WO2021261931A1

WO2021261931A1 - Ophthalmic composition comprising diquafosol

Info

Publication number: WO2021261931A1
Application number: PCT/KR2021/007923
Authority: WO
Inventors: 이준엽; 류상록; 한병현
Original assignee: 주식회사태준제약
Priority date: 2020-06-23
Filing date: 2021-06-23
Publication date: 2021-12-30
Also published as: JP2023531725A; KR20220025775A; KR20210158355A; KR102365008B1; CN115701986A; WO2021261927A1; KR20210158310A

Abstract

The present invention relates to an ophthalmic composition comprising diquafosol and specifically to an ophthalmic composition comprising diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol, and polysorbate.

Description

Eye drop composition comprising diquafosol

The present invention relates to an ophthalmic composition comprising diquafosol, and more particularly, to an ophthalmic composition comprising diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate.

Diquafosol is a P2Y ₂ purine receptor agonist and is used in the treatment of dry eye. As an eye drop containing such diquafosol as an active ingredient, Diquas® is commercially available. The eye drop is an eye drop administered 6 times a day containing diquafosol sodium at a concentration of 3 w/v%. Considering that dry eye syndrome is a chronic disease that requires long-term drug administration for at least one month to a maximum of several months or a lifetime, a large number of administrations can be a factor that lowers the patient's medication compliance. Accordingly, there is a need to provide a composition comprising diquafosol, which has improved medication compliance by reducing the number of administrations.

On the other hand, in the case of eye drops, since they are administered directly to the mucous membrane of the sensitive eye, it is necessary to exhibit physical and chemical properties suitable for application to eye tissues (eg, viscosity, pH, osmotic pressure, etc.) Stability such as maintaining physical and chemical properties and content of active ingredients is required. In addition, when the related substances are generated, the drug permeation amount and the like may be lowered, so stability to minimize the generation amount of the related substances is also required.

In addition, diquafosol has a disadvantage in that the absorption rate and durability in the eye are weak due to its strong hydrophilicity. The Diquas product released in this regard has a dosage regimen of 6 times a day. In order to solve this problem, there is a need to provide a composition having an increased duration of drug effect in the eye. For this, it is possible to think of a method of increasing the viscosity of the product in general, but improving the drug delivery rate through simple viscosity enhancement increases the discomfort of the patient due to an increase in burning sensation and foreign body sensation, and can rather lower the medication compliance. Accordingly, there is a need to provide a composition for delayed release of diquafosol while maintaining an excellent eye drop.

Therefore, it maintains properties, physical and chemical properties, and content of active ingredients during storage and minimizes the generation of related substances to show excellent stability. There is a need for the development of new eye drops.

(Prior art literature)

(Patent Literature)

Domestic Registered Patent No. 10-1867791

The present invention provides an ophthalmic composition comprising diquafosol, xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate.

The present invention provides an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum and polyvinyl alcohol.

The ophthalmic composition maintains properties, physical and chemical properties, and content of active ingredients during storage, and exhibits excellent stability by minimizing the generation of related substances. By showing a therapeutic effect, the convenience of the patient can be improved.

The terms "first", "second", etc. used herein are used only to distinguish a plurality of components or a plurality of steps, and do not indicate priority.

In the present invention, "Diquafosol (Diquafosol)" refers to a compound represented by the following Chemical Formula 1, and is generally usefully used for the treatment of dry eye syndrome.

[Formula 1]

The composition of the present invention includes diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient, and specifically may include diquafosol sodium, but is not limited thereto.

In the present specification, diquafosol may refer to all of the compound represented by Formula 1 as well as pharmaceutically acceptable salts thereof.

The diquafosol or a pharmaceutically acceptable salt thereof may be contained in the eye drop composition in a therapeutically effective amount for the prevention, improvement or treatment of dry eye syndrome. Specifically, diquafosol or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 w/v% to 18 w/v% of the total eye drop composition, and more specifically, 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 In a content of 5 w/v% to 10 w/v%, more specifically, it may be included in a content of 4.5 w/v% to 5 w/v% or 5 w/v%, but is not limited thereto. The diquafosol is 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, more specifically, of the total eye drop composition As may be included in an amount of 4.5 w/v% or more or 5 w/v% or more. The diquafosol may be included in an amount of 18 w/v% or less, 10 w/v% or less, or 6 w/v% or less of the total ophthalmic composition.

The composition of the present invention can be usefully used for prevention, improvement or treatment of dry eye syndrome or related symptoms (eg, keratoconjunctival epithelial disorder), etc. . In addition, it can be effectively used in the treatment of dry eye syndrome or obstructive meibomian gland dysfunction (MGD) with a short tear film destruction time. The dry eye syndrome or symptoms related thereto, but are not limited thereto, may include symptoms such as dry eyes, eye discomfort, eye fatigue, dullness, and eye pain.

In relation to this, in a specific embodiment of the present invention, the composition of the present invention exhibits a significant effect in TBUT (tear break-up time) and corneal fluorescent pigment staining experiments compared to the saline solution administration group, thereby reducing dry eye syndrome or related symptoms. It was confirmed that it can be usefully used for prevention, improvement or treatment (FIG. 5).

The composition of the present invention comprises Xanthan Gum.

