Ophthalmic compositions containing brimonidine

Abstract

The present invention relates to a safe ophthalmic composition that is excellent in stability and therapeutic effect and that contains brimonidine or a salt thereof, SBE-β-CD or a salt thereof, and xanthan gum.

Description

[Technical Field]

[0001] The present invention relates to ophthalmic compositions comprising brimonidine or a salt thereof. [Background technology]

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

[0003] A typical ophthalmic preparation containing brimonidine is Alphagan®-P (Allergan, Inc.), which contains 0.15% brimonidine tartrate and is prescribed to be instilled three times a day.

[0004] Ophthalmic formulations should preferably have a pH within a biocompatible range that minimizes irritation to the eyeball, and should be stable during storage without discoloration or precipitation. However, brimonidine has the property that its solubility drops sharply above pH 7, making it difficult to formulate into a clear aqueous solution at pH levels above pH 7 and below pH 8, which are biocompatible.

[0005] In particular, it is conceivable to increase the content of the active ingredient in ophthalmic formulations to ensure further therapeutic effects and ease of administration. However, in the case of brimonidine, it is difficult to dissolve it sufficiently within a pH range compatible with the body, and there are limitations to developing ophthalmic formulations containing high concentrations of brimonidine while maintaining biocompatibility. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Korean Patent Publication No. 10-2003-0017500 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides an ophthalmic composition containing brimonidine or a salt thereof, which contains stably dissolved brimonidine, can be safely administered to the eyeball, and can maintain a stable state without the occurrence of precipitation or changes in properties during storage; a preventive or therapeutic method using the same; and uses thereof. [Means for solving the problem]

[0008] The ophthalmic composition according to the present invention comprises brimonidine or a salt thereof, sulfobutylether-β-cyclodextrin (SBE-β-CD) or a salt thereof; and xanthan gum.

[0009] In the present embodiment, "brimonidine" refers to the compound with the chemical name 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline.

[0010] In embodiments of the present invention, the salt of brimonidine may include brimonidine tartrate.

[0011] In embodiments of the present invention, the ophthalmic composition may contain brimonidine or a salt thereof in an amount of 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, based on the total volume of the ophthalmic composition, and may contain 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. For example, the ophthalmic composition may contain brimonidine or a salt thereof at about 0.01 to about 10 w / v%, about 0.1 to about 5 w / v%, about 0.1 to 1 w / v%, about 0.2 to about 1 w / v%, about 0.3 to about 1 w / v%, about 0.2 to about 0.5 w / v%, about 0.3 to about 0.5 w / v%, or about 0.1 to about 0.5 w / v%.

[0012] In one embodiment, the ophthalmic composition may contain brimonidine or a salt thereof in an amount of about 0.2 w / v% or more, for example, about 0.2 to about 1 w / v%, or about 0.3 to about 1 w / v%, based on the total volume of the ophthalmic composition.

[0013] In one embodiment, the ophthalmic composition may contain brimonidine or a salt thereof in an amount of about 0.3 w / v% or more and about 0.5 w / v% or less, based on the total volume of the ophthalmic composition. For example, the ophthalmic composition may contain brimonidine or a salt thereof in an amount of about 0.3 to about 0.5 w / v%.

[0014] In an embodiment of the present invention, the salt of SBE-β-CD may include, but is not limited to, a metal salt, for example, the salt of SBE-β-CD may be a sodium salt.

[0015] In some embodiments, the ophthalmic composition may contain SBE-β-CD or a salt thereof at 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, or about 15% w / v or less, about 10% w / v or less, or about 8% w / v or less. For example, the ophthalmic composition may contain about 1 to about 15% w / v, about 1 to about 10% w / v, about 3 to about 10% w / v, about 5 to about 10% w / v, about 6 to about 10% w / v, about 5 to about 8% w / v, or about 6 to about 8% w / v of SBE-β-CD or a salt thereof.

[0016] In some embodiments, the ophthalmic composition may contain xanthan gum at about 0.01% w / v or more, about 0.1% w / v or more, or 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 contain xanthan gum at about 0.01 to about 10% w / v, about 0.01 to about 6% w / v, about 0.1 to about 3% w / v, about 0.1 to about 1% w / v, about 0.1 to about 0.6% w / v, or about 0.01 to about 1% w / v.

[0017] The ophthalmic composition of the present invention contains SBE-β-CD or a salt thereof and xanthan gum, which allows brimonidine or a salt thereof to be stably and sufficiently dissolved during the manufacturing process, and can maintain a stable state without the occurrence of precipitation or changes in properties during storage.

[0018] In embodiments of the present invention, the pH of the ophthalmic composition may be about 7.2 or more, about 7.3 or more, or about 7.4 or more, and may be about 9 or less, or about 8 or less. For example, the pH of the ophthalmic composition may be 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.

