KR102703639B1 - Ophthalmic composition containing hyaluronic acid or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to an ophthalmic composition having excellent stability, which comprises hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient. The ophthalmic composition comprising an oil component and an emulsifying component of the present invention has excellent stability, and can be used for the treatment or prevention of dry eye.

Description

Ophthalmic composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof {OPHTHALMIC COMPOSITION CONTAINING HYALURONIC ACID OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF}

The present invention relates to an ophthalmic composition with improved stability comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

Dry eye disease is a disease that causes irritation, pain, dryness, visual impairment, and various other inflammation-related symptoms in the eyes due to tear deficiency or excessive evaporation of tears. Dry eye disease is one of the most common diseases worldwide, and it has been reported that 54.3% of the world's population has mild dry eye disease. Artificial tears can be used for dry eye disease, and artificial tears perform various roles in the eye, such as replenishing tear components, diluting inflammatory substances, reducing tear osmotic pressure, and lubricating. Artificial tears can contain water-soluble polymers such as sodium hyaluronate and oil components, but there is a problem that it is difficult to produce a composition in which the water-soluble polymer and oil components exist in a stable form in an aqueous solvent.

The inventors of the present invention studied various compositions of artificial tears for treating dry eye syndrome and discovered a composition capable of stably storing polymers and oils, thereby completing the present invention.

U.S. Patent No. 10660848

The purpose of the present invention is to provide a stable ophthalmic composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention aims to provide an ophthalmic composition for treating or preventing dry eye syndrome comprising the composition.

The present invention provides an ophthalmic composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, castor oil and medium chain triglyceride as oil components, and polyoxyl35 castor oil and polyoxyl40 hydrogenated castor oil as emulsifying components.

The ophthalmic composition of the present invention may be an emulsion, and may be an oil-in-water emulsion.

In the composition of the present invention, the content of the hyaluronic acid or a pharmaceutically acceptable salt thereof may be 0.01 to 0.5 w/v%, 0.1 to 0.5 w/v%, 0.1 to 0.4 w/v% or 0.1 to 0.3 w/v%. In the composition of the present invention, the content of the hyaluronic acid or a salt thereof may be 0.01 w/v% or more, 0.1 w/v% or more, and may be 0.5 w/v% or less, 0.4 w/v% or less or 0.3 w/v% or less, and may be 0.1 w/v%, 0.2 w/v% or 0.3 w/v%.

In the composition of the present invention, the hyaluronic acid or a pharmaceutically acceptable salt thereof may be sodium hyaluronate.

In the composition of the present invention, the content of the oil may be 0.1 to 5 w/v%, 0.1 to 4 w/v%, 0.1 to 3 w/v%, 0.1 to 2.5 w/v%, 0.5 to 3 w/v% or 0.5 to 2.5 w/v%. In the composition of the present invention, the content of the oil may be 0.1 w/v% or more, 0.5 w/v% or more, and 5 w/v% or less, 4 w/v% or less, 3 w/v% or less or 2.5 w/v% or less, and may be 2.25 w/v%, 2.26 w/v%.

In the composition of the present invention, the content of the medium-chain triglyceride may be 0.1 to 2 w/v%, 0.1 to 1.5 w/v%, or 0.1 to 1 w/v%. In the composition of the present invention, the content of the medium-chain triglyceride may be 0.1 w/v% or more, 2 w/v% or less, 1.5 w/v% or less, or 1 w/v% or less, and may be 1 w/v%.

In the composition of the present invention, the medium-chain triglyceride may be caprylic/capric triglyceride, which is sold under product names such as Kollisolv® MCT 70 and Labrafac ^TM Lipophile WL 1349.

In the composition of the present invention, the content of castor oil may be 0.1 to 3 w/v%, 0.1 to 2 w/v%, or 0.1 to 1.5 w/v%. In the composition of the present invention, the content of castor oil may be 0.1 w/v% or more, 3 w/v% or less, 2 w/v% or less, or 1.5 w/v% or less, and may be 1.26 w/v%.

The content of the emulsifying component in the composition of the present invention may be 0.1 to 5 w/v%, 0.5 to 4 w/v% or 0.5 to 3 w/v%. The content of the emulsifying component in the composition of the present invention may be 0.1 w/v% or more, 0.5 w/v% or more, and 5 w/v% or less, preferably 4 w/v% or less or 3 w/v% or less, and may be 2.78 w/v%, 2.765 w/v%, or 2.75 w/v%.

In the composition of the present invention, the content of polyoxyl 35 castor oil may be 0.1 to 4 w/v%, 0.5 to 3.5 w/v%, or 0.5 to 3 w/v%. In the composition of the present invention, the content of polyoxyl 35 castor oil may be 0.1 w/v% or more, 0.4 w/v% or more, 0.5 w/v% or more, and 4 w/v% or less, 3.5 w/v% or less, or 3 w/v% or less, and may be 2.5 w/v%.

