JPS58174310A - Antiphlogistic eye drop - Google Patents

Abstract

PURPOSE:To provide an eye drop capable of inhibiting the biosynthesis of prostaglandin in the ophthalmic tissue by a small amount of application compared with oral administration, and exhibiting excellent effect to suppress the inflammation of anterior and exterior ophthalmus, by using diclofenac sodium as an active component. CONSTITUTION:The objective antiphlogistic eye drop contains diclofenac sodium [sodium 2-(2.6-dichloroanillno)-phenylacetate] as an active component at a concentration of 0.01-0.1%. Diclofenac sodium is hitherto been used as an oral drug, however, the use of the drug as an eye drop enables the rapid transfer of the active component into the humor at a small amount of application without causing the gastroenteric disorder, etc., and affords excellent suppressive effect not only to the anterior ophthalmus inflammation such as uvetitis but also to the exterior ophthalmus inflammation and IV-type allergic reaction. The pH of the solution is preferably 7-8, and the agent may contain an agent for mitigating the eye irritation (e.g. CaCl2) as well as a buffer solution, an isotonic agent, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-inflammatory eye drop characterized by 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 viruses, etc., or induce serious side effects such as the development of steroid glaucoma if used continuously, so we are developing steroids with fewer side effects and non-steroidal anti-inflammatory drugs. Its introduction into the field of ophthalmology has been long-awaited, and various studies are being carried out.

Under these circumstances, the present inventors investigated various uses of diclofenac sodium as eye drops and completed the present invention.

Diclofenac sodium has the chemical name Sodium-2-(
2,6-dichloroanilino)-phenylacetate is a non-steroidal anti-inflammatory drug developed by Ciba Geigy in Switzerland, and is used as an oral agent for rheumatoid arthritis,
This medicine is indicated for degenerative spondylosis, II pain, neuralgia, anterior segment inflammation, etc.

Although this compound is known to be effective for treating post-operative inflammation such as cataracts and uveitis when administered orally in the medical field, the present inventors were the first to establish its use as an eye drop.

Generally speaking, it is not desirable to administer drugs systemically as oral agents for local treatment. Oral administration of diclofenac sodium sometimes induces gastrointestinal disturbances;
In patients with peptic ulcer disease, the condition may worsen.

The present invention provides a novel anti-inflammatory eye drop for administering diclofenac sodium in a locally effective amount.

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 segment inflammation such as inflammation of the eye, but also on external segment inflammation and type allergic reactions, and its overuse as a medical and medical drug has been greatly expanded. There is no concern about gastrointestinal disorders, which are sometimes seen with oral preparations, and it safely exerts anti-inflammatory effects.

The eye drops of the present invention can be formulated using conventional aqueous formulations. Hereinafter, the II semi-preparation formulation will be explained.

'l The concentration of diclofenac sodium is usually 0.01 to 0.
．． The standard is 1%, and it is increased or decreased as appropriate from the intended use rL.

The pH is preferably 7-8. For slow koji carving, phosphate,
Boric acid, borax, organic acids, etc. can be used as appropriate.

An osmotic pressure ratio of about 1 is preferred. As the tonicity agent, sodium chloride, mannitol, etc. can be used.

Suitable solubilizing agents include polyoxyethylene sorbitan monooleate (trade name: Tween 80), polyoxyethylene oxystearic acid triglyceride, polyethylene glycol, α- or β-cyclodextrin, and the like.

As a thickener, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc. can also be added.

As an ophthalmic preservative, benzalkonium chloride, cetylpyridinium chloride, cloprunol, telomer, etc. can be added.

Preferably, calcium or magnesium salts are added to alleviate the limiting irritation. Salts that can be used for this purpose may be any salts with physiologically acceptable acids.9 For example, calcium chloride, calcium propionate, calcium acetate, calcium lactate, calcium pantothenate, calcium gluconate. Typical examples include calcium salts such as or corresponding magnesium salts.

These calcium salts or magnesium salts are usually 0.3 to 2 mol, preferably 1 to 1.5 mol per mol of the active ingredient.
Add in molar proportions.

