JPH0616547A - Antiphlogistic ophthalmic solution - Google Patents

Abstract

PURPOSE:To obtain an antiphlogistic ophthalmic solution having excellent storage stability free from eye irritation immediately after instillation of drop. CONSTITUTION:1mol diclofenac sodium as a main medicine is mixed with 7-50mols chemically modified water-soluble cyclodextrin such as 2- hydroxyethyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin or glucosyl-beta- cyclodextrin to give an antiphlogistic ophthalmic solution.

Description

Detailed Description of the Invention

[0001]

The present invention relates to diclofenac sodium, 2-hydroxyethyl-β-cyclodextrin (hereinafter abbreviated as 2-HE-β-CyD), hydroxypropyl-β-cyclodextrin (hereinafter HP-β-CyD).
Abbreviated), glucosyl-β-cyclodextrin (hereinafter abbreviated as G1-β-CyD), diglucosyl-β-cyclodextrin (hereinafter abbreviated as G1, G1-β-CyD),
Maltosyl-β-cyclodextrin (hereinafter G2-β-
CyD), dimaltosyl-β-cyclodextrin (hereinafter abbreviated as G2, G2-β-CyD), maltotriosyl-β-cyclodextrin (hereinafter G3-β-Cy).
D) and a water-soluble cyclodextrin selected from the group consisting of panosyl-β-cyclodextrin, alone or in combination of two or more, and relates to an eye drop capable of relieving eye irritation and storing at room temperature.

[0002]

BACKGROUND OF THE INVENTION Aqueous eye drops of diclofenac sodium, a non-steroidal anti-inflammatory drug, are used for the prevention of postoperative inflammatory symptoms during cataract surgery, intraoperative and postoperative complications due to its potent inhibitory effect on prostaglandin biosynthesis. ing. When non-steroidal anti-inflammatory drugs are used as eye drops, they almost always irritate mucous membranes and eyes, and have a strong ocular pain effect.

The present inventors have proposed ibuprofen, indomethacin, as a method for alleviating the eye irritation and ocular pain caused by the nonsteroidal anti-inflammatory drug.
A non-steroidal anti-inflammatory agent selected from ketoprofen, naproxen, and flufenamic acid as a main drug, and a salt of calcium or magnesium with a physiologically acceptable acid as an eye irritation relief agent. Anti-inflammatory eye drops that provide
2). In addition, diclofenac sodium is used as an active ingredient, and 2-amino-2 is used as a stabilizer for the active ingredient and the preservative in an aqueous solution containing a buffer, a dissolution aid and a preservative.
A therapeutic agent is disclosed which is characterized in that it comprises -hydroxymethyl-1,3-propanediol or its homologues having up to 10 carbon atoms (JP-A-62-62).
-242617). Furthermore, 2-HE-β-CyD,
A drug using the low local irritation or / and local irritation reducing action of 2,3-dihydroxypropyl-β-cyclodextrin (hereinafter abbreviated as 2,3-HP-β-CyD) and using it as a drug carrier A formulation is disclosed (Japanese Patent Laid-Open No. 64-61430).

Cyclodextrins are naturally α-cyclodextrin and β-cyclodextrin (hereinafter β-C).
abbreviated as yD) and γ-cyclodextrin are well known, and improvement of solubility, chemical stabilization, improvement of bioavailability, etc. have been reported for application to formulations (Kamakama, Pharmaceutical Journal, 101,857,1981). To improve the physical properties and functionality of natural cyclodextrin,
Derivatives in which the hydroxyl group of cyclodextrin has been chemically modified have been developed. For example, water-soluble derivatives of β-CyD include hydroxyalkylated β-cyclodextrin derivatives such as HE-β-CyD and HP-β-CyD, and G1-.
Glucosylated branched-β-cyclodextrin derivatives such as β-CyD and G2-β-CyD are known (Kamama, Pharmatech Japan, 7,143, 1991).
Pharmaceutical compositions utilizing these chemically modified cyclodextrins include HE-β-CyD and H for poorly water-soluble or unstable nonsteroidal anti-inflammatory drugs.
Water-soluble pharmaceutical composition clathrated with P-β-CyD (European Patent Application No. 0149197) and a water-soluble pharmaceutical composition in which the above-mentioned glucosylated branched cyclodextrin is allowed to coexist with a water-insoluble or poorly water-soluble pharmacologically active substance Is disclosed (JP-A-63-27440).

