Eye drop composition containing diquafosol

Abstract

The present invention relates to an eye drop composition containing diquafosol, and more particularly to an eye drop composition containing diquafosol, polysorbate, and dexpanthenol.

Description

[Technical Field]

[0001] The present invention relates to an eye drop composition containing diquafosol, and more particularly to an eye drop composition containing diquafosol, polysorbate, and dexpanthenol. [Background technology]

[0002] Diquafosol is a P2Y2 purinergic receptor agonist and is used to treat dry eye. Diquas® is an eye drop containing diquafosol as an active ingredient. This product is commercially available. The eye drops contain diquafosol sodium at a concentration of 3 w / v% and are administered six times a day, but the high number of administrations requires patients to administer the drug multiple times. For efficient treatment, it is important to administer the drug in an appropriate manner, but the product requires multiple daily administrations, making it difficult for patients to adhere to the dosage schedule.

[0003] Furthermore, due to their characteristics, eye drops have the disadvantage of a short residence time in the eyeball and a low drug delivery rate. Considering the mechanism of action of diquafosol, it is important that it be effectively dispersed into the aqueous and mucinous layers of the tear film. However, due to the strong hydrophilicity of diquafosol, its permeability into the oily layer of the tear film is low, resulting in low absorption rate and sustained efficacy. Therefore, there is a need for the development of new eye drops that improve drug delivery rate by increasing the permeability of the drug into the oily layer. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Republic of Korea Registered Patent No. 10-1867791 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides an ophthalmic composition comprising diquafosol, polysorbate, and dexpanthenol. [Means for solving the problem]

[0006] The present inventors have made extensive efforts to develop a new ophthalmic solution with improved drug permeability, and as a result have found that a composition containing diquafosol, polysorbate, and dexpanthenol improves the permeability of diquafosol, thereby completing the present invention.

[0007] The present invention provides an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof, polysorbate, and dexpanthenol.

[0008] The eye drop composition can improve the permeability of diquafosol, exhibit a sustained therapeutic effect for dry eye, and improve convenience for patients.

[0009] In the present invention, "diquafosol" means a compound represented by the following chemical formula I, which is generally useful for treating dry eye. [ka]

[0010] The composition of the present invention comprises, as an active ingredient, diquafosol or a pharmaceutically acceptable salt thereof, and may specifically comprise, but is not limited to, diquafosol sodium.

[0011] As used herein, "diquafosol" may refer not only to the compound represented by Chemical Formula I, but also to all pharmaceutically acceptable salts thereof.

[0012] The diquafosol or a pharmaceutically acceptable salt thereof may be contained in the eye drop composition in a therapeutically effective amount for preventing, ameliorating, or treating dry eye. Specifically, the diquafosol or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.1 w / v% to 18 w / v% of the total eye drop composition, 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 5 w / v% to 10 w / v%, and even more specifically, 4.5 w / v% to 5 w / v% or 5 w / v%. The diquafosol may be contained in a content 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, even more specifically 4.5 w / v% or more, or 5 w / v% or more, based on the total ophthalmic composition. The diquafosol may be contained in a content of 18 w / v% or less, 10 w / v% or less, or 6 w / v% or less, based on the total ophthalmic composition.

[0013] The composition of the present invention contains diquafosol or a pharmaceutically acceptable salt thereof, and therefore can be useful for preventing, ameliorating, or treating dry eye or symptoms related to dry eye (e.g., corneal and conjunctival epithelial disorders). It can also be effectively used to treat dry eye with a short tear film breakup time or obstructive meibomian gland dysfunction (MGD). The dry eye or symptoms related to dry eye include, but are not limited to, dryness, discomfort, fatigue, heavy eyes, and pain.

[0014] Specifically, the eye drop composition of the present invention may be for treating dry eye.

[0015] The compositions of the present invention include a polysorbate.

