JPH09295935A - Anti-opthalimic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anti-opthalmic agent for eye hardly having eye irritating property, having high safety and extremely useful for treating inflammatory of eye. SOLUTION: This anti-ophthalmic agent for eye is obtained by mixing tolfenamic acid or its pharmaceutically permissible salt with a conventional preparation carrier and preparing the mixture in a form of administration unit. An eye drop, injection, etc., to eyes and their surroundings is used for local administration and eye drop is preferably used as a local administration agent. The concentration in the case of the eye drop is usually 0.01% to 1.0% (w/v), preferably 0.1% to 1.0% as a final concentration. In the case of the eye drop and injection, etc., the pH is prepares about 6.5-9.0, preferably about 7.0 to 8.5.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel anti-ocular inflammation agent effective for treating ocular inflammation. More specifically, it relates to an anti-ocular inflammation agent containing tolfenamic acid (chemical name N- (2-methyl-3-chlorophenyl) anthranilic acid) or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Eye inflammation patients account for more than half of eye disease patients, and drugs having an anti-ocular inflammatory effect play a large role in medical practice. Currently, there are non-steroidal agents, steroidal agents, antibacterial agents and the like as drugs used for eye inflammation, but steroidal agents and antibacterial agents are the mainstream.

[0003]

[Problems to be Solved by the Invention] Steroids have clinically excellent effects on ocular inflammation and are clinically indispensable agents. However, steroidal glaucoma, infectious eye diseases, steroidal cataract There is a possibility that serious side effects such as the above may occur, and the current situation is that the drug is being administered with fear of side effects. Furthermore, antibacterial agents have a narrow spectrum of action and can be expected to be effective only for bacterial eye inflammation. Therefore, development of a nonsteroidal anti-ocular inflammatory agent effective for eye inflammation has been desired.

Currently, several tens of non-steroidal anti-inflammatory drugs are marketed as internal medicines. However, in the case of a therapeutic agent for ocular inflammation, particularly an eye drop which is a preparation for topical administration,
The drug contained has an anti-inflammatory effect and improved water solubility,
It is necessary to have properties that meet the essential conditions peculiar to eye drops, such as reduction of irritation locally in the eye and good transferability to eye tissues, and a non-steroid effective for eye inflammation satisfying these conditions. Development of systemic drugs has not been easy. Therefore, at present, there are only three drugs which are marketed as eye drops for the treatment of ocular inflammation: indomethacin, diclofenac and pranoprofen. In addition, the eye drops can be administered at a smaller dose than the oral one at a time, and the effects of the eye drops are often insufficient even if they are effective as the internal medicine. Even in the eye drops containing the above-mentioned three non-steroidal drugs, none of their anti-ocular inflammatory effects reach that of steroidal anti-inflammatory eye drops, and the development of a highly effective non-steroidal anti-inflammatory eye drop has been developed. Is desired. An object of the present invention is to provide a novel non-steroidal anti-ocular inflammation agent having an excellent anti-ocular inflammation effect and high safety.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to find an excellent drug, and as a result, tolfenamic acid, a known compound known as a nonsteroidal anti-inflammatory analgesic, It has been found that it exhibits an excellent anti-inflammatory action against inflammation, and that it can satisfy the conditions that a preparation for topical application should have, and completed the present invention. That is, the present invention provides an anti-ocular inflammation agent containing tolfenamic acid.

Tolfenamic acid and the compound name N- (2-methyl-3-chlorophenyl) anthranilic acid are known as non-steroidal anti-inflammatory and analgesic agents (Toho Medical Society Journal 1
981, 28, No. 1, pp. 76-98) It is mainly orally taken in capsules. However, it has not been known at all that tolfenamic acid can be a useful drug as an anti-ocular inflammatory agent, such as being effective for ocular inflammation, having a low local irritation effect, and being excellent in transfer to eye tissues. . That is,
Due to its poor solubility in water, tolfenamic acid is usually an unsuitable drug for eye drops in view of the above-mentioned essential conditions for eye drops. However, as described in Examples below, the present inventors used tolufenamic acid by using an appropriate solubilizing agent such as polysorbate 80 or polyvinylpyrrolidone and adjusting the pH to an appropriate range. Thus, a stable aqueous eye drop containing the same was obtained, and its excellent properties as an anti-ocular inflammation agent were clarified for the first time.

