JPH115744A - Aqueous solution preparation for external use containing hyaluronic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aqueous solution preparation for external use containing hyaluronic acid or its salt, which is useful for medicines having excellent preservative effect and retaining the stability of hyaluronic acid e.g. instillation of eye drops or nose drops, medicine applicable to the oral cavity or larynx or skin medicine for external use. SOLUTION: This aqueous solution preparation for external use is obtained by blending an aqueous solution containing 0.001 to 2% of hyaluronic acid or its salt with at least one kind of preservative agent selected from the group consisting of 0.001 to 0.01 % of benzetonium chloride, 0.001 to 0.01% of chlorhexidine hydrochloride, 0.001 to 0.02 % chlorhexidine gluconate, and 0.001 to 0.2% of alkyl diaminoethylene glycine hydrochloride based on the aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external aqueous solution comprising an aqueous solution containing hyaluronic acid or a salt thereof and one or more of benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate or alkyldiaminoethyl glycine hydrochloride as a preservative. It relates to preparations, for example, aqueous preparations such as eye drops, nasal drops, oral or pharyngeal preparations, and external preparations for skin.

[0002]

2. Description of the Related Art Hyaluronic acid is composed of D-glucuronic acid and N-glucuronic acid.
-Acetyl-D-glucosamine is a linear polymer compound mutually bonded, and is a compound used as various cosmetic components or medical drug components by utilizing its specific properties or physiological functions. For example, sodium salt of hyaluronic acid is known to exhibit strong viscosity when hydrated in an aqueous solution, and the viscosity of this aqueous solution is used to perform cataract, glaucoma and other ophthalmic surgeries, and corneal transplant surgery. A joint improving agent which is used as an auxiliary agent and protects cartilage by injecting into a joint of a knee osteoarthritis patient, and an eye drop for treating keratoconjunctival epithelial disorder and the like have been proposed. Recently, attention has been paid to the pharmacological action of hyaluronic acid or its salts, and proposals have been made as antiallergic agents, anti-inflammatory agents, anti-drying agents, external preparations for the skin or nasal drops. The value is expected to increase further in the future.

[0003] As described above, the medical utility value of an aqueous preparation for external use containing hyaluronic acid (hereinafter, hyaluronic acid or its salt is included unless otherwise specified) is extremely large, but hyaluronic acid itself is an acidic mucoprotein. Since it is a polysaccharide, its aqueous solution has favorable conditions for the growth of microorganisms, and therefore easily rots and deteriorates in a short time. For this reason, the addition of a preservative is indispensable, but there has been a problem that a suitable preservative exhibiting a preservative effect has not been found so far without impairing the stability of the aqueous solution of hyaluronic acid. In particular, quaternary ammonium salts such as benzalkonium chloride and cetylpyridinium chloride are preservatives that are widely used for preserving various external preparations. However, these quaternary ammonium salts are used in aqueous solutions containing hyaluronic acid. When formulated as a preservative, on the other hand, a precipitate is generated by the interaction with hyaluronic acid, and the aqueous solution becomes cloudy, which is not preferable as a pharmaceutical product. .

[0004] Therefore, as for an aqueous preparation containing hyaluronic acid, for example, some ophthalmic preparations for treating keratoconjunctival epithelium which do not contain a preservative have been proposed, and as preservatives other than quaternary ammonium salts. An aqueous solution formulation containing various parabens such as parahydroxybenzoate has also been proposed. On the other hand, proposals have been made in which the formulation of the aqueous solution containing hyaluronic acid is devised. For example, cyclodextrin is further blended with quaternary ammonium salts such as hyaluronic acid and benzalkonium chloride and benzethonium chloride. Thus, a method of avoiding the formation of precipitates resulting from both, or an aqueous ethanol solution in which a precipitate formed from hyaluronic acid and cetyltrimethylammonium bromide, cetyltrimethylammonium chloride or cetylpyridinium chloride is dissolved in ethanol has been proposed. ing.

When benzalkonium chloride is blended in a low concentration of about 0.003% or less with respect to an aqueous solution of hyaluronic acid, it is possible to avoid the formation of precipitates formed from both, but it is inevitable to use preservatives. Since the effect is reduced, there is difficulty in actual use. For this reason, an improved method has been proposed in which a paraoxybenzoic acid ester and a metal chelating agent are additionally added to increase the preservative effect. Recently, with respect to benzalkonium chloride as a preservative, a method using a compound in which the alkyl side chain is a single alkyl group has been proposed. That is, benzalkonium chloride, which is usually used as a preservative, is a mixture of benzalkonium chloride having 8 to 18 carbon chains in the alkyl group of the quaternary ammonium-substituted moiety. It has been reported that the use of a single C ₁₂ -benzalkonium chloride of Formula ₁₂ can avoid the formation of a precipitate due to the interaction with hyaluronic acid, and furthermore, an aqueous solution containing a chelating agent to further enhance the preservative effect. A formulation has been proposed.

