CN1173129A - anti-inflammatory eye drops - Google Patents

Abstract

Anti-inflammatory eye drop, which contains: (a) 0.05-0.7% by weight/volume of diclofenac sodium, (b) 1-10% by weight/volume of γ-cyclodextrin, and (c) 1-20% by weight/volume of polyvinylpyrrolidone , (d) 0.002-0.01% by weight/volume of benzethonium chloride or 0.002-0.005% by weight/volume of benzalkonium chloride, and its pH value is 7.0-8.5. The anti-inflammatory eye drops can contain diclofenac sodium in a wide range of concentrations, can be stable for a long time, and are slightly irritating to the eyes.

Description

anti-inflammatory eye drops

The present invention relates to an anti-inflammatory eye drop with diclofenac sodium (hereinafter abbreviated as DFNa) as an active ingredient. The eye drop is mixed with δ-cyclodextrin (hereinafter referred to as δ-CyD) which belongs to water-soluble cyclodextrin and polyethylene Pyrrolidone (hereinafter referred to as PVP) has long-term storage stability and can ease the irritation to eyes.

The water-based eye drops of the non-steroidal anti-inflammatory agent DFNa have a strong blocking effect on the biosynthesis of prostaglandins, so they are used to prevent postoperative inflammatory symptoms during cataract surgery and during and after surgery. comorbidities. When non-steroidal anti-inflammatory agents are used as eye drops, almost without exception, they will irritate mucous membranes and eyes, and show strong eye pain.

For the purpose of alleviating eye irritation or eye pain caused by non-steroidal anti-inflammatory agents in the past, the present inventors provide an anti-inflammatory eye drop, which is characterized in that it contains ibuprofen, indomethacin , ketoprofen, naproxen and flufenamic acid selected as the main drug, and also contains calcium or magnesium and physiologically acceptable acid salt formation as eye irritation mitigating agent (special fair 1-19362). In addition, there is also provided an anti-inflammatory eye drop, wherein, relative to DFNa, polyoxyethylene sorbitan monooleate or α and β cyclodextrin are contained as cosolvents in an amount (weight) 5 to 10 times that of DFNa (Extra Fair 2-6329). In addition, the present inventors have also developed such an eye drop, which contains β-cyclodextrin for chemical modification of DFNa, so that it does not irritate the eyes after the eye drop, and its storage stability is also excellent. A patent application has been filed for this eyedrop (JP-A-6-16547).

In addition, a therapeutic drug is also disclosed, which is characterized in that it contains DFNa as an active ingredient, and contains a stabilizer 2 that stabilizes the active ingredient and the preservative in an aqueous solution composed of a buffer, a cosolvent, and a preservative. -Amino-2-hydroxymethyl-1,3-propanediol or a compound having not more than 10 carbon atoms among its homologues (JP-A-62-242617). On the other hand, the following patent documents have been disclosed regarding eye drops containing cyclodextrin: 2-(2-fluoro-4-biphenyl)propionic acid or its salt and β-cyclodextrin (hereinafter referred to as β -CyD) or γ-CyD anti-inflammatory ophthalmic solution (Tepai 3-30571); containing 2-(2-fluoro-4-biphenyl)propionic acid or its salt, β-CyD or γ-CyD and Anti-inflammatory ophthalmic liquid of calcium salt or magnesium salt (Japanese Patent Application No. 60-136516); or containing 3,4-dihydro-2,8-diisopropyl-3-thio-2H-1,4- An aqueous solution containing benzoxazine-4-acetic acid or its salt as the main drug and containing cyclodextrin (JP-A-5-213757).

However, calcium salts or magnesium salts produced from physiologically acceptable acids exhibit satisfactory effects in alleviating eye irritation, but lack long-term storage stability, which is a disadvantage. α-cyclodextrin disclosed in Japanese Patent Publication No. 2-6329 has no relieving effect on eye irritation caused by DFNa, and β-CyD has weak eye irritation relieving effect, but this effect is insufficient. Afterwards, the present inventors found that as long as the water-soluble β-CyD, which acts as a chemical modification, is mixed in a molar ratio of 7 to 50 times relative to DFNa, good results can be obtained in terms of eye irritation alleviation and storage stability ( Japanese Patent Laid-Open No. 6-16547), however, when the concentration of DFNa exceeds 0.1%, the alleviation effect on eye irritation is not sufficient. The eye drops exemplified in Japanese Patent Laid-Open No. 62-242617 show a fairly good effect in terms of storage stability, but are unsatisfactory because they cause strong irritation after eye drops.