The xanthan gum is included for viscosity of the composition, stability of the composition, and delay of release of the active ingredient. The xanthan gum may be specifically included in an amount of 0.15 w/v% to 0.6 w/v% of the total ophthalmic 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%, even more specifically 0.225 w It may be included in an amount of /v% to 0.24 w/v%, but is not limited thereto. The xanthan gum is contained in an amount 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, of the total eye drop composition. may be included. The xanthan gum may be included in an amount 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, or 0.24 w/v% or less of the total eye drop composition. The xanthan gum may be included in an amount of 0.22 w/v%, 0.225 w/v%, 0.23 w/v%, or 0.24 w/v% of the total eye drop composition.

The composition of the present invention includes polyvinyl alcohol (PVA).

The polyvinyl alcohol may be included to delay the viscosity of the composition and release of the active ingredient. The polyvinyl alcohol may be specifically included in an amount of 0.01 w/v% to 1.8 w/v% of the total ophthalmic composition, 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%, more specifically 0.1 w/v% It may be included in an amount of v% to 1 w/v%, but is not limited thereto. The polyvinyl alcohol may be included in an amount 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 of the total eye drop composition. The polyvinyl alcohol is 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 of the total eye drop composition , may be included in an amount of 0.1 w/v% or less.

Polyvinyl alcohol may produce a sour taste and unpleasant odor due to acetaldehyde and acetic acid, which are substances that are decomposed over time, and may cause undesirable problems in terms of taste and smell during instillation. In addition, when polyvinyl alcohol is included in an excessively high content, problems in the manufacturing process such as difficulty in dissolving the active ingredient may occur, and stability may be deteriorated.

The polyvinyl alcohol may be included in an amount of 1 w/v% or less, specifically, 0.1 w/v% to 1 w/v%, of the total eye drop composition to prepare an eye-drop composition that is easy to prepare and has excellent lining and stability. have.

The composition of the present invention includes diquafosol, xanthan gum and polyvinyl alcohol, and delays the release of diquafosol, and has excellent lining and stability.

The composition of the present invention may be a stable composition comprising diquafosol, xanthan gum and polyvinyl alcohol and having a viscosity of 20 mPa·s or more.

The composition of the present invention may be a stable composition comprising diquafosol, xanthan gum and polyvinyl alcohol and having a viscosity of 20 mPa·s to 450 mPa·s.

The composition of the present invention may be a stable composition comprising diquafosol, xanthan gum and polyvinyl alcohol, which delays the release of diquafosol and has a viscosity of 20 mPa·s to 450 mPa·s.

The composition of the present invention includes diquafosol, xanthan gum and polyvinyl alcohol, and delays the release of diquafosol and can be administered in small numbers.

The present invention contains diquafosol, 0.15 w/v% to 0.4 w/v% xanthan gum, and 0.1 w/v% to 1 w/v% polyvinyl alcohol, and has a viscosity of 20 mPa·s to 450 mPa·% s can be provided. The present invention comprises 0.1 w/v% to 18 w/v% of diquafosol, 0.15 w/v% to 0.4 w/v% of xanthan gum, and 0.1 w/v% to 1 w/v% of polyvinyl alcohol and having a viscosity of 20 mPa·s to 450 mPa·s. The present invention comprises 0.1 w/v% to 10 w/v% of diquafosol, 0.15 w/v% to 0.4 w/v% xanthan gum, and 0.1 w/v% to 1 w/v% polyvinyl alcohol and having a viscosity of 20 mPa·s to 450 mPa·s.

The composition of the present invention has excellent stability and lining, easy to manufacture, has an appropriate viscosity, and has the effect of delaying the release of diquafosol.

In relation to this, in a specific example of the present invention, it was confirmed that the composition of the present invention had excellent stability (FIGS. 1 to 3, Tables 6 to 9, and Tables 11 to 14), and it was confirmed that the release of diquafosol was delayed. (FIGS. 4, 6 to 8). In addition, in a specific embodiment of the present invention, it was confirmed that the composition of the present invention maintains a constant viscosity at a shear rate such as blinking an eye and exhibits high viscosity ( FIGS. 9 and 10 ).

The composition of the present invention may further include povidone (PVP), polyethylene glycol (PEG) or a mixture thereof to delay the release of the active ingredient.

The povidone may be included in an amount of 0.01 w/v% to 4 w/v%, specifically 0.01 w/v% to 1.8 w/v%, 0.04 w/v% to 0.6 w/v%, or 0.04 w/v% It may be included in a content of v% to 0.12 w/v%, more specifically, in a content of 0.12 w/v%, but is not limited thereto. The povidone may be included in an amount of 0.01 w/v% or more, 0.04 w/v% or more, 0.1 w/v% or more, 0.12 w/v% or more. The povidone may be included in an amount 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.

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

The composition of the present invention contains polysorbate such as polysorbate 20 and polysorbate 80, polyoxyl castor oil, dexpantenol, or a mixture thereof to enhance the permeability of the active ingredient. may additionally include.

The composition of the present invention may further include an additive.

The composition of the present invention may further include one or more additives selected from a pH adjusting agent, a buffering agent, a tonicity agent, a viscosity adjusting agent, a solubilizing agent, a stabilizer, and a preservative.

