Eye drops in the form of an aqueous solution containing 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof

Abstract

The present invention provides an eye drop preparation in the form of an aqueous solution containing 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof, a thickener, a buffer, and a chelating agent in an aqueous medium, the eye drop preparation having a viscosity of 10 to 30 mPa s. The eye drop preparation of the present invention exhibits an appropriate retention time in the eye and exhibits excellent stability without forming precipitates even when stored for a long period of time.

Description

[Technical Field]

[0001] The present invention relates to an eye drop preparation in the form of an aqueous solution containing 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to an eye drop preparation in the form of an aqueous solution containing 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof as an active ingredient and having a specific viscosity. [Background technology]

[0002] The compound of Formula 1, whose chemical name is 8-oxo-2'-deoxyguanosine, or a pharmaceutically acceptable salt thereof, exhibits rapid corneal epithelial recovery and is therefore useful for the prevention and / or treatment of corneal injuries, including dry eye syndrome, ocular trauma, and infectious or non-infectious uveitis (Korean Patent No. 10-1816277 and U.S. Patent No. 10,675,294). <Expression 1> JPEG2025532972000001.jpg33157

[0003] To achieve effective prevention and / or treatment of corneal damage caused by repeated eye drops, a stable eye drop in the form of an aqueous solution containing a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof is required.

[0004] However, since the compound of formula 1 has a very low aqueous solubility of 1.91 mg / mL at room temperature (about 25° C.), it is difficult to prepare an eye drop in the form of an aqueous solution containing a therapeutically effective amount.

[0005] One may attempt to solubilize the compound of formula 1 by heating a mixture containing the compound of formula 1 in an aqueous solution (e.g., a mixture in the form of a suspension). However, if the aqueous solution obtained by heating is stored at room temperature, the compound of formula 1 will precipitate, making it difficult to use as an eye drop that requires repeated administration.

[0006] Alternatively, one may attempt to solubilize the compound of Formula 1 by increasing the pH of a mixture containing the compound of Formula 1 in an aqueous solution (e.g., a mixture in the form of a suspension). However, the problem is that the compound of Formula 1 cannot be solubilized in the pH range (i.e., pH 5 to 7) that can be used as an eye drop.

[0007] Furthermore, when a patient repeatedly uses an aqueous solution of eye drops, depending on the method of use, a considerable amount of the drug solution may leak from the eye. This leakage often results in a problem that the desired therapeutically effective amount of the eye drop is not retained in the eye. Therefore, there is a need to produce an aqueous solution of eye drops that exhibits an appropriate intraocular retention time. Summary of the Invention [Problem to be solved by the invention]

[0008] The present inventors conducted extensive research to develop an eye drop solution containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof in an aqueous medium, which can solve the above-mentioned problems. As a result, the present inventors discovered that an eye drop solution in the form of an aqueous solution having a specific viscosity (i.e., a viscosity of 10 to 30 mPa·s) and solubilizing the compound of Formula 1 or a pharmaceutically acceptable salt thereof exhibits an appropriate retention time in the eye. The present inventors also discovered that a combination of specific ingredients (thickeners) not only functions as a thickener but also as a stabilizer and solubilizer, thereby providing an eye drop solution in the form of an aqueous solution with excellent stability. In particular, the present inventors discovered that when an eye drop solution in the form of an aqueous solution is prepared using a specific solubilizing agent in addition to the combination of thickeners, the eye drop solution can be maintained at room temperature for 12 months without precipitation.

[0009] Therefore, an object of the present invention is to provide an eye drop in the form of a solution having a specific viscosity, which contains 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof as an active ingredient. [Means for solving the problem]

[0010] One aspect of the present invention provides an eye drop preparation in the form of an aqueous solution comprising 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; a thickening agent; a buffer; and a chelating agent in an aqueous medium, the eye drop preparation having a viscosity of 10 to 30 mPa s.

[0011] In one embodiment, the eye drop formulation of the present invention does not produce precipitation even when stored for 30 days under refrigerated conditions at about 4° C. In another embodiment, the eye drop formulation of the present invention does not produce precipitation even when stored for 60 days at room temperature at about 25° C.

[0012] In the eye drops of the present invention, 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof may be present at a concentration of 0.1 to 1.0 w / v %. In the eye drops of the present invention, the buffer may be tromethamine, borax, boric acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate, or potassium carbonate; and the chelating agent may be ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof, metaphosphoric acid or a salt thereof, or polyphosphoric acid or a salt thereof.

[0013] In the eye drops of the present invention, the thickener may comprise a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose. The polyvinylpyrrolidone may have a weight-average molecular weight of 20,000 to 100,000 and may be present at a concentration of 0.5 to 5.0 w / v%. The hydroxypropyl methylcellulose may have a weight-average molecular weight of 10,000 to 1,500,000 and may be present at a concentration of 0.1 to 0.4 w / v%.