In addition, in JP-A 60-136516 and JP-A-5-213757, which are improvements to the above-mentioned JP-A-3-30571, it is disclosed that β-CyD and γ-CyD have the effect of alleviating eye irritation to active ingredients in eye drops. However, for γ-CyD, the desired effect was not obtained in any aspect.

On the other hand, compared with chemically modified water-soluble β-CyD, it is known that γ-CyD has the same degree or higher local safety [Umamibu, Pharm.Tech.Japan, 7(2) , 143, 1991]. In the past, γ-CyD was difficult to produce in large quantities, so its price was high, about 100 times that of β-CyD, and it was almost unavailable from an economic point of view. However, due to the recent development of new manufacturing techniques, γ-CyD products can be provided at low cost, and thus its use as a pharmaceutical additive is attracting attention.

The inventors of the present invention have conducted intensive research to develop an eye drop that uses γ-CyD, is non-irritating to the eye after instillation, has long-term storage stability, and can use DFNa as the main ingredient in a wide range of concentrations. , as a result, it was found that by using DFNa, γ-CyD, PVP in combination with benzethonium chloride or benzalkonium chloride as a preservative and adjusting the pH value to a range of 7.0 to 8.5, the above-mentioned purpose can be achieved, so far The present invention has been accomplished. That is to say, the present invention relates to an anti-inflammatory eye drop containing DFNa, γ-CyD, PVP and benzethonium chloride or benzalkonium chloride with a pH value of 7.0-8.5.

The irritation of DFNa to human eyes usually becomes strong when the concentration of DFNa is greater than 0.05%. The inventors of the present invention have found that usually using γ-CyD together and adjusting the pH value to 7.0 to 8.5 can greatly alleviate the irritation to the eyes, and can be used in order to fully exert its therapeutic effect according to the symptoms of various eye disease patients. The present invention has been completed based on the novel discovery that a long-term stable eyedrop can be made into a high-concentration, and by containing PVP and benzethonium chloride or benzalkonium chloride as a preservative in combination. .

Because DFNa has a strong stimulating effect on the eyes, the upper limit of the concentration of DFNa is generally limited to 0.1% in the past as eye drops. However, in the eye drops of the present invention, by using 1 to 10% of γ-CyD in combination and adjusting the pH value to 7.0 to 8.5, the irritation to the eyes can be greatly alleviated, thereby achieving a high concentration of 0.7%. concentration, thus significantly expanding its scope of application.

Since a high concentration of DFNa can more significantly show the inhibitory effect of prostaglandins in the eye and the mydriasis effect of atropine, it can be significantly displayed not only in ophthalmic surgery (cataract, glaucoma, retinal detachment, vitreous removal, strabismus, etc.) Maintain mydriasis and anti-inflammatory or postoperative therapeutic effects, and for general eye diseases, that is, endogenous uveitis headed by Behcet's disease, external ocular inflammatory diseases (conjunctivitis, keratitis, upper Dysmenorrhea, blepharitis, stye, etc.) and other symptoms related to prostaglandins have a good therapeutic effect.

Best way to practice the invention

γ-CyD used in the present invention can significantly alleviate eye irritation caused by DFNa in a wide range of concentrations from low concentrations to high concentrations. This broad range of effects is inherent to γ-CyD and not found in other water-soluble cyclodextrins.

The PVP used in the present invention can prevent the generation of insoluble foreign matter from γ-CyD in the formulation. In JP-A-5-213757, water-soluble polymers other than PVP such as polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, carboxymethyl cellulose are disclosed. Sodium sodium, polyethylene glycol, etc. also have the effect of preventing insoluble foreign matter from being produced, but when the present inventors tried this technology, they found that water-soluble polymers other than PVP did not have this effect, which is an inherent effect of PVP.