In the composition of the present invention, the content of the polyoxyl 40 hydrogenated castor oil may be 0.01 to 1 w/v%, 0.01 to 0.5 w/v%, or 0.05 to 0.4 w/v%. In the composition of the present invention, the content of the polyoxyl 40 hydrogenated castor oil may be 0.01 w/v% or more, 0.05 w/v% or more, and may be 1 w/v% or less, 0.5 w/v% or less, or 0.4 w/v% or less, and may be 0.28 w/v%, 0.265 w/v%, or 0.25 w/v%.

In the composition of the present invention, the weight ratio of the oil component and the emulsifying component may be 1:1 or more, specifically 1:1 to 1:30, 1:1 to 1:15, 1:1 to 1:10, more specifically 1:1 to 1:5, 1:1 to 1:2, and 1:1.2.

While an emulsifying component is necessary for the stability of an emulsion, a high content thereof may have a negative effect on dry eye syndrome. Therefore, in a dry eye treatment using hyaluronic acid, the content of the emulsifying component is preferably low. The present invention provides a hyaluronic acid preparation in the form of a stable emulsion with a low content of the emulsifying component, and thus the content of the emulsifying component in the composition may be preferably 4 w/v% or less, or 3 w/v% or less.

The composition of the present invention may be an ophthalmic composition comprising: 0.1 to 0.5 w/v% of hyaluronic acid or a pharmaceutically acceptable salt thereof; an oil component comprising castor oil and medium-chain triglycerides and contained in a content of 0.1 to 3 w/v%; and an emulsifying component comprising polyoxyl-35 castor oil and polyoxyl-40 hydrogenated castor oil and contained in a content of 0.5 to 4 w/v%.

The composition of the present invention may be an ophthalmic composition comprising 0.1 to 0.5 w/v% of hyaluronic acid or a pharmaceutically acceptable salt thereof, 0.1 to 1.5 w/v% of castor oil, 0.1 to 1.5 w/v% of medium-chain triglyceride, 0.5 to 3.5 w/v% of polyoxyl 35 castor oil, and 0.01 to 0.5 w/v% of polyoxyl 40 hydrogenated castor oil.

The composition of the present invention may be an ophthalmic composition comprising 0.1 to 0.5 w/v% of hyaluronic acid or a pharmaceutically acceptable salt thereof, 0.1 to 1.5 w/v% of castor oil, 0.1 to 1.5 w/v% of medium-chain triglyceride, 0.4 to 3.5 w/v% of polyoxyl 35 castor oil, and 0.01 to 0.5 w/v% of polyoxyl 40 hydrogenated castor oil.

The ophthalmic composition of the present invention may include an aqueous solvent. The aqueous solvent may be, for example, sterile purified water, saline solution, water for injection, etc.

The ophthalmic composition of the present invention may include one or more of additives such as a buffer, a thickener, an isotonic agent, a preservative, a pH regulator, and a stabilizer.

In one embodiment, the composition can be a transparent solution, a translucent solution, or an opaque solution.

In one embodiment, the composition may be stored under various conditions (e.g., room temperature, 40°C, 55°C) for a long period of time (e.g., 1 week or more, 2 weeks or more, 1 month or more, 3 months or more, 6 months or more, 12 months or more) without exhibiting changes in properties such as phase separation or white turbidity.

In one embodiment, the composition can exhibit excellent stability in which physicochemical properties such as pH, osmotic pressure, and content are stably maintained even when stored for a long period of time (e.g., 1 week or more, 2 weeks or more, 1 month or more, 3 months or more, 6 months or more, 12 months or more) under various conditions (e.g., room temperature, 40°C, 55°C).

In one embodiment, the composition may not exhibit phase separation for 14 days at room temperature.

In one embodiment, the oil-in-water emulsion can exhibit an average particle size of less than 300 nm or less than 200 nm, and can exhibit an average particle size of from 0.1 to 300 nm or from 0.1 to 200 nm.

In one embodiment, the composition may not include one or more of polysorbate 80, polyethylene glycol 400, and propylene glycol.

The present invention provides an ophthalmic composition for treating or preventing dry eye syndrome comprising the composition.

The present invention provides a method for preparing an ophthalmic composition, which comprises the step of preparing a mixed solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof, castor oil, medium-chain triglycerides, polyoxyl-35 castor oil, polyoxyl-40 hydrogenated castor oil, and water. In the above-described method, each component and additive are substantially the same as those described above, and thus redundant descriptions are omitted.

The ophthalmic composition comprising the hyaluronic acid of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient has excellent stability and can be stably stored for a long period of time without changes in properties such as phase separation. In addition, the ophthalmic composition of the present invention can increase the tear layer retention time and thus can be used for the treatment and prevention of dry eye.

