Anti-inflammatory eyedrops

The present invention relates to an anti-inflammatory eye drop having the active ingredient diclofenac-Na (hereafter DFNa), the other two components of which are γ-cyclodextrin (hereinafter γ-CyD) water-soluble cyclodextrin derivative and polyvinylpyrrolidone (hereinafter PVP). The latter two stabilize the eye drop for long-term storage and reduce eye irritation.

BACKGROUND OF THE INVENTION

DFNa-containing aqueous eye drops - like DNFa is a non-steroidal anti-inflammatory drug - have been used to prevent inflammation during and after surgery because these anti-inflammatory drugs have potent inhibitors of prostaglandin biosynthesis. When non-steroidal anti-inflammatory drugs are used in eye drops, most of them are irritating to the mucous membranes and the eyes and cause severe pain in the eyes.

The present inventors have provided anti-inflammatory eye drops containing at least one non-steroidal anti-inflammatory drug comprising ibuprofen, indomethacin, ketoprofen, naproxen and flufenamic acid, and a calcium or magnesium salt having a physiologically acceptable acid component. The latter serves to reduce the irritant effect of non-steroidal anti-inflammatory drugs [Japanese

Examined Patent Publication (hereinafter "JP KOKOKU")

Hello 1-193621]. In addition, the inventors have prepared an anti-inflammatory eye drops containing the active ingredient DFNa,

<img file="HUT77445A_D0001.tif" />

- 3 and as a solubilizer polyoxyethylene sorbitan monooleate or? -Cyclodextrin in an amount of 5-10 times (w / w) relative to DFNa (JP KOKOKU No. Hei 2-6329). In addition, the inventors have prepared eye drops that combine chemically modified β-cyclodextrin with DFNa and which do not irritate the eye upon instillation, are well-stored and are the subject of a patent application of the Japanese non-test patent ( hereinafter "JP KOKAI) No. Hei 6-16547].

In addition, a drug containing an aqueous solution containing DFNa as an active ingredient, a buffer, a solubility excipient, a preservative and another 2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up to 10 carbon atoms has been reported active ingredient and preservative (JP KOKAI No. Sho 62-242617). On the other hand, an anti-inflammatory ophthalmic solution containing 2- (2-fluoro-4-biphenylyl) -propionic acid or a salt of β-Cyd or γ-CyD and a calcium or magnesium salt (JP KOKAI No. Sho 60-136516) has been proposed as a droplet containing cyclodextrin ); or an aqueous ophthalmic solution containing 3,4-dihydro-2,8-diisopropyl-3-thioxy-2H-1,4-benzoxadine-4-acetic acid or a salt as the base and cyclodextrin (JP KOKAI No . Hello 5-213757).

The calcium or magnesium salt of a physiologically acceptable acid satisfactorily reduces the irritation of the eye drops, but the long-term storage of the resulting eye drops is unsatisfactory. Α-cyclodextrin such as JP KOKOKU No.

Hi 2-6329, does not reduce the eye irritation effect of DFNa, whereas β-cyclodextrin has this effect, but that is not satisfactory. In view of this, the inventors have found that when chemically modified β-CyD is added to a DFNa-containing eye droplet at a rate of 7-50 times the DFNa content, the resulting eye droplet is barely irritating to the eye, and very good shelf life (JP KOKAI No. Hei 616547). But if the DFNa content of the eye drop is greater than 0.1%, this amount is no longer sufficient to reduce the irritant effect. The eye drops described in JP KOKAI No. Sho 62-242617 have good shelf life but are highly irritating to the eye immediately after instillation, so these conventional eye drops are not yet considered satisfactory.

In addition, JP KOKAI Well. Sho. 60-136516 and

In Hei 5-213757, which is an enhancement to the previous JP KOKOKU No. Hei 330571, it is stated that β-CyD and γ-CyD reduce to some extent the eye irritation of the drug, but that effect of γ-CyD is not satisfactory. case.

On the other hand, γ-CyD is well known to provide local or greater local safety than chemically modified water-soluble β-CyD (Vekama, Pharm. Tech. Japan, 1991, 7 (2), p. 143). It is traditionally difficult to produce γ-CyD on an industrial scale and is very expensive. Therefore, γ-CyD was not used at all for reasons of economy. Although a new technology has recently been developed to accomplish this, it has been marketed cheaply and has recently attracted special interest as a drug additive.