The PVP used in the present invention preferably has a Fekenscher K value (hereinafter referred to as K value) within the range of 10-95. Such PVP is commercially available under the trade names Kollidon 12PF, 17PF, 25, 30, and 90 from BASF JAPAN Co., Ltd., and under the trade names PVP K15, K30, K60, and K90 from Tokyo Chemical Industry Co., Ltd., each Goods are easily available.

The preservatives used in the present invention are intended to provide eye drops having long-term storage stability, and among them, benzethonium chloride or benzalkonium chloride are particularly preferably used. That is, according to the experiments of the present inventors, it can be clearly seen from Table 3 that benzethonium chloride or benzalkonium chloride has a superior effect of preventing foreign matter generation than other preservatives.

The preparation method of eyedrop of the present invention is, at first DFNa and gamma-CyD are dissolved in purified water, then cooperate to add PVP and benzethonium chloride or benzalkonium chloride and adjust the pH value to 7.0～7.0 with buffering agent and pH regulator. 8.5 and made.

The concentration of DFNa in the final composition of the present invention is preferably 0.05-0.7% (weight/volume%, the same below), particularly preferably 0.1-0.5%. When the concentration of DFNa is lower than 0.05%, its anti-inflammatory effect is weak, so it is not practical; and if it is higher than 0.7%, it is difficult to formulate the composition.

The concentration of γ-CyD in the final composition of the present invention is preferably 1-10%, particularly preferably 3-10%. Within the concentration range of DFNa mentioned above, if the concentration of γ-CyD is less than 1%, the irritation to the eyes cannot be relieved, and if it exceeds 10%, it is disadvantageous in terms of formulation and economical efficiency.

The concentration of PVP in the final composition of the invention is preferably 1 to 20%, particularly preferably 2 to 10%. If the concentration of PVP is less than 1%, insoluble foreign matter is generated and storage stability is poor, and if it exceeds 20%, the eye will have a strong sticky feeling when instilled, so it is not preferable.

The pH value of the eyedrop of the present invention is preferably 7.0-8.5, particularly preferably 7.5-8.5. When the pH value is below 6.5, even if the concentration of γ-CyD is 5 to 10%, the effect of alleviating eye irritation cannot be sufficiently obtained. In addition, if the pH value is more than 8.5, it deviates from the physiological pH value, so it is not good. In order to adjust the pH, a buffer such as a borate buffer or a phosphate buffer, and a pH adjuster such as a sodium hydroxide solution or dilute hydrochloric acid can be used without limitation according to conventional methods.

The benzethonium chloride and benzalkonium chloride used in the present invention can prevent the eyedrops from being polluted by microorganisms during use and have a bactericidal effect. Regarding their concentrations, for benzethonium chloride, it is preferably 0.002 to 0.01%. If the concentration of benzethonium chloride is lower than 0.002%, its bactericidal effect is too weak. In addition, if it exceeds 0.01%, it will be used more frequently. damage to the corneal epithelium. For benzalkonium chloride, it is preferably 0.002 to 0.005%. If the concentration of benzalkonium chloride is lower than 0.002%, its bactericidal effect is too weak. In addition, if it exceeds 0.005%, the eye drops of the present invention will become emulsified. Cannot be formulated.

In addition to the above-mentioned various components, the eye drop of the present invention may contain other components generally used in eye drops as long as the object of the present invention is not violated. For example, buffering agents, isotonic agents, surfactants, chelating agents and the like may be contained. As buffers, phosphates, borates and organic bases can be used. Sodium chloride, potassium chloride, boric acid, borax, etc. are mentioned as an isotonizing agent. Examples of the surfactant include polysorbate 80, polyoxyethylene hardened castor oil 60, and the like. Moreover, as a chelating agent, disodium edetate, sodium citrate, etc. are mentioned.

Hereinafter, the present invention will be explained in more detail by giving examples and prescription examples, but the present invention is not limited by these examples.