As described above, although various measures have been taken for preserving an aqueous preparation for external use containing hyaluronic acid, a practical method has not yet been established. In particular, an alcoholic aqueous solution using ethanol can be used as a disinfectant, but should be avoided as pharmaceutical preparations such as eye drops or nasal drops. There are problems such as insufficient. Further single benzalkonium chloride among benzalkonium chloride - clouding problem solution by the use of (C ₁₂ benzalkonium chloride) are are avoided, but the use of special benzalkonium chloride Therefore, there is a problem that it is expensive economically.

[0007]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned problems and impairs the stability of hyaluronic acid in an aqueous preparation containing hyaluronic acid or a salt thereof as compared with a conventional preparation. It is another object of the present invention to propose an external solution having excellent antiseptic effect.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that an aqueous solution containing hyaluronic acid or a salt thereof can be treated with benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate or An aqueous solution formulation containing any one of preservatives selected from alkyldiaminoethylglycine hydrochloride,
They newly found that they had extremely excellent storage stability, and that the preparations had excellent preservative effects without blending other preservatives other than such preservatives, and completed the present invention. .

That is, as a preservative for an aqueous solution containing hyaluronic acid or a salt thereof, any one of benzethonium chloride and chlorhexidine hydrochloride, which have been used so far in various preparations and have a preservative effect, are used. 0.001 to 0.01%
Alternatively, any one of chlorhexidine gluconate and alkyldiaminoethylglycine hydrochloride is used in an amount of 0.001 to 0.0
When blended at a concentration of 2%, it was surprisingly found that no precipitate was formed with hyaluronic acid. Moreover, hyaluronic acid or its salt and one of these preservatives
The aqueous solution formulation containing the seeds at the above concentration has an excellent preservative effect and does not show eye irritation.In addition, it does not show any change in appearance such as formation of a precipitate even during long-term storage. It was newly found.

Accordingly, the present invention provides, in a specific embodiment thereof, hyaluronic acid or a salt thereof in an amount of 0.001 to 2%.
0.001 to 0.0
1% benzethonium chloride, 0.001-0.01%
Chlorhexidine hydrochloride in an amount, chlorhexidine gluconate in an amount of 0.001-0.02% or 0.001-0.02%.
The present invention provides an aqueous preparation for external use characterized by containing any one of preservatives selected from alkyldiaminoethylglycine hydrochloride in an amount of 02%.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hyaluronic acid used in the aqueous solution provided by the present invention is hyaluronic acid which can be used as an aqueous preparation for external use, and has a molecular weight of about 10,000 to 500.
Thousands are suitable. Further, the salt of hyaluronic acid is a conventional non-toxic salt, such as a salt of hyaluronic acid and an inorganic base, such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg,
Calcium salt, magnesium salt, etc.), and among them, the sodium salt is particularly preferable. In the aqueous solution preparation of the present invention, since the application purpose is an aqueous solution preparation such as eye drops, nasal drops, oral or pharyngeal preparations or external preparations for skin, the content of hyaluronic acid is 0% as an aqueous preparation. 0.001 to 2%.

The aqueous preparation for external use of the present invention may be any one selected from the group consisting of benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate or alkyldiaminoethylglycine hydrochloride as a preservative in an aqueous solution containing hyaluronic acid in the above amount. These preservatives are blended with seeds, and all of these preservatives have a preservative effect, and are commercially available inexpensive compounds that are used in various external preparations. The amount of these preservatives may be such that the aqueous solution for external use of the present invention can exhibit a preservative effect to the extent that it does not cause decay or deterioration.Specifically, benzethonium chloride and hydrochloric acid are added to the aqueous solution. In the case of chlorhexidine, the concentration is in the range of 0.001 to 0.01%, and in the case of chlorhexidine gluconate and alkyldiaminoethylglycine hydrochloride, the amount is 0.001 to 0.1%.
It is preferable to mix in an amount that gives a concentration range of 02%. When these preservatives were blended in the hyaluronic acid-containing aqueous solution within such a range, it was found that the aqueous solution did not show any white turbidity due to the formation of a precipitate, and a sufficient preservative effect was secured.