- 5 ····· &lt;* ·· · · ·· ··· · · · * ··*·· · · · · • · « ··· · ····

Megold an embodiment of the invention

Under these conditions, the inventors have attempted to develop a basic DFNa-containing eye drop that does not irritate the eye immediately after instillation, and can be stored in a stable state for long periods of time due to the use of γ-CyD over a wide concentration range of DFNa. Experiments have shown that this goal can be achieved by combining DFNa, γ-CyD, PVP and benzethonium chloride or benzalkonium chloride. The latter two are preservatives. A further condition is that the pH should be in the range of 7.0-8.5. This is the subject of this patent. In other words, the present invention relates to anti-inflammatory eye drops comprising DFNa, γ-CyD, PVP and benzethonium chloride or benzalkonium chloride and having a pH between 7.0 and 8.5.

The stimulatory effect of DFNa on the human eye is generally at a concentration of at least 0.05%. The inventors have surprisingly found that the stimulating effect of DFNa on the human eye can be significantly improved if higher concentrations of DFNa can be used. As a result, a therapeutic effect can be induced in a number of disease conditions using γ-CyD and simultaneously DFNa, maintaining the pH between 7.0 and 8.5. The eye drops thus prepared have good storage stability and can be stored for a long time due to the preservative action of PVP and benzethonium chloride or benzalkonium chloride. This object of the present invention has been accomplished by the present inventors.

The concentration of DFNa in conventional eye drops was below 0.1% due to its strong irritant effect. According to the invention

- 6 · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · can be used in higher concentrations, usually up to 0.7% in the eye drops. This effect is due to the use of 1-10% γ-CyD in the pH range of 7.0 to 8.5. Therefore, the resulting eye drop can be widely used.

High concentrations of DFNa are also likely to exert an intraocular prostaglandin inhibitor effect and have an atropine-induced mydriatic effect. Therefore, not only does it play a major role in maintaining mydriasis and in preventing inflammation during surgery (e.g. cataracts, glaucoma, retinal damage, vitreous removals and strabismus) and not only has a therapeutic effect after surgery, but is also useful in treating a number of eye diseases, i.e. it affects all symptoms in which prostaglandin plays a role. Behcet's disease, endogenous uveitis, inflammation of the outside of the lens (e.g. conjunctivitis, keratitis, episcleritis, pinguecula and hordeolum).

BEST MODE FOR CARRYING OUT THE INVENTION:

The use of γ-CyD in the present invention is capable of reducing the irritant effect of DFNa over a wide concentration range from low to high concentrations. The efficacy at such a high concentration range is only characteristic of γ-CyD because other water-soluble cyclodextrins do not have such a good effect.

According to the invention, PVP prevents the formation of water-insoluble materials from γ-CyD. According to AJP KOKAI No. Hei 5-213757, many substances have such effects. Such materials include certain water-soluble polymers such as polyvinyl alcohol, hydroxyethylcellulose, methylcellulose, hydroxypropylmethyl, and the like. cellulose, sodium alginate, sodium carboxymethyl cellulose, and polyethylene glycol. The inventors have carried out additional studies in this regard and found that other water-soluble polymers other than PVP are not suitable for this effect, which is specific to PVP.

The PVP used in the present invention preferably has a Fikentscher's K value of 10-95. Such PVP is commercially available from BASF Japan Co., Ltd under the trade names Kollidone ™ 12PF, Kollidone ™ 17PF, Kollidone ™ 25, Kollidone ™ 30 and Kollidone ™ 90; and Tokyo Chemical Industry Co., Ltd, trade names:

PVP K15, PVP K30, PVP K60 and PVP K90 are all easy to obtain.

The preservatives of the invention are benzethonium chloride or benzalkonium chloride. These are used for long-term storage of eye drops to ensure storage stability. Specifically, the inventors' experiments show that benzethonium chloride or benzalkonium chloride, as shown in Table 3, has a very high property of inhibiting the formation of foreign substances. In this respect, they are many times superior to other preservatives.

The eye drops of the present invention are prepared by dissolving DNFa and γ-CyD in purified water, then adding PVP and benzethonium chloride or benzalkonium chloride to the resulting solution, and then pH 7.0-8.5. with buffer and pH adjuster.

The final concentration of DNFa in the composition is 0.05-0.7% w / v (hereinafter "%"), most preferably 0.1-0.5%. If the concentration of DNFa is less than 0.05%, eye drops are impractical because the anti-inflammatory effect is not sufficient, whereas if the concentration is greater than 0.7%, it is difficult to produce the eye drops.

The final concentration of γ-CyD in the composition according to the invention is 1-10%, particularly preferably 3-10%. If the concentration of DNFa falls within the above limits, less than 1% of γ-CyD will not achieve the desired target, ie it will not sufficiently reduce the irritant effect. If the concentration is above 10%, it would be uneconomic and would not be used in pharmaceutical formulations at such concentration.

The concentration of PVP in the final composition of the invention is 1-20%, particularly preferably 2-10%. If the concentration of PVP is less than 1%, insoluble materials are formed and the resulting formulation has insufficient storage stability. However, if the PVP concentration is greater than 20%, the resulting formulation may cause discomfort to the eye when instilled.

The pH of the eye drop according to the invention is from 7.0 to 8.5, particularly preferably from 7.5 to 8.5. If the pH is less than 6.5, there is no reduction in irritation even if the γ-CyD concentration is within the desired 5-10% range. But if the pH is set to above 8.5, this is not advantageous because it is outside the physiological pH range. The pH may be controlled by a buffering agent, such as a borate buffer or a phosphate buffer, or may be a pH adjuster such as an aqueous solution of sodium hydroxide or a dilute solution.

Hydrochloric acid 9, when used in the usual manner, but not limited to the above modes according to the invention.

The benzethonium chloride or benzalkonium chloride used in the present invention is bactericidal and can protect the eye droplet from any contamination during use.

Preferably the concentration is 0.002-0.01% benzethonium chloride.

If the concentration of benzethonium chloride is less than 0.002%, the bactericidal effect in the eye drops will not be satisfactory, while if the concentration in the eye drops is above 1.01%, the eye drops may cause corneal epithelial damage when used frequently. The concentration of benzalkonium chloride is preferably 0.002-0.005%. If the concentration of benzalkonium chloride in the eye drops is less than 0.002%, the bactericidal effect will be unsatisfactory, whereas if the concentration is greater than 0.005%, the eye drops will be cloudy and thus the eye drops of the invention cannot be prepared.

The eye drops of the present invention may also contain other components which are commonly used in eye drops in addition to the prior art components as long as the subject matter of the invention is realized. Such additional additives include, for example, buffers, isotonizing agents, surfactants and chelating agents. Examples of the buffers are phosphoric acid salts, boric acid salts and organic bases. Examples of isotonizing agents include common salt, potassium chloride, boric acid and sodium borate. Examples of surfactants are polysorbate 80 and polyoxyethylene hydrogenated castor oil 60.

Examples of chelating agents are sodium edetate and sodium citrate.

The following examples are intended to illustrate the invention but are not intended to limit its scope.

First example

Diclofenac Sodium 0.1 g γ-CyD (available from Wacker Chemicals

East Asia Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP K30 (Kollidon ™ 30: available from BASF

Japan Co., Ltd.) 2.0 g benzethonium chloride 0.005 g

0.1 N HCl / 0.1 N NaOH, made up to 100 ml with purified water to reach pH 8.0.

diclofenac sodium is added to ml of purified water,

-CyD, boric acid, sodium borate, PVP K30^_the'^tL and ^the benzethonium chloride. All this is dissolved in water. The resulting solution was adjusted to pH 8.0 with 0.1 N hydrochloric acid or 0.1 N sodium hydroxide, then made up to 100 ml with purified water and sterilized by filtration. This is how we make the eye drops.

Second example

Diclofenac Sodium 0.05 g γ-CyD (available from Wacker Chemicals

East Asia Co., Ltd.) 10.0 g of boric acid

1.60g • · · · ·

-11nátrium borate

PVP K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) benzethonium chloride

0, 1N HCl / 0, 1N NaOH in purified water to pH 7.0

100 ml from

0.16 g

10.0 g

0.005 g Required amount Required quantity.

The procedure of Example 1, except that the above is used instead of the materials of Example 1 for the preparation of eye drops.

Third example

Diclofenac Sodium 0.05 g of γ-CyD (Wacker Chemicals East

Asia Co., Ltd.) 1.0 g boric acid 1.10 g sodium borate 2.10 g

PVP _K90 (Kollidon ™ 90: BASF Japan Co., Ltd.) 1.0 g benzethonium chloride 0.005 g

0.1N HCl / 0.1N NaOH pH 8.5 Purified water to 100 mL.

