JP2838720B2 - Stable eye drops - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an aqueous solution containing lysozyme or a salt thereof, and glycyrrhizic acid or a salt thereof, which is combined with a quaternary ammonium salt or a quaternary ammonium salt. By mixing one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester and polyoxyethylene polyoxypropylene ether, cloudiness and precipitation occur. Not about stable eye drops.

[Prior art and problems to be solved by the invention] Lysozyme is a mucopolysaccharide-degrading enzyme, which exhibits an antibacterial action by lysing certain bacterial cell walls, and has an antibacterial effect by forming a complex with an inflammatory protein. Shows inflammatory effects. In addition, it is a useful protein known to have a mucosal repair effect, an immunostimulatory effect, and the like, and it has recently been found to be particularly useful for eye diseases caused by hay fever. Therefore, they are formulated into eye drops for the purpose of such antibacterial and anti-inflammatory effects. On the other hand, glycyrrhizic acid or a salt thereof exhibits an anti-inflammatory effect by suppressing metabolism of steroid hormones, and also exhibits an inhibitory effect on both immediate and delayed allergies, and is highly safe. It is widely used as an ingredient.

However, lysozyme is known as a basic protein, that is, glycyrrhizic acid or a salt of glycyrrhizic acid or a salt thereof, which is known as a positively charged substance in an aqueous solution, and is known as a substance having a negatively charged and nonpolar skeleton triterpene in an aqueous solution. When formulated, it forms an electrically insoluble complex and causes cloudiness and precipitation. Therefore, formulations that avoid the combination of both have been made. However, stable eye drops containing both of these characteristic components have been desired. Was rare.

An object of the present invention is to provide a stable aqueous ophthalmic solution in which lysozyme or a salt thereof is combined with glycyrrhizic acid or a salt thereof while preventing cloudiness and precipitation.

[Means for Solving the Problems] The present inventors have conducted intensive studies on means for achieving the above-mentioned object, and as a result, have found that an aqueous ophthalmic solution containing lysozyme or a salt thereof and glycyrrhizic acid or a salt thereof together. , Quaternary ammonium salts, or one selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene polyoxypropylene ether together with quaternary ammonium salts or By combining two or more, a stable eye drop free of clouding and precipitation was successfully obtained. Benzalkonium chloride and benzethonium chloride, which are quaternary ammonium salts in the present invention, are formulated in consideration of the possibility of secondary contamination that occurs after consumers purchase eye drops manufactured in a sterile environment. It is a type of preservative that is often used, and has been used in many eye drops because of its broad antibacterial spectrum and high safety. Polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester or polyoxyethylene polyoxypropylene ether are blended in eye drops for the purpose of solubilizing fat-soluble components.

The present invention relates to an ophthalmic solution containing both lysozyme or a salt thereof and glycyrrhizic acid or a salt thereof,
One or more selected from quaternary ammonium salts or quaternary ammonium salts and polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester and polyoxyethylene polyoxypropylene ether Is greatly different from the prior art in that it provides a stable ophthalmic solution which does not cause cloudiness or precipitation, which is a major feature of the present invention. Lysozyme or its salt used in the present invention is lysozyme chloride, and glycyrrhizic acid or its salt is glycyrrhizic acid,
Dipotassium glycyrrhizinate, monoammonium glycyrrhizinate and the like. Also, as polyoxyethylene hydrogenated castor oil, Nikkor HCO 40 (Nikko Chemicals), Nikkor HCO 50 (Nikko Chemicals),
Nichol HCO 60 (Nikko Chemicals) and other polyoxyethylene sorbitan fatty acid esters include Nikkor TO 10M (Nikko Chemicals) and other polyoxyethylene fatty acid esters.
Pluronic F68 as polyoxyethylene polyoxypropylene ether (such as Nikko Chemicals)
(Manufactured by Asahi Denka Kogyo KK) and the like.

The stable eye drops of the present invention, for example, dissolving lysozyme chloride in purified water, dissolving benzalkonium chloride or benzethonium chloride as quaternary ammonium salts, or further dissolving polyoxyethylene hydrogenated castor oil, It is obtained by dissolving glycyrrhizic acid or a salt thereof.

The stable eye drop of the present invention comprises lysozyme or a salt thereof.
0.1-0.5 w / v%, glycyrrhizic acid or its salt 0.05%
~ 0.25w / v%, quaternary ammonium salts 0.01 ~ 0.05w / v
%, One or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester and polyoxyethylene polyoxypropylene ether.
It is preferable to mix them in such a ratio as to be from 01 to 0.5 w / v%. The ophthalmic solution thus obtained is a stable ophthalmic solution in which clouding and precipitation are prevented.

The stable eye drops of the present invention include naphazoline hydrochloride, decongestant components such as tetrahydrozoline hydrochloride and allantoin,
Inflammatory astringent components such as ε-aminocaproic acid, berberine chloride, etc .; Sand, buffer salts such as sodium phosphate, tonicity agents such as sodium chloride and potassium chloride, preservatives such as chlorobutanol and alkylparaben,
Additives such as alcohols such as ethanol and propylene glycol can also be added.