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

The buffer includes acetic acid and/or salts thereof, citric acid and/or salts thereof, phosphoric acid and/or salts thereof (eg sodium hydrogen phosphate and/or hydrates thereof, sodium dihydrogen phosphate and/or hydrates thereof), boric acid And/or salts thereof may be used, and specifically, phosphate, citric acid and/or salts thereof, or mixtures thereof may be used, but the present invention is not limited thereto.

As the isotonic agent, glycerol, mannitol, sorbitol, sodium chloride, potassium chloride, boric acid, and the like may be used.

As the viscosity modifier, alginic acid or a salt thereof, carbomer, bentonite, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, etc. may be used, and in order to obtain an appropriate viscosity, a required amount may be added by a method known to those skilled in the art. can

The solubilizing agents include benzoalkonium chloride, sodium lauryl sulfate, sorbitan monopalmitate, nonoxynol 10, oxynol 9, tyloxapol, poloxamers, diethylene glycol monoethyl ether, polyethylene glycol polyoxyl 15 Hydrogenated stearic acid or the like can be used.

The stabilizer includes sodium edetate, aminocaproic acid, carnitine, vitamin E and/or derivatives (eg tocopherol acetate, etc.), sorbitol, ascorbic acid, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, poloxamer, poly Propylene glycol, guar gum, carbomer, alginic acid and salts thereof, gellan gum, carrageenan, chitosan, and the like can be used.

The preservative includes quaternary ammonium compounds including benzalkonium chloride, benzethonium chloride, cetalkonium chloride, polyquaternium-1 (eg, polyquad) and the like; guanidine-based compounds including PHMB and chlorhexidine; chlorobutanol; mercury preservatives including thimerosal, phenylmercury acetate and phenylmercury nitrate; And a stabilized oxychloro complex (eg, furite), an oxidizing preservative including an alkyl para-hydroxy acid (eg, methyl para-hydroxy acid (PM), etc. may be used.

The composition of the present invention contains a high concentration of diquafosol and has excellent stability and stability while delaying its release.

The composition of the present invention is a stable composition comprising a high concentration of diquafosol and having a viscosity of 20 mPa·s to 450 mPa·s while delaying its release.

The composition of the present invention includes a high concentration of diquafosol and delays its release to reduce the number of administration.

The composition of the present invention may be administered up to 4 times a day, specifically 3 times a day or less, 2 times a day or less, more specifically 2 to 4 times a day, even more specifically 3 times a day It may be administered in a circuit, but is not limited thereto.

In the present invention, single administration may mean one instillation.

The composition of the present invention can increase medication compliance by reducing the number of administration.

The present invention provides 4 w/v% to 18 w/v% of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w/v% to 0.4 w/v% of xanthan gum, polyvinyl alcohol, polyethylene glycol and poly An ophthalmic composition comprising sorbate is provided.

The present invention provides 4 w/v% to 10 w/v% of diquafosol or a pharmaceutically acceptable salt thereof, 0.2 w/v% to 0.4 w/v% of xanthan gum, polyvinyl alcohol, polyethylene glycol and poly An ophthalmic composition comprising sorbate is provided.

The composition may further comprise dexpanthenol.

The composition may further comprise povidone or polyoxyl castor oil.

The composition may further include one or more additives selected from a pH adjusting agent, a buffering agent, a tonicity agent, a viscosity adjusting agent, a solubilizing agent, a stabilizer, and a preservative.

The present invention may provide a composition comprising 5 w/v% of diquafosol or a pharmaceutically acceptable salt thereof, greater than 0.2 w/v% of xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate. . The present invention contains 5 w/v% of diquafosol or a pharmaceutically acceptable salt thereof, more than 0.2 w/v% of xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate, and is administered three times a day. compositions may be provided. Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.4 w/v% or less. Xanthan gum of the composition may be included in an amount of 0.22 to 0.4 w/v%. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.25 w/v% or less. Xanthan gum of the composition may be included in an amount of 0.22 to 0.25 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention may 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 contains 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, and is administered 4 times a day or less It is possible to provide a composition that Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 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 It may be included in w/v% or 4.5 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention may 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 contains 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, administered 4 times a day or less It is possible to provide a composition that Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 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 It may be included in w/v% or 4.5 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention may 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 contains 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 3 times a day or less It is possible to provide a composition that Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 5 to 18 w/v%, 5 to 10 w/v%, 5 to 9 w/v%, 5 to 8 w/v%, 5 to 7 It may be included in w/v% or 5 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

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 contains 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, and is administered three times a day or less. A composition to be administered can be provided. Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.4 w/v% or less. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.25 w/v% or less. The xanthan gum of the composition may be included in 0.22 to 0.4 w/v% or 0.22 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 5 to 18 w/v%, 5 to 10 w/v%, 5 to 9 w/v%, 5 to 8 w/v%, 5 to 7 It may be included in w/v% or 5 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention may 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 contains 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, and is administered three times a day or less. A composition to be administered can be provided. Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.4 w/v% or less. The xanthan gum of the composition may be included in an amount of more than 0.2 w/v% and 0.25 w/v% or less. Xanthan gum of the composition may be included in an amount of 0.22 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.22 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 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 It may be included in w/v% or 4.5 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention may 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 contains 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, administered 4 times a day or less It is possible to provide a composition that Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 4 to 18 w/v%, 4 to 10 w/v%, 4 to 9 w/v%, 4 to 8 w/v%, 4 to 7 It may be included in w/v% or 4 to 6 w/v%. The composition may further include dexpanthenol. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention provides 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 provides 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, and may provide a composition administered up to 4 times a day. Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.15 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 4 to 18 w/v%, 4 to 10 w/v%, 4 to 9 w/v%, 4 to 8 w/v%, 4 to 7 It may be included in w/v% or 4 to 6 w/v%. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