The procedure of Example 1, except that

First Instead of using the materials of Example 1, the above is used to prepare the eye drops.

• · · · • · ·

-124. example

Diclofenac sodium 0.1 g

V-CyD (Wacker Chemicals East Asia Co., Ltd.) boric acid sodium borate

PVP K25 (Kollidon ™ 25: BASF Japan Co., Ltd.) benzalkonium chloride

0, 1N HCl / 0, 1N NaOH purified water

The procedure of Example 1, except that

First The materials used in the example above are used instead.

3.0 g

1.10g

2.10g

5.0 g

0.005 g

PH 8.5 to 100 ml.

5th example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 3.0 g of benzalkonium chloride 0.002 g

0.1 N HCl / 0.1 N NaOH pH 8 Purified water to 100 mL.

Example 1 except that the above materials are used in place of Example 1.

<td> -13-</td><td> ·· · · · ·· · • · · · · · * • «···· · · _Λ _ ...........</td>

<td>Example 6</td><td></td>

<td>Diclofenac sodium</td><td>0.5 g</td>

γ-CyD (Wacker Chemicals East Asia

<td>Co., Ltd.)</td><td>10.0 g</td>

<td>boric acid</td><td>1.10 g</td>

<td>Sodium borate</td><td>2.10 g</td>

<td>PVP K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>10.0 g</td>

<td>benzethonium chloride</td><td>0.005 g</td>

O, 1N HCl / O, 1N NaOH pH 8.5 Purified water to 100 ml.

Example 1 except that the above materials are used in place of Example 1.

7th example

<td>Diclofenac sodium</td><td>0.7 g</td>

<td>γ-CyD (Wacker Chemicals East Asia</td><td></td>

<td>Co., Ltd.)</td><td>10.0 g</td>

<td>boric acid</td><td>1.10 g</td>

<td>Sodium borate</td><td>2.10 g</td>

<td>PVP K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>10.0 g</td>

<td>benzethonium chloride</td><td>0.01 g</td>

<td>0, IN HCl / 0, IN NaOH</td><td>pH to 8.5</td>

cleaned water

100 mL.

• · · · ·

<td> • -14-</td><td> ·· · · · · · · • · · · · · · • · ···· · · . ♦ ·* · ··· · ····</td>

Example 1 except that the above materials are used in place of Example 1.

8th example

<td>Diclofenac sodium</td><td>0.1 g</td>

<td>γ-CyD (Wacker Chemicals East Asia</td><td></td>

<td>Co., Ltd.)</td><td>3.0 g</td>

<td>boric acid</td><td>1.45 g</td>

<td>Sodium borate</td><td>0.35 g</td>

<td>PVP K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>10.0 g</td>

<td>benzethonium chloride</td><td>0.002 g</td>

<td>0, IN HCl / 0, IN NaOH</td><td>pH to 7.5</td>

<td>cleaned water</td><td>To 100 ml.</td>

Example 1 except that the above materials are used in place of Example 1.

9th example

<td>Diclofenac sodium</td><td>0.05 g</td>

<td>γ-CyD (Wacker Chemicals East Asia</td><td></td>

<td>Co., Ltd.)</td><td>10.0 g</td>

<td>boric acid</td><td>1.10 g</td>

<td>Sodium borate</td><td>2, 10 g</td>

<td>PVP K12 (Kollidon ™ 12: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>20.0 g</td>

<td>benzethonium chloride</td><td>0.002 g</td>

0, 1N HCl / 0, 1N NaOH to pH 8.5

-15 purified water up to 100 ml.

Example 1 except that the above materials are used in place of Example 1.

10th example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _K90 (Kollidon ™ 90: BASF

Japan Co., Ltd.) 1.0 g benzethonium chloride 0.005 g

0, 1N HCl / 0, 1N NaOH purified water

The above materials according to Example 1 are used up to pH 8.0

100 mL.

procedure except that Example 1 was used.

11th example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 3.0 g benzethonium chloride 0.005 g

-16Ο, ΙΝ HCl / O, 1N NaOH pH 8.0 Purified water to 100 ml.

Example 1 except that the above materials are used in place of Example 1.

Example 12

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 5.0 g benzethonium chloride 0.005 g

0.1N HCl / 0.1N NaOH pH 8.0 to 100 mL of purified water.

Example 1 except that the above materials are used in place of Example 1.

13th example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 7.0 g

-17benzethonium chloride 0.005 g

Ο, ΙΝ HCl / Ο, ΙΝ NaOH pH 8.0 Purified water to 100 ml.