[0014] The eye drops of the present invention may further contain polyethylene glycol and polysorbate as solubilizing agents. The polyethylene glycol may have a weight-average molecular weight of 380 to 420 and may be present at a concentration of 2.0 to 5.0 w / v%. The polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80 and may be present at a concentration of 0.05 to 0.15 w / v%. [Effects of the Invention]

[0015] According to the present invention, it has been found that an aqueous solution of eye drops having a specific viscosity (i.e., a viscosity of 10 to 30 mPa·s) and solubilizing the compound of Formula 1 or a pharmaceutically acceptable salt thereof exhibits an appropriate retention time in the eye. It has also been found that a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose functions not only as a thickener but also as a stabilizer and solubilizer, thereby providing an aqueous solution of eye drops with excellent stability. In particular, it has been found that when an aqueous solution of eye drops is prepared using a specific solubilizing agent (i.e., polyethylene glycol and polysorbate) in addition to the combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, a stable eye drop can be obtained that does not exhibit precipitation for 12 months at room temperature. Therefore, the eye drops of the present invention exhibit an appropriate retention time in the eye and excellent stability without precipitation even when stored for a long period of time, making them useful for long-term repeated administration (repeated instillation). DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides an eye drop preparation in the form of an aqueous solution comprising 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; a thickening agent; a buffer; and a chelating agent in an aqueous medium, wherein the eye drop preparation has a viscosity of 10 to 30 mPa s.

[0017] In one embodiment, the eye drop formulation of the present invention does not produce precipitation even when stored for 30 days under refrigerated conditions at about 4° C. In another embodiment, the eye drop formulation of the present invention does not produce precipitation even when stored for 60 days at room temperature at about 25° C.

[0018] In the eye drops of the present invention, examples of the aqueous medium include distilled water for injection, sterilized purified water, and physiological saline.

[0019] In the eye drops of the present invention, 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount. For example, the eye drops of the present invention may contain 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof at a concentration of 0.1 to 1.0 w / v%, preferably about 0.25 w / v%, but this is not intended to be limiting. The pharmaceutically acceptable salt of 8-oxo-2'-deoxyguanosine may be selected from various salts disclosed in Korean Patent No. 10-1816277, such as its acid addition salts.

[0020] The eye drops of the present invention may contain additives such as a buffering agent and a chelating agent. The buffering agent may be tromethamine, borax, boric acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate, or potassium carbonate, preferably tromethamine. The buffering agent may be used in an amount sufficient to provide an appropriate buffering effect. For example, the buffering agent may be present at a concentration of 0.5 to 2.0 w / v%, preferably about 1.0 w / v%. The chelating agent may be ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof, metaphosphoric acid or a salt thereof, or polyphosphoric acid or a salt thereof, preferably sodium ethylenediaminetetraacetate. The chelating agent may be used in an amount commonly used in the field of eye drops. For example, the chelating agent may be present at a concentration of 0.01 to 0.3 w / v%, preferably about 0.1 w / v%.

[0021] According to the present invention, it has been found that a specific thickener, i.e., a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, functions not only as a thickener but also as a stabilizer and solubilizer, thereby providing an eye drop in the form of an aqueous solution having excellent stability. Therefore, the eye drop of the present invention may preferably contain a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose as a thickener.

[0022] The polyvinylpyrrolidone may have a weight average molecular weight of 20,000 to 100,000. Preferably, the polyvinylpyrrolidone may have a weight average molecular weight of 30,000 to 50,000 (e.g., polyvinylpyrrolidone K-25, K-30, etc.), more preferably a weight average molecular weight of about 50,000. The polyvinylpyrrolidone may be present at a concentration of 0.5 to 5.0 w / v%, preferably 1.0 to 3.0 w / v%, more preferably about 2.0 w / v%.

[0023] The hydroxypropyl methylcellulose may have a weight-average molecular weight of 10,000 to 1,500,000. Preferably, the hydroxypropyl methylcellulose may have a weight-average molecular weight of 15,000 to 400,000 (e.g., hydroxypropyl methylcellulose 2910 606, hydroxypropyl methylcellulose 2910 60SH, hydroxypropyl methylcellulose 2910 E4M, hydroxypropyl methylcellulose 2910 603, etc.), more preferably a weight-average molecular weight of about 400,000 (e.g., hydroxypropyl methylcellulose 2910 E4M, etc.). The hydroxypropyl methylcellulose may be present at a concentration of 0.1 to 0.4 w / v%, preferably 0.3 to 0.4 w / v%, more preferably about 0.4 w / v%.