Example 1

Diclofenac Sodium 0.1g

γ-CyD 3.0g

(Wacker Chemicals East Asia Co., Ltd.)

Boric acid 1.30g

Borax 0.88g

PVP _K30 2.0g

(manufactured by Kollidon BASF JAPAN Co., Ltd.)

Benzethonium Chloride 0.005g

0.1N HCl/0.1N NaOH Adjust to pH8.0

Refined water to make up to 100ml

Add diclofenac sodium, γ-CyD, boric acid, borax, PVP _K30 , and benzethonium chloride to 80 ml of purified water to dissolve them completely. Adjust the pH value to 8.0 with 0.1N hydrochloric acid or 0.1N sodium hydrochloride, make up to 100ml with purified water, and obtain eyedrops after filter sterilization.

Example 2

Diclofenac Sodium 0.05g

γ-CyD 10.0g

(Wacker Chemicals East Asia Co., Ltd.)

Boric acid 1.60g

Borax 0.16g

PVP _K25 10.0g

(Kllidon BASF JAPAN Co., Ltd.,)

Benzethonium Chloride 0.005g

0.1N HCl/0.1N NaOH Adjust to pH7.0

Refined water to make up to 100ml

According to above-mentioned prescription, carry out operation similarly with embodiment 1, obtain eye drop.

Example 3

Diclofenac Sodium 0.05g

γ-CyD 1.0g

(Wacker chemicals East Asia Co., Ltd.)

Boric acid 1.10g

Borax 2.10g

PVP _K90 1.0g

(Kollidon BASF JAPAN Co., Ltd.)

Benzethonium Chloride 0.005g

0.1N HCl/0.1N NaOH Adjust to pH8.5

Refined water to make up to 100ml

According to above-mentioned prescription, carry out operation similarly with embodiment 1, obtain eye drop.

Example 4

Diclofenac Sodium 0.1g

γ-CyD 3.0g

(Wacker chemicals East Asia Co., Ltd.)