The anti-ocular inflammatory agent containing tolfenamic acid of the present invention can be in a dosage form for local administration or systemic administration. When it is a preparation for local administration, it is a highly useful anti-ocular inflammation agent that has strong efficacy against ocular inflammation and has little eye irritation. It is an excellent anti-ocular inflammation drug with few side effects. The tolfenamic acid used in the anti-ocular inflammation agent of the present invention is, for example, Japanese Patent Publication No.
It can be produced by referring to the method described in 8-42053, or a commercially available product can be used (Sigma.
Company a).

The salt of tolfenamic acid which can be used in the anti-ocular inflammation agent of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, sodium, potassium, calcium, magnesium, aluminum, ammonium, Examples include diethylamine, monoethanome amine and triethanolamine. Further, a hydrate of tolfenamic acid is also included in the present invention.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The anti-ocular inflammation agent of the present invention can be produced by mixing tolfenamic acid or a pharmaceutically acceptable salt thereof with a conventional pharmaceutical carrier and preparing an appropriate dosage unit form. . As the dosage unit form, various ordinary forms can be arbitrarily selected. For example, for topical administration, eye drops, eye ointment, injections to the eye and its surrounding tissues, nasal drops, ear drops, etc., and for systemic administration, tablets, granules, injections, solutions, powders, Examples thereof include capsules. Particularly, the anti-ocular inflammation agent of the present invention is preferably used in the form of eye drops.

The concentration of tolfenamic acid used in the present invention in the case of eye drops is usually 0.01% as the final concentration.
(W / v) to 1.0%, preferably 0.1% to 1.0
%, More preferably 0.3% to 1.0%. When the formulation of the present invention is used as an eye ointment, the final concentration is usually 0.01 to 10.0%, preferably 0.1% to.
It is 5.0%, more preferably 0.1 to 3.5%. In addition, the dose for injections into the eye and surrounding tissues is 1
~ 30 mg. Furthermore, the concentration for nasal drops is 0.1
It is preferable that the concentration in the case of ear drops is 0.1 to 1.0%. In the case of a formulation for systemic administration, in the case of oral administration, it may be in a dose range established as an anti-inflammatory / analgesic agent, and usually in the range of 1 to 300 mg. In the case of a preparation for parenteral administration, it is usually in the range of 1 to 30 mg.

The anti-inflammatory agent of the present invention can be produced by a method known to those skilled in the art, using tolfenamic acid or its salt and a suitable liquid or solid carrier used in the art. In the formulation, as long as it is not against the object of the present invention, a preservative, a buffer, a thickener, a solubilizing agent,
Various additives usually used in the field of formulation such as a chelating agent, a stabilizer, a pH adjusting agent and an isotonicity agent may be added.