[0016] In the present invention, the polysorbate may specifically be at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, and more specifically may be polysorbate 20 or polysorbate 80, but is not limited thereto.

[0017] The polysorbate may be contained in an amount of 0.01 w / v% to 5 w / v% in the entire ophthalmic composition, specifically, 0.01 w / v% to 1 w / v%, 0.1 w / v% to 1 w / v%, 0.1 w / v% to 0.5 w / v%, or 0.2 w / v% to 0.3 w / v%, more specifically, 0.2 w / v%. The polysorbate may be contained in the total ophthalmic composition at a content of 0.01 w / v% or more, 0.1 w / v% or more, 0.2 w / v% or more, or 0.3 w / v% or more. The polysorbate may be contained in the total ophthalmic composition at a content of 5 w / v% or less, 1 w / v% or less, 0.5 w / v% or less, 0.3 w / v% or less, or 0.2 w / v% or less.

[0018] In order to reduce the irritation felt when applied to the eyes, polysorbate may be contained within the above content range.

[0019] The compositions of the present invention contain dexpanthenol. h enol).

[0020] The dexpanthenol may be contained in an amount of 0.001 w / v% to 1 w / v% in the entire ophthalmic composition, specifically, 0.001 w / v% to 0.1 w / v%, 0.001 w / v% to 0.05 w / v%, or 0.001 w / v% to 0.01 w / v%. The dexpanthenol may be contained in the total eye drop composition at a content of 0.001 w / v% or more, more specifically, but not limited to, 0.01 w / v% or more. The dexpanthenol may be contained in the total eye drop composition at a content of 1 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.01 w / v% or less.

[0021] The composition of the present invention comprises polyvinyl alcohol (Polyvin y l Alcohol;P At least one selected from the group consisting of VA, povidone (PVP), and polyethylene glycol (PEG). It may further include:

[0022] Such ingredients may be included to improve the viscosity of the composition, the stability of the composition, or to delay the release of the active ingredient.

[0023] The polyvinyl alcohol may be contained in an amount of 0.01 w / v % to 1.8 w / v % in the total ophthalmic composition, specifically, 0.03 w / v % to 1.4 w / v % or 0.03 w / v % to 0.28 w / v %, and more specifically, 0.1 w / v %, but is not limited thereto.

[0024] The povidone may be contained in an amount of 0.01 w / v% to 4 w / v% in the total ophthalmic composition, specifically, 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%, more specifically, 0.12 w / v%, but is not limited thereto.

[0025] The polyethylene glycol may be contained in an amount of 0.01 w / v % to 2 w / v % in the entire ophthalmic composition, specifically, 0.1 w / v % to 2 w / v %, or 1 w / v % to 2 w / v %, and more specifically, 1 w / v %. However, the amount is not limited thereto.

[0026] The compositions of the present invention may further comprise Xanthan Gum.

[0027] The xanthan gum may be contained in an amount of, specifically, 0.15 w / v % to 0.6 w / v % of the total ophthalmic composition, more specifically, 0.2 w / v % to 0.4 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, 0.225 w / v % to 0.24 w / v %, but is not limited thereto.

[0028] The composition of the present invention may further comprise additives.

[0029] The composition of the present invention may further comprise one or more additives selected from a pH adjusting agent, a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a solubilizing agent, a stabilizer, and a preservative.

[0030] The pH adjuster may be sodium hydroxide, hydrochloric acid, or the like, and may be added in a required amount by a method known to those skilled in the art to obtain an appropriate pH.

[0031] The buffering agent may be, but is not limited to, acetic acid and / or a salt thereof, citric acid and / or a salt thereof, phosphoric acid and / or a salt thereof (e.g., sodium hydrogen phosphate and / or a hydrate thereof, sodium dihydrogen phosphate and / or a hydrate thereof), boric acid and / or a salt thereof, or the like. Specifically, phosphate salts, citric acid and / or a salt thereof, or a mixture thereof may be used.