Hereinafter, prescription examples of eye drops will be shown based on J4.

Prescription example 1゜diclofenac sodium 10011F, borax 57
3Iv, boric acid 868#, sodium chloride 29011P
and β-cyclodextrin 10001119 were dissolved in about 80 swj of distilled water, and calcium lactate 150 swj was dissolved in this.
Add IIg and dissolve.2. diluted with distilled water to 100
sf and sterilized through filtration to obtain eye drops.

Prescription example 2゜diclofenac sodium 100#, NaH
2PO4 (anhydrous) 200 "l', Na, HK4
(Anhydrous) 710111P, Sodium Chloride 3009
and β-cyclodextrin 1000M9 in distilled water
150 Da of calcium pantothenate is added thereto, dissolved, diluted with X-distilled water, sealed with 100 Da, and sterilized and filtered to obtain eye drops.

The following is a description of the transport of the eye drops of the present invention into the anterior chamber, prostaglandin biosynthesis inhibiting effect, and ocular inflammation treatment effect using test examples.

The materials used in the test are as follows.

(1) Animal weight2. A white rabbit of θ~3.1Ce was used after confirming that there were no abnormalities in the eyes using a slit lamp.

(2) Follow drug prescription example 1, reduce the amount of crude drugs as appropriate, and use 01-, o.
, o5s, and 0025- diclofenac sodium ophthalmic solutions (hereinafter abbreviated as rDFNaAll solution) were prepared and used.

Test Example 1 50ILt of 0.1% DFNa All solution was instilled into the eyes of 6 white rabbits in 1 group for 15 minutes, 30 minutes, 45 minutes, 60 minutes, and 90 minutes.

Aqueous humor was collected using a syringe needle after 120 minutes, 180 minutes, 240 minutes, and 360 minutes, and this was used as primary aqueous humor. Then, 90 minutes after the primary aqueous humor was collected, the aqueous humor was collected again, and this was used as the secondary aqueous humor. For the primary aqueous humor, the DFNa concentration was measured using liquid chromatography, and this value was calculated as DFN! I
The amount of aqueous humor transferred was

For secondary aqueous humor, the method of Lowry et al. (J, Bi
ol.

chem. The test results are shown in Table 131.

Table 1 (Concentrations in the table are shown as the average value of 6 birds per group.) As is clear from the results in Table 1, the eye drops of the present invention had a negative effect on the eyes after 2 drops.
It quickly moves into the aqueous humor.

11:・The maximum concentration was reached after about 90 minutes. The inhibitory effect on protein increase by anterior chamber puncture showed the highest inhibition rate when the primary puncture was performed 45 minutes after instillation.

Test Example 2: Concentrations of 0.11%, 0.05%, and 6 white rabbits in 1 group.
and 0.025- DFNa eye drops were instilled into the eyes, and the 30
After 5 minutes, 51AA solution 5oPt dissolved in sesame oil was instilled into the eyes.

AA fluid point [Aqueous humor was collected after 30 minutes, and the protein concentration in the aqueous humor was measured in the same manner as in Test Example 1. For comparison, DF
Protein concentrations in the aqueous humor were also measured 30 minutes after instillation when only AA solution was instilled without Na eye drops and when only sesame oil was instilled.

The test results are shown in Table 2.

Table 2 When AA solution is instilled into the eye, the protein concentration in the aqueous humor reaches the normal limit of 0.
It increased from 88■/sg to 5.10~/-.

The DFNaA eye preparation of the present invention almost completely suppressed the protein increase caused by these five patients.

Test Example 3 A white domestic rabbit was fixed in a prone position under urethane anesthesia and cannulated. The cannula (-m) was connected to a lungiscer, and changes in intraocular pressure after instillation of 20p1 of 2N sodium hydroxide solution into the eyes were continuously measured for 3 hours. Similarly, twice 30 minutes and 60 minutes before instillation of sodium hydroxide solution, 0.1
Intraocular pressure was also measured continuously for 3 hours when 96 DFNa eye drops were instilled into the eyes in advance and when only cannulation was performed without instillation of sodium hydroxide solution.

