JP2014012743A - Method for suppressing viscosity reduction of aqueous preparation containing hyaluronic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for suppressing viscosity reduction of an aqueous preparation containing hyaluronic acid with increased viscosity.SOLUTION: A method for suppressing viscosity reduction of an aqueous preparation containing hyaluronic acid with increased viscosity comprises the step of formulating boric acid. The boric acid serving as free acid is preferably formulated with 0.5 to 2 wt.%. The hyaluronic acid is preferably sodium salt. The aqueous preparation preferably contains 0.001 to 0.5 wt.% of the hyaluronic acid. Preferably, pH of the aqueous preparation is 5 to 7.5, and thickening of the aqueous preparation containing hyaluronic acid is performed by formulating the boric acid.

Description

The present invention relates to a thickener for an aqueous preparation containing dissolved hyaluronic acid, a thickening method, a method for producing a thickened hyaluronic acid-containing aqueous preparation, and a method for suppressing a decrease in viscosity of the hyaluronic acid-containing aqueous preparation.

Hyaluronic acid is a high-molecular polysaccharide widely present in mammalian connective tissues. It has a structure in which N-acetylglucosamine and glucuronic acid are linked in an alternating linear form, and aqueous solutions exhibit strong viscosity. It is used as an injection, injection or external preparation for the treatment of cataracts and glaucoma, eye surgery such as corneal transplantation, osteoarthritis, and burns. It is also used as eye drops for the treatment of eye tissue surface damage and dry eye syndrome. In order to utilize the viscosity of an aqueous solution of hyaluronic acid, it is desirable to increase the viscosity of the aqueous solution as much as possible. For this purpose, a preparation in which hyaluronic acid salt is dissolved in non-electrolyte water such as glycerin and glucose is proposed. (Japanese Patent Laid-Open No. 58-57319).

However, this preparation cannot be applied in the case of a preparation containing an electrolyte such as sodium chloride, and is unavoidable in practical application. The present invention seeks to provide a hyaluronic acid aqueous solution having a high viscosity without being subject to such restrictions.

The present inventors have found that when preparing an isotonic aqueous solution by mixing sodium hyaluronate with sodium chloride and boric acid in various proportions, increasing the concentration of boric acid increases the viscosity at the time of preparation.

The present invention is based on this finding, a thickener for an aqueous preparation containing dissolved hyaluronic acid composed of boric acid, a method for increasing the viscosity of an aqueous preparation containing dissolved hyaluronic acid, characterized by containing boric acid, The present invention also relates to a method for producing a hyaluronic acid-containing aqueous preparation with increased viscosity, characterized in that boric acid is added to an aqueous preparation containing dissolved hyaluronic acid.

Since hyaluronic acid and boric acid are dissolved in water in the form of free acid or salt and can be transferred to each other according to pH in an aqueous solution, unless otherwise specified in the present invention, free acid form and salt form are designated as hyaluronic acid or boric acid. It shall be named generically. As hyaluronic acid, those having a molecular weight of 100,000 to 3,000,000 are generally used.

The viscosity of the aqueous hyaluronic acid solution tends to gradually decrease over time, but when boric acid is blended, not only does the viscosity increase at the beginning of the solution preparation, but also the viscosity after the passage of time passes. A remarkable high viscosity can be maintained despite the daily decline.

The density | concentration in the aqueous solution of the boric acid mix | blended is 0.1 to 3%, Preferably it is 0.5 to 3%, More preferably, it is 1.5 to 2.5%. In addition to the components described above, the aqueous preparation can contain other medicinal ingredients, isotonic agents, buffers, and pH adjusters as long as the object of the present invention can be achieved. Examples of other medicinal ingredients include antibacterial agents, chelating agents, anti-inflammatory agents, antiallergic agents, antibiotics, analgesics, intraocular pressure-lowering agents, immunomodulators and the like. Examples of tonicity agents include sodium chloride, potassium chloride, sugars, polyhydric alcohols, and the like, and examples of buffering agents include sodium acetate, sodium borate, sodium citrate, etc., or acids corresponding to these salts. And are used together. Borates such as sodium borate can act as a thickener as well as a buffer.

The present invention provides the following.
(Item 1)
A thickener for an aqueous preparation containing boric acid and containing hyaluronic acid.
(Item 2)
The thickener according to item 1, wherein the hyaluronic acid is a sodium salt.
(Item 3)
The thickener according to item 1, wherein the aqueous preparation contains 0.001 to 0.5% by weight of hyaluronic acid.
(Item 4)
The thickener according to item 1, wherein the pH of the aqueous preparation is 5 to 7.5.
(Item 5)
A method for increasing the viscosity of an aqueous preparation containing hyaluronic acid, comprising boric acid.
(Item 6)
6. The method according to item 5 above, wherein the aqueous preparation contains 0.001 to 0.5% by weight of hyaluronic acid.
(Item 7)
6. The method according to item 5, wherein boric acid is blended in an amount of 0.1 to 5% by weight as a free acid.
(Item 8)
7. The method according to item 6 above, wherein boric acid is added as a free acid in an amount of 0.5 to 2% by weight.
(Item 9)
6. The method according to item 5 above, wherein the hyaluronic acid is a sodium salt.
(Item 10)
6. The method according to item 5 above, wherein the pH of the aqueous preparation is 5 to 7.5.
(Item 11)
A method for producing a hyaluronic acid-containing aqueous preparation with increased viscosity, characterized in that boric acid is added to an aqueous preparation containing hyaluronic acid.
(Item 12)
Item 12. The method according to Item 11, wherein the hyaluronic acid is a sodium salt.
(Item 13)
12. The production method according to item 11, wherein the pH of the aqueous preparation is 5 to 7.5.
(Item 14)
A method for suppressing a decrease in viscosity of a hyaluronic acid-containing aqueous preparation with increased viscosity, characterized by comprising boric acid.