The present invention provides 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 provides 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, and may provide a composition administered three times a day or less. Polyvinyl alcohol of the composition may be included in an amount of 0.1 to 1 w/v%. Polyethylene glycol of the composition may be included in an amount of 0.01 to 2 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 5 w/v%. Polysorbate of the composition may be included in an amount of 0.01 to 1 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.4 w/v%. Xanthan gum of the composition may be included in an amount of 0.2 to 0.25 w/v%. The xanthan gum of the composition may be included in an amount greater than 0.2 w/v% and less than or equal to 0.4 w/v%, 0.22 to 0.4 w/v%, or 0.22 to 0.25 w/v%. Diquafosol of the composition and a pharmaceutically acceptable salt thereof are 5 to 18 w/v%, 5 to 10 w/v%, 5 to 9 w/v%, 5 to 8 w/v%, 5 to 7 It may be included in w/v% or 5 to 6 w/v%. Dexpanthenol in the composition may be included in an amount of 0.0001 to 1 w/v%.

Each component, effect, etc. included in the composition is the same as described above.

In relation to this, in a specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits a continuous dry eye treatment effect even with a small number of administrations compared to a commercial product (FIG. 5).

The composition of the present invention exhibits physical and chemical properties (eg, viscosity, pH, osmotic pressure, etc.) suitable for application to eye tissue.

The viscosity of the composition of the present invention may be 1 mPa·s to 450 mPa·s when measured using a single cylindrical rotational viscometer and a spindle S61, and specifically, 10 mPa·s to 450 mPa·s, 20 mPa·s to 450 mPa·s, 10 mPa·s to 200 mPa·s, more specifically 20 mPa·s to 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.

The pH of the composition of the present invention may be 5 to 9, specifically 6 to 8, but is not limited thereto.

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

The composition of the present invention can exhibit excellent stability by maintaining properties, physical and chemical properties, and content of active ingredients and minimizing the amount of related substances during storage.

In relation to this, in a specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits excellent stability by maintaining stable pH, osmotic pressure, viscosity, and content of active ingredients during storage (FIGS. 3, Tables 6 to 9, Tables 11 to 14), it was also confirmed that the amount of related substances generated during storage showed excellent stability (FIG. 2).

In addition, in a specific embodiment of the present invention, it was confirmed that the composition of the present invention did not change its properties during storage and improved property stability (FIG. 1).

The composition of the present invention can exhibit excellent durability and delayed release effect while maintaining excellent eye drop.

In relation to this, in a specific example of the present invention, it was confirmed that the composition of the present invention exhibits excellent eye drop (Table 20).

In addition, in a specific embodiment of the present invention, it was confirmed that the composition of the present invention exhibits excellent durability ( FIGS. 9 and 10 ), and exhibits a delayed release effect ( FIGS. 4 and 6 to 8 ).

The composition of the present invention is specially formulated for topical application, and may be administered topically by formulations such as solutions, emulsions, suspensions, gels, or ointments.

The present invention provides an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol and polyethylene glycol.

Each component included in the composition, the content of each component, effects, etc. are the same as described above.

The present invention provides an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polysorbate and dexpanthenol.

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

The present invention may provide a method for preparing an ophthalmic composition, comprising mixing diquafosol, xanthan gum and polyvinyl alcohol.

The manufacturing method may further include adding an additive or carrier such as polyethylene glycol, povidone, polysorbate, and dexpanthenol.

The present invention provides a method for preventing or treating dry eye, comprising administering the above-described eye drop composition to a subject.

For example, the present invention provides a method for preventing dry eye syndrome, comprising administering to a subject an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate. or a method of treatment.

The present invention also provides the use of the above-mentioned eye drop composition for the preparation of a medicament for the prevention or treatment of dry eye syndrome.

For example, the present invention relates to an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate for the preparation of a medicament for the prevention or treatment of dry eye syndrome. provide use.

The present invention also provides the use of the above-mentioned eye drop composition for the prevention or treatment of dry eye syndrome.

For example, the present invention provides the use of an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, xanthan gum, polyvinyl alcohol, polyethylene glycol and polysorbate for the prevention or treatment of dry eye syndrome. .

In the present invention, the "individual" may refer to all animals, including humans, who have been diagnosed with dry eye syndrome or are likely to be diagnosed with dry eye syndrome. The animal may be a mammal, such as a cow, a horse, a sheep, a pig, a goat, a camel, an antelope, a dog, or a cat, in need of treatment for symptoms similar to those of a human as well as humans, but is not limited thereto.

In the present invention, the "administration" means introducing the eye drop composition of the present invention to a patient by any suitable method, and the route of administration of the present invention may be topical administration to the eye due to the nature of the composition as an eye drop. The method for treating dry eye syndrome of the present invention includes administering the eye drop composition of the present invention in a therapeutically effective amount.