[0032] The isotonic agent may be glycerol, mannitol, sorbitol, sodium chloride, potassium chloride, boric acid, or the like.

[0033] The viscosity adjuster may be alginic acid or a salt thereof, carbomer, bentonite, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, or the like, and may be added in the required amount by a method known to those skilled in the art to obtain an appropriate viscosity.

[0034] Examples of the solubilizing agent that may be used include benzalkonium chloride, sodium lauryl sulfate, sorbitan monopalmitate, nonoxynol 10, oxynol 9, tyloxapol, poloxamers, diethylene glycol monoethyl ether, polyethylene glycols, and polyoxyl 15 hydrogenated stearic acid.

[0035] Examples of the stabilizer that may be used include sodium edetate, aminocaproic acid, carnitine, vitamin E and / or derivatives (e.g., tocopherol acetate, etc.), sorbitol, ascorbic acid, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, poloxamer, polypropylene glycol, guar gum, carbomer, alginic acid and salts thereof, gellan gum, carrageenan, and chitosan.

[0036] Examples of the preservative include quaternary ammonium compounds including benzalkonium chloride, benzethonium chloride, cetalkonium chloride, polyquaternium-1 (e.g., polyquad), and the like; guanidine compounds including PHMB, chlorhexidine, and the like; chlorobutanol; Mercury preservatives including thimerosal, phenylmercuric acetate, and phenylmercuric nitrate; and antioxidants including stabilized oxychloro complexes (e.g., Purite), alkyl parahydroxybenzoates (e.g., methyl parahydroxybenzoate (PM)), and the like may also be used.

[0037] The composition of the present invention can improve the permeability of diquafosol and reduce the frequency of administration.

[0038] The composition of the present invention can improve transmittance while maintaining an excellent feeling when applied to the eye.

[0039] The compositions of the present invention may be administered four or fewer times per day, specifically three or fewer times per day, two or fewer times per day, more specifically two to four times per day, and even more specifically three or fewer times per day, but are not limited thereto.

[0040] In this regard, in one embodiment of the present invention, it was confirmed that the composition of the present invention improves the permeability of diquafosol (FIGS. 1 to 3).

[0041] In the present invention, one administration may mean one infusion.

[0042] The composition of the present invention can improve compliance by reducing the frequency of administration.

[0043] The composition of the present invention exhibits physicochemical properties (eg, viscosity, pH, osmotic pressure, etc.) suitable for application to ocular tissue.

[0044] The viscosity of the composition of the present invention, when measured using a single-cylinder rotational viscometer and spindle S61, may be, but is not limited to, 1 mPa·s to 450 mPa·s, specifically 10 mPa·s to 450 mPa·s, 20 mPa·s to 450 mPa·s, or 10 mPa·s to 200 mPa·s, or more specifically 20 mPa·s to 70 mPa·s.

[0045] The pH of the composition of the present invention may be 5 to 9, specifically 6 to 8, but is not limited thereto.

[0046] 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.

[0047] The compositions of the present invention are specially formulated for topical application and may be administered topically in the form of a solution, emulsion, suspension, gel, or ointment.

[0048] The present invention provides a method for preventing or treating dry eye, which comprises administering the above-described eye drop composition to an individual.

[0049] For example, the present invention provides a method for preventing or treating dry eye, comprising administering to an individual an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, polysorbate, and dexpanthenol.

[0050] The present invention also provides use of the aforementioned eye drop composition for the manufacture of a medicament for the prevention or treatment of dry eye.

[0051] For example, the present invention provides use of an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, polysorbate, and dexpanthenol for the manufacture of a medicament for the prevention or treatment of dry eye.

[0052] The present invention also provides use of the aforementioned eye drop composition for the prevention or treatment of dry eye.

[0053] For example, the present invention provides use of an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, polysorbate, and dexpanthenol for the prevention or treatment of dry eye.