[0019] In an embodiment of the present invention, the ophthalmic composition may comprise about 0.2 w / v % or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum.

[0020] In an embodiment of the present invention, the ophthalmic composition may comprise about 0.3 w / v % or more of brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum.

[0021] In an embodiment of the present invention, the ophthalmic composition comprises 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.

[0022] In an embodiment of the present invention, the ophthalmic composition may comprise at least about 0.2 w / v % 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.

[0023] In an embodiment of the present invention, the ophthalmic composition may comprise about 0.3 w / v% or more 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.

[0024] In an embodiment of the present invention, the ophthalmic composition may comprise about 0.3 to about 0.5 w / v % brimonidine or a salt thereof; about 1 to about 10 w / v % SBE-β-CD or a salt thereof; and about 0.1 to about 0.6 w / v % xanthan gum, and may have a pH of about 7.2 to about 8.

[0025] In an embodiment of the present invention, the ophthalmic composition may contain additives such as a buffering agent, a pH adjusting agent, a solubilizing agent, a sustained-release agent, a thickening agent, and a tonicity agent.

[0026] In an embodiment of the present invention, the buffer may be one or more of, but is not limited to, acetic acid, phosphoric acid, boric acid, salts thereof and / or hydrates or anhydrides thereof, etc. The buffer may be added in an appropriate amount to maintain an appropriate pH.

[0027] In the present embodiment, the pH adjusting agent may be hydrochloric acid, sodium hydroxide, etc. The pH adjusting agent may be used in an amount necessary to obtain a pH in an appropriate range.

[0028] In an embodiment of the present invention, the ophthalmic composition may contain polysorbate 20, polysorbate 80, etc. as a solubilizing agent.

[0029] In an embodiment of the present invention, the ophthalmic composition may contain polyvinylpyrrolidone, a cellulose-based compound, etc. as a thickener.

[0030] The ophthalmic composition of the present invention may be a transparent solution containing water. In an embodiment of the present invention, the water used as the aqueous medium may be sterilized purified water, water for injection, or the like, suitable for producing ophthalmic preparations. In one embodiment, the ophthalmic composition of the present invention may be an aqueous eye drop composition containing water.

[0031] In an embodiment of the present invention, the ophthalmic composition may be a continuously clear and stable solution for at least three months when stored at a temperature of about 20°C to about 40°C. In an embodiment of the present invention, the ophthalmic composition may be a continuously clear and stable solution when stored at a temperature of about 70°C for at least two weeks.

[0032] In an embodiment of the present invention, the ophthalmic composition contains brimonidine or a salt thereof as an active ingredient and exhibits the pharmacological activity of brimonidine or a salt thereof. Specifically, the ophthalmic composition can be effectively used for the prevention, amelioration, or treatment of glaucoma and / or ocular hypertension. It can be used.

[0033] In an embodiment of the present invention, the ophthalmic composition may further comprise an additional active ingredient in addition to brimonidine or its salt. Examples of the additional active ingredient include latanoprost, bimatoprost, travoprost, tafluprost, netarsudil, carteolol, timoptic, timolol, betaloxol, levobunolol, metipranolol, brinzolamide, dorzolamide, acetazolamide, methazolamide, or a pharmaceutically acceptable salt thereof, which may be used alone or in combination with brimonidine or its salt.

[0034] In an embodiment of the present invention, the ophthalmic composition may be a single-use or multi-use type, specifically a single-use type. When the ophthalmic composition is a multi-use type, the composition may further contain a preservative. The preservative may be a quaternary ammonium compound such as benzalkonium chloride or polyquaternium-1 (e.g., polyquad), a guanidine-based compound such as chlorhexidine, chlorobutanol, a mercury preservative, or the like.

[0035] In some embodiments of the present invention, the ophthalmic composition may be administered one to three times daily. For example, the ophthalmic composition may be administered one, two, or three times daily.

[0036] The ophthalmic composition of the present invention can be provided as a transparent aqueous solution by containing stably dissolved brimonidine. Furthermore, the ophthalmic composition of the present invention can maintain a stable state without precipitation or changes in properties such as color during storage. Furthermore, the ophthalmic composition maintains its physicochemical properties, such as the content of the active ingredient and pH, and exhibits excellent stability with minimal generation of related substances. Therefore, the ophthalmic composition of the present invention can maintain a stable state for a long period of time and can be safely administered to the eyeball, thereby exhibiting excellent therapeutic effects without side effects.

[0037] The above-described ophthalmic composition according to the present invention may be a composition for reducing intraocular pressure.