The present invention will be described in detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.05 g of benzalkonium chloride was added thereto.
Then, 0.2 g of lysozyme chloride was dissolved, and an appropriate amount of borax was added to adjust the pH to 6.0. This aqueous solution was made up to a total volume of 100 ml with purified water, filtered through a 0.22 μm membrane filter, and then aseptically filled into a 10 ml ophthalmic container and stoppered to give an ophthalmic solution.

Example 2 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.03 g of benzalkonium chloride was added thereto.
After dissolving 0.1 g of Nikkor HCO 60, 0.2 g of lysozyme chloride was dissolved and adjusted to pH 6.0 by adding an appropriate amount of borax. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 3 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.03 g of benzalkonium chloride was added thereto.
After dissolving 0.1 g of Nikkor TO 10M, 0.2 g of lysozyme chloride was dissolved and adjusted to pH 6.0 by adding an appropriate amount of borax. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 4 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.03 g of benzalkonium chloride was added thereto.
After dissolving 0.1 g of Nikkor MYS 40 and 0.2 g of lysozyme chloride, the pH was adjusted to 6.0 by adding an appropriate amount of borax. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 5 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.03 g of benzalkonium chloride was added thereto.
After dissolving 0.1 g of Pluronic F68 and 0.2 g of lysozyme chloride, an appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 6 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and 0.03 g of benzalkonium chloride was added thereto.
And Nikkor HCO 60 0.05g, Nikkor MYS 40
After dissolving 0.05 g, dissolve 0.2 g of lysozyme chloride,
An appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, Example 1
An eye drop was prepared in the same manner as described above.

Comparative Example 1 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water.
After dissolving 02 g, lysozyme chloride 0.2 g was dissolved, and an appropriate amount of borax was added to adjust to pH 6.0. At this time, since the aqueous solution became cloudy, the total amount was adjusted to 100 ml with purified water, filtered through a 0.22 μm membrane filter, and then aseptically filled into a 10 ml ophthalmic container and stoppered to obtain an ophthalmic solution.

Comparative Example 2 0.05 g of dipotassium glycyrrhizinate and 1 g of boric acid were dissolved in purified water, and methyl paraoxybenzoate was added thereto.
After dissolving 02 g and Nikkol HCO 60 0.1 g, lysozyme chloride 0.2 g was dissolved, and an appropriate amount of borax was added to adjust to pH 6.0. Hereinafter, the same operation as in Comparative Example 1 was performed to obtain an eye drop.

[Action] 1) In each example, the results of observing the appearance of the aqueous solution before filtration with a membrane filter are shown in Table 1.

In the comparative example, cloudiness and precipitation occurred immediately after dissolution, whereas in the examples, the appearance was not changed and the samples were stable.

2) Lysozyme chloride and dipotassium glycyrrhizinate immediately after production were quantified, and the residual ratio is shown in Table 2.

Column: Inertsil ODS (manufactured by Gaschrom Industry Co., Ltd.) Mobile phase: water / acetonitrile / glacial acetic acid mixture (100: 55: 2) Detection: UV 254 nm As is clear from each table, in the comparative example, lysozyme chloride and dipotassium glycyrrhizinate were used. Was low, whereas in each of the examples, a residual rate almost equivalent to the initial addition amount was obtained.

3) Table 3 shows the results of observation of the appearance immediately after production and over time.

As is evident from Table 3, in the comparative example, white turbidity and precipitation occurred immediately after the production, whereas in each of the examples, the appearance was not changed and the samples were stable.

[Effects of the Invention] The present invention is an ophthalmic solution of an aqueous solution containing lysozyme or a salt thereof and glycyrrhizic acid or a salt thereof.
It is extremely useful as a stable eye drop preventing precipitation.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Shinya Sugawara 2512 Numagami Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture Investigator, Central Research Laboratory, Zeria Shinyaku Kogyo Co., Ltd. Takanobu Morii (56) References JP-A-63-156728 (JP, A) JP-A-61-12617 (JP, A) JP-A-64-16728 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 38/00-38 / 58 A61K 9/00-9/72 A61K 47/00-47/48 A61K 31/19, 31/70 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] An ophthalmic solution of an aqueous solution containing lysozyme or a salt thereof and glycyrrhizic acid or a salt thereof,
An eye drop comprising a quaternary ammonium salt. 2. An ophthalmic solution of an aqueous solution containing lysozyme or a salt thereof, glycyrrhizic acid or a salt thereof, and a quaternary ammonium salt, wherein polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene fatty acid are used. An ophthalmic solution comprising one or more selected from esters and polyoxyethylene polyoxypropylene ethers. 3. The eye drop according to claim 1, wherein the quaternary ammonium salt is benzalkonium chloride or benzethonium chloride. 4. A lysozyme or a salt thereof of 0.1 to 0.5 w / v.
%, Glycyrrhizic acid or a salt thereof at 0.05 to 0.25 w / v%
The ophthalmic solution according to claim 1 or 2, which is blended at a ratio of: