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 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 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 Art

[0002] The compound of Formula 1, the chemical name of which is 8-oxo-2'-deoxyguanosine, or a pharmaceutically acceptable salt thereof exhibits rapid corneal epithelial recovery and is thus 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 US Patent No. 10,675,294). <Formula 1> JPEG0007886490000001.jpg33157

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

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

[0005] It may be attempted to solubilize the compound of Formula 1 by heating a mixture containing the compound of Formula 1 in an aqueous solution (for example, a mixture in the form of a suspension). However, when the aqueous solution obtained by heating is stored at room temperature, the compound of Formula 1 precipitates, making it difficult to use as an eye drop that requires repeated eye drops.

[0006] Furthermore, it is possible to 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 (for example, a mixture in the form of a suspension). However, there is a problem in that the compound of formula 1 cannot be solubilized in the pH range in which it can be used as eye drops (i.e., pH 5-7).

[0007] Furthermore, if patients repeatedly use eye drops in aqueous solution form, a considerable amount of the medication may leak from the eye depending on the method of use. This leakage often leads to the problem that the desired therapeutically effective amount of eye drops is not retained in the eye. Therefore, there is a need to manufacture eye drops in aqueous solution form that exhibit an appropriate intraocular residence time. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The inventors conducted various studies to develop an eye drop solution containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof in an aqueous medium that can solve the above problems. As a result, the inventors found 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 residence time in the eye. Furthermore, the inventors found that a specific combination of components (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 inventors found that when an eye drop solution in the form of an aqueous solution is produced using a specific solubilizer in addition to the aforementioned combination of thickeners, a precipitate can be obtained for 12 months under room temperature conditions.

[0009] Therefore, an object of the present invention is to provide an eye drop in solution form having a specific viscosity, containing 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 in the form of an aqueous solution comprising 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof; a thickener; a buffer; and a chelating agent in an aqueous medium, wherein the eye drop has a viscosity of 10 to 30 mPa·s.

[0011] In one embodiment, the eye drops of the present invention do not precipitate even when stored for 30 days under refrigerated conditions at approximately 4°C. In another embodiment, the eye drops of the present invention do not precipitate even when stored for 60 days at room temperature at approximately 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 buffering agent may be tromethamine, borax, boric acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate, or potassium carbonate; the chelating agent may be ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof, metaphosphate or a salt thereof, or polyphosphate or a salt thereof.

[0013] In the eye drops of the present invention, the thickening agent may include 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 solubilizers. 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 residence time in the eye. Furthermore, according to the present invention, it has been found that a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose not only functions as a thickener but also as a stabilizer and solubilizer, thereby providing an aqueous solution of eye drops with excellent stability. In particular, according to the present invention, when an aqueous solution of eye drops is produced using the combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose in addition to specific solubilizers (i.e., polyethylene glycol and polysorbate), it has been found that a stable eye drop that does not show precipitation for 12 months under room temperature conditions can be obtained. Therefore, the eye drops of the present invention exhibit an appropriate residence time in the eye and show excellent stability without precipitation even after long-term storage, making them useful for long-term repeated administration (repeated eye drops). [Modes for carrying out the invention]

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

[0017] In one embodiment, the eye drops of the present invention do not precipitate even when stored for 30 days under refrigerated conditions at approximately 4°C. In another embodiment, the eye drops of the present invention do not precipitate even when stored for 60 days at room temperature at approximately 25°C.

[0018] In the eye drops of the present invention, examples of aqueous media include distilled water for injection, sterile 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, but are not limited to, 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%. The pharmaceutically acceptable salt of 8-oxo-2'-deoxyguanosine may be selected from the various salts disclosed in Korean Patent No. 10-1816277, for example, its acid addition salts.

[0020] The eye drops of the present invention may contain additives such as buffers and chelating agents. The buffer may be tromethamine, borax, boric acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate, or potassium carbonate, and preferably tromethamine. The buffer may be used in an amount sufficient to provide a suitable buffering effect. For example, the buffer 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, and preferably sodium ethylenediaminetetraacetic acid. 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 thickening agent, namely a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, not only functions as a thickening agent but also as a stabilizer and solubilizer, thereby providing an eye drop in aqueous solution form with excellent stability. Therefore, the eye drop of the present invention may preferably contain a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose as a thickening agent.

[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 (for example, polyvinylpyrrolidone K-25, K-30, etc.), and 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%, and 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 (for example, hydroxypropyl methylcellulose 2910 606, hydroxypropyl methylcellulose 2910 60SH, hydroxypropyl methylcellulose 2910 E4M, hydroxypropyl methylcellulose 2910 603, etc.), and more preferably, a weight-average molecular weight of about 400,000 (for example, 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%, and more preferably about 0.4 w / v%.