The composition of the present invention can be administered in a pharmaceutically effective amount. The pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's health condition, disease type, severity, The activity of the drug, the sensitivity to the drug, the administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well known in the medical field may be determined according to factors. Specifically, according to the judgment of the doctor or pharmacist, it may be administered in divided doses from once to several times a day at regular time intervals, and 0.01 ml to 0.1 ml may be administered per one administration, but is not limited thereto.

Matters mentioned in the ophthalmic composition, use, and treatment method of the present invention are equally applicable as long as they do not contradict each other.

The composition of the present invention exhibits excellent stability by maintaining properties, physical and chemical properties, and content of active ingredients during storage and minimizing the generation of related substances, and can exhibit continuous effects through delayed release of active ingredients. The composition of the present invention maintains an excellent eye drop and can exhibit excellent durability. The composition of the present invention can reduce the number of administration, thereby improving medication compliance. Accordingly, the composition of the present invention may be usefully used for prevention or treatment of dry eye syndrome or related symptoms.

1 is a photograph showing the result (property evaluation) of stability evaluation (1) of Experimental Example 1.

2 is a graph showing the results of the stability evaluation (1) of Experimental Example 1 (associated substance generation amount evaluation).

3 is a graph showing the results of the stability evaluation (2) of Experimental Example 2.

4 is a graph showing the results of the delayed release evaluation (1) of Experimental Example 3.

5 is a graph showing the evaluation results of dry eye syndrome treatment effect of Experimental Example 4.

6 is a graph showing the results of delayed release evaluation (2) of Experimental Example 7.

7 is a graph showing the results of delayed release evaluation (3) of Experimental Example 8.

8 is a graph showing the results of delayed release evaluation (4) of Experimental Example 9.

9 is a graph showing the results of the evaluation of the durability of Experimental Example 11 (A).

10 is a graph showing the results of the durability evaluation (B) of Experimental Example 11.

Hereinafter, the present invention will be described in more detail through experimental examples. These experimental examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these experimental examples.

<실험예 1> 안정성 평가 (1) - 성상 안정성 및 유연물질 발생량<Experimental Example 1> Stability evaluation (1) - Stability of properties and generation of related substances

The compositions of Example 1 and Comparative Example 1 were prepared according to the composition of Table 1 below.

Example 1: Polyvinyl alcohol and xanthan gum were added to sterile purified water, hydrated at a high temperature (60 to 70° C. or higher), and high-temperature and high-pressure sterilization was performed to prepare a first solution. Separately, diquafosol sodium and disodium hydrogen phosphate dihydrate were added and dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare a second solution. The composition of Example 1 having a pH of about 7.2 ± 0.2 was prepared by mixing the first solution and the second solution prepared above.

Comparative Example 1: A composition of Comparative Example 1 having a pH of about 7.2 ± 0.2 was prepared in the same manner as in Example 1, except that the input of xanthan gum was omitted.

[Table 1]

Example 1 and Comparative Example 1 prepared as described above were stored at 70 ° C. (humidity 55%) for 4 weeks, then the properties were observed and the content of related substances was measured, and the results are shown in FIGS. 1 and 2 .

As can be seen from the results of FIG. 1 , in the case of Comparative Example 1, it was confirmed that the appearance was changed to yellow (photo on the right), whereas in the case of Example 1, the appearance did not change (photo on the left). From this, it can be seen that the composition of the present invention has improved property stability.

As can be seen from the results of FIG. 2 , in Comparative Example 1, relatively large amounts of related substances were generated, whereas in Example 1 according to the present invention, relatively few related substances were generated.

From this, it can be seen that the composition of the present invention reduces the amount of related substances generated.

<실험예 2> 안정성 평가 (2) - pH, 삼투압 및 점도 변화<Experimental Example 2> Stability evaluation (2) - pH, osmotic pressure and viscosity change

The composition of Example 2 was prepared according to the composition of Table 2 below.

Example 2 : Xanthan gum and povidone were added to sterilized purified water, hydrated at a high temperature (60 to 70° C. or higher), and dissolved by adding polyethylene glycol, followed by high-temperature and high-pressure sterilization to prepare a first solution. Separately, polyvinyl alcohol is added to sterilized purified water and dissolved at a high temperature (60 ~ 70 ℃ or higher), then dexpanthenol, disodium hydrogen phosphate dihydrate, polysorbate, diquafosol sodium and an isotonic agent are added and dissolved to dissolve 0.2 A second solution was prepared by filtration through a μm membrane filter. The composition of Example 2 was prepared by mixing the first solution and the second solution prepared above.

[Table 2]

pH, osmotic pressure, and viscosity were measured while storing the prepared Example 2 at 55 ° C. (humidity 75%) for 14 days, and the results are shown in FIG. 3 . As can be seen from FIG. 3 , it was confirmed that the pH, osmotic pressure and viscosity of Example 2 according to the present invention were stably maintained. From this, it can be seen that the composition of the present invention exhibits excellent physical and chemical stability.

<실험예 3> 지연 방출 (1)<Experimental Example 3> Delayed release (1)

Compositions of Example 3 and Comparative Example 2 were prepared according to the composition of Table 3 below.

Example 3 : Polyvinyl alcohol and xanthan gum were added to sterile purified water, hydrated at a high temperature (60-70° C. or higher), and high-temperature and high-pressure sterilization was performed to prepare a first solution. Separately, diquafosol sodium and buffer were added and dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare a second solution. The composition of Example 3 having a pH of about 7.2 ± 0.2 was prepared by mixing the first solution and the second solution prepared above.

Comparative Example 2 : Diquafosol sodium and buffer were dissolved in sterile purified water and filtered through a 0.2 μm membrane filter to prepare a composition having a pH of about 7.2 ± 0.2.

[Table 3]

For the compositions of Example 3 and Comparative Example 2 prepared as described above, the release pattern of the active ingredient over time was observed using a semi-permeable membrane (Float A lyzer) and a dissolution device (SOTAX™). Specifically, the composition was put into the semi-permeable membrane and put into an eluator containing a simulated tear fluid (STF) solution, and the amount of active ingredient released was measured using a liquid chromatogram.

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

<실험예 4> 안구 건조증 치료 효과<Experimental Example 4> Dry eye syndrome treatment effect

Compositions of Examples 4-1 and 4-2 were prepared according to the composition of Table 4 below.

Examples 4-1 and 4-2 : Xanthan gum and povidone were added to sterile purified water, hydrated at a high temperature (60 to 70° C. or higher), and dissolved by adding polyethylene glycol, followed by high-temperature and high-pressure sterilization to prepare the first solution prepared. Separately, polyvinyl alcohol was added to sterile purified water, dissolved at a high temperature (60-70° C. or higher), and filtered through a 0.2 μm membrane filter to prepare a second solution. A mixed solution was prepared by mixing the first solution and the second solution prepared previously. Separately, diquafosol sodium, buffer, dexpanthenol, polysorbate and isotonic agent were added and dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare a third solution. The composition of Examples 4-1 and 4-2 having a pH of about 7.2 ± 0.2 was prepared by mixing the previously prepared mixture and the third solution.

[Table 4]

In the New Zealand White Rabbit dry eye disease animal model, the dry eye treatment effect of commercially available products, DIQUAS® ophthalmic solution 3%, saline solution, and Examples 4-1 and 4-2 was confirmed, and the results were reviewed. 5 is shown. Diquas ophthalmic solution (G1) was instilled 6 times, and Example 4-1 (G2), Example 4-2 (G3) and saline solution were each instilled 3 times.

As can be seen from FIG. 5 , TBUT (Tear break-up time) and corneal fluorescent dye staining experiments were all compared to the saline solution administration group in the groups administered with Diquas eye drops and Examples 4-1 and 4-2 according to the present invention. was confirmed to have a significant effect.

From this, it can be seen that the composition of the present invention exhibits a continuous dry eye treatment effect even with a small number of administrations compared to commercial products.

<실험예 5> 안정성 평가 (3)<Experimental Example 5> Stability evaluation (3)

Compositions of Examples 5 to 7 were prepared according to the components and contents of Table 5 below.

Examples 5 to 7 : Polyvinyl alcohol and xanthan gum were added to sterile purified water, hydrated at a high temperature (60-70° C. or higher), and high-temperature and high-pressure sterilization was performed to prepare a first solution. Separately, a solution was prepared by dissolving diquafosol sodium and a buffer in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare a second solution. By mixing the first solution and the second solution prepared above, the compositions of Examples 5 to 7 having a pH of about 7.2 ± 0.2 were prepared.

[Table 5]

After storing the prepared Examples 5 to 7 at 55 ° C. (75% humidity) for 28 days and at 70 ° C. (humidity 55%) for 14 days, the properties, pH, osmotic pressure, viscosity, and the content of diquafosol were evaluated, and the The results are shown in Tables 6 to 9 below. Viscosity was measured at 25° C. and a torque value of 80% or more using a single cylindrical rotational viscometer and spindle S61.

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

As can be seen from the results of Tables 6 to 9, Examples 5 to 7 according to the present invention exhibited excellent stability without significant changes in pH, osmotic pressure and viscosity even after storage under the above conditions (Tables 6 to 8 ), it was confirmed that the change in the content of diquafosol was also very small (Table 9).

[Table 6]

[Table 7]

[Table 8]

[Table 9]

<실험예 6> 안정성 평가 (4)<Experimental Example 6> Stability evaluation (4)

Compositions of Examples 8 to 10 were prepared according to the compositions shown in Table 10 below.

Examples 8 to 10 : Polyvinyl alcohol and xanthan gum were added to sterile purified water, hydrated at high temperature (60 to 70° C. or higher), and high-temperature and high-pressure sterilization was performed to prepare a first solution. Diquafosol sodium and buffer were dissolved in sterile purified water and filtered through a 0.2 μm membrane filter to prepare a second solution. By mixing the first solution and the second solution prepared above, the compositions of Examples 8 to 10 having a pH of about 7.2 ± 0.2 were prepared.

[Table 10]

After storing Examples 8 to 10 at 55 ° C. (75% humidity) for 28 days and 70 ° C. (humidity 55%) for 14 days, the properties, pH, osmotic pressure, viscosity, and the content of diquafosol were evaluated, and the results were evaluated. It is shown in Tables 11 to 14 below. Viscosity was measured in the same manner as in Experimental Example 5.

