JP4922588B2 - Treatment for keratoconjunctival disorder - Google Patents

Description

  The present invention comprises (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid (etodolac enantiomer) or a salt thereof as an active ingredient. The present invention relates to a therapeutic agent for keratoconjunctive disorders such as dry eye, corneal ulcer, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratitis, conjunctivitis, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, filiform keratitis and the like.

  The cornea is a transparent avascular tissue with a diameter of about 1 cm and a thickness of about 1 mm. The conjunctiva is a mucous membrane covering the surface of the eyeball behind the corneal margin and the back of the eyelid. It is known to have a significant effect on visual function. Keratoconjunctival disorders caused by various diseases such as corneal ulcer, dry eye, keratitis, conjunctivitis, etc., if repair is delayed for some reason or prolonged without repair, the tissue where the cornea and conjunctiva are connected Therefore, the normal construction of the epithelium is adversely affected, and even the structure and function of the corneal stroma and the endothelium may be impaired. In recent years, with the development of cell biology, factors involved in cell division, migration, adhesion, extension, differentiation, etc. have been elucidated, and these factors play an important role in the repair of corneal disorders. (Non-Patent Document 1, Non-Patent Document 2).

  On the other hand, Patent Document 1 discloses an invention relating to a therapeutic agent for ocular inflammatory diseases containing a drug that selectively inhibits cyclooxygenase-2 as an active ingredient, and etodolac (1,8-diethyl-1,3,4,9-). Drugs that selectively inhibit cyclooxygenase-2 such as tetrahydropyrano [3,4-b] indole-1-acetic acid) have a therapeutic effect on anterior ocular inflammatory diseases such as after cataract surgery. It is described that the occurrence of corneal epithelial disorder (side effects) is less than that of ocular inflammatory agents. Patent Document 2 discloses an invention relating to a method for treating dawn by administering a nonsteroidal anti-inflammatory agent such as indomethacin, diclofenac, etodolac, etc., and is caused by inflammatory diseases such as conjunctivitis and uveitis. It is described that it is useful for the treatment of dawn and dawn after ophthalmic surgery.

However, etodolac or its enantiomer (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid was examined for its pharmacological action against keratoconjunctival disorders. There is no report to do.
WO99 / 59634 pamphlet WO95 / 18604 pamphlet Eyesight, 46, 738-743 (1992) Ophthalmic Surgery, 5, 719-727 (1992)

  Finding effective drugs for eye diseases, especially keratoconjunctival disorders, is an interesting task.

  The inventors of the present invention conducted intensive research to search for effective drugs for keratoconjunctival disorders. In a corneal disorder healing test using a corneal disorder model, etodolac did not show an improvement effect on corneal disorders. On the other hand, potassium (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetate exerts an excellent improvement effect on corneal disorders. As a result, they have reached the present invention.

That is, the present invention
(1) Dry eye and cornea containing (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid or a salt thereof as an active ingredient Therapeutic agent for ulcer, punctate superficial keratopathy, corneal epithelial defect or conjunctival epithelial defect ,
(2 ) The therapeutic agent according to (1), wherein the dosage form is an eye drop or an eye ointment.

  In the present invention, the salt of (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid may be a pharmaceutically acceptable salt. There are no particular restrictions, such as sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, etc. Examples thereof include salts with organic acids, and quaternary ammonium salts are also included in the salts of the present invention. More preferred salts are sodium and potassium salts. In addition, (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid is in the form of hydrate and solvate. Also good.

  In the present invention, corneal and conjunctival disorders refer to those in which the cornea and conjunctiva are damaged by various factors, such as dry eye, corneal ulcer, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, Examples include keratitis, conjunctivitis, dry keratoconjunctivitis, upper ring keratoconjunctivitis, and filiform keratitis.

  The therapeutic agent for keratoconjunctival disorder of the present invention can be administered orally or parenterally.

  Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops are particularly preferable. These can be prepared using commonly used techniques. For example, the eye drops are isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil A surfactant such as sodium citrate and sodium edetate, and a preservative such as benzalkonium chloride and paraben can be used as necessary. The pH may be in the range acceptable for ophthalmic preparations, but is preferably in the range of 4-8.

  The eye ointment can be prepared using a widely used base such as white petrolatum or liquid paraffin. Also, oral preparations such as tablets, capsules, granules, powders, etc. are fillers such as lactose, crystalline cellulose, starch, vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropyl cellulose, polyvinyl Binding agents such as pyrrolidone, disintegrants such as carboxymethylcellulose calcium, low-substituted hydroxypropylmethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol, silicone resin, gelatin coating, etc. A film agent or the like can be added and prepared as necessary.

