JPH0782143A - Stable eye drops - Google Patents

Abstract

(57) [Summary] [Structure] Points A, B, C, D, and E on the triangular chart shown in Fig. 1 for lysozyme, vitamin A, and nonionic surfactants.
And F are blended in the ratio of the shaded area formed, and p
Eye drops with H adjusted to 5-8. [Effect] It is possible to obtain an aqueous ophthalmic solution containing lysozyme and vitamin A, which prevents precipitation and decomposition and is excellent in appearance and stability over time.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an eye drop containing lysozyme and vitamin A, more specifically, lysozyme, vitamin A and a nonionic surfactant are mixed in a specific ratio, and The present invention relates to an eye drop which has a stable appearance by adjusting pH to a specific range without causing turbidity or precipitation, and which does not decompose with time.

[0002]

2. Description of the Related Art Lysozyme is a mucopolysaccharide hydrolase contained in tear fluid, and exhibits a bactericidal (bacteriolytic) action on bacteria that cause inflammation by hydrolyzing the cell membrane of certain bacteria. Furthermore, since lysozyme has a wide range of pharmacological actions such as antiviral action, anti-infection action, anti-allergic action, anti-inflammatory action, mucosal tissue repair action, and analgesic action, it is often used in eye drops for the purpose of treating keratoconjunctivitis, etc. ing. Vitamin A, including vitamin A oil and vitamin A fatty acid ester, has the function of maintaining normal vision and mucous membranes of humans or animals, and its deficiency causes night blindness, keratoconjunctival dryness, etc. , An essential fat-soluble vitamin for the eye. On the other hand, when an aqueous eye drop containing both lysozyme and vitamin A useful for the eye at the same time is to be obtained, a precipitation, particularly a precipitation derived from lysozyme, is generated, and the stability of both components over time is impaired. There was a problem in the formulation such as That is, lysozyme is generally extremely unstable in an aqueous solution, for example, a substance formed by oxidation or the like becomes a precipitate, and this phenomenon is caused by the coexistence of fat-soluble substances such as vitamins A, liquid neutrality, and alkaline regions. It is known to become more prominent with metastasis. On the other hand, the stability of vitamins A over time is relatively good in the neutral region where lysozyme is generally unstable in appearance, but is conversely extremely poor in the acidic region where lysozyme is stable in appearance. ing. further,
Since vitamins A are fat-soluble, it is essential to add a solubilizer such as a nonionic surfactant to obtain the aqueous eye drop. The use of an appropriate amount of the solubilizer is useful in stabilizing lysozyme because it also dissolves an insoluble substance derived from lysozyme, but use of a large amount of the solubilizer causes problems such as irritation to the eyes. As described above, since there is an antinomy phenomenon in the lysozyme-vitamin A coexisting system, it was extremely difficult to stabilize both lysozyme and vitamin A at the same time without impairing the appearance stability.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to an eye drop containing lysozyme and vitamin A at the same time, which is an aqueous eye drop which does not impair the stability of appearance and has improved stability over time. The purpose is to provide.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted diligent studies to improve the appearance and stability of lysozyme and vitamin A-containing eye drops, and as a result, lysozyme, vitamin A and An eye drop having extremely high appearance stability and good stability over time of both components by blending a nonionic surfactant which is a solubilizing agent in a specific ratio and further adjusting the pH in a specific range. The inventors have found that the following can be obtained and completed the present invention. That is, the eye drop of the present invention comprises lysozyme, vitamins A, and nonionic surfactants at points A, B, C on the triangular diagram shown in FIG.
Blended in the ratio of the shaded area formed by connecting D, E and F,
In addition, the pH is adjusted to 5 to 8. Further, the range in which a more preferable effect is obtained is a specific range represented by a double mesh region formed by connecting points A ', B', C ', D', E'and F'on the same triangular chart. .

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Lysozyme, which is the first essential component of the present invention, means lysozyme or a salt thereof. Lysozyme may be derived from any source such as egg white and human, and is not particularly limited, but generally, egg white extracted and purified from egg white by a conventional method is often used. Examples of lysozyme include lysozyme chloride, and specific examples include lysozyme chloride manufactured by Eisai Co., Ltd. Lysozyme can be usually added to the eye drop composition in an amount of 0.01 to 5% by weight, preferably 0.05 to 1% by weight.

Vitamin A which is the second essential ingredient of the present invention
In addition to vitamin A itself, the types include vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid esters. Specifically, 1.7 million international units (I.U.) of retinol palmitate manufactured by Nippon Roche Co., Ltd. may be mentioned. Vitamin A can be usually added to the eye drop composition in an amount of 0.003 to 0.1% by weight, preferably 0.01 to 0.05% by weight.