According to the present invention, the viscosity of the solution can be easily increased by adding boric acid to the hyaluronic acid aqueous solution, and the high viscosity can be maintained even after aging, and an electrolyte is added as necessary. Thus, the viscosity can be adjusted, so that it can be advantageously used for an aqueous preparation used, for example, during ophthalmic surgery.

The present invention will be further described below with reference to experimental examples and examples.

Experimental example 1
Aqueous solutions were prepared according to the formulations in Tables 1 and 2, and their viscosities were measured over time. The results are shown in Table 3 and Table 4.

（表１と２のヒアルロン酸ナトリウムは分子量２００万（株）資生堂製）

(The sodium hyaluronate in Tables 1 and 2 has a molecular weight of 2 million manufactured by Shiseido Co., Ltd.)

In Table 3, Table 4, Table 7, and Table 8 below,

As apparent from Table 1, Table 2, Table 3, and Table 4, the viscosity at the beginning of the preparation increased as the amount of boric acid increased, and this tendency was maintained even after aging. In addition, the above tendency was not changed even when chlorhexidine gluconate was used in combination.

Experimental example 2
Aqueous solutions were prepared according to the formulations in Tables 5 and 6, and their viscosities were measured over time. The results are shown in Table 7 and Table 8.

（ヒアルロン酸ナトリウムは分子量２００万（株）資生堂製）

(Sodium hyaluronate has a molecular weight of 2 million manufactured by Shiseido Co., Ltd.)

〔ヒアルロン酸ナトリウムは分子量６０〜１２０万（平均９５．５５万）、 （株）資生堂製〕

[Sodium hyaluronate has a molecular weight of 60 to 1,200,000 (average 95.550,000), manufactured by Shiseido Co., Ltd.]

In the formulation of Table 5, sodium hyaluronate is increased twice as much as the formulation of Table 1, so the viscosity of the aqueous solution is high as shown in Table 7, but the amount of boric acid is increased. As a result, the viscosity at the beginning of the preparation increased and the tendency was maintained even after the lapse of time. As is clear from Tables 6 and 8, even though the molecular weight of sodium hyaluronate was reduced to about half compared to 2 million in Table 5, the above tendency did not change as the amount of boric acid increased. In addition, with respect to pH 5 and pH 7.5, the initial viscosity increased due to the incorporation of boric acid.

0.01 g sodium hyaluronate in 100 mL
Naphazoline hydrochloride 0.005g
Chlorpheniramine maleate 0.05g
Boric acid 1.5g
Methyl paraoxybenzoate 0.02g
0.01 g propyl paraoxybenzoate
Hydrochloric acid appropriate amount sterilized purified water appropriate amount (pH 5.0)

0.01 g sodium hyaluronate in 100 mL
Allantoin 0.005g
Methyl sulfate neostigmine 0.005g
Flavin adenine dinumreotide 0.01g
Epsilon aminocapron 0.1g
Boric acid 2.0g
Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount (pH 7.5)

0.005 g sodium hyaluronate in 100 mL
Sodium chloride 0.5g
Potassium chloride 0.2g
Boric acid 1.2g
0.05g dry sodium carbonate
Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount (pH 7.0)

In 100 mL
Sodium hyaluronate 0.005g
Retinol palmitate 100,000 I.I. U.
Polysorbate 80 0.2g
Concentrated glycerin 0.5g
Boric acid 1.5g
Sodium edetate 0.05g
Borax appropriate amount
Sterilized purified water appropriate amount (pH 7.0)

JP 58-57319 A

Claims (6)

A method for inhibiting a decrease in viscosity of a thickened hyaluronic acid-containing aqueous preparation, comprising boric acid.   2. The method according to claim 1, wherein boric acid is blended as a free acid in an amount of 0.5 to 2% by weight.   The method according to claim 1 or 2, wherein the hyaluronic acid is a sodium salt.   The method according to any one of claims 1 to 3, wherein the aqueous preparation contains 0.001 to 0.5% by weight of hyaluronic acid.   The method according to any one of claims 1 to 4, wherein the pH of the aqueous preparation is 5 to 7.5. The method according to any one of claims 1 to 5, wherein thickening of the hyaluronic acid-containing aqueous preparation is performed by blending boric acid.