JPH026329B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anti-inflammatory eye drop containing diclofenac sodium as an active ingredient. Ocular inflammation is caused by trauma, allergens, or infection, and steroid eye drops are currently the mainstay of treatment. However, there are concerns that steroid eye drops may aggravate infections caused by bacteria, viruses, etc., or cause serious side effects such as steroid glaucoma if used continuously. Its introduction into the ophthalmology field is long-awaited, and various studies are being conducted. Under these circumstances, the present inventors investigated various uses of diclofenac sodium as eye drops, and completed the present invention. Diclofenatuc sodium, whose chemical name is sodium-2-(2,6-dichloroanilino)-phenylacetate, is a non-steroidal anti-inflammatory drug developed by Ciba Geigy in Switzerland. This medicine is indicated for spondylosis, low back pain, neuralgia, anterior segment inflammation, etc. In the field of ophthalmology, this compound is known to be effective against postoperative inflammation such as cataracts and uveitis when administered orally, but the present inventors were the first to establish its use as an eye drop. Generally, it is not desirable to administer drugs systemically as oral agents for local treatment.
Oral administration of diclofenac sodium can sometimes induce gastrointestinal distress and may worsen the condition of patients with peptic ulcer disease. The present invention provides a novel anti-inflammatory eye drop for administering an effective amount of diclofenac sodium locally to the eye. According to the eye drops of the present invention, the active ingredient is quickly transferred into the aqueous humor by administering a negligible amount of the drug compared to conventional oral preparations, inhibits prostaglandin biosynthesis in the ocular tissue, and It has an excellent suppressive effect not only on anterior eye inflammation such as inflammation of the eye, but also on extraocular inflammation and type allergic reactions, and its scope of application as an ophthalmic drug has been greatly expanded.
Furthermore, there is no concern about gastrointestinal disorders that are sometimes seen with oral preparations, and it safely exerts its anti-inflammatory effect. The eye drops of the present invention can be formulated using conventional aqueous formulations. The standard drug formulation will be explained below. The concentration of diclofenac sodium is usually 0.01
The standard value is ~0.1%, and increase or decrease as appropriate depending on the purpose of use. PH is preferably 7-8. As the buffer, phosphates, boric acid, borax, organic acids, etc. can be used as appropriate. An osmotic pressure ratio of about 1 is preferred. Sodium chloride, mannitol, etc. can be used as the isoblastic agent. Suitable solubilizing agents include polyoxyethylene sorbitan monooleate (trade name: Tween 80), polyoxyethylene oxystearic acid triglyceride, polyethylene glycol, α- or β-cyclodextrin, and the like. Polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc. can also be added as a thickener. Benzalkonium chloride, cetylpyridinium chloride, chlorobutanol, tyromesal, etc. can be added as an ophthalmic preservative. Since chlorobutanol has both bactericidal and local anesthetic effects, the addition of chlorobutanol improves the shelf life of the eye drops and significantly alleviates eye irritation. Also, calcium or magnesium salts can be added to alleviate eye irritation. Any salt that can be used for this purpose may be a salt with a physiologically acceptable acid.
For example, calcium salts such as calcium chloride, calcium propionate, calcium acetate, calcium lactate, calcium pantothenate, calcium gluconate, or the corresponding magnesium salts are representative examples. These calcium salts or magnesium salts are added at a ratio of usually 0.3 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of the active ingredient. Specific prescription examples of eye drops are shown below. Prescription example 1 Diclofenac sodium 100mg, borax 573
mg, boric acid 868 mg, sodium chloride 290 mg and β-
Dissolve 1000 mg of cyclodextrin in about 80 ml of distilled water, add and dissolve 150 mg of calcium lactate, dilute with distilled water to make 100 ml, and filter for sterilization to obtain eye drops. Prescription example 2 Diclofenuc sodium 100mg,
NaH ₂ PO ₄ (anhydrous) 200 mg, Na ₂ HPO ₄ (anhydrous) 710
Dissolve 300 mg of sodium chloride and 1000 mg of β-cyclodextrin in about 80 ml of distilled water, add and dissolve 150 mg of calcium pantothenate, dilute with distilled water to make 100 ml, and filter for sterilization to obtain eye drops. . Prescription example 3 Diclofenuc sodium 100mg, borax 450
1,500 mg of boric acid, 500 mg of chlorobutanol, 3,000 mg of polyvinylpyrrolidone K25, and 500 mg of polysorbate 80 (Tween 80) are dissolved in sterile purified water to make a total volume of 100 ml to obtain eye drops. Hereinafter, the penetration into the anterior chamber, prostaglandin biosynthesis inhibiting effect, and ocular inflammation treatment effect of the eye drops of the present invention will be explained using test examples. The materials used in the test are as follows. (1) Animals White domestic rabbits weighing 2.0 to 3.0 kg were used after confirming that there were no abnormalities in their eyes using a slit lamp. (2) Drugs According to Prescription Example 1, reduce the amount of the main drug to 0.1
%, 0.05%, and 0.025% diclofenac sodium ophthalmic solutions (hereinafter abbreviated as "DFNa ophthalmic solutions") were prepared and used. Test Example 1 [Test on the effect of DFNa ophthalmic solution on aqueous humor transfer and inhibition of aqueous humor protein increase by anterior chamber puncture] 0.1% DFNa ophthalmic solution was administered at 50 μm to 6 white rabbits per group.
Instillation, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes
Minutes, 180 minutes, 240 minutes, and 360 minutes later, aqueous humor was collected using a syringe needle and used as primary aqueous humor. Then, 90 minutes after the primary aqueous humor was collected, aqueous humor was collected again, and this was used as secondary aqueous humor. Regarding the primary aqueous humor, the DFNa concentration was measured by liquid chromatography, and this value was taken as the amount of DFNa transferred to the aqueous humor. For secondary aqueous humor, the method of Lowry et al. [J.Biol.
chem. 193 , 265 (1951). ], and the inhibition rate against protein increase due to aqueous humor puncture was calculated using the case where DFNa eye drops were not administered as a control. The test results are shown in Table 1.