When the anti-ocular inflammation agent of the present invention is an eye drop, an injection for the eye and surrounding tissues, a nasal drop, and an ear drop, its pH may be within an ophthalmically acceptable range. In order to obtain an aqueous eye drop that stably contains poorly water-soluble tolfenamic acid, the pH is adjusted to a range of about 6.5 to 9.0, preferably about 7.0 to 8.5 by a known method. good. The osmotic pressure of the eye drop of the present invention, the injection to the eye and its surrounding tissues, the nasal drop, and the ear drop can be adjusted to 0.5 to 5 by a known method.
It is preferable to adjust the pressure ratio to about 0.8 to 2. Eye drops of the present invention, injections to the eye and its surrounding tissues, nasal drops,
As a preservative that may be contained in the ear drops, chlorobutanol, sodium dehydroacetate, benzalkonium chloride,
Examples thereof include cetylpyridinium chloride, phenethyl alcohol, paraoxybenzoic acid esters, benzethonium chloride and the like. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, acetate buffer, citrate buffer and the like. As the thickener, methyl cellulose,
Examples thereof include hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, chondroitin sulfate and salts thereof. A solubilizing agent can also be appropriately selected from known ones, but as a solubilizing agent that is used to stably dissolve poorly soluble tolfenamic acid in water, polyvinylpyrrolidone, polyoxyethylene hydrogenated castor oil, polyethylene glycol , Polysorbate 80, polyoxyethylene monostearate and the like. In particular, polysorbate 80 and polyvinylpyrrolidone, which are highly safe and have low eye irritation, are preferred for the eye drop of the present invention. Examples of the chelating agent include sodium edetate, citric acid and the like. Examples of the stabilizer include sodium edetate, sodium bisulfite and the like. As the pH adjuster, sodium hydroxide, potassium hydroxide, sodium carbonate hydrochloric acid, citric acid,
Examples thereof include phosphoric acid and acetic acid. Examples of the tonicity agent include saccharides such as sorbitol, mannitol and glucose, sodium chloride, potassium chloride, glycerin, polyhydric alcohol and the like. Examples of soothing agents include benzalnium chloride and procaine hydrochloride.

When the anti-ocular inflammation agent of the present invention is an ophthalmic ointment, a conventional base can be used, and specific examples thereof include ophthalmic white petrolatum, propet, plastibase and the like. Liquid paraffin or the like is used as an additive. further,
If desired, any additive selected from the above-mentioned preservatives, stabilizers and the like can be added. When the anti-ocular inflammation agent of the present invention is a preparation for systemic administration, it can be prepared into capsules, tablets, injections and the like by a conventional method using a non-toxic preparation carrier.

The dosage and administration of the eye drop of the present invention varies depending on the patient's symptoms, age, etc., but is usually 1 to 6 times daily.
One to two drops are instilled. For eye ointments, usually 1
It is used by applying an appropriate amount to the conjunctival sac once or twice a day. For ear drops, instill 1 to 6 times a day, 1 to 2 drops at a time, and for nasal drops, spray 1 to 6 times a day, 1 to 2 times at a time , Or 1-2 drops. In the case of an injection for the eye and its surrounding tissues, the administration is divided into 1 to several times a day. In the case of systemic administration, it is usually administered once or several times. Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

[0015]

Example 1 Tolufenamic acid 300 mg Monoethanolamine 1 ml Polyvinylpyrrolidone 5000 mg Benzalkonium chloride 10 mg 0.3 N hydrochloric acid aqueous solution Appropriate amount sterile purified water Appropriate amount 100 ml Sterilized purified water 60 ml monoethanolamine After polyvinylpyrrolidone and benzalkonium chloride are added and dissolved, tolfenamic acid is added and diluted hydrochloric acid is added in an appropriate amount to dissolve. Finally, sterilized purified water is added to bring the total volume to 100 ml. Thus, a sterile preparation is prepared and used as an eye drop. pH 8.5, osmotic pressure ratio 1.0.

Example 2 In 100 ml of ophthalmic solution Tolfenamic acid 500 mg Boric acid 1500 mg Borax 2500 mg Polysorbate 80 2000 mg 0.3N aqueous hydrochloric acid solution Appropriate amount of sterilized purified water Appropriate amount of total amount 100 ml A sterile preparation was prepared by the known method using the above components. Prepare and use as an eye drop. pH 8.1, osmotic pressure ratio 1.5.

Example 3 Eye ointment 100 g Tolfenamic acid 3.5 g Liquid paraffin 5.0 g Ophthalmic white petrolatum Appropriate amount Total 100.0 g An aseptic preparation was prepared by a known method using the above components, and an eye ointment was prepared. Use as an agent.

Example 4 Nasal drops In 100 ml of tolfenamic acid 300 mg Boric acid 1500 mg Borax 2500 mg Glycerin 500 mg Polysorbate 80 500 mg 0.3N hydrochloric acid aqueous solution Appropriate amount of sterilized purified water Appropriate amount of total amount 100 ml According to a known method using the above components. Prepare a sterile preparation and use it as a nasal drop. pH 8.1, osmotic pressure ratio 1.6.