[0005]

However, although calcium or magnesium salts of physiologically acceptable acids have shown satisfactory effects in alleviating eye irritation, they have the drawback of lacking long-term storage stability. Also, JP-A-62-1
The eye drops exemplified by 242617 show a considerable effect on storage stability, but the irritation immediately after eye drops is strong, and it cannot be said to be satisfactory. JP-A-64-61
430 includes 2-HE-β-CyD and 2,3-HP-β-.
The low hemolytic activity, the hemolytic activity-reducing action, and the low muscle irritation of CyD are exemplified, but the eye irritation alleviating effect of the stimulant drug is not described. In addition, European Patent Application No. 0
149197 and Japanese Patent Laid-Open No. 63-27440 show only the solubilization of poorly water-soluble drugs and the stabilization of unstable drugs, and there is no suggestion or disclosure about alleviation of eye irritation of water-soluble drugs such as diclofenac sodium. It has not been.

On the other hand, it has been reported that a nonsteroidal anti-inflammatory drug containing diclofenac sodium is included in β-CyD (Kamagama et al., Chem. Pharm. B.
all. 23, 201, 1975). According to the experiments conducted by the present inventors, it was possible to prepare a 0.01 to 0.3% aqueous solution of diclofenac sodium at a useful concentration as an eye drop at pH 8, and β-CyD was added to the aqueous solution. It is also possible to prepare a solution. However, the intended ophthalmic irritation could not be obtained by the eye drop containing 3 to 4 times mol of β-CyD with respect to diclofenac sodium. In addition, European Patent Application No. Tested with diclofenac sodium as a drug according to 0149197, but no eye irritation was obtained.

[0007]

[Means for Solving the Problem] Therefore, the present inventors have conducted diligent research to develop an eye drop containing diclofenac sodium as a main drug, which is free of eye irritation immediately after instillation and has excellent storage stability. The inventors have found that the desired object can be achieved by incorporating the chemically modified water-soluble cyclodextrin in an aqueous solution of sodium at a ratio of 7 mol or more relative to 1 mol of diclofenac sodium, and completed the present invention.

In the present invention, 2-HE-β is used as the water-soluble cyclodextrin used as an eye irritation relieving agent.
-CyD, HP-β-CyD, G1-β-CyD, G
1, G1-β-CyD, G2-β-CyD, G2, G2
-Β-CyD, G3-β-CyD and panosyl-β-
CyD is mentioned. More specifically, HP-β-Cy
As D, 2-hydroxypropyl-β-cyclodextrin (hereinafter abbreviated as 2-HP-β-CyD), 3-hydroxypropyl-β-cyclodextrin (hereinafter 3-
Abbreviated as HP-β-CyD) and 2,3-HP-β-Cy
D is mentioned. The eye drop of the present invention can be produced by a conventional aqueous formulation using the above-mentioned main drug and eye irritation relieving agent.

The standard pharmaceutical formulation will be described below.
The concentration of diclofenac sodium, which is usually used for eye drops, is 0.01 to 0.3% by weight / volume%, and the concentration lower than the above concentration does not have sufficient anti-inflammatory effect, and the concentration higher than the above concentration is not recommended. However, the anti-inflammatory effect is not significantly improved, which is rather uneconomical.

2-HE-β-CyD, HP-β-Cy
D, G1-β-CyD, G1, G1-β-CyD, G2
-Β-CyD, G2, G2-β-CyD, G3-β-C
When a water-soluble cyclodextrin selected from yD and panosyl-β-CyD is used alone or in combination of two or more,
The concentration is preferably 7 to 50 times in molar ratio with respect to diclofenac sodium. If the concentration of the water-soluble cyclodextrin is lower than this concentration, the eye irritation is not sufficiently relieved, and even if the concentration is higher than this concentration, the effect does not change and it is uneconomical. 2-HE-β-Cy
Degree of molecular substitution of D and HP-β-CyD (Molar
Substitution (MS) is preferably 0.6 to 1.6. When the molecular substitution degree is lower than the above range, the solubility of cyclodextrin is lowered, and when it is higher than the above range, eye irritation is not sufficiently relaxed, which is not preferable.
The preferred pH of this eye drop is 7.5 to 8.5, and if the pH is lower than the above range, the eye irritation is not sufficiently relaxed, and if it is higher than the above range, it deviates from the physiological pH, which is not preferable. The osmotic pressure ratio is preferably 0.6 to 1.6. As the buffer agent, phosphate, borate, organic acid salt and the like can be used. As the tonicity agent, sodium chloride, potassium chloride, boric acid, mannitol and the like can be used. Preservatives include benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate and other inverse soaps, methylparaben, ethylparaben, propylparaben and butylparaben and other parabens, chlorobutanol, phenylethyl alcohol and benzyl alcohol and other alcohols. Can be used. Further, a thickener, a surfactant and a chelating agent can be added as appropriate. Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the examples.