Example 1 except that the above materials are used in place of Example 1.

14.

example

Diclofenac Sodium γ-CyD (Wacker Chemicals East Asia

0.1 g

Co., Ltd.) boric acid sodium borate

PVP K25 (Kollidon ™ 25:

Japan Co., Ltd.) benzethonium chloride

0.1N HCl / 0.1N NaOH purified water

The materials of Example 1 above are used

3.0 g

1.30 g

0.88 g

BASF

10.0 g

0.005 g to pH 8.0

100 mL.

procedure except that Example 1 was used.

15th example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP K17 (Kollidon ™ 17PF: BASF

-18 * ·· »·« V «

Japan Co., Ltd.) benzethonium chloride

0, 1N HCl / 0, 1N NaOH purified water

12.0 g

0.005 g to pH 8.0

100 mL.

Example 1 except that the above materials are used in place of Example 1.

16th example

Diclofenac Sodium γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) boric acid sodium borate

PVP _Ki5 (Tokyo Chemical Industry

Co., Ltd.) benzethonium chloride

0, 1N HCl / 0, 1N NaOH purified water

Example 1 except that the above materials are used in place of Example 1.

0.1 g

3.0 g

1.30 g

0.88 g

15.0 g

0.005 g to pH 8.0

100 mL.

17th example

Diclofenac Sodium γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) boric acid sodium borate

0.1 g

3.0 g

1.30 g

0.88 g

<td> -19-</td><td>* ·· ;: .í “· * • · · · · «« » • * · 4 · * • · «« · «- · - »* ·« »4 4 4» · 4</td>

<td>PVP _K12 (Kollidon ™ 12PF: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>20.0 g</td>

<td>benzethonium chloride</td><td>0.005 g</td>

<td>0, IN HCl / 0, IN NaOH</td><td>pH to 8.0</td>

<td>cleaned water</td><td>To 100 ml.</td>

Example 1 except that the above materials are used in place of Example 1.

First Comparative example

<td>Diclofenac sodium</td><td>0.05 g</td>

<td>boric acid</td><td>1.30 g</td>

<td>Sodium borate</td><td>0.88 g</td>

<td>0, IN HCl / 0, IN NaOH</td><td>pH to 8.0</td>

<td>cleaned water</td><td>To 100 ml.</td>

Example 1 except that the above materials are used in place of Example 1.

Second Comparative example

<td>Diclofenac sodium</td><td>0.1 g</td>

<td>γ-CyD (Wacker Chemicals East Asia</td><td></td>

<td>Co., Ltd.)</td><td>0.7 g</td>

<td>boric acid</td><td>1.45 g</td>

<td>Sodium borate</td><td>0.35 g</td>

<td>PVP K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>3.0 g</td>

<td>benzethonium chloride</td><td>0.005 g</td>

0, 1N HCl / 0, 1N NaOH pH 8.0

<img file="HUT77445A_D0002.tif" />

-20 purified water up to 100 ml.

Example 1 except that the above materials are used in place of Example 1.

Third Comparative example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 10.0 g Boric acid 1.70 g Sodium borate 0.07 g

PVP k25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 10.0 g benzethonium chloride 0.005 g

0.1 N HCl / 0.1 N NaOH pH 6.5 Purified water to 100 mL.

Example 1 except that the above materials are used in place of Example 1.

4th Comparative example

Diclofenac Sodium α-CyD (CELDEX ™: Nihon

Kako Co., Ltd.) boric acid sodium borate

0, IN HCl / 0, IN NaOH

0.1 g

Shokulin

5.0 g

1.30 g

0.88 g purified water to pH 9.0

100 mL.

-21The procedure of Example 1, except that the above materials are used instead of Example 1

5th Comparative example

Diclofenac Sodium β-CyD (RINGDEX ™ BR:

Ltd.) boric acid sodium borate

0, IN HCl / 0, IN NaOH

0.1 g

Mercian Co.,

1.0 g

1.30 g

0.88 g of water purified to pH 8.0 to 100 ml.