Boric acid 1.10g borax 2.10gPVP _K25 5.0g (Kollidon BASF JAPAN Co., Ltd.) Chlorobenzylamine 0.005g0.1N HCl/0.1N NaOH adjusted to pH8.5 purified water to make up to 100ml according to the above prescription, and Example 1 Carry out operation similarly, obtain eye drops. Example 5 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 3.0g (Kollidon BASF JAPAN Co., Ltd.) Chlorobenzylamine 0.002g 0.1N HCl /0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Example 6 Diclofenac sodium 0.5g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.10g Borax 2.10gPVP _K25 10.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.005g 0.1N HCl /0.1N NaOH adjusted to pH 8.5 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was performed to obtain eye drops. Example 7 Diclofenac sodium 0.7g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.10g Borax 2.10gPVP _K25 10.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.01g 0.1N HCl /0.1N NaOH adjusted to pH 8.5 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was performed to obtain eye drops. Example 8 Diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.45g Borax 0.35gPVP _K25 10.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.002g 0.1N HCl /0.1N NaOH adjusted to pH 7.5 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was performed to obtain eye drops. Example 9 Diclofenac sodium 0.05g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.10g Borax 2.10gPVP _K12 20.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.002g 0.1N HCl /0.1N NaOH adjusted to pH 8.5 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was performed to obtain eye drops. Example 10 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K90 1.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.005g 0.1N HCl /0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Example 11 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 3.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.005g 0.1N HCl /0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Example 12 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 5.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.005g 0.1N HCl /0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Example 13 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 7.0g (Kollidon BASF JAPAN Co., Ltd.) Benzethonium chloride 0.005g 0.1N HCl /0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Example 14 Diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88gPVP _K25 10.0g (Kollidon 25: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Example 15 Diclofenac sodium 0.1g γ-CyD 3.0g (Wacker Chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K17 12.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005 g0.1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, proceed in the same way as in Example 1 to obtain eyedrops. Example 16 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker Chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88gPVP _K15 15.0g (Tokyo Chemical Industry Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/ Adjust the pH to 8.0 with 0.1N NaOH and make up to 100ml with purified water. According to the above prescription, proceed in the same way as in Example 1 to obtain eyedrops. Example 17 Diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88gPVP _K12 20.0g (Kollidon 12PF: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative Example 1 Diclofenac sodium 0.05g boric acid 1.30g borax 0.88g0.1N HCl/0.1N NaOH adjusted to pH 8.0 purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Comparative example 2 diclofenac sodium 0.1g γ-CyD 0.7g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.45g borax 0.35gPVP _K25 3.0g (Kollidon 25: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 7.5 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative example 3 diclofenac sodium 0.1g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.70g borax 0.07gPVP _K25 10.0g (Kollidon 25: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 6.5 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative Example 4 Diclofenac Sodium 0.1g α-CyD 5.0g (CELDEX: Nippon Food Chemicals Co., Ltd.) boric acid 1.30g Borax 0.88g0.1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml according to the above prescription, and Example 1 was operated in the same manner to obtain eye drops. Comparative example 5 diclofenac sodium 0.1g β-CyD 1.0g (RINGDEX BR: Mercian Co., Ltd.) boric acid 1.30g borax 0.88g0.1N HCl/0.1N NaOH adjusted to pH8.0 refined water supplemented to 100ml according to the above prescription, with Example 1 was operated in the same manner to obtain eye drops. Comparative example 6 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88gPVP _K25 23.0g (Kollidon 25: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative example 7 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88gPVP _K12 25.0g (Kollidon 12PF: BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0. 1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative Example 8 γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88g0.1N HCl/0.1N NaOH adjusted to pH8.0 purified water to make up to 100ml according to the above prescription, the same as in Example 1 Operate accordingly to obtain eyedrops. Comparative example 9 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g borax 0.88g benzethonium chloride 0.005g0.1N HCl/0.1N NaOH adjusted to pH8.0 purified water supplemented to 100ml According to the above prescription, the operation is carried out in the same way as in Example 1 to obtain eye drops. Comparative Example 10 Diclofenac Sodium 0.05g α-CyD 1.0g CELDEX: Nippon Food Chemical Co., Ltd.) boric acid 1.60g borax 0.16gPVP _K25 2.0g (Kollidon 25: BASF JAPAN Co., Ltd.) 0.1N HCl/0.1N NaOH adjusted to Purified water with pH 7.0 was added to 100ml according to the above prescription, and the operation was carried out in the same manner as in Example 1 to obtain eye drops. Comparative Example 11 Diclofenac Sodium 0.05g β-CyD 0.9g (RINGDEX BR: Mercian Co., Ltd.) Boric acid 1.60g Borax 0.16g PVP _K25 2.0g (Kollidon 25: BASF JAPAN Co., Ltd.) 0.1N HCl/0.1N NaOH Adjust the pH to 7.0 and make up to 100ml with purified water. According to the above prescription, perform the same operation as Example 1 to obtain eye drops. Comparative Example 12 Diclofenac Sodium 0.05g α-CyD 1.0g (CELDEX: Nippon Food & Chemical Co., Ltd.) boric acid 1.60g Borax 0.16g PVP _K25 2.0g (Kollidon 25: BASF JAPAN Co., Ltd.) Disodium edetate 0.1g 0.1N HCl/0.1N NaOH adjusted to pH 7.0 Purified water to make up to 100ml Comparative example 13 Diclofenac sodium 0.05g β-CyD 0.9g (RING DEX BR: Mercian Co., Ltd.) Boric acid 1.60g Borax 0.16g PVP _K25 2.0 g (Kollidon 25: BASF JAPAN Co., Ltd.) disodium edetate 0.1g 0.1N HCl/0.1N NaOH adjusted to pH 7.0 purified water to make up to 100ml according to the above prescription, the same as in Example 1 Operate and get eyedrops. Comparative Example 14 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.45g Borax 0.35g Hydroxyethylcellulose 0.5g (FUJICHEMI HEC CF-G: Fuji Chemical Co., Ltd.) Benzethonium chloride 0.005g0.1N HCl/0.1N NaOH adjusted to pH 7.5 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Comparative Example 15 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.45g Borax 0.35g METOLOSE SM400 0.5g (Shin-Etsu Chemical Co., Ltd.) benzethonium chloride 0.005g 0.1N HCl/0.1 Adjust the pH to 7.5 with N NaOH and make up to 100ml with purified water. According to the above prescription, perform the same operation as in Example 1 to obtain eyedrops. Comparative Example 16 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 3.0g (Kollidon 25: BASF JAPAN Co., Ltd.) Cetyl pyridinium chloride Onium 0.005g 0.1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as in Example 1 was carried out to obtain eye drops. Comparative Example 17 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 3.0g (Kollidon 25: BASF JAPAN Co., Ltd.) Dextran Chlorhexidine 0.005 g0.1N HCl/0.1N NaOH adjusted to pH 8.0 Purified water to make up to 100ml According to the above prescription, the same operation as Example 1 was carried out to obtain eye drops. Comparative Example 18 Diclofenac Sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) Boric acid 1.30g Borax 0.88g PVP _K25 3.0g (Kollidon 25: BASF JAPAN Co., Ltd.) Methylparaben 0.026 g Propyl p-hydroxybenzoate 0.014g 0.1N HCl/0.1N NaOH Adjust to pH 8.0 Purified water to make up to 100ml Add methyl p-hydroxybenzoate and p-hydroxybenzoic acid to 80ml of purified water preheated to about 60°C Propyl ester, stir well to dissolve completely. After the solution was cooled to room temperature, γ-CyD, boric acid, borax, diclofenac sodium, and PVP _K25 were added and dissolved therein. Adjust the pH to 8.0 with 0.1N HCl or 0.1N NaOH, make up to 100 ml with purified water, filter and sterilize to obtain eye drops.

The relieving effect of the preparation of the present invention on the eye irritation of diclofenac sodium is illustrated below by test examples.

Test Example 1 (Human Usability Test (Eye Irritation))

One drop of the preparations of physiological saline, Examples 1 to 9, and Comparative Examples 1 to 5 was instilled in the eyes of human beings (10 persons), and the feeling in use (eye irritation) from the instillation to 3 minutes after the instillation was evaluated. The results are shown in Table 1. The criteria for judging the sense of use listed in Table 1 are as follows:

0: no stimulation

1: slightly tingling

2: Tingling

3: Pain or strong tingling

Table 1 Human use (eye irritation) total average 1 2 3 4 5 6 7 8 9 10 normal saline 0 0 0 0 0 0 0 0 1 0 1 0.1 Example 1 0 0 1 0 0 0 0 0 1 0 2 0.2 2 1 0 1 0 0 0 1 0 2 0 5 0.5 3 0 0 1 0 0 0 0 1 1 0 3 0.3 4 0 0 0 0 0 0 0 0 1 0 1 0.1 5 1 0 1 0 0 0 0 0 1 0 3 0.3 6 1 0 1 0 0 1 0 0 1 0 4 0.4 7 1 0 1 0 0 1 0 0 2 0 5 0.5 8 1 0 1 0 0 1 0 0 1 0 4 0.4 9 0 0 1 0 0 0 0 0 1 0 2 0.2 comparative example 1 3 3 3 3 3 3 3 3 3 3 30 3.0 2 2 1 2 3 2 2 2 3 3 2 twenty two 2.2 3 3 2 3 3 2 2 3 3 3 2 26 2.6 4 3 2 3 3 3 2 3 3 3 2 27 2.7 5 3 2 2 2 2 2 2 3 3 2 twenty three 2.3

According to the results in Table 1, it can be proved that the preparation of the present invention can obviously alleviate the eye irritation caused by diclofenac sodium, and its stimulating effect is equal to that of normal saline.

These test examples show that the appropriate concentration of PVP used in the preparation of the present invention is 1 to 20%.

