JPH11116477A - Treating agent for allergic conjunctival disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject treating agent capable of effectively suppressing an increase in conjunctival vascular permeability in a rat passively sensitized with ovalbumin, which is a typical I type allergic reaction by including ramatroban as an active ingredient therein. SOLUTION: This treating agent contains 3-(4-fluorophenylsulfonamido)-1,2,3,4 tetrahydro-9-carbazolepropanoic acid or its pharmaceutically acceptable salt (e.g. the compound represented by the formula and commonly named ramatroban) as an active ingredient. The compound has one asymmetric carbon atom and the R type is especially suitable. The daily dose thereof for an adult is usually preferably about 0.5-10 mg/kg by oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the formula (I)

[0002]

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A compound represented by the formula: 3- (4-fluorophenylsulfonamide) -1,2,3,4-tetrahydro-9-carbazolepropanoic acid (generic name: ramatroban) or a physiologically acceptable salt thereof The present invention relates to a therapeutic agent for allergic conjunctival disease, characterized by containing as an active ingredient.

[0004]

BACKGROUND OF THE INVENTION Allergic conjunctival diseases
Type (immediate type) allergy is involved, such as hay fever, seasonal allergic conjunctivitis that develops in a specific season, and symptoms are persistent throughout the year due to antigens resident in the living environment such as mites and fungi Five forms of allergic allergic conjunctivitis, atopic keratoconjunctivitis, which is a chronic conjunctivitis that accompanies atopic dermatitis, spring catarrh with proliferative changes in the conjunctiva, and giant papillary conjunctivitis caused by wearing contact lenses and artificial eyes It is said that mast cells and various inflammatory cells play an important role in the pathogenesis (the latest internal medicine system <Progress 4> immune and allergic diseases, pages 290-295, Nakayama Shoten 1997) September 25). That is, through the IgE mast cells are activated by antigen stimulation of conjunctival, histamine, PAF, leukotrienes, prostaglandins such, the various chemical mediators such as thromboxane A ₂ released, these mediators in the conjunctival Is considered to cause hyperemia and edema of the conjunctiva, increase secretions, or stimulate trigeminal nerve endings to cause subjective symptoms such as lacrimation, foreign body sensation, and pruritus.

[0005] ramatroban has platelet aggregation inhibitory action and thromboxane A ₂ receptor antagonism, thrombosis, thromboembolism, treatment of ischemia, also anti-asthmatic agents, anti-allergic agents, allergic dermatitis It is known that it is useful as a therapeutic agent (for example, Japanese Patent Publication No. 4-50301,
-175991). On the other hand, it is also known that certain drugs having a thromboxane A ₂ antagonistic action can suppress the enhancement of guinea pig conjunctival vascular permeability induced by a thromboxane A ₂ analog (J. Pharmacol. Exp. Ther.
255: 23-27, 1991). However, the effect of ramatroban on conjunctival vascular permeability was not known at all.

Conventionally, as a drug treatment for allergic conjunctival disease, local administration (eye drops) or oral administration of a histamine receptor antagonist, a histamine release inhibitor, a non-steroidal anti-inflammatory drug, a steroidal anti-inflammatory drug and the like are known. Have been. The most effective are steroidal anti-inflammatory drugs, but they have side effects such as increased intraocular pressure when instilled, induction of infection, and inhibition of growth during oral administration, and the development of therapeutics with excellent efficacy and safety is awaited. I have.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have examined the pharmacological action of ramatroban in detail, and found that ramatroban is a typical type I allergic reaction. The present inventors have found that the present invention can effectively suppress the increase in the concentration and can be a therapeutic agent for allergic conjunctival disease, and have reached the present invention.

[0008] Thus, the present invention provides an agent for treating allergic conjunctival disease, which comprises ramatroban as an active ingredient.

[0009] Ramatroban is a compound known per se, and can be produced, for example, by the method described in Japanese Patent Publication No. 4-50301 mentioned above. Ramatroban has one asymmetric carbon atom and can exist in the form of the R-form, the S-form or a mixture (racemate) thereof, with the R-form being preferred.

The pharmaceutically acceptable salts of ramatroban include, for example, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, magnesium salt and calcium salt; ammonium salt;
Examples thereof include salts with organic amines such as di- or triethylamine, di- or tri-ethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, and ethylenediamine.

Ramatroban or a salt thereof can be administered to a human or a warm-blooded non-human animal as an agent for treating or preventing allergic conjunctival disease, ie, a therapeutic agent.