[0024] According to the present invention, it has been found that when an eye drop in the form of an aqueous solution is prepared using specific solubilizing agents (i.e., polyethylene glycol and polysorbate) in addition to the combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, a stable eye drop that does not exhibit precipitation for 12 months at room temperature can be obtained. Therefore, the eye drop of the present invention preferably further contains polyethylene glycol and polysorbate as solubilizing agents.

[0025] The polyethylene glycol may have a weight-average molecular weight of 380 to 420. For example, polyethylene glycol 400 may be preferably used. The polyethylene glycol may be present at a concentration of 2.0 to 5.0 w / v%, preferably 2.0 to 4.0 w / v%, and more preferably about 2.0 w / v%. The polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. The polysorbate may be present at a concentration of 0.05 to 0.15 w / v%, preferably 0.1 to 0.15 w / v%, and more preferably about 0.15 w / v%.

[0026] In one embodiment of the present invention, there is provided an eye drop solution comprising, in an aqueous medium, 0.1 to 1.0 w / v% 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; 0.5 to 2.0 w / v% buffering agent; 0.01 to 0.3 w / v% chelating agent; 0.5 to 5.0 w / v% polyvinylpyrrolidone; 0.1 to 0.4 w / v% hydroxypropylmethylcellulose; 2.0 to 5.0 w / v% polyethylene glycol; and 0.05 to 0.15 w / v% polysorbate.

[0027] In a preferred embodiment of the present invention, there is provided an eye drop solution comprising, in an aqueous medium, 0.25 w / v% 8-oxo-2'-deoxyguanosine; 1.0 w / v% tromethamine; 0.1 w / v% sodium ethylenediaminetetraacetate; 2.0 w / v% polyvinylpyrrolidone; 0.4 w / v% hydroxypropylmethylcellulose; 2.0 w / v% polyethylene glycol; and 0.15 w / v% polysorbate.

[0028] The pH of the aqueous solution-type eye drops of the present invention may be 5.0 to 7.0, preferably about 6.5.

[0029] The present invention will be described in more detail below with reference to examples. However, these examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0030] In the following examples, HL262 refers to 8-oxo-2'-deoxyguanosine. [Example]

[0031] Tromethamine, sodium edetate, and thickeners (polyvinylpyrrolidone and / or hydroxypropyl methylcellulose) were dissolved in sterile purified water according to the ingredients and amounts shown in Table 1, followed by dissolution of HL262. Polyvinylpyrrolidone and hydroxypropyl methylcellulose were used within the maximum amounts recommended by the FDA (HPMC: 0.5 w / v%, PVP K30: 2.0 w / v%). The pH of each solution was adjusted to approximately 6.5 with a pH adjuster (hydrochloric acid), and the final volume was adjusted to approximately 100 mL with sterile purified water to produce each eye drop. The viscosity of each formulation was evaluated using the capillary viscometer method (K = 0.0839) according to General Test Method 1 of the Korean Pharmacopoeia. The resulting formulations were stored at approximately 4°C (i.e., refrigerated conditions) for 30 days and evaluated daily for the presence or absence of precipitation. The resulting formulations were also stored at approximately 25°C (i.e., room temperature conditions) for 60 days and evaluated daily for the presence or absence of precipitation. If precipitation was observed in the eye drops, the precipitation evaluation was discontinued. The results obtained by evaluating viscosity and precipitation as described above are shown in Table 1 below. [Table 1]

[0032] As can be seen from the results in Table 1, when a large amount of hydroxypropyl methylcellulose is used as a thickener, or when polyvinylpyrrolidone and hydroxypropyl methylcellulose are used in combination as thickeners, a viscosity (10 to 30 mPa·s) that provides an appropriate retention time in the eye can be achieved.

[0033] Furthermore, when polyvinylpyrrolidone or hydroxypropyl methylcellulose was used alone as a thickener, precipitation occurred under both refrigerated and room temperature conditions. In contrast, when polyvinylpyrrolidone and hydroxypropyl methylcellulose were used in combination as a thickener, excellent physical stability was observed under both refrigerated and room temperature conditions. Therefore, it was confirmed that polyvinylpyrrolidone and hydroxypropyl methylcellulose function not only as thickeners but also as stabilizers and solubilizers in HL262-containing eye drops. [Example]