Figure 1 is a graph showing the tear layer maintenance time of the composition 17 and saline solution administration groups in an animal model of dry eye.

Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily practice the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

The present invention will be described in more detail through the following examples; however, the following examples are for the purpose of explanation only and are not intended to limit the scope of the present invention.

[Manufacturing Example 1]

Preparation of ophthalmic compositions

Compositions were prepared according to the ingredients and contents (w/v%) of Table 1 below. Specifically, medium-chain triglycerides, castor oil, polyoxyl 35 castor oil, polysorbate 80, polyethylene glycol 400, propylene glycol, and glycerin were mixed according to the compositions of Table 1 below at 70°C, and then water was added to prepare Solution 1. Sodium hyaluronate was hydrated in water and the pH was adjusted to 7.3 using sodium hydroxide to prepare Solution 2. Solutions 1 and 2 were mixed at 50°C, and water was added to prepare Compositions 1 to 3.

Composition Content (w/v%) Composition 1 Composition 2 Composition 3 Sodium hyaluronate 0.2 0.2 0.2 Medium chain triglycerides
(Caprylic-capric triglyceride) 1.0 1.0 1.0 Castor oil 1.26 1.26 1.26 Polyoxyl 35 Castor Oil 2.4 5.0 - Polysorbate 80 - - 15.0 Polyethylene glycol 400 0.6 5.0 - Propylene glycol - - 5.0 glycerin 2.2 1.0 1.5 NaOH Appropriate amount Appropriate amount Appropriate amount

[Manufacturing Example 2]

Preparation of ophthalmic compositions

Compositions were prepared according to the ingredients and contents (w/v%) of Table 2 below. Specifically, medium-chain triglyceride, castor oil, polyoxyl 35 castor oil, polysorbate 80, polyoxyl 40 stearate, polyoxyl 40 hydrogenated castor oil, and glycerin were mixed according to the compositions of Table 2 below at 70°C, and then water was added to prepare Solution 1. Sodium hyaluronate was hydrated in water and the pH was adjusted to 7.3 using sodium hydroxide to prepare Solution 2. Solutions 1 and 2 were mixed at 50°C, and water was added to prepare Compositions 4 to 9.

Composition Content (w/v%) Composition 4 Composition 5 Composition 6 Composition 7 Composition 8 Composition 9 Sodium hyaluronate 0.2 0.2 0.2 0.2 0.2 0.2 Medium chain triglycerides (caprylic-capric triglyceride) 1.0 1.0 1.0 1.0 1.0 1.0 Castor oil 1.26 1.26 1.26 1.26 1.26 1.26 Polyoxyl 35 Castor Oil - 5.0 - 5.0 - 5.0 Polysorbate 80 15.0 - - 15.0 15.0 - Polyoxyl 40 stearate 7.0 7.0 7.0 - - - Polyoxyl 40 hydrogenated castor oil - - 0.53 - 0.53 0.53 glycerin 2.2 1.5 1.0 1.5 1.5 1.5 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

[Manufacturing Example 3]

Preparation of ophthalmic compositions

A composition was prepared according to the ingredients and contents (w/v%) in Tables 3 and 4 below.

Specifically, medium-chain triglycerides, castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and glycerin were mixed according to the compositions in Tables 3 and 4 below at 70°C, and water was added to prepare Solution 1. Sodium hyaluronate was hydrated in water, and the pH was adjusted to 7.3 using sodium hydroxide to prepare Solution 2. The above Solutions 1 and 2 were mixed at 50°C, and water was added to prepare Compositions 10 to 20.

Composition Content (w/v%) Composition 10 Composition
11 Composition 12 Composition 13 Composition 14 Composition 15 Sodium hyaluronate 0.2 0.2 0.2 0.2 0.2 0.2 Medium chain triglycerides
(Caprylic-capric triglyceride) 0.1 0.1 0.3 0.3 0.5 0.5 Castor oil 0.126 0.126 0.378 0.378 0.63 0.63 Polyoxyl 35 Castor Oil 0.5 2.5 2.5 3.5 2.5 3.5 Polyoxyl 40 hydrogenated castor oil 0.053 0.265 0.265 0.371 0.265 0.371 glycerin 1.5 1.5 1.5 1.5 1.5 1.5 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

Composition Content (w/v%) Composition 16 Composition 17 Composition 18 Composition 19 Composition 20 Sodium hyaluronate 0.2 0.2 0.4 0.1 0.3 Medium chain triglycerides (caprylic-capric triglyceride) 0.7 1 1 0.2 0.7 Castor oil 0.882 1.26 1.26 0.29 0.882 Polyoxyl 35 Castor Oil 2.5 2.5 3.5 1 2.5 Polyoxyl 40 hydrogenated castor oil 0.265 0.265 0.371 0.2 0.265 glycerin 1.5 1.5 1.5 1.5 1.5 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

[Experimental Example 1]

Confirmation of the properties of the ophthalmic composition manufactured in Manufacturing Example 1

The compositions 1 to 3 above were stored at room temperature and visually observed to see if any changes in properties occurred.