Accordingly, the present invention relates to a more specific embodiment, for example, by adding hyaluronic acid or a salt thereof to 0.001.
Topical aqueous solution containing 0.001 to 0.01% benzethonium chloride as a preservative in an aqueous solution containing 0.1% to 2%, external solution containing 0.001 to 0.01% chlorhexidine hydrochloride, and 0% chlorhexidine gluconate. 0.001 to 0.02
% External aqueous solution formulation, and alkyldiaminoethylglycine hydrochloride 0.001 to
An external aqueous solution formulation containing 0.02% is also provided.

In the aqueous solution for external use provided by the present invention, various bases, buffers, pH adjusters and the like, which are commonly used in pharmacology, are added, if necessary, in addition to the above components. be able to. Examples of such a base include polyhydric alcohols such as glycerin and propylene glycol; sugar alcohols such as sorbitol, mannitol and glucose; inorganic salts such as sodium chloride and potassium chloride; glycine, glutamic acid or a salt thereof, epsilon aminocaproic acid; Amino acids such as aspartic acid; and surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil, and polyoxystearate 40, sodium edetate, sulfite, and benzyl alcohol. These components are preferably used so that the osmotic pressure of the intended external aqueous solution preparation of the present invention is about 0.2 to 2, preferably about 0.8 to 1.5.

As a buffer, a phosphate buffer, a borate buffer, a citrate buffer and the like can be used.
Further, examples of the pH adjusting agent include acids such as hydrochloric acid, sulfuric acid, lactic acid, and acetic acid, and bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate. ~ 9, preferably 5
It is good to mix so that it may be set to ~ 8.

In the aqueous preparation for external use of the present invention, other medicinal ingredients can be combined together, and such combined medicinal ingredients include, for example, non-steroidal anti-steroidal drugs such as diclofenac sodium and pranoprofen. Inflammatory agents;
Vasoconstrictors such as tetrahydrozoline hydrochloride, phenylephrine hydrochloride, and naphazoline hydrochloride; antiallergic agents such as ketotifen fumarate and sodium cromoglycate; antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; antihistamines such as glycyrrhizinate and epsilon-aminocaproic acid Inflammatory agents; skin and mucous membrane repair agents such as allantoin and taurine; vitamins such as pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, panthenol, tocopherol acetate, and retinol acetate; and other antibiotics and intraocular pressure reducing agents .

The preparation of the aqueous solution preparation for external use of the present invention is not particularly limited, and can be carried out using a preparation technique commonly used in pharmacology. For example, as an example,
A buffer, a base, a preservative, hyaluronic acid and, if necessary, other medicinal ingredients are sequentially added to an appropriate amount of purified water, and the mixture is stirred and dissolved to form a uniform solution. Thereafter, the solution is adjusted to a desired amount with purified water to obtain a desired external aqueous solution preparation. In addition, the preparation method of the external aqueous solution preparation of the present invention is not limited to the above, and it goes without saying that it can be prepared in various modifications. The thus prepared external aqueous solution preparation of the present invention is excellent in the long-term storage stability of hyaluronic acid as compared with conventional preparations, the aqueous solution is not cloudy at all, and its preservative effect is also good. Therefore, it can be a clinically excellent aqueous solution preparation such as eye drops, nasal drops, oral or pharyngeal preparations, and external preparations for skin.

[0018]

EXAMPLES The present invention will be described below in detail with reference to examples, but the technical scope of the present invention is not limited to these examples.

Example 1 : 100 m sodium hydrogen phosphate
g, crystalline sodium dihydrogen phosphate 90 mg, sodium edetate 10 mg, epsilon-aminocaproic acid 40
After dissolving 0 mg, 770 mg of sodium chloride and 25 mg of an aqueous chlorhexidine gluconate solution (20% aqueous solution) in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Next, the total amount was adjusted to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 2 : 100 m sodium hydrogen phosphate
g, crystalline sodium dihydrogen phosphate 90 mg, sodium edetate 10 mg, epsilon-aminocaproic acid 40
0 mg, sodium chloride 450 mg, glycerin 100
After dissolving 0 mg and benzethonium chloride in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Next, the total amount was adjusted to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 3 Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
After dissolving 30 mg and an alkyldiaminoethylglycine hydrochloride aqueous solution (30% aqueous solution) 33 mg in an appropriate amount of purified water,
100 mg of sodium hyaluronate is added and dissolved. Next, the total amount was adjusted to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 4 Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
After dissolving 30 mg and 5 mg of chlorhexidine hydrochloride in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Next, the total amount was adjusted to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 5 : Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
30 mg and chlorhexidine gluconate aqueous solution (20
% Aqueous solution) is dissolved in an appropriate amount of purified water, and 100 mg of sodium hyaluronate is added and dissolved. Next, 100 mg of pranoprofen and 20 of polysorbate 80 were added.
After adding 0 mg and dissolving uniformly, the total amount is 100 ml.
To give an external aqueous solution preparation of the present invention.