[Suppression effect test on aqueous humor protein increase by arachidonic acid (hereinafter abbreviated as "AA") eye drops]

DFNa eye drops with concentrations of 0.1%, 0.05%, and 0.025% were instilled into the eyes of six white rabbits per group, and 30 minutes later, 50μ of a 5% AA solution dissolved in sesame oil was instilled into the eyes.
Aqueous humor was collected 30 minutes after instillation of the AA solution, and the protein concentration in the aqueous humor was measured in the same manner as in Test Example 1. For comparison, eye drops 30 were obtained when only AA solution was instilled without DFNa eye drops and when only sesame oil was instilled.
The protein concentration in the aqueous humor was also measured after 1 minute. The test results are shown in Table 2.

[Suppressive effect test on increased intraocular pressure due to alkali burn]

A white rabbit was fixed in the prone position under urethane anesthesia and cannulated. Connect one end of the cannula to the transducer and add 20μ of 2N sodium hydroxide solution.
Changes in intraocular pressure after instillation were continuously measured for 3 hours.
In the same way, the intraocular pressure was continuously measured for 3 hours when 0.1% DFNa ophthalmic solution was instilled twice, 30 minutes and 60 minutes before the sodium hydroxide solution was instilled, and when the sodium hydroxide solution was not instilled only by cannulation. was measured. The results are shown in Figure 1, and the results are as shown in Figure 1.
DFNa eye drops almost completely inhibited the second-phase increase in intraocular pressure caused by alkali burn. Test Example 4 [Efficacy test against experimental uveitis] 1 group of 5 white rabbits received 5 ml/kg of dog serum.
Inject subcutaneously in the anterior shoulder on days 1, 3, and 5. 8
On the 9th day, 0.05ml of dog serum was injected into the vitreous body.
Hyperemia of the iris on the 10th, 11th and 12th days,
The degree of response for the three items of iris, edema, and intracameral exudate is graded from no response to maximum response as 0, 1,
The degree of inflammation was evaluated using numerical values of 2 and 3, and the value obtained by adding the numerical values of each item (total score). The 0.1%, 0.05%, and 0.025% DFNa eye drops of the present invention were instilled into the eyes at 50μ doses every hour for 6 hours before the intravitreal injection of dog serum, and after the injection, 50μ doses were applied every hour for 5 days. Table 3 shows the results of applying the eye drops every hour 10 times a day.

[Efficacy test on acute inflammation caused by chili pepper tincture]

50μ of chili pepper tincture for 1 group of 5 white rabbits
30 minutes after instillation, apply various concentrations of
30 DFNa eye drops and saline alone as a control
The eye drops were applied 6 times every minute and then 5 times every hour thereafter, and then 3 times a day every day.The degree of inflammation was observed over time and evaluated using the total score according to the criteria in Table 4.

[Table] When 50μ of chili pepper tincture was applied to the eyes of a rabbit, the rabbit showed symptoms of agony accompanied by severe eye closure, and strong inflammation occurred mainly in the outer eye area. This severe inflammation lasted for about 6 hours in the control group, then gradually decreased and was reduced by half after 72 hours, but the DFNa eye drop group clearly showed a superior anti-inflammatory effect. Table 5 shows the results of evaluating the degree of inflammation every 24 hours after applying the chili pepper tincture to the eyes.

[Table] Showed inhibitory effect. Test Example 6 [Suppression effect test on delayed corneal reaction] Ovalbumin (hereinafter abbreviated as "EA") 10
mg/0.2ml and 0.8ml of Freund's Complete Adjuvant (hereinafter referred to as "FCA") or Incomplete Adjuband (hereinafter referred to as "FIA") [both products of Difco],
Make a water/oil emulsion and inject 0.2ml subcutaneously into the footpads of guinea pigs to sensitize them, and 19 days after sensitization, EA20
The mg/ml solution was challenged to produce a 2 mm diameter opacity in the guinea pig cornea. Immediately after the challenge, 0.1% DFNa ophthalmic solution 25μ was instilled into the eyes, then every hour for 7 times, and then once for 3 days.
Apply eye drops 3 times a day, 24 hours, 48 hours after challenge and
The degree of corneal opacity was observed at 72 hours. The degree of corneal opacity was evaluated using a numerical value from 1 to 4 from minimum to maximum, and Table 5 shows the results of comparison with cases in which DFNa eye drops were not instilled.

[Table] As is clear from the above tests, the eye drops of the present invention move into the aqueous humor immediately after instillation, sufficiently inhibit prostaglandin biosynthesis in the ocular tissue, and prevent uveitis, etc. Not just eye inflammation,
It also showed excellent suppressive effects on extraocular inflammation and delayed allergic reactions.

[Brief explanation of drawings]

FIG. 1 shows the results of the test for suppressing the increase in intraocular pressure caused by alkali burn in Test Example 3. The vertical axis shows intraocular pressure (mmHg), and the horizontal axis shows time (minutes). −○− is the value of alkali burn only,
-●- indicates the value of 0.1% DFNa administration, and ○... indicates the value of normal eye.

Claims (1)

[Claims] 1. Anti-inflammatory eye drops containing diclofenac sodium as an active ingredient, which contains polyoxyethylene sorbitan monooleate or cyclodextrin in an amount (weight) 5 to 10 times that of diclofenac sodium.