[0034] Tromethamine, sodium edetate, thickeners (polyvinylpyrrolidone and / or hydroxypropylmethylcellulose), and solubilizers (polyethylene glycol and polysorbate) were dissolved in sterile purified water according to the ingredients and amounts shown in Table 2, followed by dissolution of HL262. The pH of each solution was adjusted to approximately 6.5 with a pH adjuster (hydrochloric acid), and the final volume was adjusted to approximately 100 mL with sterile purified water to prepare each eye drop. The viscosity of each formulation was evaluated using the capillary viscometer method (K = 0.0839) according to General Test Method 1 of the Korean Pharmacopoeia. The resulting formulations were stored at approximately 4°C (i.e., refrigerated conditions) for 30 days and evaluated daily for the presence or absence of precipitation. The resulting formulations were also stored at approximately 25°C (i.e., room temperature conditions) for 12 months and evaluated daily for the presence or absence of precipitation. If precipitation was observed in the eye drop solution, the precipitation evaluation was discontinued. The results of the viscosity and precipitation evaluations described above are shown in Table 2 below. [Table 2]

[0035] As can be seen from the results in Table 2, the formulation of Example 2-1 (containing no thickener) and the formulation of Example 2-3 (containing only polyvinylpyrrolidone as a thickener) did not exhibit a viscosity sufficient to ensure adequate intraocular retention. Furthermore, these formulations exhibited precipitation under both refrigerated and room temperature conditions. Furthermore, the formulation of Example 2-2 (containing only hydroxypropyl methylcellulose as a thickener) also exhibited precipitation under both refrigerated and room temperature conditions. In contrast, the formulation of Example 2-4, which used a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose as a thickener and polyethylene glycol and polysorbate as solubilizers, exhibited a viscosity sufficient to ensure adequate intraocular retention. Furthermore, these formulations exhibited excellent physical stability under both refrigerated and room temperature conditions. In particular, the eye drops of Example 2-4 showed no precipitation at all for 12 months at room temperature.

Claims

1. An eye drop in the form of an aqueous solution comprising 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; a thickening agent; a buffer; and a chelating agent in an aqueous medium, the eye drop having a viscosity of 10 to 30 mPa·s.

2. 2. The eye drop preparation according to claim 1, which does not produce precipitation even when stored under refrigerated conditions at about 4°C for 30 days.

3. 2. The eye drop preparation according to claim 1, which does not precipitate even when stored at room temperature of about 25°C for 60 days.

4. 2. The eye drop preparation of claim 1, wherein the 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 1.0 w / v %.

5. 2. The eye drop of claim 1, wherein the buffering agent is tromethamine, borax, boric acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate, or potassium carbonate.

6. 2. The eye drop preparation according to claim 1, wherein the chelating agent is ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof, metaphosphoric acid or a salt thereof, or polyphosphoric acid or a salt thereof.

7. 7. The eye drop preparation of claim 1, wherein the viscosity increasing agent comprises a combination of polyvinylpyrrolidone and hydroxypropylmethylcellulose.

8. 8. The eye drop preparation according to claim 7, wherein the polyvinylpyrrolidone has a weight average molecular weight of 20,000 to 100,000.

9. 8. The eye drop preparation of claim 7, wherein the polyvinylpyrrolidone is present at a concentration of 0.5 to 5.0 w / v %.

10. 8. The eye drop preparation according to claim 7, wherein the hydroxypropyl methylcellulose has a weight average molecular weight of 10,000 to 1,500,000.

11. 8. The eye drop preparation of claim 7, wherein the hydroxypropyl methylcellulose is present at a concentration of 0.1 to 0.4 w / v %.

12. The eye drop according to claim 7, further comprising polyethylene glycol and polysorbate as solubilizing agents.

13. The eye drop according to claim 12, wherein the polyethylene glycol has a weight average molecular weight of 380 to 420.

14. 13. The eye drop preparation of claim 12, wherein the polyethylene glycol is present at a concentration of 2.0 to 5.0 w / v %.

15. 13. The eye drop preparation of claim 12, wherein the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

16. 13. The eye drop preparation of claim 12, wherein the polysorbate is present at a concentration of 0.05 to 0.15 w / v %.

17. In an aqueous medium, 0.1 to 1.0 w / v % 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; 0.5 to 2.0 w / v % buffer; 0.01 to 0.3 w / v % of a chelating agent; 0.5 to 5.0 w / v % polyvinylpyrrolidone; 0.1 to 0.4 w / v % hydroxypropyl methylcellulose; 2.0 to 5.0 w / v % polyethylene glycol; and 0.05 to 0.15 w / v% polysorbate The eye drop of claim 1 , comprising:

18. In an aqueous medium, 0.25 w / v% 8-oxo-2'-deoxyguanosine; 1.0% w / v tromethamine; 0.1 w / v% sodium ethylenediaminetetraacetate; 2.0 w / v% polyvinylpyrrolidone; 0.4% w / v hydroxypropyl methylcellulose; 2.0% w / v polyethylene glycol; and 0.15 w / v% polysorbate The eye drop of claim 1 , comprising:

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