[0011]

【Example】

Example 1 Sodium diclofenac 0.1 g G1-β-CyD 3.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 1.30 g Borax 0.86 g Methylparaben 0.026 g Propylparaben 0.014 g 0.1N hydrochloric acid / 0 1N sodium hydroxide until pH 8.0 purified water up to 100 ml methyl paraben in 80 ml of purified water preheated to about 60 °,
Add propylparaben and stir well to dissolve. After cooling this solution to room temperature, G1-β-CyD, boric acid,
Add borax and diclofenac sodium to dissolve.
Adjust the pH to 8.0 with 0.1N hydrochloric acid or 0.1N sodium hydroxide, adjust to 100 ml with purified water,
Sterilize and filter to obtain eye drops.

Example 2 Diclofenac sodium 0.1 g G2-β-CyD 4.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 1.30 g Borax 0.86 g Benzalkonium chloride 0.005 g 0.1N hydrochloric acid / 0.1N sodium hydroxide until pH becomes 8.0 purified water up to 100 ml purified water 80 ml into diclofenac sodium, G2-β
Add CyD, boric acid, borax, benzalkonium chloride and dissolve. The pH is adjusted to 8.0 with 0.1N hydrochloric acid or 0.1N sodium hydroxide, the volume is adjusted to 100 ml with purified water, and sterilized and filtered to obtain an eye drop.

Example 3 Diclofenac sodium 0.1 g G1-β-CyD 1.5 g (manufactured by Shimizu Minato Sugar Co., Ltd.) 2-HP-β-CyD 1.5 g (MS = 0.6 Shimizu Minami Sugar Co., Ltd.) Boric acid 1.30 g borax 0.86 g methylparaben 0.026 g propylparaben 0.014 g 0.1N hydrochloric acid / 0.1N sodium hydroxide until pH 8.0 Purified water up to 100 ml Same as Example 1 with the above formulation Operate to make eye drops.

Example 4 Sodium diclofenac 0.1 g 2-HE-β-CyD 1.5 g (MS = 0.6 manufactured by Shimizu Co., Ltd.) 2-HP-β-CyD 1.5 g (MS = 0. 6 salt water Port Sugar Co., Ltd. boric acid 1.30 g borax 0.86 g methylparaben 0.026 g propylparaben 0.014 g 0.1N hydrochloric acid / 0.1N sodium hydroxide until pH 8.0 purified water up to 100 ml The formulation is operated in the same manner as in Example 1 to obtain an eye drop.

Example 5 Diclofenac sodium 0.1 g 2-HE-β-CyD 2.0 g (MS = 1.6 manufactured by Shimizu Minato Sugar Co., Ltd.) 2-HP-β-CyD 2.0 g (MS = 0. 9 salt water port refined sugar Co., Ltd. boric acid 1.30 g borax 0.86 g methylparaben 0.026 g propylparaben 0.014 g 0.1N hydrochloric acid / 0.1N sodium hydroxide until pH 8.0 purified water up to 100 ml The formulation is operated in the same manner as in Example 1 to obtain an eye drop.

Example 6 Diclofenac sodium 0.1 g 2-HE-β-CyD 1.5 g (MS = 0.6 manufactured by Shimizu Minato Sugar Co., Ltd.) G1-β-CyD 1.5 g (Shimizu Minato Sugar Co., Ltd.) Boric acid 1.30 g borax 0.86 g benzalkonium chloride 0.005 g 0.1N hydrochloric acid / 0.1N sodium hydroxide until pH 8.0 Purified water up to 100 ml Operated in the same manner as in Example 2 with the above formulation. And use it as eye drops.

Example 7 Diclofenac sodium 0.1 g G1-β-CyD 2.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) G2-β-CyD 2.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 1.30 g Borax 0.86 g Benzalkonium chloride 0.005 g 0.1N hydrochloric acid / 0.1N sodium hydroxide Until pH becomes 8.0 Purified water up to 100 ml The above formulation was followed in the same manner as in Example 2 to obtain an eye drop. .

Example 8 Diclofenac sodium 0.01 g G1-β-CyD 2.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 1.45 g Borax 0.34 g Methylparaben 0.026 g Propylparaben 0.014 g 0.1N Hydrochloric acid / 0.1N sodium hydroxide until pH 7.5 Purified water up to 100 ml The above formulation is operated in the same manner as in Example 1 to obtain an eye drop.