As a result, it was confirmed that all of Compositions 1 to 3 exhibited phase separation within 1 day after manufacture, and thus were not suitable as compositions of the present invention. Accordingly, it was found that polyoxyl 35 castor oil, polysorbate 80, polyethylene glycol 400, propylene glycol, or a combination thereof in the emulsion of the present invention are not suitable.

[Experimental Example 2]

Confirmation of the properties of the ophthalmic composition manufactured in Manufacturing Example 2

The compositions 4 to 9 above were stored at room temperature or 55°C and visually observed to see if any changes in properties occurred.

Stability 4 5 6 7 8 9 Storage stability (room temperature, day 7) stability Phase separation Phase separation stability Phase separation stability Storage stability (55℃, day1) Phase separation - - Increased turbidity - stability

As a result, as shown in Table 6, it was confirmed that only Composition 9 exhibited excellent stability.

Therefore, it can be seen that the combination of polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil in the emulsion of the present invention exhibits the best stability.

[Experimental Example 3]

Confirmation of the properties of the ophthalmic composition manufactured in Manufacturing Example 3

The compositions 10 to 20 were stored at room temperature for 14 days and then visually observed for their properties. As a result, all of the compositions 10 to 20 were capable of being manufactured into stable emulsions, and maintained stable emulsions without problems such as phase separation even after 14 days of storage.

[Experimental Example 4]

Measurement of average particle size of ophthalmic composition manufactured in manufacturing example 3

The above compositions 10 to 20 were stored at room temperature for 14 days, and then the average particle size was measured. The average particle size was measured using a Zetasizer (RA001) after each composition was diluted 10-fold with purified water.

In the case of unstable emulsions, problems such as particle size gradually increasing over time may occur, but as shown in Tables 10 and 11 below, it was confirmed that the particle size of the compositions 10 to 20 remained stable even over time. In addition, it was confirmed that the compositions 10 to 20 had an average particle size of 200 nm or less and exhibited a uniform and small particle size distribution.

Unit (nm) 10 11 12 13 14 15 Average particle size (day 0) 38.47 17.42 24.6 21.13 39.67 26.59 Average particle size (day 14) 36.27 16.84 23.4 20.26 49.22 26.46

Unit (nm) 16 17 18 19 20 Average particle size (day 0) 65.27 104.6 137.5 42.67 72.56 Average particle size (day 14) 59.41 96.92 112.7 41.60 75.32

[Experimental Example 5]

Confirmation of the therapeutic effect of the composition in an animal model of dry eye disease

After inducing dry eye syndrome in New Zealand White Rabbits, the composition 17 or saline solution was instilled into the eyes five times a day for four weeks, and the eyes were stained using fluorescent dye test paper (Fluorescein, HAAG-STREIT AG, Switzerland) to measure the tear layer maintenance time (TBUT (tear break-up time)).

As a result, as shown in Fig. 1, it was confirmed that the tear layer maintenance time of the group administered with composition 17 was much longer than that of the group administered with saline solution. From this, it can be seen that the composition of the present invention exhibits an excellent effect in the treatment of dry eye.

Claims (11)

Containing hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient,
Contains castor oil and medium chain triglycerides as oil components.
An ophthalmic composition comprising polyoxyl35 castor oil and polyoxyl40 hydrogenated castor oil as emulsifying components.
An ophthalmic composition in claim 1, wherein the oil component is contained in an amount of 0.1 to 5 w/v%.
An ophthalmic composition in claim 1, wherein the oil component is contained in an amount of 0.1 to 4 w/v%.
An ophthalmic composition in claim 1, wherein the emulsifying component is contained in an amount of 0.1 to 5 w/v%.
An ophthalmic composition in claim 1, wherein the content ratio of the oil component and the emulsifying component is 1:1 or more.
An ophthalmic composition in claim 1, wherein the content ratio of the oil component and the emulsifying component is 1:1 to 1:30.
In the first aspect, the medium-chain triglyceride is an ophthalmic composition which is caprylic/capric triglyceride.
An ophthalmic composition in claim 1, which does not exhibit phase separation for 14 days at room temperature.
An ophthalmic composition in claim 1, wherein the composition is an oil-in-water emulsion.
An ophthalmic composition in claim 9, wherein the oil-in-water emulsion has an average particle size of 300 nm or less.
In claim 1, the composition is an ophthalmic composition for treating or preventing dry eye.