  The dose can be appropriately selected depending on symptoms, age, dosage form, etc., but the eye drop is 0.0001 to 5% (w / v), preferably 0.001 to 3% (w / v) per day. It may be instilled once to several times. Oral preparations are usually administered in an amount of 0.1 to 5000 mg, preferably 1 to 1000 mg per day, once or in several divided doses.

  As described later, when a corneal disorder healing efficacy test was performed, potassium (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetate Since it exhibits an excellent improvement effect in a corneal disorder model, dry eye, corneal ulcer, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratitis, conjunctivitis, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, It is useful as a therapeutic agent for fibrokeratitis. It should be noted that etodolac, which is a racemate, did not have a significant corneal disorder improving effect.

  The results of pharmacological tests and formulation examples using (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-potassium acetate are shown below. These examples are for better understanding of the present invention and are not intended to limit the scope of the present invention.

[Pharmacological test]
Test for Curing Efficacy of Corneal Disorder A model of corneal injury was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96-100 (2001)). After the corneal injury model was created, the improvement rate of corneal injury was determined by the method of Murakami et al. (New Ophthalmology 21 (1): 87-90 (2004)).

(experimental method)
Male SD rats were used to administer Nembutal and general anesthesia, and then the extraorbital lacrimal gland was removed to induce corneal damage over 2 months.

  Next, rats with induced corneal injury were treated with potassium (1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetate (hereinafter “this” Compound)) and 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid (hereinafter referred to as “Comparative Compound”) as follows: did.

This compound administration group:
A physiological phosphate buffer (PBS) solution of this compound (0.002%) was instilled into both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).

Comparative compound administration group:
A PBS solution of the comparative compound (0.002%) was instilled into both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).

  In the control group, PBS was applied to both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).

  14 days after the start of instillation, the damaged part of the cornea was stained with fluorescein. The degree of staining with fluorescein was scored according to the following criteria for each of the upper, middle and lower parts of the cornea, and the average value of the total of those scores was calculated.

  Furthermore, the average value of the total score was also obtained for normal eyes.

(Criteria)
0: Not stained 1: Staining is sparse and each point-like stained portion is separated 2: Staining is moderate, and part of the point-like stained portion is adjacent 3: Dyeing Dense, each dot-like stained part is adjacent (result)
Using the average value of the total scores in the control group (PBS) as a reference (improvement rate: 0%), the improvement rates of the present compound administration group and the comparative compound administration group were calculated by the following formulas. Moreover, the statistical test result (p value) of the difference of this compound administration group score with respect to a control group score and a comparison compound administration group score was computed. These values are shown in Table 1. The score value is an average of 8 cases ± standard error value.

Improvement rate (%) = {(control)-(this compound or comparative compound)} / degree of failure × 100
Disability level = {(control) − (normal eye)}
Statistical significance was determined to be significant when the p value calculated by Student's t-test based on the control group was 0.05 or less, and indicated by * in the table.

(Discussion)
As is clear from the results of the pharmacological test using the above rats (Table 1, FIG. 1), the present compound ((1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3, 4-b] indole-1-potassium acetate) was found to significantly improve corneal damage. Moreover, the efficacy was proved by a statistical test result showing an extremely low p value with respect to the control group. On the other hand, the comparative compound which is a racemate did not show a significant effect, and no statistically significant difference from the control group was observed. From the above, it has been clarified that this compound exhibits an effect of improving corneal injury that is not found in the racemic comparative compound.

[Formulation example]
The typical formulation example using this compound is shown below.

Formulation Example 1
This compound 10mg in 100ml
Sodium chloride 900mg
Sterilized purified water

  By changing the addition amount of this compound, the concentration is 0.001% (w / v), 0.03% (w / v), 0.1% (w / v), 0.3% (w / v). ), 1.0% (w / v), 3.0% (w / v) eye drops.

Formulation Example 2
This compound 0.3g in 100g
Liquid paraffin 10.0g
White petrolatum

  By changing the addition amount of this compound, an eye ointment having a concentration of 1% (w / w) and 3% (w / w) can be prepared.

FIG. 1 is a graph showing the fluorescein staining scores of a control group, a present compound administration group, and a comparative compound administration group after subtracting the normal eye score average value.

Claims (2)

(1R) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid or a salt thereof as an active ingredient , dry eye, corneal ulcer, spot A therapeutic agent for surface keratosis, corneal epithelial defect or conjunctival epithelial defect . The therapeutic agent according to claim 1, wherein the dosage form is an eye drop or an eye ointment.

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