The procedure of Example 1, except that the above materials are used instead of Example 1

6th Comparative example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) boric acid sodium borate

PVP _K25 (Kollidon ™ 25:

Japan Co., Ltd.) benzethonium chloride

0, 1N HCl / 0, 1N NaOH purified water

The materials of Example 1 above are used

3.0 g

1.30 g

0.88 g

BASF

23.0 g

0.005 g to pH 8.0

100 mL.

method, except that Example 1 was used

-22• · · ·· ·

7th Comparative example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP _Ki2 (Kollidon ™ 12PF: BASF

Japan Co., Ltd.) 25.0 g benzethonium chloride 0.005 g

0.1N HCl / 0.1N NaOH pH 8.0 to 100 mL of purified water.

Example 1 except that the above materials are used in place of Example 1.

8th Comparative Example γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) boric acid sodium borate

0.1N HCl / 0.1N NaOH purified water

Example 1 except that the above materials are used in place of Example 1.

9th Comparative example

Diclofenac sodium

3.0 g

1.30 g

0.88 g to pH 8.0

100 mL.

0.1g • «

<img file="HUT77445A_D0003.tif" />

γ-CyD (Wacker Chemicals East Asia

<td>Co., Ltd.)</td><td>3.0 g</td>

<td>boric acid</td><td>1.30 g</td>

<td>Sodium borate</td><td>0.88 g</td>

<td>benzethonium chloride</td><td>0.005 g</td>

<td>0.1N HCl / 0.1N NaOH</td><td>pH to 8.0</td>

<td>cleaned water</td><td>To 100 ml.</td>

Example 1 except that the above materials are used in place of Example 1.

10th Comparative example

Diclofenac Sodium 0.05 g α-CyD (CELDEX ™: Nihon Shokuhin

Kako Co., Ltd.) 1.0 g boric acid 1.60 g sodium borate 0.16 g

PVP K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 2.0 g

0.1N HCl / 0.1N NaOH pH 7.0 Purified water to 100 mL.

Example 1 except that the above materials are used in place of Example 1.

11th Comparative example

Diclofenac Sodium 0.05 g β-CyD (RINGDEX ™ BR: Mercian

Co., Ltd.)

0.9 g

-241, 60 g

0.16 g

2.0 g to pH 7.0

100 mL.

boric acid sodium borate

PVP _K25 (Kollidon ™ 25: BASF Japan Co., Ltd.)

0, 1N HCl / 0, 1N NaOH purified water

The procedure of Example 1, except that the above materials are used instead of those of Example 1.

that

12th Comparative example

Diclofenac Sodium 0.05 g α-CyD (CELDEX ™: Nihon Shokuhin

Kako Co., Ltd.) boric acid sodium borate

PVP _K25 (Kollidon ™ 25:

Japan Co., Ltd.)

0, 1N HCl / 0, 1N NaOH purified water

The materials of Example 1 above are used

1.0 g

1.60 g

0.16 g

BASF

2.0 g to pH 7.0

100 mL.

method, except that Example 1 was used

13th Comparative example

Diclofenac Sodium 0.05 g β-CyD (RINGDEX ™ BR: Mercian

Co., Ltd.) 0.9 g of boric acid

1.60g • ·

Sodium borate 0.16 g

PVP _K25 (Kollidon ™ 25: BASF Japan Co., Ltd.) sodium acetate

O, 1N HCl / O, 1N NaOH purified water

The procedure of Example 1, except that the above materials are used instead of those of Example 1

2.0 g

0.1 g to pH 7.0

100 mL.

that

14th Comparative example

Diclofenac Sodium γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) boric acid sodium borate hydroxyethyl cellulose (FUJICHEMI HEC ™ CF-G: Fuji Chemical Co., Ltd.) benzethonium chloride

0.1N HCl / 0.1N NaOH purified water

The procedure of Example 1, except that the above materials are used instead of those of Example 1

0.1 g

3.0 g

1.45 g

0.35 g

0.5 g to 0.005 g pH 7.5

100 mL.

that

15th Comparative example

Diclofenac sodium

0.1 g γ-CyD (Wacker Chemicals East Asia ···

-26Co., Ltd.) boric acid sodium borate

METOLOSE ™ SM400 (Shin-Etsu Chemichal Co., Ltd.) benzethonium chloride

O, 1N HCl / O, 1N NaOH purified water

In the same manner as in Example 1, the above materials are used in Example 1.

3.0 g

1/45 yrs

0.35 g

0.5 g to 0.005 g pH 7.5

100 mL.

also with the difference that they are exemplary.