[0054] In the present invention, the term "individual" refers to all animals, including humans, who have been diagnosed with or may be diagnosed with dry eye. The term "animal" refers not only to humans, but also to other animals, such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats, that require treatment for similar symptoms. It may be, but is not limited to, a mammal.

[0055] In the present invention, the term "administration" refers to introducing the eye drop composition of the present invention into a patient by any appropriate method, and since the composition is an eye drop, the administration route of the present invention may be topical administration to the eyeball. The method for treating dry eye of the present invention comprises administering a therapeutically effective amount of the eye drop composition of the present invention.

[0056] The compositions of the invention may be administered in a pharmaceutically effective amount, that is sufficient to treat the disease at a reasonable benefit / risk ratio applicable to any medical treatment and with few side effects. The effective dose level can be determined depending on factors including the patient's health condition, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the administration method, administration time, administration route and excretion rate, treatment period, combination or concomitant drugs, and other factors well known in the medical field. Specifically, at the discretion of a doctor or pharmacist, the drug may be administered once or several times a day at regular intervals, and 0.01 ml to 0.1 ml per administration may be administered, but is not limited to this.

[0057] The matters mentioned in relation to the eye drop composition, use and treatment method of the present invention are equally applicable unless they contradict each other. [Effects of the Invention]

[0058] The composition of the present invention has excellent ophthalmic sensation, improves the permeability of diquafosol, exhibits sustained efficacy, and improves medication compliance, and therefore can be useful for the prevention or treatment of dry eye or symptoms related thereto. [Brief explanation of the drawings]

[0059] [Figure 1] FIG. 1 is a graph showing the transmittance of Diquafosol in Example 1, Example 2, and Comparative Example 1. [Figure 2] FIG. 2 is a graph showing the transmittance of Diquafosol in Example 3 and Comparative Example 1. [Figure 3] FIG. 3 is a graph showing the transmittance of Diquafosol in Example 4 and Comparative Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0060] The present invention will be described in more detail below with reference to examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of illustrating the present invention and that the scope of the present invention is not limited by these examples. [Example]

[0061] <Experimental Example 1> Transmittance (1)

[0062] Compositions were prepared according to the ingredients and amounts shown in Table 1 below. Diquafosol sodium, polysorbate 20 (Example 1 only), polysorbate 80 (Example 2 only), dexpanthenol (Examples 1 and 2 only), a buffer, and sodium chloride were dissolved in sterile purified water, and then filtered through a 0.2 μm membrane filter to prepare the compositions. The pH of the prepared solution was , approximately 7.2±0.2, and the osmolality was 300±30 mOsmol / kg. [Table 1]

[0063] The prepared Examples 1, 2, and Comparative Example 1 were placed in a semi-permeable membrane (Float-A-Lyzer), and then placed in a lyzer (SOTAX) containing STF (Simulated Tear Fluid) solution. TM ) and the amount of active ingredient released was evaluated using liquid chromatography. In release pattern experiments using a semipermeable membrane, the semipermeable membrane is generally activated with an organic solvent such as ethanol or isopropanol. However, in Experimental Example 1, the release pattern was observed without activating the semipermeable membrane in order to evaluate the permeability of polysorbate and dexpanthenol.

[0064] As shown in FIG. 1, it was confirmed that the permeability of diquafosol was high in Examples 1 and 2 containing polysorbate and dexpanthenol.

[0065] <Experimental Example 2> Transmittance (2)

[0066] A composition was prepared according to the ingredients and amounts shown in Table 2 below. Diquafosol sodium, polysorbate 80 (Example 3 only), dexpanthenol (Example 3 only), a buffer, and sodium chloride were dissolved in sterile purified water, and the solution was then filtered through a 0.2 μm membrane filter to prepare the composition. The pH of the prepared solution was approximately 7.2±0.2, and the osmolality was 300±30 mOsmol / kg. [Table 2]

[0067] In the same manner as in Experimental Example 1, the release patterns of the diquafosols prepared in Example 3 and Comparative Example 1 were evaluated. As shown in FIG. 2, Example 3 containing polysorbate and dexpanthenol showed a high permeability of diquafosol.