[0038] The ophthalmic composition according to the present invention can prevent or treat at least one of glaucoma and ocular hypertension.

[0039] The above-described ophthalmic composition according to the present invention can reduce intraocular pressure in a subject suffering from at least one of glaucoma and ocular hypertension.

[0040] In the present invention, "subject" can mean any animal, including humans.

[0041] The present invention provides a method for preventing or treating at least one of glaucoma and ocular hypertension, which comprises administering the above-described ophthalmic composition to a subject.

[0042] The present invention provides a use of the above-mentioned ophthalmic composition for the prevention or treatment of at least one of glaucoma and ocular hypertension.

[0043] The present invention relates to a drug for preventing or treating at least one of glaucoma and ocular hypertension. The present invention provides a use of the aforementioned ophthalmic composition for the manufacture of an agent.

[0044] The matters mentioned in relation to the ophthalmic composition, use, and method for treating or preventing a disease of the present invention are equally applicable unless they contradict each other.

[0045] (1) The ophthalmic composition according to the present invention comprises brimonidine or a salt thereof; SBE-β-CD or a salt thereof; and xanthan gum. (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. (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. (4) The ophthalmic composition according to any one of (1) to (3) above may contain brimonidine tartrate as a salt of brimonidine. (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 to about 15 w / v % based on the total volume of the composition. (6) The ophthalmic composition according to any one of (1) to (5) above may contain xanthan gum in an amount of about 0.01 to about 1 w / v % based on the total volume of the composition. (7) The ophthalmic composition according to any one of (1) to (6) above may have a pH of about 7.2 to about 8. (8) The ophthalmic composition according to any one of (1) to (7) above may be a transparent solution containing water. (9) The ophthalmic composition according to any one of (1) to (8) above may contain at least one additive selected from a buffering agent, a pH adjusting agent, a solubilizing agent, a sustained-release agent, and a thickening agent. (10) The ophthalmic composition according to any one of (1) to (9) above may be a transparent solution continuously for at least 3 months when stored at a temperature of about 20°C to about 40°C, or may be a transparent solution continuously for at least 2 weeks when stored at a temperature of about 70°C. (11) The present invention provides a method for preventing or treating at least one of glaucoma and ocular hypertension, comprising administering to a subject an ophthalmic composition, wherein the ophthalmic composition may be any one of the ophthalmic compositions described above in (1) to (10). (12) The present invention provides a use of an ophthalmic composition for the prevention or treatment of at least one of glaucoma and ocular hypertension, wherein the ophthalmic composition may be any one of the ophthalmic compositions described above in (1) to (10). (13) The present invention provides a use of an ophthalmic composition for the manufacture of a medicament for the prevention or treatment of at least one of glaucoma and ocular hypertension, wherein the ophthalmic composition may be any one of the ophthalmic compositions described above in (1) to (10).

[0046] A method for producing an ophthalmic composition according to the present invention includes the step of preparing a mixed solution containing brimonidine or a salt thereof, SBE-β-CD or a salt thereof, and xanthan gum.

[0047] In an embodiment of the present invention, the step of preparing the mixed solution may be performed by dissolving brimonidine or a salt thereof, SBE-β-CD or a salt thereof, and xanthan gum in water.

[0048] In an embodiment of the present invention, the mixed solution may be a solution that has been subjected to a sterilization process.

[0049] In an embodiment of the present invention, the step of preparing the mixed solution includes: dissolving brimonidine or a salt thereof and SBE-β-CD or a salt thereof in water to prepare a first solution; dissolving xanthan gum in water to form a second solution; and The method may include mixing the first solution and the second solution.

[0050] In one embodiment, the first solution and the second solution may be mixed together to produce the mixed solution after a sterilization process has been performed on them.

[0051] In an embodiment of the present invention, the first solution, the second solution and the mixed solution in the step of preparing the mixed solution may each independently further contain additives such as a buffer, a pH adjuster, a solubilizing agent, a sustained-release agent, a thickener, an isotonicity agent, etc.

[0052] In an embodiment of the present invention, at least one of the first solution, the second solution and the mixed solution in the step of preparing the mixed solution may further contain an additional active ingredient in addition to brimonidine or a salt thereof.

[0053] The method for producing an ophthalmic composition according to the present invention may include a step of adding a pH adjuster to the mixed solution.