16th Comparative example

Diclofenac Sodium 0.1 g γ-CyD (Wacker Chemicals East Asia

Co., Ltd.) 3.0 g boric acid 1.30 g sodium borate 0.88 g

PVP K25 (Kollidon ™ 25: BASF

Japan Co., Ltd.) 3.0 g of cetylpyridinium chloride 0.005 g

0.1N HCl / 0.1N NaOH purified water

The above materials according to Example 1 are used up to pH 8.0

100 mL.

method, except that Example 1 was used

17th Comparative example

Diclofenac sodium

0.1 g

-27γ-CyD {Wacker Chemicals East Asia

<td>Co., Ltd.)</td><td>3.0 g</td>

<td>boric acid</td><td>1.30 g</td>

<td>Sodium borate</td><td>0.88 g</td>

<td>PVP _K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>3.0 g</td>

<td>klórhixidin gluconate</td><td>0.005 g</td>

<td>O, 1N HCl / O, 1N NaOH</td><td>pH to 8.0</td>

<td>cleaned water</td><td>To 100 ml.</td>

The procedure of Example 1, except that

<td>the above materials are used in Example 1</td><td>instead.</td>

<td>18. Comparative Example</td><td></td>

<td>Diclofenac sodium</td><td>0.1 g</td>

<td>γ-CyD (Wacker Chemicals East Asia</td><td></td>

<td>Co., Ltd.)</td><td>3.0 g</td>

<td>boric acid</td><td>1.30 g</td>

<td>Sodium borate</td><td>0.88 g</td>

<td>PVP K25 (Kollidon ™ 25: BASF</td><td></td>

<td>Japan Co., Ltd.)</td><td>3.0 g</td>

<td>metilparabénklorid</td><td>0.026 g</td>

<td>propyl paraben</td><td>0.014 g</td>

<td>0, IN HCl / 0, IN NaOH</td><td>pH to 8.0</td>

<td>cleaned water</td><td>To 100 ml.</td>

Methyl paraben and propyl paraben were added to ml of purified water preheated to 60 ° C and stirred until dissolved.

Cool to room temperature, add γ-CyD, boric acid, a

-28 Sodium borate, diclofenac sodium and PVP 25, and then dissolved. The resulting solution was adjusted to pH 8.0 with 0.1 N HCl or 0.1 N NaOH, and the mixture was made up to 100 mL with purified water and filtered to sterile. this is how we prepare the eye drops.

The following test example examines whether eye drops are less eye irritating than conventionally prepared diclofenac sodium formulations.

First Test Example [Eye Drop Sensation (Eye Irritation)]

Physiological saline; and Examples 1-5. Preparations of Comparative Examples were instilled (1 drop of each) into the eyes of 10 people and tested for the sensation of eye drops (eye irritation) directly from instillation for 3 minutes. The result of this is shown in Table 1.

In Table 1, the evoked sensation is represented by the following scale:

: no eye irritation: slight hot feeling: hot feeling: pain or severe hot feeling

<img file="HUT77445A_D0004.tif" />

-291. Spreadsheet

Sensation caused by eye drops (eye irritation) (Full evaluation)

<td></td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td colspan="3"> 10</td>

<td>physiological saline</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 1</td><td> 0,1</td>

<td>Examples 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 2</td><td> 0,2</td>

<td> 2</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 2</td><td> 0</td><td> 5</td><td> 0,5</td>

<td> 3</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 1</td><td> 0</td><td> 3</td><td> 0, 3</td>

<td> 4</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 1</td><td> 0,1</td>

<td> 5</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 3</td><td> 0,3</td>

<td> 6</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 4</td><td> 0,4</td>

<td> 7</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 2</td><td> 0</td><td> 5</td><td> 0,5</td>

<td> 8</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 4</td><td> 0,4</td>

<td> 9</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 2</td><td> 0,2</td>

<td colspan="13">Comparative</td>

<td>Examples 1</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 30</td><td> 3,0</td>

<td> 2</td><td> 2</td><td> 1</td><td> 2</td><td> 3</td><td> 2</td><td> 2</td><td> 2</td><td> 3</td><td> 3</td><td> 2</td><td> 22</td><td> 2,2</td>

<td> 3</td><td> 3</td><td> 2</td><td> 3</td><td> 3</td><td> 2</td><td> 2</td><td> 3</td><td> 3</td><td> 3</td><td> 2</td><td> 26</td><td> 2,6</td>

<td> 4</td><td> 3</td><td> 2</td><td> 3</td><td> 3</td><td> 3</td><td> 2</td><td> 3</td><td> 3</td><td> 3</td><td> 2</td><td> 27</td><td> 2,7</td>

<td> 5</td><td> 3</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 3</td><td> 3</td><td> 2</td><td> 23</td><td> 2,3</td>

The results of Table 1 clearly show that the formulations of the present invention exhibit a significantly less potent irritant effect of diclofenac sodium and that the effect of the eye drops is practically equivalent to that of physiological saline.

