alcohol was added to another sterile purified water and dissolved at high temperature (60-70°C or higher). Then, dexpanthenol, polysorbate, buffer, and diquafosol sodium were dissolved, and the mixture was filtered through a 0.2 μm membrane filter to produce the second solution. The first and second solutions were mixed to produce the composition of Example 17 with a pH of approximately 7.2 ± 0.2.

[0179] [Table 21]

[0180] (stomach)

[0181] The manufactured Example 17 and the aforementioned Diquas eye drops were respectively STF (Simulated After mixing with Tear Fluid solution in a 30:7 ratio, the rheometer (MCR) was used to increase the shear rate at 35°C. The viscosity was measured using 302), and the results are shown in Figure 9.

[0182] As can be seen from Figure 9, the composition of Example 17 according to the present invention has a shear rate of approximately 3000 S -1 However, while it maintains a constant viscosity, Diquas eye drops have a shear rate of approximately 900 S. -1 It was confirmed that it could no longer maintain a certain viscosity. Furthermore, the composition of Example 17 was found to have a minimum shear rate of 1000 S due to typical blinking. -1 Even above, it shows high viscosity. Confirmed.

[0183] (b)

[0184] Further, after mixing the composition of Example 17 with a STF (Simulated Tear Fluid) solution at a ratio of 30:7, the shear rate was changed from 1 S -1 to 5000 S -1 and then again from 5000 S -1 to 1 S -1 while measuring the viscosity under the condition of 35°C, and the results are shown in FIG. 10.

[0185] As can be seen from FIG. 10, it was confirmed that the composition of Example 17 according to the present invention rapidly and completely recovers the viscosity that instantaneously decreased at a high shear rate. Thus, it was found that the eye drop composition of the present invention can maintain a continuous and excellent viscosity even under a shear stress such as a blink.

[0186] As described above, specific parts of the present invention have been described in detail. However, for those with ordinary knowledge in the art, such specific descriptions are merely preferred implementation examples, and it is clear that the scope of the present invention is not limited thereto. Therefore, it can be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, and polyvinyl alcohol.

2. The eye drop composition according to claim 1, wherein the diquafosol or a pharmaceutically acceptable salt thereof is diquafosol sodium.

3. The eye drop composition according to claim 1, wherein the diquafosol or a pharmaceutically acceptable salt thereof is contained in an amount of 0.1 w / v% to 18 w / v% in the total eye drop composition.

4. The eye drop composition according to claim 1, wherein the xanthan gum is contained in an amount of 0.15 w / v% to 0.6 w / v% of the total eye drop composition.

5. The eye drop composition according to claim 1, wherein the polyvinyl alcohol is contained in an amount of 0.01 w / v% to 1.8 w / v% in the total eye drop composition.

6. The eye drop composition according to claim 1, further comprising povidone, polyethylene glycol, or a mixture thereof.

7. The eye drop composition according to claim 6, wherein the povidone is contained in an amount of 0.01 w / v% to 4 w / v% of the total eye drop composition.

8. The eye drop composition according to claim 6, wherein the polyethylene glycol is contained in an amount of 0.01 w / v% to 2 w / v% of the total eye drop composition.

9. The eye drop composition according to claim 1, further comprising polysorbate, polyoxyl castor oil, dexpanthenol, or a mixture thereof.

10. The eye drop composition according to claim 1, wherein the composition is administered four times or less per day.

11. The eye drop composition according to claim 1, further comprising one or more additives selected from pH adjusters, buffers, isotonic agents, viscosity modifiers, solubilizers, stabilizers, and preservatives.

12. The eye drop composition according to claim 1, wherein the viscosity of the composition is 20 mPa·s to 450 mPa·s.

13. The eye drop composition according to claim 1, further comprising polyethylene glycol, polysorbate, dexpanthenol, or a mixture thereof, wherein the diquafosol or a pharmaceutically acceptable salt thereof is contained in an amount of 4 w / v% to 18 w / v%, the xanthan gum is contained in an amount of 0.15 w / v% to 0.6 w / v%, the polyvinyl alcohol is contained in an amount of 0.1 w / v% to 1 w / v%, the polyethylene glycol is contained in an amount of 0.01 w / v% to 2 w / v%, and the polysorbate is contained in an amount of 0.01 to 5 w / v%.

14. The composition further comprises polyethylene glycol, polysorbate, dexpanthenol, or a mixture thereof, wherein the diquafosol or a pharmaceutically acceptable salt thereof is present in the total eye drop composition in an amount of 4.5 w / v% to 18 w / v%, and the xa The eye drop composition according to claim 1, wherein thontan gum is contained in a content of 0.15 w / v% to 0.6 w / v%, polyvinyl alcohol is contained in a content of 0.1 w / v% to 1 w / v%, polyethylene glycol is contained in a content of 0.01 w / v% to 2 w / v%, and polysorbate is contained in a content of 0.01 to 5 w / v%.

15. The eye drop composition according to claim 1, further comprising polyethylene glycol, polysorbate, dexpanthenol, or a mixture thereof, wherein the diquafosol or a pharmaceutically acceptable salt thereof is contained in an amount of 5 w / v% to 18 w / v%, the xanthan gum is contained in an amount of 0.2 w / v% to 0.6 w / v%, the polyvinyl alcohol is contained in an amount of 0.1 w / v% to 1 w / v%, the polyethylene glycol is contained in an amount of 0.01 w / v% to 2 w / v%, and the polysorbate is contained in an amount of 0.01 to 5 w / v%.

16. The eye drop composition according to claim 1, wherein the composition is for the prevention or treatment of dry eye.

17. Use of the eye drop composition according to any one of claims 1 to 16 for the manufacture of an agent for the prevention or treatment of dry eye.

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