The administration can be carried out orally, parenterally or topically. In particular, topical administration such as eye drops is recommended for ease of administration. The dosage depends on the severity of the symptoms, age,
It can vary over a wide range depending on body weight, administration route, gender, doctor's judgment, etc.
0.5 to 10 mg / kg / day orally, preferably 1 to 5
mg / kg / day may be administered once or several times a day. In the case of topical administration (eye drops) to the conjunctiva, 0.00
It is preferable to administer 1 to 10 mg, preferably 0.01 to 1 mg once or several times a day.

[0013] Ramatroban or a salt thereof may be administered, for example, in the form of fine granules, granules, or the like depending on the administration route.
Oral preparations such as capsules, tablets, liquids and syrups; Parenteral preparations such as injections, drops and suppositories; Formulations such as topical external preparations such as eye drops, ointments and creams can do.

[0014] Formulation of ramatroban or a salt thereof can be carried out by formulating ramatroban or a salt thereof with an additive according to a conventional method. Examples of additives that can be used in the production of an oral administration preparation include, for example, starches such as corn starch and potato starch;
Lactose, sucrose, glucose, sugars such as mannitol, calcium carbonate, inorganic salts such as synthetic aluminum silicate, paraffin, wax, fats and oils such as higher fatty acids, and excipients such as celluloses; starches such as corn starch and potato starch; , Lactose, sucrose, glucose, saccharides such as mannitol, dextrin, gum arabic, tragacanth,
Binders such as natural substances such as carrageenin, sodium alginate, and gelatin; cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; and synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol; Disintegrants such as powders, low-substituted hydroxypropylcellulose and crystalline cellulose; lubricating agents such as magnesium stearate, talc and synthetic aluminum silicate;
Coloring agents such as various food colorings; various natural and artificial sweeteners; acidulants such as organic acids; flavoring and smelling agents such as peppermint oil; solubilizing agents such as various surfactants; stabilization of benzoic acid esters and the like Agents (in the case of liquids).

As a solvent in the case of a solution, an eye drop or an injection, water is preferably used, and if necessary, a buffer adjusted to an appropriate pH can be used. In addition, various amino acids, saccharides, Isotonic agents such as salts, preservatives such as benzalkonium chloride and paraoxybenzoate, stabilizers such as sodium edetate, sodium sulfite, and ascorbic acid, alcohols, polyethylene glycol, sodium lauryl sulfate, and polysorbate. Dissolution aids can be included.

In semi-solid preparations such as ointments and creams, the bases are emulsion / water-soluble bases such as hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic vaseline, lanolin, polyethylene glycol and the like; vaseline, paraffin, Simple ointments, oily bases such as white ointment and the like can be used, and preservatives such as paraoxybenzoates, glycerin,
In addition to humectants such as propylene glycol and butylene glycol, surfactants and the like can be blended.

[0017]

The present invention will be described more specifically with reference to Test Examples and Preparation Examples.

Test Example 1 Effect of Ramatroban on Conjunctival Vascular Permeability in Ovalbumin Passively Sensitized Rats [Test Drug] Ramatroban was dissolved in 0.1N HCl.
The pH was adjusted to 7.2 with 0.1 N NaOH and used.

Ovalbumin (hereinafter abbreviated as OA) is Sig
ma.

[Test Method] (1) Preparation of OA rat antiserum OA / inactivated pertussis suspension 4 mg / 2 × 10 ¹⁰ cells / ml
Was first immunized by subcutaneously dividing the Norwegian rat's forelimbs into four parts (forefoot 0.1 ml, hindpaw 0.15 ml) and administering 0.5 ml. Five days later, a booster immunization was performed by intramuscularly administering an OA physiological saline solution (0.5 mg / 0.5 ml / animal) to the hind thigh. Nine days after the first immunization, blood was collected from the abdominal aorta and left overnight for 4 days.
The antiserum was obtained by centrifugation at rpm for 15 minutes. The obtained antiserum was used after being diluted with physiological saline so as to have an antibody titer of 1: 8 in a PCA reaction.

(2) Test method Rats (Slc: S
D (SPF), 6-week-old, male, Japan SLC, Inc.) was sensitized by injecting 50 μl under the binocular conjunctiva, and 48 hours later, 2.0% OA saline and 1% ev.
An equivalent mixture of ans blue physiological saline was administered into the tail vein at a rate of 3 ml / kg to induce a reaction. The animals were sacrificed by exsanguination 30 minutes after the induction of the reaction, and the stained sites were removed. The excised conjunctiva was placed in a test tube, 1 ml of 1 NKOH was added, and the mixture was incubated overnight at 37 ° C. Thereafter, 9 ml of a 0.6N phosphoric acid / acetone mixture (5:13) was added, and the mixture was shaken well, filtered through a filter paper, and colorimetrically determined at 620 nm. The test drug ramatroban was instilled 5 minutes before the induction of the reaction.