[0068] <Experimental Example 3> Transmittance (3)

[0069] Compositions were prepared according to the ingredients and amounts listed in Table 3 below. Specifically, polyvinyl alcohol, xanthan gum, and povidone were hydrated in sterile purified water at high temperatures (e.g., 60-70°C or higher), polyethylene glycol was dissolved, and the solution was then sterilized under high temperature and high pressure to prepare a solution. Diquafosol sodium, polysorbate 20 (Example 4 only), dexpanthenol (Example 4 only), a buffer, and an isotonic agent were dissolved in sterile purified water, filtered through a 0.2 μm membrane filter, and mixed with the solution prepared above to prepare a composition. The pH of the prepared solution was approximately 7.2±0.2. [Table 3]

[0070] The prepared Example 4 and Comparative Example 2 were placed in a semi-permeable membrane (Float-A-Lyzer) and then placed in a lyzer (SOTAX) containing STF (Simulated Tear Fluid) solution. TM ) and the amount of active ingredient released over time was evaluated using liquid chromatography.

[0071] As shown in FIG. 3, it was confirmed that Example 4 exhibited excellent Diquafosol permeability.

[0072] The results show that polysorbate and dexpanthenol increased membrane permeability of diquafosol. These results predict that compositions containing polysorbate and dexpanthenol will have a higher tear film permeability than compositions without polysorbate and dexpanthenol.

[0073] Therefore, it was found that the composition of the present invention has improved diquafosol permeability.

[0074] Although specific portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred implementations and do not limit the scope of the present invention. Therefore, the true scope of the present invention can be said to be defined by the appended claims and their equivalents.

Claims

1. An eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof, polysorbate, and dexpanthenol.

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

3. 2. 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 % based on the total amount of the eye-drop composition.

4. 2. The eye drop composition of claim 1, wherein the polysorbate is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

5. 2. The eye drop composition according to claim 1, wherein the polysorbate is contained in an amount of 0.01 w / v % to 5 w / v % based on the total weight of the eye drop composition.

6. 2. The eye drop composition according to claim 1, wherein the dexpanthenol is contained in an amount of 0.001 w / v % to 1 w / v % based on the total weight of the eye drop composition.

7. 2. The ophthalmic composition of claim 1, further comprising at least one selected from the group consisting of polyvinyl alcohol (PVA), povidone (PVP), and polyethylene glycol (PEG).

8. 8. The eye drop composition according to claim 7, wherein the polyvinyl alcohol is contained in an amount of 0.01 w / v % to 1.8 w / v % based on the total weight of the eye drop composition.

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

10. 8. The eye drop composition according to claim 7, wherein the polyethylene glycol is contained in an amount of 0.01 w / v % to 2 w / v % based on the total weight of the eye drop composition.

11. 10. The ophthalmic composition of claim 1, wherein the composition further comprises xanthan gum.

12. 12. The eye drop composition according to claim 11, 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.

13. 2. The ophthalmic composition according to claim 1, further comprising one or more additives selected from a pH adjusting agent, a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a solubilizing agent, a stabilizer, and a preservative.

14. 10. The eye drop composition of claim 1, wherein the composition is administered no more than four times daily.

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

16. 2. The eye drop composition of claim 1, wherein the pH of the composition is 5 to 9.

17. 2. The eye drop composition according to claim 1, wherein the osmolality of the composition is 250 mOsmol / kg to 500 mOsmol / kg.

18. The eye drop composition according to claim 1 , wherein the composition is a composition for preventing or treating dry eye.

19. Use of the eye drop composition according to any one of claims 1 to 18 for the manufacture of a medicament for the prevention or treatment of dry eye.

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