Ophthalmic compositions comprising brimonidine

Abstract

The present invention relates to an ophthalmic composition comprising brimonidine or a salt thereof, SBE-beta-CD or a salt thereof, and xanthan gum, which is safe and has excellent stability and therapeutic effects.

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition comprising brimonidine or a salt thereof. Background Art

[0002] Brimonidine is an alpha-2-adrenergic agonist that is a drug used to reduce intraocular pressure in patients with glaucoma and / or ocular hypertension.

[0003] As a representative ophthalmic preparation containing brimonidine, BREFOX-P (Allergan, Inc.) contains 0.15% brimonidine tartrate and is prescribed for administration three times a day.

[0004] Due to the nature of ophthalmic preparations, it is preferred to have a pH within a biocompatible range that minimizes irritation to the eyeball, and storage stability is required so that discoloration or precipitation does not occur. However, brimonidine has a property that its solubility decreases rapidly under conditions above pH 7, so it is difficult to formulate brimonidine into an aqueous solution having a transparent property at a pH greater than 7 to 8, or at a lower pH within the biocompatible range.

[0005] In particular, increasing the content of the active ingredient can be considered to ensure further increased therapeutic effects and ease of administration of ophthalmic preparations, but in the case of brimonidine, it is difficult to fully dissolve brimonidine within the biocompatible pH range, and thus the development of ophthalmic preparations containing high concentrations of brimonidine while maintaining biocompatibility is limited.

[0006] <Related technical references>

[0007] <Patent Documents>

[0008] Korean Unexamined Patent Application Publication No. 10-2003-0017500 DETAILED DESCRIPTION OF THE INVENTION

[0010] Technical issues

[0011] The present invention can provide an ophthalmic composition comprising brimonidine or a salt thereof, a preventive or therapeutic method using the ophthalmic composition, and uses thereof, wherein the composition comprises brimonidine stably dissolved therein, can be safely administered to the eyeball, and can maintain a stable state during storage without precipitation and changes in its appearance.

[0012] Technical Solution

[0013] The ophthalmic composition according to the present invention may include brimonidine or a salt thereof; sulfobutyl ether-β-cyclodextrin (SBE-β-CD) or a salt thereof; and xanthan gum.

[0014] In an embodiment of the present invention, "brimonidine" may refer to a compound having a chemical name of 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline.

[0015] In an embodiment of the present invention, the salt of brimonidine may include brimonidine tartrate.

[0016] In an embodiment of the present invention, the amount of brimonidine or a salt thereof included in the ophthalmic composition may be about 0.01 w / v% or more, about 0.1 w / v% or more, about 0.2 w / v% or more, or about 0.3 w / v% or more, and the amount may be about 10 w / v% or less, about 5 w / v% or less, about 1 w / v% or less, about 0.9 w / v% or less, about 0.8 w / v% or less, about 0.7 w / v% or less, about 0.6 w / v% or less, or about 0.5 w / v% or less, based on the total volume of the ophthalmic composition. For example, the ophthalmic composition may include brimonidine or a salt thereof in an amount of about 0.01 w / v% to about 10 w / v%, about 0.1 w / v% to about 5 w / v%, about 0.1 w / v% to 1 w / v%, about 0.2 w / v% to about 1 w / v%, about 0.3 w / v% to about 1 w / v%, about 0.2 w / v% to about 0.5 w / v%, about 0.3 w / v% to about 0.5 w / v%, or about 0.1 w / v% to about 0.5 w / v%.

[0017] In one embodiment, the ophthalmic composition may include brimonidine or its salt in an amount of about 0.2 w / v% or more, based on the total volume of the ophthalmic composition. As an example, the ophthalmic composition may include brimonidine or its salt in an amount of about 0.2 w / v% to about 1 w / v% or about 0.3 w / v% to about 1 w / v%.

[0018] In one embodiment, the ophthalmic composition may include brimonidine or a salt thereof in an amount of about 0.3 w / v% or more, and in an amount of about 0.5 w / v% or less, based on the total volume of the ophthalmic composition. As an example, the ophthalmic composition may include brimonidine or a salt thereof in an amount of about 0.3 w / v% to about 0.5 w / v%.

[0019] In an embodiment of the present invention, the salt of SBE-β-CD is not particularly limited, but may include a metal salt. For example, the salt of SBE-β-CD may be a sodium salt.

