Eye drop formulation in form of aqueous solution comprising 8-oxo-2 '-deoxyguanosine or pharmaceutically acceptable salt thereof

Abstract

The present invention provides an eye drop formulation in the form of an aqueous solution comprising 8-oxo-2 '-deoxyguanosine, or a pharmaceutically acceptable salt thereof, in an aqueous medium; a thickening agent; a buffering agent; and a chelating agent, wherein the viscosity of the eye drop preparation is from 10 mPa.s to 30 mPa.s. The eye drop preparation of the present invention has an appropriate retention time in eyes, and has excellent stability without precipitation even if stored for a long time.

Description

Technical Field

[0001] The present invention relates to an eye drop preparation in the form of an aqueous solution, which contains 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, which contains 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof as an active ingredient and has a certain viscosity. Background Art

[0002] The compound of Formula 1, whose chemical name is 8-oxo-2'-deoxyguanosine, or a pharmaceutically acceptable salt thereof, exhibits rapid corneal epithelial restoration and is therefore useful for preventing and / or treating corneal damage, including dry eye syndrome, ocular trauma, and infectious uveitis or non-infectious uveitis (Korean Patent No. 10-1816277 and U.S. Patent No. 10,675,294).

[0003] <Formula 1>

[0004]

[0005] In order to achieve effective prevention and / or treatment of corneal damage by repeated instillation, a stable eye drop formulation in the form of an aqueous solution is needed, which contains a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0006] However, since the compound of Formula 1 has very low water solubility of 1.91 mg / mL at room temperature (about 25° C.), it is difficult to prepare an eye drop formulation in the form of an aqueous solution containing a therapeutically effective amount.

[0007] It is possible to attempt to dissolve the compound of Formula 1 by heating an aqueous solution mixture (e.g., a mixture in the form of a suspension) containing the compound of Formula 1. 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 preparation that requires repeated instillation.

[0008] In addition, it is also possible to attempt to dissolve the compound of Formula 1 by increasing the pH of an aqueous solution mixture (e.g., a mixture in the form of a suspension) containing the compound of Formula 1. However, there is a problem that the compound of Formula 1 cannot be dissolved within a pH range that can be used as an eye drop formulation (i.e., pH 5 to 7).

[0009] In addition, when patients repeatedly use eye drop preparations in the form of aqueous solutions, a large amount of drug solution will flow out of the eyes according to the method of use. The outflow usually leads to the problem that the required therapeutically effective amount of eye drop preparation cannot be retained in the eyes. Therefore, it is necessary to prepare eye drop preparations in the form of aqueous solutions, which have a suitable retention time in the eyes. Summary of the invention

[0010] In order to develop an eye drop preparation in the form of a solution including a compound of formula 1 or its pharmaceutically acceptable salt in an aqueous medium that can solve the above problem, the inventors have conducted various studies. As a result, the inventors found that the eye drop preparation in the form of an aqueous solution with a certain viscosity (i.e., a viscosity of 10mPa s to 30mPa s) and dissolved with a compound of formula 1 or its pharmaceutically acceptable salt has a suitable retention time in the eye. In addition, the inventors found that the combination of certain ingredients (thickeners) can be used not only as a thickener, but also as a stabilizer and a solubilizing agent, thereby providing an eye drop preparation in the form of an aqueous solution with excellent stability. In particular, the inventors found that when an eye drop preparation in the form of an aqueous solution is prepared by using a certain solubilizing agent other than the combination of the above-mentioned thickeners, a stable eye drop in which no precipitation occurs within 12 months at room temperature can be obtained.

[0011] Therefore, an object of the present invention is to provide an eye drop preparation in the form of a solution, which comprises 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the eye drop preparation has a certain viscosity.

[0012] Technical Solution

[0013] According to one aspect of the present invention, an eye drop preparation in the form of an aqueous solution is provided, the eye drop preparation 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 viscosity of the eye drop preparation is 10 mPa·s to 30 mPa·s.

[0014] In one embodiment, the eye drop formulation of the present invention does not precipitate when stored under refrigeration conditions at about 4° C. for 30 days. In another embodiment, the eye drop formulation of the present invention does not precipitate when stored at room temperature of about 25° C. for 60 days.

[0015] In the eye drop preparation of the present invention, 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof may be present in a concentration of 0.1 weight / volume % to 1.0 weight / volume %. In the eye drop preparation 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; 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.

[0016] In the eye drop formulation of the present invention, the thickener may include a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose. The weight average molecular weight of polyvinyl pyrrolidone may be 20,000 to 100,000, and may be present in a concentration of 0.5% to 5.0% by weight / volume. The weight average molecular weight of hydroxypropyl methylcellulose may be 10,000 to 1,500,000, and may be present in a concentration of 0.1% to 0.4% by weight / volume.

[0017] The eye drop formulation of the present invention can also include polyethylene glycol and polysorbate as solubilizing agents. The weight average molecular weight of polyethylene glycol can be 380 to 420, and can be present in a concentration of 2.0 weight / volume % to 5.0 weight / volume %. Polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, and can be present in a concentration of 0.05 weight / volume % to 0.15 weight / volume %.

[0018] Beneficial Effects

[0019] The present invention has found that the eye drop preparation in the form of an aqueous solution with a certain viscosity (i.e., a viscosity of 10mPa s to 30mPa s) and dissolved with a compound of Formula 1 or a pharmaceutically acceptable salt thereof shows a suitable retention time in the eye. In addition, the present invention has found that the combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose can be used not only as a thickener, but also as a stabilizer and a solubilizing agent, thereby providing an eye drop preparation in the form of an aqueous solution with excellent stability. In particular, the present invention also finds that when an eye drop preparation in the form of an aqueous solution is prepared by using a certain solubilizing agent (i.e., polyethylene glycol and polysorbate) other than a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose, a stable eye drop in which no precipitation occurs within 12 months at room temperature can be obtained. Therefore, the eye drop preparation of the present invention has a suitable retention time in the eye, and has excellent stability without precipitation even if stored for a long time, so that it can be effectively administered for a long time and repeatedly administered (repeated instillation). DETAILED DESCRIPTION

[0020] 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 thickener, a buffer, and a chelating agent in an aqueous medium, wherein the viscosity of the eye drop preparation is 10 mPa·s to 30 mPa·s.

[0021] In one embodiment, the eye drop formulation of the present invention does not precipitate when stored under refrigeration conditions at about 4° C. for 30 days. In another embodiment, the eye drop formulation of the present invention does not precipitate when stored at room temperature of about 25° C. for 60 days.

[0022] In the eye drop preparation of the present invention, the aqueous medium includes distilled water for injection, sterile purified water, physiological saline and the like.

[0023] In the eye drop preparation of the present invention, a therapeutically effective amount of 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof may be used. For example, the eye drop preparation of the present invention may contain 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof at a concentration of 0.1 weight / volume % to 1.0 weight / volume %, preferably about 0.25 weight / volume %, but not limited thereto. A pharmaceutically acceptable salt of 8-oxo-2'-deoxyguanosine, such as an acid addition salt thereof, may be selected from the various salts disclosed in Korean Patent No. 10-1816277.

[0024] The eye drop preparation of the present invention can include excipients such as buffers, chelating agents, etc. The buffer can be tromethamine, borax, boric acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate or potassium carbonate, preferably tromethamine. The amount of the buffer is sufficient to provide a suitable buffering effect. For example, the buffer can be present in a concentration of 0.5 weight / volume % to 2.0 weight / volume %, preferably about 1.0 weight / volume %. The chelating agent can be ethylenediaminetetraacetic acid or its salt, citric acid or its salt, metaphosphoric acid or its salt or polyphosphoric acid or its salt, preferably sodium ethylenediaminetetraacetate. The chelating agent can be used in the conventional amount in the field of eye drop preparations. For example, the chelating agent can be present in a concentration of 0.01 weight / volume % to 0.3 weight / volume %, preferably about 0.1 weight / volume %.

[0025] The present invention has found that a certain thickener, namely a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose, can be used not only as a thickener but also as a stabilizer and solubilizer, thereby providing an eye drop formulation in the form of an aqueous solution with excellent stability. Therefore, the eye drop formulation of the present invention may preferably contain a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose as a thickener.

[0026] The weight average molecular weight of polyvinyl pyrrolidone may be 20000 to 100000. Preferably, the weight average molecular weight of polyvinyl pyrrolidone may be 30000 to 50000 (e.g., polyvinyl pyrrolidone K-25, K-30, etc.), more preferably, the weight average molecular weight may be about 50000. Polyvinyl pyrrolidone may be present in a concentration of 0.5% to 5% by weight / volume, preferably 1.0% to 3.0% by weight / volume, more preferably about 2.0% by weight / volume.

[0027] The weight average molecular weight of hydroxypropyl methylcellulose can be 10000 to 1500000. Preferably, the weight average molecular weight of hydroxypropyl methylcellulose can be 15000 to 400000 (e.g., hydroxypropyl methylcellulose 2910 606, hydroxypropyl methylcellulose 2910 60SH, hydroxypropyl methylcellulose 2910E4M, hydroxypropyl methylcellulose 2910 603, etc.), and more preferably the weight average molecular weight can be about 400000 (e.g., hydroxypropyl methylcellulose 2910E4M, etc.). Hydroxypropyl methylcellulose can be present in a concentration of 0.1% by weight / volume to 0.4% by weight / volume, preferably 0.3% by weight / volume to 0.4% by weight / volume, and more preferably about 0.4% by weight / volume.

[0028] The present invention has found that when a certain solubilizing agent (i.e., polyethylene glycol and polysorbate) other than a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is used to prepare an eye drop formulation in the form of an aqueous solution, a stable eye drop can be obtained in which no precipitation occurs within 12 months at room temperature. Therefore, the eye drops of the present invention preferably further comprise polyethylene glycol and polysorbate as solubilizing agents.

[0029] The weight average molecular weight of polyethylene glycol can be 380 to 420. For example, polyethylene glycol 400 is preferably used. Polyethylene glycol can be present in a concentration of 2.0 weight / volume % to 5.0 weight / volume %, preferably 2.0 weight / volume % to 4.0 weight / volume %, and more preferably about 2.0 weight / volume %. Polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. Polysorbate can be present in a concentration of 0.05 weight / volume % to 0.15 weight / volume %, preferably 0.1 weight / volume % to 0.15 weight / volume %, and more preferably about 0.15 weight / volume %.

[0030] In an embodiment of the present invention, an eye drop formulation is provided, which comprises 0.1 weight / volume % to 1.0 weight / volume % of 8-oxo-2'-deoxyguanosine or a pharmaceutically acceptable salt thereof in an aqueous medium; 0.5 weight / volume % to 2.0 weight / volume % of a buffer; 0.01 weight / volume % to 0.3 weight / volume % of a chelating agent; 0.5 weight / volume % to 5.0 weight / volume % of polyvinyl pyrrolidone; 0.1 weight / volume % to 0.4 weight / volume % of hydroxypropyl methylcellulose; 2.0 weight / volume % to 5.0 weight / volume % of polyethylene glycol; and 0.05 weight / volume % to 0.15 weight / volume % of polysorbate.

[0031] In a preferred embodiment of the present invention, an eye drop formulation is provided, which comprises 0.25 weight / volume 8-oxo-2'-deoxyguanosine; 1.0 weight / volume tromethamine; 0.1 weight / volume ethylenediaminetetraacetic acid sodium; 2.0 weight / volume % polyvinylpyrrolidone; 0.4 weight / volume hydroxypropyl methylcellulose; 2.0 weight / volume % polyethylene glycol; and 0.15 weight / volume % polysorbate in an aqueous medium.

[0032] The pH of the eye drop preparation in the form of an aqueous solution of the present invention may be 5.0 to 7.0, preferably about 6.5.

[0033] The present invention will be described in detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0034] In the following examples, HL262 represents 8-oxo-2'-deoxyguanosine.

[0035] Example 1

[0036] According to the components and contents shown in Table 1, tromethamine, sodium edetate and thickener (polyvinyl pyrrolidone and / or hydroxypropyl methylcellulose) were dissolved in sterile purified water, and then HL262 was dissolved therein. Polyvinyl pyrrolidone and hydroxypropyl methylcellulose (HPMC: 0.5 weight / volume%, PVPK30: 2.0 weight / volume%) were used within the maximum amount range recommended by the FDA. The pH of each resulting solution was adjusted to about 6.5 with a pH control agent (hydrochloric acid), and its final volume was adjusted to about 100 mL with sterile purified water to prepare various eye drop preparations. The viscosity of each resulting preparation was evaluated by a capillary viscometer method (method 1 (K=0.0839) in the general test of the Korean Pharmacopoeia). The resulting preparations were stored at about 4°C (i.e., refrigerated conditions) for 30 days, and the precipitation was evaluated every day. And the resulting preparations were stored at about 25°C (i.e., room temperature conditions) for 60 days, and the precipitation was evaluated every day. If precipitation was observed in the eye drop preparation, the evaluation of its precipitation was stopped. The results obtained by evaluating the viscosity and precipitation as described above are shown in Table 1 below.

[0037] [Table 1]

[0038]

[0039] From the results in Table 1, it can be seen that using a high content of hydroxypropyl methylcellulose as a thickener, or using a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose as a thickener can provide a viscosity (ie, 10 to 30 mPa·s) that can have a suitable retention time in the eye.

[0040] In addition, when polyvinyl pyrrolidone or hydroxypropyl methylcellulose was used alone as a thickener, precipitation occurred both under refrigerated conditions and at room temperature. In contrast, the combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose as a thickener showed excellent physical stability both under refrigerated conditions and at room temperature. Therefore, it can be confirmed that polyvinyl pyrrolidone and hydroxypropyl methylcellulose can be used as stabilizers and solubilizers in eye drop preparations containing HL262.