[0054] In the method for preparing the ophthalmic composition according to the present invention, brimonidine or a salt thereof, SBE-β-CD or a salt thereof, xanthan gum, and the additives and active ingredients to be added are substantially the same as those described above, and therefore, a detailed description thereof will be omitted. [Effects of the Invention]

[0055] The ophthalmic composition of the present invention can be provided as a transparent aqueous solution by containing stably dissolved brimonidine. Furthermore, the ophthalmic composition of the present invention can be maintained in a stable state during storage without causing precipitation or changes in properties such as color. In addition, the ophthalmic composition maintains its physicochemical properties such as the content of the active ingredient and pH, and generates little related substances, resulting in excellent stability. Therefore, the ophthalmic composition of the present invention can be safely administered to the eyeball for a long period of time and can maintain a stable state, thereby exhibiting excellent therapeutic effects without side effects. [Brief explanation of the drawings]

[0056] [Figure 1] FIG. 1 is a diagram showing the results of Experimental Example 1. [Figure 2] FIG. 10 is a diagram showing the results of Experimental Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention will be described in more detail below through experimental examples. It will be obvious to those skilled in the art that these experimental examples are merely for the purpose of illustrating the present invention and that the scope of the present invention is not to be construed as being limited by these experimental examples.

[0058] Production Example 1: Production of Ophthalmic Compositions 1 to 3 Compositions 1 to 3 were prepared using the ingredients and amounts shown in Table 1 below. Specifically, brimonidine tartrate, anhydrous sodium monohydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium SBE-β-CD were dissolved in water and then sterilized by filter to prepare a first solution. Separately, xanthan gum was dissolved in water and sterilized under high temperature and high pressure to prepare a second solution. The first and second solutions were mixed, and the pH was adjusted with sterilized sodium hydroxide to prepare Composition 1. Composition 2 was prepared in the same manner as Composition 1, except for sodium SBE-β-CD. Composition 3 is prepared by preparing a first solution that has undergone a sterilization process and adjusting the pH with sodium hydroxide. It was manufactured using this method. The pH of the prepared compositions 1 to 3 was about 7.2.

[0059] [Table 1]

[0060] Experimental Example 1: Properties and Stability Evaluation It was confirmed that precipitation occurred immediately after preparation of Compositions 2 and 3. On the other hand, Composition 1 was obtained as a clear solution (FIG. 1). 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 then observed for the presence or absence of precipitation. As a result, it was confirmed that the transparency was maintained without precipitation under all of the storage conditions. This demonstrates that composition 1 of the present invention, which contains SBE-β-CD and xanthan gum, has excellent stability.

[0061] Preparation Example 2: Preparation of Ophthalmic Compositions 4 to 8 Compositions 4 to 8 were prepared according to the ingredients and amounts listed in Table 2 below in the same manner as in the preparation of Composition 1.

[0062] [Table 2]

[0063] Experimental Example 2: Properties and Stability Evaluation All of Compositions 4 to 8 were produced as clear solutions, and no compositions showed precipitation. Furthermore, it was confirmed that all of Compositions 4 to 8 maintained their transparency without any change in color or precipitation even after storage at 70°C for two weeks (Figure 2). This demonstrates that the composition of the present invention containing SBE-β-CD and xanthan gum has excellent stability.

[0064] Experimental Example 3: Stability evaluation Composition 6 was stored at 70°C for 1 week, and then the pH, osmotic pressure, and viscosity were measured. The viscosity was measured using a Brookfield viscometer at a torque of 100% at 25±0.5°C with a spindle of 18. It was confirmed that the pH, osmolality, and viscosity of Composition 6 remained stable without substantial change even after storage (Table 3).

[0065] [Table 3]

[0066] This demonstrates that the composition of the present invention containing SBE-β-CD and xanthan gum has excellent stability.

[0067] Although certain aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention is to be defined by the appended claims and their equivalents.

Claims

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

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

3. 3. The ophthalmic composition of claim 2, comprising brimonidine or a salt thereof in an amount of 0.2 w / v % to 1 w / v % based on the total volume of the composition.

4. 2. The ophthalmic composition of claim 1, comprising brimonidine tartrate as the salt of brimonidine.

5. 2. The ophthalmic composition according to claim 1, comprising SBE-β-CD or a salt thereof in an amount of 1 to 15 w / v % based on the total volume of the composition.

6. 6. The ophthalmic composition according to claim 1, wherein the xanthan gum is present in an amount of 0.01 to 1 w / v % based on the total volume of the composition.

7. 3. The ophthalmic composition of claim 1, wherein the pH is from 7.2 to 8.

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

9. The ophthalmic composition comprises:

2. The ophthalmic composition according to claim 1, further comprising at least one additive selected from the group consisting of a buffer, a pH adjuster, a solubilizing agent, a sustained-release agent, and a viscosity enhancer.

10. 2. The ophthalmic composition of claim 1, which remains a clear solution continuously for at least three months when stored at a temperature of 20°C to 40°C, or remains a clear solution continuously for at least two weeks when stored at a temperature of 70°C.

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

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

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

Images