[0020] In an embodiment of the present invention, the amount of SBE-β-CD or a salt thereof included in the ophthalmic composition may be about 1 w / v% or more, about 3 w / v% or more, about 5 w / v% or more, or about 6 w / v% or more, and the amount thereof may be about 15 w / v% or less, about 10 w / v% or less, or about 8 w / v%. For example, the ophthalmic composition may include SBE-β-CD or a salt thereof in an amount of about 1 w / v% to about 15 w / v%, about 1 w / v% to about 10 w / v%, about 3 w / v% to about 10 w / v%, about 5 w / v% to about 10 w / v%, about 6 w / v% to about 10 w / v%, about 5 w / v% to about 8 w / v%, or about 6 w / v% to about 8 w / v%.

[0021] In an embodiment of the present invention, the amount of xanthan gum included in the ophthalmic composition may be about 0.01 w / v% or more, or about 0.1 w / v% or more, and the amount may be about 10 w / v% or less, about 6 w / v% or less, about 3 w / v% or less, about 1 w / v% or less, about 0.8 w / v% or less, or about 0.6 w / v% or less. For example, the ophthalmic composition may include the following amount of xanthan gum: about 0.01 w / v% to about 10 w / v%, about 0.01 w / v% to about 6 w / v%, about 0.1 w / v% to about 3 w / v%, about 0.1 w / v% to about 1 w / v%, about 0.1 w / v% to about 0.6 w / v%, or about 0.01 w / v% to about 1 w / v%.

[0022] The ophthalmic composition according to the present invention may include SBE-β-CD or a salt thereof and xanthan gum to stably and sufficiently dissolve brimonidine or a salt thereof during the preparation process and to maintain a stable state without precipitation and appearance change during storage.

[0023] In an embodiment of the present invention, the ophthalmic composition may have a pH of about 7.2 or greater, about 7.3 or greater, or about 7.4 or greater, and may have a pH of about 9 or less, or about 8 or less. For example, the ophthalmic composition may have a pH of about 7.2 to about 9, about 7.2 to about 8, about 7.3 to about 8, or about 7.4 to about 8.

[0024] In an embodiment of the present invention, the ophthalmic composition may include about 0.2 w / v% or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum.

[0025] In an embodiment of the present invention, the ophthalmic composition may include about 0.3 w / v% or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum.

[0026] In an embodiment of the present invention, the ophthalmic composition may include brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum, and may have a pH of about 7.2 to about 8.

[0027] In an embodiment of the present invention, the ophthalmic composition may include about 0.2 w / v% or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum, and may have a pH of about 7.2 to about 8.

[0028] In an embodiment of the present invention, the ophthalmic composition may include about 0.3 w / v% or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum, and may have a pH of about 7.4 to about 8.

[0029] In an embodiment of the present invention, the ophthalmic composition may include brimonidine or a salt thereof in an amount of about 0.3 w / v% to about 0.5 w / v%; SBE-β-CD or a salt thereof in an amount of about 1 w / v% to about 10 w / v%; and xanthan gum in an amount of about 0.1 w / v% to about 0.6 w / v%, and may have a pH of about 7.2 to about 8.

[0030] In an embodiment of the present invention, the ophthalmic composition may include additives such as a buffer, a pH adjuster, a dissolution aid, a sustained-release agent, a thickener, an isotonic agent, and the like.

[0031] In an embodiment of the present invention, the buffer used herein may include at least one of acetic acid, phosphoric acid, boric acid, their salts and / or their hydrates or anhydrides, etc., but is not limited thereto. The buffer may be added in an amount suitable for maintaining an appropriate pH.

[0032] In an embodiment of the present invention, the pH adjuster used herein may include hydrochloric acid, sodium hydroxide, etc. The pH adjuster may be used in an amount necessary to obtain an appropriate pH range.

[0033] In an embodiment of the present invention, the ophthalmic composition may include polysorbate 20, polysorbate 80, etc. as the dissolution aid.

[0034] In an embodiment of the present invention, the ophthalmic composition may include polyvinyl pyrrolidone, a cellulose-based compound, or the like as the thickener.

[0035] The ophthalmic composition of the present invention can be a solution with a transparent appearance comprising water. In an embodiment of the present invention, the water used as the aqueous medium can be sterile purified water, water for injection, etc., which are suitable for preparing the ophthalmic preparation. In one embodiment, the ophthalmic composition of the present invention can be an aqueous ophthalmic composition comprising water.

[0036] In an embodiment of the present invention, the ophthalmic composition can be a transparent and stable solution for at least three consecutive months when stored at a temperature of about 20°C to about 40°C.