Test example 2 (human usability test (sticky))

Humans (10 persons) were instilled with physiological saline, the preparations of Examples 10 to 17 and Comparative Examples 6 to 7, and the feeling in use (stickiness) after 3 minutes from the instillation was evaluated. The results are shown in Table 2. The criteria for judging the sense of use listed in Table 2 are as follows:

0: No stickiness, no discomfort

1: slightly sticky, but no discomfort

2: Slightly sticky, slightly unpleasant feeling 3: Sticky, unpleasant feeling

Table 2 Human usability (sticky) total average 1 2 3 4 5 6 7 8 9 10 normal saline 0 0 1 0 0 0 0 0 1 0 2 0.2 Example 10 1 1 1 0 1 1 2 0 1 1 9 0.9 11 1 1 1 0 1 0 2 0 1 1 8 0.8 12 1 1 1 1 1 1 2 1 1 1 11 1.1 13 2 1 2 1 1 1 1 1 1 1 12 1.2 14 2 2 1 1 2 1 2 1 1 1 14 1.4 15 2 1 2 1 1 1 2 1 1 1 13 1.3 16 2 1 2 1 2 1 2 1 1 1 14 1.4 17 2 1 2 1 1 1 2 1 2 1 14 1.4 comparative example 6 3 3 3 2 2 2 3 1 3 2 twenty four 2.4 7 3 2 2 2 2 2 2 1 2 2 20 2.0

According to the results in Table 2, it can be proved that when the concentration of PVP used in the preparation of the present invention is 1-20%, there is almost no sticky feeling.

These test examples show that the preparation of the present invention is stable even under severe conditions and does not generate insoluble foreign matter.

Test example 3 (storage stability test)

The formulations of Examples 1-9, Comparative Example 1 and Comparative Examples 8-18 were sealed into glass ampoules, stored at 40°C for 1 month, and the occurrence of insoluble foreign matter was observed. The results are shown in Table 3. The evaluation criteria in Table 3 are as follows.

-: No insoluble foreign matter

*: Insoluble foreign matter

In addition, for Examples 1 to 8, the formulations were sealed in glass ampoules and stored at 40° C. for 6 months, and the residual rate of diclofenac sodium was measured. The results are shown in Table 4.

table 3 Insoluble foreign matter Example 1 - 2 - 3 - 4 - 5 - 6 - 7 - 8 - 9 - comparative example 1 - 8 * 9 * 10 * 11 * 12 * 13 * 14 * 15 * 16 * 17 * 18 * Table 4 Residual rate of diclofenac sodium (%) Example 1 99.8 2 98.2 3 100.3 4 101.1 5 99.6 6 98.2 7 98.0 8 100.1

From the results in Table 3 and Table 4, it can be seen that the formulation of the present invention is stable even under harsh conditions.

Possibility of industrial use

According to the present invention, it is possible to provide an anti-inflammatory eye drop which contains DFNa, is stable for a long period of time, is not irritating to eyes, and can use DFNa in a wide range of concentrations. Said eye drops can be used to keep mydriasis during eye surgery such as cataract, omentum peeling, vitreous removal, strabismus, and can be used for anti-inflammatory or postoperative treatment, or in the treatment of Behcet's disease, endogenous It is used as an effective eye drop in the treatment of uveitis, conjunctivitis, keratitis, epiduralitis, blepharitis, stye and other external eye inflammatory diseases.

Claims (6)

1. anti-inflammatory eyecrops, wherein contain:

(a) diclofenac sodium 0.05～0.7 weight/volume %,

(b) gamma-cyclodextrin 1～10 weight/volume %,

(c) polyvinylpyrrolidone 1～20 weight/volume %,

(d) benzethonium chloride 0.002～0.01 weight/volume % or benzyl chloride alkanamine 0.002～0.005 weight/volume %, its pH value is 7.0～8.5.

2. drop as claimed in claim 1, wherein the content of diclofenac sodium is 0.1～0.5 weight/volume %.

3. drop as claimed in claim 1 or 2, wherein the content of gamma-cyclodextrin is 3～10 weight/volume %.

4. as each described drop in the claim 1～3, wherein the content of polyvinylpyrrolidone is 2～10 weight/volume %.

5. as each described drop in the claim 1～4, its pH value is 7.5～8.5.

6. as each described drop in the claim 1～5, wherein the K value of the Fei Kenxieer of polyvinylpyrrolidone is 10～95.