Examples of the nonionic surfactant which is the third essential component of the present invention include higher fatty acid esters such as water-soluble polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, and the like. There are polyoxyethylene (p = 60) hydrogenated castor oil and polyoxyethylene (p = 20) sorbitan monooleate. In addition, p shows the average addition mole number of ethylene oxide.

Specifically, Nikkor HCO-40, HCO-50, HCO-60, T manufactured by Nikko Chemicals Co., Ltd.
There are O-10 etc. The nonionic surfactant can be usually added to the eye drop composition in an amount of 0.01 to 1.0% by weight, preferably 0.05 to 0.2% by weight.

The pH of the lysozyme- and vitamin A-containing eye drops of the present invention is adjusted in the range of 5 to 8, more preferably 5.5 to 7.5. The pH of the eye drop is 5 to above.
When it is out of the range of 8, lysozyme and vitamin A,
Alternatively, the stability of both is significantly reduced.

The essential components must be blended in a ratio within the shaded area surrounded by points A, B, C, D, E and F in the triangular chart shown in FIG. 1, and preferably point A '. ，
It is blended in proportions within the double-hatched area surrounded by B ', C', D ', E'and F'. In the triangular diagram of FIG. 1, the apex indicates the 100% position of each component, and the coordinates of each point are represented by (vitamin A, lysozyme, nonionic surfactant) as follows. Point A (20.0 40.0 40.0) Point B (7.7 76.9 15.4) Point C (0.8 82.7 16.5) Point D (0.7 66.2 33. 1) Point E (1.4 28.2 70.4) Point F (12.5 25.0 62.5) Point A '(10.3 64.1 25.6) Point B' (6.3 78 .1 15.6) Point C '(1.6 82.0 16.4) Point D' (1.4 70.4 28.2) Point E '(2.2 54.3 43.5) Point F '(8.2 51.0 40.8)

If necessary, the vitamin A solubilizing eye drops of the present invention may contain other vitamins such as epsilon-aminocaproic acid, chlorpheniramine maleate, naphazoline hydrochloride, potassium aspartate, zinc sulfate and sulfa. Drugs such as methoxazole and allantoin; preservatives such as benzalkonium chloride, chlorobutanol, and paraoxybenzoic acid esters; isotonic agents such as potassium chloride, sodium chloride, propylene glycol, polyethylene glycol, glycerin; boric acid, A buffer such as glacial acetic acid; a sugar such as mannitol; a flavor such as l-menthol; a flavor such as a pH adjuster such as hydrochloric acid and sodium hydroxide;

The method for preparing the eye drop of the present invention is not particularly limited. For example, vitamin A such as vitamin A acetate is dissolved in water with a nonionic surfactant such as polyoxyethylene hydrogenated castor oil 60. After that, lysozyme such as lysozyme chloride is added, and if necessary, a drug such as epsilon-aminocaproic acid, a buffering agent such as boric acid, and a pH adjusting agent such as dilute acid are added to adjust the pH to 5-8. Thus, it is possible to obtain an eye drop containing lysozyme and vitamin A, which has a stable appearance and good stability over time.

[0013]

According to the present invention, lysozyme, vitamin A and a nonionic surfactant are mixed in a specific ratio and the pH is adjusted to 5 to 8 to prevent precipitation, In the case of lysozyme and vitamin A compound-containing eye drops that have been decomposed and have poor stability over time, an aqueous eye drop excellent in appearance and stability over time can be obtained.

[0014]

【Example】

Examples 1 to 7 and Comparative Examples 1 to 5 Eye drops having the formulations shown in Tables 1 to 3 were prepared and filled in a container,
After storing at 60 ° C. for 2 weeks, the stability of appearance and the residual ratio of lysozyme chloride and vitamin A palmitate were examined, and the results are shown in the same table. The pH of the eye drop was adjusted with sodium hydroxide or dilute hydrochloric acid as needed. The appearance stability was visually evaluated according to the following criteria. ○: Clear ×: White turbidity or precipitation The content of vitamin A palmitate in the eye drop was measured by a high performance liquid chromatographic method, and the content of lysozyme chloride was measured by an external standard / lysozyme chloride quantification method. The residual rate was calculated using the formula shown in Equation 2.