[0037] In an embodiment of the present invention, the ophthalmic composition can be a transparent and stable solution for at least two weeks when stored at a temperature of about 70°C.

[0038] In an embodiment of the present invention, the ophthalmic composition may include brimonidine or a salt thereof as an active ingredient and may exhibit the pharmacological activity of brimonidine or a salt thereof. In particular, the ophthalmic composition may be advantageously used for preventing, improving or treating glaucoma and / or ocular hypertension.

[0039] In an embodiment of the present invention, in addition to brimonidine or its salt, the ophthalmic composition may further comprise an additional active ingredient. Examples of the additional active ingredients may include latanoprost, bimatoprost, travoprost, tafluprost, netarsudil, carteolol, Timoptic, timolol, betaxolol, levobunolol, metipranolol, brinzolamide, dorzolamide, acetazolamide, methazolamide or their pharmaceutically acceptable salts, each of which may be used alone in combination with brimonidine or its salt, or two or more of which may be used together in combination with brimonidine or its salt.

[0040] In an embodiment of the present invention, the ophthalmic composition can be used for single use or multiple use, in particular single use. When the ophthalmic composition is used for multiple use, the composition may further contain a preservative. The preservative may be a quaternary ammonium compound, such as benzalkonium chloride, polyquaternium-1 (such as Polyquad), etc.; a guanidine compound, such as chlorhexidine, etc.; chlorobutanol; a mercuric preservative, etc.

[0041] In an embodiment of the present invention, the ophthalmic composition can be administered once to three times a day. For example, the ophthalmic composition can be administered once, twice or three times a day.

[0042] The ophthalmic composition of the present invention can contain brimonidine stably dissolved therein, and thus can be provided as an aqueous liquid with a transparent appearance. In addition, the ophthalmic composition of the present invention can maintain a stable state during storage without precipitation and appearance changes, such as color, etc. In addition, the ophthalmic composition can have excellent stability because its physicochemical properties such as the content of the active ingredient, pH, etc. are well maintained, and the amount of impurities generated is small. Therefore, the ophthalmic composition of the present invention can maintain a stable state for a long time, and therefore can be safely administered to the eyeball and can show excellent therapeutic effects without side effects.

[0043] The above-mentioned ophthalmic composition according to the present invention may be a composition for reducing intraocular pressure.

[0044] The ophthalmic composition according to the present invention can prevent or treat at least one of glaucoma and ocular hypertension.

[0045] The above-mentioned ophthalmic composition according to the present invention can reduce the intraocular pressure of an individual suffering from at least one of glaucoma and ocular hypertension.

[0046] In the present invention, the "individual" may refer to all animals, including humans.

[0047] The present invention may provide a method for preventing or treating at least one of glaucoma and ocular hypertension, the method comprising administering the above-mentioned ophthalmic composition to an individual.

[0048] The present invention may provide use of the ophthalmic composition for preventing or treating at least one of glaucoma and ocular hypertension.

[0049] The present invention can provide use of the ophthalmic composition for preparing a medicament for preventing or treating at least one of glaucoma and ocular hypertension.

[0050] The matters mentioned in the ophthalmic composition, use and method for treating or preventing a disease of the present invention may be equally applied unless they contradict each other.

[0051] (1) The ophthalmic composition according to the present invention may include brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum.

[0052] (2) The ophthalmic composition according to (1) above may contain brimonidine or a salt thereof in an amount of about 0.2 w / v% or more based on the total volume of the composition.

[0053] (3) The ophthalmic composition according to (1) or (2) above may contain brimonidine or a salt thereof in an amount of about 0.2 w / v % to about 1 w / v % based on the total volume of the composition.

[0054] (4) The ophthalmic composition according to any one of (1) to (3) above may contain brimonidine tartrate as a salt of brimonidine.

[0055] (5) The ophthalmic composition according to any one of (1) to (4) above may contain SBE-β-CD or a salt thereof in an amount of about 1 w / v % to about 15 w / v % based on the total volume of the composition.

[0056] (6) The ophthalmic composition according to any one of (1) to (5) above may contain xanthan gum in an amount of about 0.01 w / v% to about 1 w / v% based on the total volume of the composition.

[0057] (7) The ophthalmic composition according to any one of (1) to (6) above may have a pH of about 7.2 to about 8.

[0058] (8) The ophthalmic composition according to any one of (1) to (7) above may be a transparent solution containing water.

[0059] (9) The ophthalmic composition according to any one of (1) to (8) above may contain at least one additive selected from a buffer, a pH adjuster, a dissolution aid, a sustained release agent, and a thickener.