[0024] According to the present invention, in addition to the combination of the polyvinylpyrrolidone and hydroxypropylmethylcellulose, when producing an eye drop in the form of an aqueous solution using specific solubilizing agents (i.e., polyethylene glycol and polysorbate), it has been found that a stable eye drop showing no precipitation under room temperature conditions for 12 months 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%, 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%, more preferably about 0.15 w / v%.

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

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

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

[0029] Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only and do not limit the scope of the present invention.

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

Example

[0031] According to the components and amounts shown in Table 1, tromethamine, sodium edetate, and a thickener (polyvinylpyrrolidone and / or hydroxypropylmethylcellulose) were dissolved in sterile purified water, and then HL262 was dissolved. Polyvinylpyrrolidone and hydroxypropylmethylcellulose 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 obtained solution was adjusted to about pH 6.5 with a pH adjuster (hydrochloric acid), and the final volume was adjusted to about 100 mL with sterile purified water to produce each eye drop. The viscosity of each obtained preparation was evaluated by the capillary viscometer method (K = 0.0839) of General Test Method 1 of the Korean Pharmacopoeia. The obtained preparations were stored at about 4 °C (i.e., refrigerated conditions) for 30 days, and the presence or absence of precipitation was evaluated daily. Also, the obtained preparations were stored at about 25 °C (i.e., room temperature conditions) for 60 days, and the presence or absence of precipitation was evaluated daily. When precipitation was observed in the eye drops, the precipitation evaluation was terminated. 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 thickening agent, or when polyvinylpyrrolidone and hydroxypropyl methylcellulose are used in combination as thickening agents, a viscosity (10-30 mPa·s) that provides an appropriate residence time in the eye can be achieved.

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

[0034] According to the ingredients and quantities shown in Table 2, tromethamine, sodium edetate, thickeners (polyvinylpyrrolidone and / or hydroxypropyl methylcellulose), and solubilizers (polyethylene glycol and polysorbate) were dissolved in sterile purified water, and then HL262 was dissolved. The pH of each resulting solution was adjusted to approximately pH 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 resulting preparation was evaluated using the capillary viscometer method (K=0.0839) according to General Test Method 1 of the Korean Pharmacopoeia. The resulting preparations were stored at approximately 4°C (i.e., under refrigerated conditions) for 30 days, and the presence or absence of precipitation was evaluated daily. The resulting preparations were also stored at approximately 25°C (i.e., under room temperature conditions) for 12 months, and the presence or absence of precipitation was evaluated daily. If precipitation was observed in the eye drops, the precipitation evaluation was stopped. The results obtained by evaluating viscosity and precipitation as described above are shown in Table 2 below. [Table 2]

[0035] As can be seen from the results in Table 2, the formulations of Example 2-1 (without a thickener) and Example 2-3 (containing only polyvinylpyrrolidone as a thickener) did not exhibit a viscosity sufficient to show an appropriate residence time in the eye. Furthermore, these formulations showed precipitation under both refrigerated and room temperature conditions. Similarly, the formulation of Example 2-2 (containing only hydroxypropyl methylcellulose as a thickener) also showed precipitation under both refrigerated and room temperature conditions. In contrast, when a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose was used as a thickener, and polyethylene glycol and polysorbate were used as solubilizers (formulation of Example 2-4), it showed a viscosity sufficient to show an appropriate residence time in the eye. Furthermore, this formulation showed excellent physical stability under both refrigerated and room temperature conditions. In particular, it can be confirmed that the eye drops of Example 2-4 showed no precipitation at all for 12 months under room temperature conditions.

Claims

1. An eye drop in the form of an aqueous solution comprising: 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof in an aqueous medium; a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose as a thickener; a buffer; and a chelating agent, wherein the eye drop has a viscosity of 10 to 30 mPa·s.

2. The eye drops according to Claim 1, wherein no precipitate forms even when stored for 30 days under refrigerated conditions at 4°C.

3. The eye drops according to Claim 1, wherein no precipitate forms even when stored at room temperature of 25°C for 60 days.

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

5. The eye drop according to 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. The eye drop 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. The eye drop according to claim 1, wherein the polyvinylpyrrolidone has a weight-average molecular weight of 20,000 to 100,000.

8. The eye drops according to claim 1, wherein the polyvinylpyrrolidone is present at a concentration of 0.5 to 5.0 w / v%.

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

10. The eye drop according to claim 1, wherein the hydroxypropyl methylcellulose is present in a concentration of 0.1 to 0.4 w / v%.

11. The eye drop according to claim 1, further comprising polyethylene glycol and polysorbate as solubilizing agents.

12. The eye drop according to claim 11, wherein the polyethylene glycol has a weight-average molecular weight of 380 to 420.

13. The eye drop according to claim 11, wherein the polyethylene glycol is present in a concentration of 2.0 to 5.0 w / v%.

14. The eye drop according to claim 11, wherein the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

15. The eye drop according to claim 11, wherein the polysorbate is present in a concentration of 0.05 to 0.15 w / v%.

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

17. 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 An eye drop according to claim 1, comprising:

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