[0015]

[Equation 1]

[0016]

[Equation 2]

[0017]

Table 1 Example Example Example Comparative Example Comparative Example Comparative Example Comparative Example 1 2 1 2 3 4 Compounding amount (g / 100ml): Lysozyme chloride 0.2 0.2 0.2 0.2 0.2 0.2 Vitamin A palmitate 0.005 0.015 0.015 0.015 0.005 0.005 (1.7 million I.U.) TO-10 *¹0. Ten. 1 − 0. 7 0. Ten. 1 Propylene glycol 0. 5 0. 5 0. 5 0. 5 0. 5 0. 5 10% benzal chloride 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 Conium solution Sodium chloride 0. 6 0. 6 0. 6 0. 6 0. 6 0. 6 Dilute hydrochloric acid − − − − − Proper amount Sodium hydroxide − − − − Proper amount − Distilled water Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount pH 6.5 6.5 6.5 6.5 9.0 4.0 Coordinate position of triangle chart: Lysozyme 65.6 63.5 93.0 21.9 65.6 65.6 Vitamin A 1.6 4.8 7.0 1.6 1.6 1.6 Nonionic surfactant 32.8 31.7 0 76.5 32.8 32.8 Evaluation results: Appearance stability ○ ○ × ○ × ○ Lysozyme chloride residual rate (%) 100 101 89 98 90 100 Vitamin A palmitate 80 82 17 60 61 36 Survival rate(%) * 1) TO-10: Polyoxyethylene (20) sorbitan monooleate

[0018]

[Table 2] Example Example Example Example Comparative Example Example Example 3 4 5 5 6 7 Blending amount (g / 100ml): Lysozyme chloride 0.5 0.5 0.3 2.0 0.5 0.5 Vitamin A palmitate 0.04 0.04 0.03 0.03 0.04 0.005 (1.7 million IU) Tetrahydrozoline hydrochloride 0.05 0.05 0.05 0.05 − − Naphazoline hydrochloride − − − − − 0.003 Neostigmine methyl sulfate − 0.003 − − − 0.003 Chlorine maleate 0.03 0.03 0.03 0.03 0.03 − Phenylamine allantoin − 0.1 0.1 0.1 − − Epsilon − 1.0 − − − 0.5 − Aminocaproic acid Pyridoxine hydrochloride − 0.1 − − 0.1 0.1 Panthenol − − 0.02 0.02 − 0.02 Aminoethyl Sulfonic acid 1.0 --- 1.0-L-potassium aspartate-1.0 1.0 1.0 0.5-TO-10 *¹− − 0.2 0.2 0.2 0.2 HCO-60 *²0.1 0.2 − − − − Ethylenediaminetetraacetic acid 0.005 0.005 0.005 0.005 0.005 0.005 Disodium boric acid − 0.81 − − − − Borax − 0.08 − − − − * 1) TO-10: Polyoxyethylene (20) sorbitan monooleate * 2) HCO-60: Polyoxyethylene (60) hydrogenated castor oil

[0019]

[Table 3] Example Example Example Example Comparative Example Example Example 3 4 5 5 6 7 Compounding amount (g / 100ml): Sodium dihydrogen phosphate − − 0.22 0.22 − 0.22 Disodium hydrogen phosphate − − 1.2 1.2 − 1.2 Propylene glycol 0.5 0.5 0.5 0.5 − 0.5 l-Menthol 0.005 0.005 0.005 0.005 − 0.005 10% Chloride Benzal 0.05 0.05 − − 0.05 0.025 Conium solution Methyl paraben − − 0.1 0.1 − 0.1 Propyl parapen − − 0.01 0.01 − 0.01 Dilute hydrochloric acid Appropriate amount − − − − Appropriate amount Sodium hydroxide − − Appropriate amount Proper amount − Distilled water Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount pH 6.5 6.5 6.5 6.5 7.5 5.5 Coordinate position of triangle chart: Lysozyme 78.1 67.6 56.6 89.7 67.6 70.9 Vitamin A 6.3 5.4 5.7 1.3 5.4 0.71 Nonionic surfactant 15.6 27.0 37.7 9.0 27.0 28.4 Evaluation results: Appearance stability ○ ○ ○ ○ ○ ○ Lysozyme chloride residual rate (%) 103 100 100 97 100 105 Vitamin A palmitate 81 85 81 56 86 85 Survival rate(%)

[Brief description of drawings]

FIG. 1 is a triangular chart showing the mixing ratio of lysozyme, vitamin A and a nonionic surfactant. (Lysozyme,
The coordinates of each point representing the ratio of vitamins A and nonionic surfactant are as follows. Point A (20.0 40.0 40.0) Point B (7.7 76.9 15.4) Point C (0.8 82.7 16.5) Point D (0.7 66.2 33. 1) Point E (1.4 28.2 70.4) Point F (12.5 25.0 62.5) Point A '(10.3 64.1 25.6) Point B' (6.3 78 .1 15.6) Point C '(1.6 82.0 16.4) Point D' (1.4 70.4 28.2) Point E '(2.2 54.3 43.5) Point F '(8.2 51.0 40.8)

Claims (1)

[Claims] 1. Lysozyme, vitamin A, and nonionic surfactant are points A, B, and C on the triangular chart shown in FIG.
Blended in the ratio of the shaded area formed by connecting D, E and F,
And the eye drop characterized by adjusting pH to 5-8.