[0041] Example 2

[0042] According to the components and contents shown in Table 2, tromethamine, sodium ethylenediaminetetraacetate, thickeners (polyvinyl pyrrolidone and / or hydroxypropyl methylcellulose) and solubilizers (polyethylene glycol and polysorbate) were dissolved in sterile purified water, and then HL262 was dissolved therein. The pH of each resulting solution was adjusted to about 6.5 with a pH control agent (hydrochloric acid), and its final volume was adjusted to about 100 mL with sterile purified water to prepare various eye drop preparations. The viscosity of each resulting preparation was evaluated by a capillary viscometer method (method 1 (K=0.0839) in the general test of the Korean Pharmacopoeia). The resulting preparations were stored at about 4°C (i.e., refrigerated conditions) for 30 days, and the precipitation was evaluated every day. And the resulting preparations were stored at about 25°C (i.e., room temperature conditions) for 12 months, and the precipitation was evaluated every day. If precipitation is observed in the eye drop preparation, the evaluation of its precipitation is stopped. The results obtained by evaluating the viscosity and precipitation as described above are shown in Table 2 below.

[0043] [Table 2]

[0044]

[0045] As can be seen from the results of Table 2, the preparation of Example 2-1 (not including thickener) and the preparation of Example 2-3 (containing only polyvinyl pyrrolidone as a thickener) do not provide a viscosity that can have a suitable retention time in the eye. The preparation also precipitates under both refrigerated conditions and room temperature conditions. And embodiment 2-2 (including only hydroxypropyl methylcellulose as a thickener) precipitates under both refrigerated conditions and room temperature conditions. On the contrary, using a combination of polyvinyl pyrrolidone and hydroxypropyl methylcellulose as a thickener and using polyethylene glycol and polysorbate as a solubilizing agent (preparation of embodiment 2-4), a viscosity that can have a suitable retention time in the eye is provided. In addition, the preparation also shows excellent physical stability under both refrigerated conditions and room temperature conditions. In particular, it can be confirmed that the eye drop preparation of embodiment 2-4 has no precipitation at all for 12 months under room temperature conditions.

Claims

1. An eye drop preparation 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 preparation has a viscosity of 10 mPa·s to 30 mPa·s.

2. The eye drop preparation according to claim 1, wherein no precipitation occurs when stored under refrigeration conditions at about 4°C for 30 days.

3. The eye drop preparation according to claim 1, wherein no precipitation occurs when stored at room temperature of about 25°C for 60 days. 4 . The eye drop formulation according to claim 1 , wherein 8-oxo-2′-deoxyguanosine or a pharmaceutically acceptable salt thereof is present in a concentration of 0.1 weight / volume % to 1.0 weight / volume %.

5. The eye drop preparation according to claim 1, wherein the buffer is tromethamine, borax, boric acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, sodium hydroxide, sodium carbonate or potassium carbonate. 6 . 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. The eye drop formulation according to any one of claims 1 to 6, wherein the thickener comprises a combination of polyvinylpyrrolidone and hydroxypropylmethylcellulose. 8 . The eye drop preparation according to claim 7 , wherein the weight average molecular weight of the polyvinyl pyrrolidone is 20,000 to 100,000.

9. The eye drop formulation according to claim 7, wherein the polyvinylpyrrolidone is present in a concentration of 0.5 weight / volume % to 5.0 weight / volume %.

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

11. The eye drop formulation according to claim 7, wherein the hydroxypropyl methylcellulose is present in a concentration of 0.1 weight / volume % to 0.4 weight / volume %.

12. The eye drop preparation according to claim 7, further comprising polyethylene glycol and polysorbate as solubilizers. The eye drop preparation according to claim 12 , wherein the weight average molecular weight of the polyethylene glycol is 380 to 420.

14. The eye drop formulation according to claim 12, wherein the polyethylene glycol is present in a concentration of 2.0 weight / volume % to 5.0 weight / volume %. 15 . The eye drop preparation according to claim 12 , wherein the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

16. The eye drop formulation according to claim 12, wherein the polysorbate is present in a concentration of 0.05 weight / volume % to 0.15 weight / volume %.

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

18. The eye drop preparation according to claim 1, comprising in an aqueous medium: 0.25 weight / volume 8-oxo-2'-deoxyguanosine; 1.0 weight / volume % tromethamine; 0.1 weight / volume % sodium EDTA ； 2.0 weight / volume % polyvinylpyrrolidone; 0.4 weight / volume % hydroxypropyl methylcellulose; 2.0 weight / volume % polyethylene glycol; and 0.15 weight / volume % polysorbate.

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