As a result, even after storage at 55 ° C. and 70 ° C., all of Examples 8 to 10 maintained a transparent and clear state without any change in properties, confirming excellent property stability.

Examples 8 to 10 exhibited excellent stability without significant changes in pH, osmotic pressure and viscosity even after storage under the above conditions (Tables 11 to 13), and it was confirmed that they were stable with very little change in active ingredient content (Table 14). It can be seen that Examples 8 to 9 exhibit improved stability due to less osmotic pressure and pH fluctuations compared to Example 10, and are more preferable because the viscosity is also maintained high.

[Table 11]

[Table 12]

[Table 13]

[Table 14]

<실험예 7> 지연 방출 평가 (2)<Experimental Example 7> Delayed release evaluation (2)

Compositions of Comparative Example 3 and Examples 11 to 12 were prepared according to the compositions shown in Table 15 below.

Comparative Example 3 : Diquafosol sodium and buffer were dissolved in sterile purified water and filtered through a 0.2 μm membrane filter to prepare the composition of Comparative Example 3 having a pH of about 7.2 ± 0.2.

Examples 11 and 12 : Polyvinyl alcohol and xanthan gum were added to sterile purified water, hydrated at high temperature (60-70° C. or higher), and high-temperature and high-pressure sterilization was performed to prepare a first solution. Separately, diquafosol sodium and buffer were dissolved in sterile purified water and filtered through a 0.2 μm membrane filter to prepare a second solution. By mixing the first solution and the second solution prepared above, the compositions of Examples 11 and 12 having a pH of about 7.2 ± 0.2 were prepared.

[Table 15]

The release pattern of the active ingredient according to time of Comparative Example 3 and Examples 11 to 12 prepared using a semi-permeable membrane (Float A lyzer) and an elution device (SOTAX™) was observed. Specifically, the composition was put into the semi-permeable membrane and put into an eluator containing a simulated tear fluid (STF) solution to evaluate the release amount of the active ingredient using a liquid chromatogram, and the results are shown in FIG. 6 .

As can be seen from FIG. 6 , in Examples 11 and 12 according to the present invention, it was confirmed that the release of the active ingredient was effectively delayed compared to Comparative Example 3 which did not contain xanthan gum and polyvinyl alcohol at all.

<실험예 8> 지연 방출 평가 (3)<Experimental Example 8> Delayed release evaluation (3)

Compositions of Comparative Examples 4 and 13 were prepared according to the compositions shown in Table 16 below. Comparative Example 4 was prepared in the same manner as in Comparative Example 3, Example 13 was prepared in the same manner as in Example 11, and the pH of the prepared composition was about 7.2 ± 0.2.

[Table 16]

In the same manner as in Experimental Example 7, using a semi-permeable membrane (Float A lyzer) and a dissolution device (SOTAX™), the release pattern of the active ingredient according to time of Comparative Examples 4 and 13 was observed, and the results are shown in FIG. indicated.

As can be seen from FIG. 7 , it was confirmed that the release of the active ingredient was effectively delayed in Example 13 according to the present invention compared to Comparative Example 4 which did not contain xanthan gum and polyvinyl alcohol at all.

<실험예 9> 지연 방출 평가 (4)<Experimental Example 9> Delayed release evaluation (4)

Compositions of Comparative Example 5 and Examples 14 to 15 were prepared according to the composition of Table 17 below. Comparative Examples 5 and 15 were prepared in the same manner as in Comparative Examples 3 and 11, respectively, and the pH of the prepared composition was about 7.2 ± 0.2.

Example 14 : Xanthan gum and povidone were added to sterile purified water, hydrated at high temperature (60 to 70° C. or higher), and polyethylene glycol was added to dissolve, followed by high-temperature and high-pressure sterilization to prepare a first solution. Separately, add polyvinyl alcohol to sterile purified water and dissolve at high temperature (60 ~ 70 ℃ or higher), then, after dissolving buffer and sodium diquafosol, filter through a 0.2 μm membrane filter, mix with the solution prepared above, and adjust the pH to about The composition of Example 14 of 7.2±0.2 was prepared.

[Table 17]

The prepared Examples 14 to 15 and Comparative Example 5 were put in a semi-permeable membrane (Float A lyzer) and put into an eluator (SOTAX™) containing a STF (Simulated Tear Fluid) solution, and the release amount of the active ingredient was measured using a liquid chromatogram. evaluated, and the results are shown in FIG. 8 .

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

<실험예 10> 점안감 평가 - 자극성<Experimental Example 10> Eye drop evaluation - irritation

The composition of Example 16 was prepared according to the composition of Table 18 below.

Example 16 : Xanthan gum and povidone were added to sterilized purified water, hydrated at a high temperature (60 to 70° C. or higher), and dissolved by adding polyethylene glycol, followed by high-temperature and high-pressure sterilization to prepare a first solution. Separately, polyvinyl alcohol is added to sterilized purified water and dissolved at a high temperature (60 ~ 70 ℃ or higher), then dexpanthenol, polysorbate, buffer and diquafosol sodium are dissolved, filtered through a 0.2 μm membrane filter, and the second solution was prepared. By mixing the first solution and the second solution prepared above, the composition of Example 16 having a pH of about 7.2 ± 0.2 was prepared.