In addition, the test example also shows that the concentration of PVP in the composition of the invention is 1-20% advantageous.

Second Test Example [Eye Drop Feeling Human (Sticky Feeling)]

Physiological saline and 10-17. Examples 6 to 7; The formulations of Comparative Examples were instilled (1 drop per each) into the eyes of 10 people and tested for the droplet-induced sensation (sticky feeling) directly from instillation for 3 minutes. The result is summarized in Table 2.

The evaluation was done according to the following scale:

: sticky, no discomfort: slightly sticky, but not unpleasant: sticky, and quite unpleasant: sticky, unpleasant

-312. Spreadsheet

Feeling triggered (stickiness (Full evaluation)

123456789 10

physiological

<td>saline</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 0</td><td> 2</td><td> 0,2</td>

<td>Examples 10</td><td> 1</td><td> 1</td><td> 1</td><td> 0</td><td> 1</td><td> 1</td><td> 2</td><td> 0</td><td> 1</td><td> 1</td><td> 9</td><td> 0,9</td>

<td> 11</td><td> 1</td><td> 1</td><td> 1</td><td> 0</td><td> 1</td><td> 0</td><td> 2</td><td> 0</td><td> 1</td><td> 1</td><td> 8</td><td> 0,8</td>

<td> 12</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 11</td><td> 1,1</td>

<td> 13</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 12</td><td> 1,2</td>

<td> 14</td><td> 2</td><td> 2</td><td> 1</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 14</td><td> 1,4</td>

<td> 15</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 13</td><td> 1,3</td>

<td> 16</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 14</td><td> 1,4</td>

<td> 17</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 14</td><td> 1,4</td>

Comparative

<td>Examples 6</td><td> 3</td><td> 3</td><td> 3</td><td> 2</td><td> 2</td><td> 2</td><td> 3</td><td> 1</td><td> 3</td><td> 2</td><td> 24</td><td> 2,4</td>

<td> 7</td><td> 3</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 1</td><td> 2</td><td> 2</td><td> 20</td><td> 2,0</td>

The data in Table 2 clearly show that the compositions of the present invention do not produce a sticky feeling when the concentration of PVP is 1-20%.

··

Test Example 3 shows that the compositions of the present invention are stable even under difficult conditions and do not precipitate.

• · ···

Third Test Example (Storage Stability)

1-9. Examples 1 and 8 to 18; The formulations of Comparative Examples were stored in glass ampoules at 40 ° C for one month to see if they were precipitated. The results are shown in Table 3. In Table 3, the evaluation was done according to the following scale:

-: no separation *: there is a separation.

In addition, the formulations of Examples 1-8 were stored in glass ampoules at 40 ° C for 6 months and the remaining drug was evaluated. The results are shown in Table 4.

-333. spreadsheet

Number of examples

secession

<img file="HUT77445A_D0005.tif" />

9

Number of comparative examples:

11 12

-344. spreadsheet

<td>Examples</td><td>The remaining diclofenac-</td>

<td>number</td><td>sodium (%)</td>

<td> 1</td><td> 99,8</td>

<td> 2</td><td> 98,2</td>

<td> 3</td><td> 100, 3</td>

<td> 4</td><td> 101,1</td>

<td> 5</td><td> 99, 6</td>

<td> 6</td><td> 98,2</td>

<td> 7</td><td> 98,0</td>

<td> 8</td><td> 100,1</td>

The results of Tables 3 and 4 clearly show that the compositions of the invention are stable even under difficult conditions.

Industrial applicability

The present invention provides a DFNa-containing anti-inflammatory eye drop which is stable for a long period of time, is non-irritating to the eye and is capable of containing DFNa over a wide concentration range. This eye drop is not only effective against mydriasis and is not only used as an anti-inflammatory during surgery, but also for example cataracts, glaucoma, retinal damage, · · n «• · ·

-35 glaucoma removal in strabismus or in postoperative therapy, but also in Behcet's disease in endogenous uveitis or in inflammation of the outer eye areas such as conjunctivitis, keratitis, epischleritis, pinguencula and hordeolum.