[0060] (10) The ophthalmic composition according to any one of (1) to (9) above can be a clear solution for at least three consecutive months when stored at a temperature of about 20°C to about 40°C, or can be a clear solution for at least two consecutive weeks when stored at a temperature of about 70°C.

[0061] (11) The present invention may provide a method for preventing or treating at least one of glaucoma and ocular hypertension, the method comprising administering the ophthalmic composition to an individual. In this case, the ophthalmic composition may be the ophthalmic composition described in any one of (1) to (10) above.

[0062] (12) The present invention may provide a use of the ophthalmic composition for preventing or treating at least one of glaucoma and ocular hypertension. In this case, the ophthalmic composition may be the ophthalmic composition described in any one of (1) to (10) above.

[0063] (13) The present invention may provide a use of the ophthalmic composition for preparing a medicament for preventing or treating at least one of glaucoma and ocular hypertension. In this case, the ophthalmic composition may be an ophthalmic composition as described in any one of (1) to (10) above.

[0064] The method for preparing the ophthalmic composition according to the present invention may include preparing a mixed solution including brimonidine or a salt thereof, SBE-β-CD or a salt thereof, and xanthan gum.

[0065] In an embodiment of the present invention, the mixed solution may be prepared by dissolving brimonidine or a salt thereof, SBE-β-CD or a salt thereof, and xanthan gum in water.

[0066] In an embodiment of the present invention, the mixed solution may be a solution subjected to a sterilization process.

[0067] In an embodiment of the present invention, the preparation of the mixed solution may include:

[0068] preparing a first solution by dissolving brimonidine or a salt thereof and SBE-β-CD or a salt thereof in water;

[0069] preparing a second solution by dissolving xanthan gum in water; and

[0070] The first solution and the second solution are mixed.

[0071] In one embodiment, the first solution and the second solution may be subjected to a sterilization process and then mixed to prepare the mixed solution.

[0072] In an embodiment of the present invention, the first solution, the second solution and the mixed solution in preparing the mixed solution may each independently further comprise additives such as a buffer, a pH adjuster, a dissolution aid, a sustained-release agent, a thickener, an isotonic agent, and the like.

[0073] In an embodiment of the present invention, at least one of the first solution, the second solution, and the mixed solution in preparing the mixed solution may further contain an additional active ingredient in addition to brimonidine or a salt thereof.

[0074] The method for preparing the ophthalmic composition according to the present invention may include adding a pH adjuster to the mixed solution.

[0075] In the method for preparing the ophthalmic composition according to the present invention, brimonidine or its salt, SBE-β-CD or its salt and xanthan gum as well as additional additives and additional active ingredients may be substantially the same as described above, and thus any redundant detailed description is omitted.

[0076] Beneficial Effects

[0077] The ophthalmic composition of the present invention may include brimonidine stably dissolved therein, and thus may be provided as an aqueous solution having a transparent appearance.

[0078] Furthermore, the ophthalmic composition of the present invention can maintain a stable state during storage without precipitation and changes in appearance such as color and the like.

[0079] Furthermore, the ophthalmic composition can have excellent stability because its physicochemical properties such as the content of the active ingredient, pH, etc. are well maintained and the amount of impurities generated is small.

[0080] Therefore, the ophthalmic composition of the present invention can be safely administered to the eyeball and maintain a stable state for a long time, and thus can exhibit excellent therapeutic effects without side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 The graph shows the results of Experimental Example 1.

[0082] Figure 2 The figure shows the results of Experimental Example 2. DETAILED DESCRIPTION

[0083] Hereinafter, the present invention is described in more detail by experimental examples. These experimental examples are provided only for the purpose of illustrating the present invention, and therefore, those skilled in the art will appreciate that the scope of the present invention is not limited thereto.

[0084] Preparation Example 1: Preparation of ophthalmic compositions 1 to 3

[0085] Compositions 1 to 3 were prepared according to the ingredients and contents shown in Table 1 below.

[0086] Specifically, brimonidine tartrate, anhydrous disodium hydrogen phosphate, monosodium dihydrogen phosphate and SBE-β-CD sodium are dissolved in water, and then filtered and sterilized to prepare a first solution. Xanthan gum is dissolved in water separately and sterilized at high temperature and high pressure to prepare a second solution. Composition 1 is prepared by mixing the first solution and the second solution and adjusting the pH with sterile sodium hydroxide.

[0087] Composition 2 was prepared in the same manner as Composition 1 except for sodium SBE-β-CD.