[Test results] Ramatroban significantly reduced the amount of dye leakage as compared with the vehicle group at a concentration of 0.3% or more,
Increased vascular permeability was suppressed (see Table 1).

Table 1 Administered group Administered solution Volume No. of subjects Dye leakage * Inhibition rate (μl) (μg / site) (%) Medium (saline) 510 13.4 ± 0.9- Ramatroban 0.1% 5 10 14.1 ± 1.5-5.2 Ramatroban 0.3% 5 10 9.2 ± 1.2 ** 31.3 Ramatroban 1.0% 5 10 9.0 ± 0.8 ** 32. 8 * Mean ± SE ** Significantly different p <0.05 vs Vehicle-administered group (Dunnett's test) Formulation Example 1 : aqueous ophthalmic solution Ramatroban 0.1 g, 0.1 N sodium hydroxide
4 g, 0.1 g of sodium citrate and 0.9 g of sodium chloride are added and dissolved in about 90 ml of sterilized purified water. Further, benzalkonium chloride 0.005 g, then an appropriate amount of 1
The pH was adjusted to 7.5 by adding N hydrochloric acid, and the pH was adjusted to 1 with sterile purified water.
Make it 00 ml. This aqueous solution is sterilized and filtered through a membrane filter, and then filled into a previously sterilized container to produce an eye drop.

Formulation Example 2 : Suspended eye drops 0.3 g of methylcellulose, 0.2 g of sodium dihydrogen phosphate and 0.005 g of benzalkonium chloride are added to about 90 ml of sterile purified water and dissolved. The pH is adjusted to 7.5 by adding sodium. After sterilizing and filtering this aqueous solution with a membrane filter, 1 g of ramatroban finely pulverized by aseptic operation is suspended, and the suspension is made up to 100 ml with sterile purified water. Fill in pre-sterilized containers to produce eye drops.

Formulation Example 3 : Ophthalmic ointment 10 g of ramatroban pulverized by aseptic operation was dispersed in 90 g of liquid paraffin sterilized by dissolving 0.05 g of methyl parahydroxybenzoate in advance and added to about 900 g of sterilized ophthalmic white petrolatum. Mix. This ointment is filled into a previously sterilized container to produce an eye ointment.

Formulation Example 4 : Capsule 100 g of pulverized ramatroban is added to corn starch 2
50 g, lactose 260 g and microcrystalline cellulose 216 g, and this mixture is mixed with polyvinylpyrrolidone 25, 20
g, and then dried. The granulate was sieved and mixed with 4 g of magnesium stearate. The mixture was filled into capsules so as to contain 425 mg, and a capsule containing 50 mg of the drug in one capsule was produced.

Formulation Example 5 Tablets The granules produced as in Formulation Example 4 were sieved and mixed with 4 g of magnesium stearate. This mixture was compressed into 425 mg tablets weighing 11 mm.

Formulation Example 6 Fine Granules 50 g of finely pulverized ramatroban was added to D-mannitol 45
0 g, lactose 363 g and microcrystalline cellulose 100 g.
g, and then dried. The granules were sieved and the coarse granules were crushed and mixed again. Further, it was mixed with 2 g of light anhydrous silicic acid to produce fine granules.

[0029]Formulation Example 7: Dry syrup preparation Saccharose 940 obtained by pulverizing 50 g of pulverized ramatroban
g, tragacanth powder 3 g, citric anhydride 2 g and citric acid
3 g of sodium and the mixture is treated with hydroxypro
Granulate with an aqueous solution containing 3 g of pill cellulose, then dry
did. The granules are sieved and the coarse granules are ground
Mixing again produced a dry syrup. Formulation Example 8 : Injection In an appropriate amount of water for injection, 24 g of 0.1N sodium hydroxide,
Add 1 g of sodium enoate and 9 g of sodium chloride
After dissolution, 1 g of ramatroban was dissolved. Then about
The pH was adjusted to 7.5 by adding 1.3 g of 1N hydrochloric acid,
Make up to 1 liter with water for injection. Add this aqueous solution to the membrane
Filtration by filter, filling into ampoules to produce injections
did.

Claims (1)

[Claims] 1. A composition comprising 3- (4-fluorophenylsulfonamido) -1,2,3,4-tetrahydro-9-carbazolepropanoic acid or a pharmaceutically acceptable salt thereof as an active ingredient. For treating allergic conjunctival diseases.