The results are shown in FIG. 1, and the DFNa eye drops of the present invention almost completely suppressed the second phase increase in decompression caused by alkaline paan.

Test Example 4 [Experimental uveitis efficacy test 31 groups of 5 white rabbits were given dog serum 5-/noodles for one day.

Inject subcutaneously in the anterior shoulder on the 3rd and 5th day. On the 8th day, 0.05 g of dog serum was injected into the vitreous body, and on the 9th day.

On the 10th, 11th, and 12th (2 days) ■Iris hyperemia.

■Iris, edema, and ■Anterior chamber exudate.The degree of response is 0.1, 2, 3 from no response to maximum response.
The degree of inflammation was evaluated by adding the values of each item (total score).

Present invention (7) 0.1%, 0.05% and 0.025
50pt of $DFNa eye drops were instilled into the eyes 5 times every hour starting 6 hours before the vitreous injection of large serum, 5 times every hour after the injection, and then 10 times a day for 3 days every hour. are shown in Table 3.

As a result of the test, all the limited agents of the present invention showed significant effects throughout the entire observation period.
It showed sufficient anti-inflammatory effect.

Test Example 5 A group of 5 white rabbits were given 5opt of Capsicum Tenki in their eyes. 30 minutes after the 2nd drop, DFNa eye drops of various concentrations and physiological saline alone were applied every 30 minutes 6 times thereafter. □After that, apply the eye drops every hour (15 times each).

Thereafter, the inflammation was measured three times a day, and the degree of inflammation was observed over time, and evaluated using the 4 total score according to the criteria in Table 4.

Table 4 (Inflammation Evaluation Criteria) When 50pt of Capsicum Tenki was applied to the eyes of a rabbit, the rabbit exhibited symptoms of agony accompanied by strong eye opening, and strong inflammation mainly occurred in the outer limits. This severe inflammation lasted for about 6 hours in the control group.
After that, it gradually decreased and was reduced to half after 72 hours, but DFNa
The point group clearly showed superior anti-inflammatory effects.

Every 24 hours after applying the capsicum tincture to the eyes I: The results of evaluating the degree of inflammation are shown in the Is table.

Table 5 (Inflammation Observation Results) Test Example 6゜Egg Albumin (hereinafter abbreviated as "EA") 10■/0
．． 2 sd and Freund's combination asier band (
(hereinafter abbreviated as rFcAJ) or Incombined Agie Band (hereinafter abbreviated as [FIAj) [both are Di
Thoroughly mix fco product] 08-.

Make 100 liters of water/oil emulsion and apply it under the skin of the guinea pig's heel.
．． 2- Sensitize by injection and gAzoMv 19 days after sensitization
/- solution was challenged until two hazes of opacity appeared in the guinea pig cornea.

Immediately after the challenge, instill 0.14 DFNa A remover 25~ into the eyes, then every hour 7 times, then 3 times a day for 3 days.
The eye drops were applied once, and the degree of corneal opacity was observed 24 hours, 48 hours, and 72 hours after the challenge.

Table 5 shows the results of evaluating the degree of corneal opacity on a scale of 1 to 4 from minimum to maximum, and comparing the results with DFNa point solution and no upper limit solution.

Table 5 Corneal reaction As is clear from each of the above tests, 1:1 of the present invention: The eye drops immediately migrate into water after instillation, sufficiently inhibit prostaglandin biosynthesis in the eye tissue, It showed excellent suppressive effects not only on anterior segment inflammation such as uveitis, but also on extraocular segment inflammation and delayed allergic reactions.

[Brief explanation of the drawing]

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 (■Hp), and the horizontal axis shows time (minutes). −〇−
is the value for Alkali Paan only, -・- is 0.1% DF
Values for Na administration, . . . indicate values for normal eyes, respectively. 1.::. Patent applicant Wakamoto Pharmaceutical Co., Ltd.

Claims (1)

[Claims] An anti-inflammatory eye drop containing diclofenac sodium as an active ingredient.