[0088] Composition 3 was prepared by preparing a first solution subjected to a sterile process and adjusting the pH with sodium hydroxide.

[0089] Compositions 1 to 3 were prepared to have a pH of about 7.2.

[0090] [Table 1]

[0091]

[0092]

[0093] Experimental Example 1: Appearance and Stability Evaluation

[0094] It was confirmed that compositions 2 and 3 caused precipitation immediately after their preparation. In contrast, composition 1 was obtained as a clear solution ( Figure 1 ).

[0095] Furthermore, Composition 1 was stored at room temperature (25°C), 30°C and 40°C for three months, and at 70°C for two weeks, and precipitation was observed. The results confirmed that a transparent appearance was maintained without precipitation under all the above storage conditions.

[0096] Therefore, it can be seen that the composition 1 comprising SBE-β-CD and xanthan gum of the present invention has very excellent stability.

[0097] Preparation Example 2: Preparation of ophthalmic compositions 4 to 8

[0098] According to the ingredients and contents shown in Table 2 below, Compositions 4 to 8 were prepared by the same method as that of preparing Composition 1.

[0099] [Table 2]

[0100]

[0101] Experimental Example 2: Appearance and Stability Evaluation

[0102] Compositions 4 to 8 were all prepared as clear solutions, and no composition precipitated.

[0103] Furthermore, it was confirmed that all of Compositions 4 to 8 maintained a transparent appearance without color change and precipitation even when stored at 70° C. for two weeks ( Figure 2 ).

[0104] Therefore, it can be seen that the composition comprising SBE-β-CD and xanthan gum of the present invention has very excellent stability.

[0105] Experimental Example 3: Stability Evaluation

[0106] Composition 6 was stored at 70°C for one week and then pH, osmotic pressure and viscosity were measured. Viscosity was measured using a rotational viscometer (Brookfield viscometer) using a No. 18 spindle, a temperature of 25±0.5°C and a speed that gave a torque value as high as 100%.

[0107] It was confirmed that the pH, osmotic pressure and viscosity of Composition 6 remained substantially stable and did not change even after storage (Table 3).

[0108] [Table 3]

[0109]

[0110] It can be seen from this that the composition comprising SBE-β-CD and xanthan gum of the present invention has very excellent stability.

[0111] Although specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for illustrating exemplary embodiments and should not be interpreted as limiting the scope of the present invention. Therefore, it should be understood that the essential scope of the present invention is limited by the appended claims and their equivalents.

Claims

1. An ophthalmic composition, comprising: Brimonidine or its salts; Sulfobutyl ether-β-cyclodextrin (SBE-β-CD) or a salt thereof; and Xanthan gum.

2. The ophthalmic composition according to claim 1, wherein the amount of brimonidine or a salt thereof contained is 0.2 w / v% or more based on the total volume of the composition.

3. The ophthalmic composition according to claim 2, wherein the amount of brimonidine or a salt thereof contained is 0.2 w / v% to 1 w / v% based on the total volume of the composition. The ophthalmic composition according to claim 1 , comprising brimonidine tartrate as the salt of brimonidine. The ophthalmic composition according to claim 1 , wherein SBE-β-CD or a salt thereof is contained in an amount of 1 w / v % to 15 w / v % based on the total volume of the composition. 6 . The ophthalmic composition according to claim 1 , wherein the xanthan gum is contained in an amount of 0.01 w / v % to 1 w / v % based on the total volume of the composition.

7. The ophthalmic composition according to claim 1 or 2, wherein the pH is 7.2 to 8.

8. The ophthalmic composition according to claim 1, wherein the ophthalmic composition is a clear solution comprising water.

9. The ophthalmic composition according to claim 1, wherein the ophthalmic composition comprises at least one additive selected from the group consisting of a buffer, a pH adjuster, a dissolution aid, a sustained-release agent, and a thickener.

10. The ophthalmic composition of claim 1, wherein the ophthalmic composition is a clear solution for at least three consecutive months when stored at a temperature of 20°C to 40°C, or a clear solution for at least two consecutive weeks when stored at a temperature of 70°C.

11. A method for preventing or treating at least one of glaucoma and ocular hypertension, the method comprising: The ophthalmic composition of any one of claims 1 to 10 is administered to a subject.

12. Use of the ophthalmic composition according to any one of claims 1 to 10 for preventing or treating at least one of glaucoma and ocular hypertension.

13. Use of the ophthalmic composition according to any one of claims 1 to 10 for preparing a medicament for preventing or treating at least one of glaucoma and ocular hypertension.

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