Example 9 Diclofenac sodium 0.3 g 2-HP-β-CyD 3.0 g (MS = 0.6 manufactured by Shimizu Minato Sugar Co., Ltd.) G1-β-CyD 3.0 g (Minako Shimizu Sugar Co., Ltd.) G2-β-CyD 4.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 0.92 g Borax 1.64 g Benzalkonium chloride 0.005 g 0.1N hydrochloric acid / 0.1N sodium hydroxide pH 8.5 Purified water up to 100 ml The above formulation is operated in the same manner as in Example 2 to give an eye drop.

Comparative Example 1 Sodium diclofenac 0.1 g Boric acid 1.30 g Borax 0.86 g 0.1N hydrochloric acid / 0.1N sodium hydroxide Until pH 8.0 Purified water up to 100 ml Purified water 80 ml with diclofenac sodium and borax acid,
Add borax and dissolve. 0.1N hydrochloric acid or 0.1N
Adjust the pH to 8.0 with sodium hydroxide and add 1 with purified water.
Make up to 00 ml and filter to remove the bacteria to obtain eye drops.

Comparative Example 2 Sodium diclofenac 0.1 g Heptakis (2,3,6-tri-O-methyl) -β-cyclodextrin (manufactured by Wako Pure Chemical Industries, Ltd.) 3.0 g Boric acid 1.30 g Borax 0.86 g Methylparaben 0.026 g Propylparaben 0.014 g 0.1N hydrochloric acid / 0.1N sodium hydroxide Until pH becomes 8.0 Purified water up to 100 ml The above formulation was used in the same manner as in Example 1 to prepare an eye drop. .

Comparative Example 3 Sodium diclofenac 0.1 g Boric acid 1.9 g 2-Amino-2-hydroxymethyl-1.3-propanediol 0.6 g Cremophor EL 5.0 g Benzalkonium chloride 0.01 g Purified water up to 100 ml Diclofenac sodium, boric acid, 80 ml of purified water,
2-Amino-2-hydroxymethyl-1,3-propanediol, Cremophor EL, and benzalkonium chloride are added and dissolved, the volume is made up to 100 ml with purified water, and sterilized and filtered to obtain an eye drop.

Comparative Example 4 Sodium diclofenac 0.1 g G1-β-CyD 3.0 g (manufactured by Shimizu Minato Sugar Co., Ltd.) Boric acid 1.60 g Borax 0.16 g Methylparaben 0.026 g Propylparaben 0.014 g 0.1N Hydrochloric acid / 0.1N sodium hydroxide until pH 7.0 Purified water up to 100 ml The above formulation is operated in the same manner as in Example 1 to obtain an eye drop.
The formulations of Examples 1 to 9 were stable in both appearance and content after storage at 40 ° for 3 months. The results are shown in Table 1.

[0024]

[Table 1] It is shown in Test Examples that the eye irritation of diclofenac sodium is alleviated by the preparation of the present invention. Test Example 1 (Rabbit Blink Response Test) Rabbits were instilled with 50 μl of physiological saline and the formulations of Examples 1 to 7 and Comparative Examples 1 to 3, and the number of blinks for 1 minute immediately after instillation was measured to stimulate the rabbit. Sex (Fukui, Ikemoto; modern clinical,
4, 227, 1970). The results are shown in Table 2. The formulation according to the present invention significantly reduces the number of blinks compared to the comparative example,
It became equivalent to physiological saline.

[0025]

[Table 2] Test Example 2 (Human feeling test) A single drop of physiological saline and the preparations of Examples 1 to 7 and Comparative Examples 1 to 4 was applied to humans to evaluate the feeling of use. The results are shown in Table 3. The preparation according to the present invention markedly improved the eye irritation caused by diclofenac sodium, and became equivalent to physiological saline.

[0026]

[Table 3]

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Claims (3)

[Claims] 1. Diclofenac sodium as a main drug, 2-hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β.
-A water-soluble cyclodextrin selected from cyclodextrin, maltosyl-β-cyclodextrin, dimaltosyl-β-cyclodextrin, maltotriosyl-β-cyclodextrin and panosyl-β-cyclodextrin, alone or in combination of two or more. , An anti-inflammatory eye drop, wherein the amount of the water-soluble cyclodextrin is 7 to 50 mol per 1 mol of diclofenac sodium. 2. The eye drop preparation according to claim 1, wherein the degree of molecular substitution (MS) of 2-hydroxyethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin is 0.6 to 1.6. 3. The eye drop preparation according to claim 1, which has a pH of 7.5 to 8.5.