Test Example 1 : Effect on anterior chamber puncture-induced uveitis The anti-inflammatory effect of the eye drop of the present invention was examined using rabbits.
According to the formulation shown in Example 1, 0, 0.01, 0.1, 0.3 and 1.0% eye drops having different concentrations of tolfenamic acid were prepared. 1 test drug on both eyes of Japanese white male rabbit
50 μl each was administered once in total. One hour later, aqueous humor was collected from both eyes of the test drug rabbit by anterior chamber puncture (primary aqueous humor) to cause anterior segment uveitis. Inflammation 30
After a minute, the aqueous humor was collected again (secondary aqueous humor), and the difference in protein concentration from the primary aqueous humor was determined and used as an index of inflammation. Table 1 shows the relationship between the concentration of tolfenamic acid in the test drug administered by eye drop and the secondary aqueous humor protein concentration suppression rate.

[0020]

[Table 1] As shown in Table 1, as a result of breakage of the aqueous humor barrier due to anterior chamber puncture, the concentration of protein leaked out was 0.1% for tolfenamic acid eye drops.
There was a significant and dose-dependent decrease at concentrations above 01%.

Test Example 2 : Effect on carrageenin-induced conjunctivitis model The anti-inflammatory effect of the eye drop of the present invention was examined using rats. According to the formulation shown in Example 1, 0, 0.01, 0.1 and 1.0% eye drops having different concentrations of tolfenamic acid were prepared. The test drug was administered to both eyes of Wistar male 7-week-old rats by instillation of 10 μl each once for 5 times in total at 1 hour intervals. One hour after the first administration, 30 μl of 0.5% carrageenin was injected under the conjunctiva of both upper eyelids of rats to induce conjunctivitis. Edema was removed 4 hours after the induction of inflammation, and the weight was used as an index of inflammation. A commercially available eye drop, which is a steroid eye drop containing fluorometholone as a main component, was used as a positive control. Table 2 shows the relationship between the concentration of tolfenamic acid in the test drug administered by eye drop and the edema inhibition rate.

[0022]

[Table 2] As shown in Table 2, with respect to carrageenin-induced conjunctivitis, tolfenamic acid eye drops dose-dependently and significantly suppressed edema formation at a concentration of 0.01% or more. Further, at 1.0%, the inhibitory effect exceeding that of a commercially available steroid eye drop (commercially available eye drop A) was exhibited.

Test Example 3 : Eye irritation test by blink reaction Eye irritation was examined using rabbits. A comparative test was conducted using the 0.3% tolfenamic acid eye drops described in Example 1 as a test drug and a commercially available non-steroidal anti-inflammatory eye drop containing diclofenac as a main component (commercially available eye drop B). The method is a blink reaction method that can detect eye irritation more sensitively than the Draize method that is commonly used for eye irritation tests (Tanaka et al.,
New ophthalmology, 2,1127 (1985)), a test drug was instilled into one eye of a Japanese white rabbit and a control drug into the other eye, and the number of blinks for 2 minutes after the administration was counted. The results of Test Example 3 are shown in Table 3.

[0024]

[Table 3] As shown in Table 3, tolfenamic acid eye drops showed the same eye irritation as commercially available non-steroidal eye drops B, which is hardly irritating to humans.

[0025]

EFFECTS OF THE INVENTION The anti-ocular inflammation agent of the present invention exhibits excellent effects on ocular inflammation, has an effect comparable to that of steroid eye drops, has little eye irritation, and is extremely safe. It is extremely useful for treating eye inflammation.

Claims (3)

[Claims] 1. An anti-ocular inflammation agent containing tolfenamic acid or a pharmaceutically acceptable salt thereof. 2. The anti-ocular inflammation agent according to claim 1, wherein the dosage form is a topical preparation. 3. The anti-ocular inflammation agent according to claim 2, wherein the dosage form is an eye drop.