Example 6 : Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
30 mg and chlorhexidine gluconate aqueous solution (20
% Aqueous solution) is dissolved in an appropriate amount of purified water, and 100 mg of sodium hyaluronate is added and dissolved. Next, 100 mg of tetrahydrozoline hydrochloride was added and uniformly dissolved, and then the whole amount was made up to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 7 : Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
30 mg and chlorhexidine gluconate aqueous solution (20
% Aqueous solution) is dissolved in an appropriate amount of purified water, and 100 mg of sodium hyaluronate is added and dissolved. Next, 75.6 mg of ketrifen fumarate was added and uniformly dissolved, and then the whole amount was made up to 100 ml to obtain an aqueous solution for external use of the present invention.

Example 8 : Boric acid 500 mg, Borax 20
mg, sodium edetate 10 mg, sodium chloride 6
30 mg and chlorhexidine gluconate aqueous solution (20
% Aqueous solution) is dissolved in an appropriate amount of purified water, and 100 mg of sodium hyaluronate is added and dissolved. Next, 500 mg of chlorpheniramine maleate was added and uniformly dissolved, and then the whole amount was made up to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 9 : 100 m sodium hydrogen phosphate
g, crystalline sodium dihydrogen phosphate 90 mg, sodium edetate 10 mg, epsilon-aminocaproic acid 40
After dissolving 0 mg, 770 mg of sodium chloride and 25 mg of an aqueous chlorhexidine gluconate solution (20% aqueous solution) in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Next, dipotassium glycyrrhizinate 300
mg and 200 mg of polysorbate 80 were added and uniformly dissolved, and then the whole amount was made up to 100 ml to obtain an external aqueous solution preparation of the present invention.

Example 10 : Boric acid 500 mg, Borax 2
0 mg, sodium edetate 10 mg, sodium chloride 630 mg and chlorhexidine gluconate aqueous solution (2
After dissolving 25 mg of a 0% aqueous solution in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Next, 200 mg of allantoin was added and uniformly dissolved, and then the whole amount was made up to 100 ml to obtain an external aqueous solution preparation of the present invention.

Comparative Example 1 : 100 m of sodium hydrogen phosphate
g, crystalline sodium dihydrogen phosphate 90 mg, sodium edetate 10 mg, epsilon-aminocaproic acid 40
After dissolving 0 mg, 770 mg of sodium chloride and 5 mg of benzalkonium chloride in an appropriate amount of purified water, 100 mg of sodium hyaluronate is added and dissolved. Then the total amount is 10
The solution was made up to 0 ml to obtain an external aqueous solution preparation of Comparative Example 1.

Comparative Example 2 : An external aqueous solution preparation of Comparative Example 2 having the following composition was obtained. Sodium hyaluronate 100mg sodium 700mg potassium 150mg epsilon - aminocaproic acid 400mg edetate sodium 10 mg C ₁₂ - amounts to benzalkonium chloride 3mg hydrochloride qs Sodium hydroxide qs Purified water total amount 100ml

During the preparation of an aqueous solution for external use,
Recognition test : At the time of preparing the aqueous preparations of Examples 1 and 2 which are the aqueous preparations for external use of the present invention and the aqueous preparation of Comparative Example 1, the formation of white turbidity in the aqueous solution due to the addition of a preservative was visually observed. The preservatives incorporated in the aqueous preparations of Examples 1 and 2 of the present invention were benzethonium chloride and chlorhexidine gluconate, respectively.
Preservative is benzalkonium chloride. The preservatives were used in the same amount for all three.
Although the aqueous solution preparations for external use of Examples 1 and 2 could be prepared to be colorless and clear, the aqueous solution preparation of Comparative Example 1 did not have clearness immediately after preparation and exhibited a stagnant white turbidity. As is clear from the results, as the preservative compounded in the present invention, for example, benzethonium chloride 0.001
By using a concentration range of from 0.001% to 0.01% or from 0.001% to 0.02% of chlorhexidine gluconate, no precipitate such as cloudiness is formed in the aqueous solution, and an external aqueous solution of hyaluronic acid or a salt thereof is used. It turns out that the formulation can be prepared. Note that the aqueous solution preparations of the other examples also exhibited a colorless and clear state.