[Table 18]

Using the prepared Example 16, evaluation of irritation was performed. After administering 30 μL of the composition of Example 16 to both eyes of 23 healthy adults, a burning sensation, a foreign body sensation, blurred vision, and residual sensation felt after 6 hours for 3 minutes were evaluated according to the criteria in Table 19.

[Table 19]

[Table 20]

Table 20 shows the average values of the evaluation scores. As a result of the evaluation, burning sensation, foreign body feeling, blurred vision, and residual feeling were not felt or appeared to be insignificant, indicating that the ophthalmic composition of the present invention has very excellent ocular feeling (Table 20).

<실험예 11> 지속력 평가<Experimental Example 11> Durability evaluation

The composition of Example 17 was prepared according to the composition of Table 21 below.

Example 17 : Xanthan gum was added to sterile purified water, hydrated at a high temperature (60 to 70° C. or higher), and dissolved by adding polyethylene glycol, followed by high-temperature and high-pressure sterilization to prepare a first solution. Separately, polyvinyl alcohol is added to sterilized purified water and dissolved at a high temperature (60 ~ 70 ℃ or higher), then dexpanthenol, polysorbate, buffer and diquafosol sodium are dissolved, filtered through a 0.2 μm membrane filter, and the second solution was prepared. By mixing the first solution and the second solution prepared above, the composition of Example 17 having a pH of about 7.2 ± 0.2 was prepared.

[Table 21]

(go)

After mixing each of the prepared Example 17 and the aforementioned Diquas ophthalmic solution with a simulated tear fluid (STF) solution in a ratio of 30:7, the shear rate was increased at 35° C. while increasing the shear rate with a rheometer (Rheometer MCR). 302) to measure the viscosity, and the results are shown in FIG. 9 .

As can be seen from FIG. 9 , the composition of Example 17 according to the present invention ^{maintains a constant viscosity even at a shear rate of about 3000 S −1} , whereas the Diquas ophthalmic solution has a constant viscosity at a shear rate of about 900 S ⁻¹ It was confirmed that it could not be maintained. In addition, it was confirmed that the composition of Example 17 exhibits high viscosity even at a minimum shear rate of 1000 S ^{-1 or higher due to a general blink.}

(me)

In addition, after mixing the composition of Example 17 with a STF (Simulated Tear Fluid) solution in a ratio of 30:7, the shear rate at regular time intervals is changed from 1 S ^-1 to 5000 S ^-1 to 5000 S again. ^{While changing from -1} to 1 S ^-1 , the viscosity was measured at 35° C., and the results are shown in FIG. 10 .

As can be seen from FIG. 10 , it was confirmed that the instantaneously dropped viscosity at a high shear rate was quickly and completely recovered in the composition of Example 17 according to the present invention. Accordingly, it can be seen that the eye drop composition of the present invention maintains excellent and continuous viscosity even under shear stress such as eye blinking.

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.

Claims

4 w/v% to 18 w/v% of diquafosol or a pharmaceutically acceptable salt thereof, 0.15 w/v% to 0.4 w/v% of xanthan gum, polyvinyl alcohol ( An eye drop composition comprising polyvinyl alcohol), polyethylene glycol and polysorbate.
The ophthalmic composition of claim 1, wherein the diquafosol or a pharmaceutically acceptable salt thereof is diquafosol sodium.
The ophthalmic composition according to claim 1, wherein the polyvinyl alcohol is included in an amount of 0.1 w/v% to 1 w/v% of the total ophthalmic composition.
The ophthalmic composition according to claim 1, wherein the polyethylene glycol is included in an amount of 0.01 w/v% to 2 w/v% of the total ophthalmic composition.
The ophthalmic composition according to claim 1, wherein the polysorbate is included in an amount of 0.01 to 5 w/v% of the total ophthalmic composition.
The eye drop composition of claim 1, wherein the composition further comprises dexpantenol.
The ophthalmic composition according to claim 6, wherein the dexpanthenol is included in an amount of 0.0001 to 1 w/v% of the total ophthalmic composition.
The composition according to claim 1, wherein the composition is administered up to 4 times a day.
The ophthalmic composition of claim 1, wherein the composition further comprises one or more additives selected from a pH adjusting agent, a buffering agent, a tonicity agent, a viscosity adjusting agent, a surfactant, a stabilizer, and a preservative.
According to claim 1, wherein the viscosity of the composition will be 20 mPa·s to 450 mPa·s, the eye drop composition.
According to claim 1, wherein the pH of the composition is 5 to 9, the eye drop composition.
According to claim 1, wherein the osmotic pressure of the composition is 250 mOsmol / kg to 500 mOsmol / kg, the eye drop composition.
The eye drop composition of claim 1, wherein the composition is for the treatment of dry eye syndrome.
A method for preventing or treating dry eye, comprising administering the eye drop composition of any one of claims 1 to 13 to a subject.
Use of the eye drop composition according to any one of claims 1 to 13 for the manufacture of a medicament for the prevention or treatment of dry eye syndrome.
Use of the eye drop composition according to any one of claims 1 to 13 for the prevention or treatment of dry eye syndrome.