Storage Efficacy Test : Method: E. coli (E.
i), Pseudomonas aeruginosa and Staphylococcus aureus, typical fungi as Candida albicans and Aspergillus (A
spergillus fumigatus) and inoculated with the number of bacteria shown in the table, respectively, into the external aqueous solution preparations of Example 1 and Example 2 and the aqueous solution preparation of Comparative Example 2; The number of bacteria was counted. Results: The results are summarized in Tables 1, 2 and 3 below.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

As is clear from the results in each table, all three samples of the external aqueous preparations of Examples 1 and 2 of the present invention and the aqueous preparation of Comparative Example 2 passed the preservation efficacy test. Was. That is, the viable bacterial count of all three specimens decreased to 0.1% or less of the inoculated bacterial count on the 14th day.
Eight days later, the level was maintained. In addition, the viable cell count of the fungi was 14 days and 28 days after inoculation, and the inoculated cell count was lower than the acceptable cell count in all three tested samples. Somewhat less, the preservative effect was excellent. As can be seen from the above results, preservatives formulated into an aqueous solution containing hyaluronic acid of the present invention include benzalkonium chloride having 12 carbon atoms - their potency more compared to (C ₁₂ benzalkonium chloride) Therefore, it is possible to prepare an aqueous preparation for external use having an excellent preservative effect using inexpensive benzethonium chloride or chlorhexidine gluconate.

Ocular mucosal irritation test : Example 1 and Comparative Example 2
Each group of three rabbits was subjected to short-term frequent instillation (15 times a day at 30-minute intervals) using aqueous solution preparations and physiological saline solutions as control solutions. Rabbit eye irritation after administration was evaluated by the Draize method and the fluorescein method. As a result, there was no significant difference in the eye irritation test among the three test solutions. Therefore, it was confirmed that the aqueous solution preparation of the present invention is an external aqueous solution preparation containing hyaluronic acid which has an excellent preservative effect and does not cause eye irritation.

Long-term storage test : A severe test was conducted in which 5 ml each of the external aqueous solution preparation of each Example of the present invention was filled in a polyethylene container and left in a 60 ° C constant temperature room for 2 weeks and 4 weeks. As a result, no precipitate was found in any of the test solutions, and no change in appearance was observed. Even when each test solution was allowed to stand at room temperature for 6 months, no precipitation was observed and no change in appearance was observed, and the aqueous solution maintained its clarity during preparation. Was.

[0039]

As described above, the present invention relates to an aqueous preparation for external use containing hyaluronic acid or a salt thereof, wherein benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate or alkyldiaminoethylglycine hydrochloride is used as a preservative. By using the compound, precipitates are not generated in the aqueous solution, and the antiseptic effect that can store hyaluronic acid stably for a long time is excellent,
It has the advantage of being able to provide an inexpensive hyaluronic acid-containing external aqueous solution formulation without eye irritation or the like at a low cost, and makes a great contribution to medical treatment.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Inventor Isao Hanase, 26 Misato, Toyama City, Toyama Prefecture, Toa Pharmaceutical Co., Ltd.

Claims (5)

[Claims] 1. The method according to claim 1, wherein the amount of hyaluronic acid or a salt thereof is 0.001.
0.002 to 2% aqueous solution
Benzethonium chloride in an amount of 0.01%, 0.001-0.
Chlorhexidine hydrochloride in an amount of 0.01%, 0.001 to 0.0
Chlorhexidine gluconate in 2% amount or 0.001
An aqueous solution for external use characterized by containing any one of preservatives selected from alkyldiaminoethylglycine hydrochloride in an amount of 0.02%. 2. The method according to claim 1, wherein the amount of hyaluronic acid or a salt thereof is 0.001.
An external aqueous solution preparation comprising 0.001 to 0.01% of benzethonium chloride as an antiseptic in an aqueous solution containing 2%. 3. Hyaluronic acid or a salt thereof is added in an amount of 0.001.
An aqueous preparation for external use wherein 0.001 to 0.01% of chlorhexidine hydrochloride is added as an antiseptic to an aqueous solution containing 〜2%. 4. Hyaluronic acid or a salt thereof in an amount of 0.001
An aqueous solution for external use comprising 0.001 to 0.02% of chlorhexidine gluconate as a preservative in an aqueous solution containing 水溶液 2%. 5. The method according to claim 5, wherein the amount of hyaluronic acid or a salt thereof is 0.001.
An aqueous solution for external use comprising 0.001 to 0.02% of an alkyldiaminoethylglycine hydrochloride as a preservative in an aqueous solution containing 2%.