JP2005350451A - Agent for treating keratoconjunctival trouble - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmaceutical application of 5-[p-[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidione and 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidione. <P>SOLUTION: The 5-[p-[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidione, the 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidione or a salt thereof exhibits excellent ameliorating effects in keratoconjunctival trouble model. Therefore, the compounds are useful as the agents for treating the keratoconjunctival troubles such as dry eye, corneal ulcer, keratitis and pinkeye. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to 5- [p- [2- (methyl-2-pyridylamino) ethoxy] benzyl] -2,4-thiazolidinedione, which is a thiazolidinedione derivative, 5-[[4- [2- (5-ethyl- The present invention relates to a therapeutic agent for keratoconjunctival disorders such as dry eye, corneal ulcer, keratitis, and conjunctivitis containing 2-pyridinyl) ethoxy] phenyl] methyl] -2,4-thiazolidinedione or a salt thereof as an active ingredient.

 The cornea is a transparent avascular tissue having 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. The cornea and conjunctiva are It is known to have a significant effect on visual function. Keratoconjunctival disorders caused by various diseases such as corneal ulcer, keratitis, conjunctivitis, dry eye, 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 describes an invention relating to a substituted thiazolidinedione derivative such as 5- [p- [2- (methyl-2-pyridylamino) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: rosiglitazone). These compounds are said to be useful as therapeutic or prophylactic agents for hyperglycemia. Patent Document 2 discloses an invention relating to a thiazolidine derivative such as 5-[[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: pioglitazone). These compounds have a blood glucose and blood lipid lowering action and are said to be useful as a therapeutic agent for diabetes. Patent Document 3 discloses that an insulin resistance improving agent such as rosiglitazone or pioglitazone is effective as a therapeutic agent for inflammatory diseases.

However, there is no report examining the pharmacological action of the above compounds on eye diseases such as keratoconjunctival disorders.
Japanese Patent No. 2614497 JP-A 61-267580 International Publication No. 02/13812 Pamphlet Eyesight, 46, 738-743 (1992) Ophthalmic Surgery, 5, 719-727 (1992)

  5- [p- [2- (methyl-2-pyridylamino) ethoxy] benzyl] -2,4-thiazolidinedione, a 5-[[4- [2- (5-ethyl-2-pyridinyl)] thiazolidinedione derivative Searching for new pharmaceutical uses of [ethoxy] phenyl] methyl] -2,4-thiazolidinedione is an interesting task.

  The inventors of the present invention conducted intensive research to search for a new pharmaceutical use of the above compound, and in a corneal disorder healing efficacy test using a corneal disorder model, the above compound or a salt thereof is excellent against corneal disorder. The present inventors have found that the improvement effect is exhibited and have reached the present invention.

  That is, the present invention relates to 5- [p- [2- (methyl-2-pyridylamino) ethoxy] benzyl] -2,4-thiazolidinedione (hereinafter referred to as “rosiglitazone”), 5-[[4- [2- Dry eye, corneal ulcer, keratitis, conjunctivitis, etc. containing (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (hereinafter referred to as “pioglitazone”) or a salt thereof as an active ingredient It is a therapeutic agent for keratoconjunctival disorder.

The rosiglitazone and pioglitazone of the present invention are thiazolidinedione derivatives represented by the following chemical structural formulas, respectively.

 Further, the salt of rosiglitazone or pioglitazone of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, succinic acid. And salts with organic acids such as acid and tartaric acid. More preferred salts are hydrochloride and maleate. Moreover, the quaternary ammonium salt of rosiglitazone or pioglitazone of the present invention is also included in the salt of the present invention. The rosiglitazone or pioglitazone of the present invention may take the form of hydrates and solvates. Furthermore, geometrical isomers, optical isomers, tautomers, polymorphs and the like of rosiglitazone and pioglitazone are also included in the scope of the present invention.

  In the present invention, the keratoconjunctival disorder means that the cornea or the conjunctiva is damaged due to various factors, and examples thereof include dry eye, corneal ulcer, keratitis, and conjunctivitis.

  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 formulated using widely 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 of the eye drop 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 commonly used base such as white petrolatum or liquid paraffin. Oral preparations such as tablets, capsules, granules, powders, etc. are bulking agents such as lactose, crystalline cellulose, starch, vegetable oil, lubricants such as magnesium stearate, 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 the symptoms, age, dosage form, etc. The eye drop is 0.0001 to 1% (w / v), preferably 0.001 to 1% (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 will be described later, when a corneal disorder healing efficacy test was conducted, rosiglitazone and pioglitazone hydrochloride of the present invention both exhibited an excellent improvement effect in a corneal disorder model. It is useful as a therapeutic agent for keratoconjunctival disorders such as conjunctivitis.

  The results of pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[Pharmacological test]
Test for Curing Efficacy of Corneal Disorders A corneal injury model was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96-100 (2001)). After creating a corneal injury model, the method (new ophthalmology 21 (1): 87-90 (2004)) with a modification to the method of Miyata et al. (Ophthalmology Clinical Medical Journal 48 (2): 183-188 (1994)) The cure rate of corneal injury was determined.

(experimental method)
Nembutal was administered to male SD rats for general anesthesia. Subsequently, the extraorbital lacrimal gland was removed and corneal injury was induced over 2 months.

 Next, this compound (rosiglitazone, pioglitazone hydrochloride) was administered as follows.

Rosiglitazone ophthalmic group:
A physiological saline solution of rosiglitazone (0.02%) was instilled into both eyes 6 times a day for 14 days (8 animals per group).

Pioglitazone ophthalmic group:
A physiological saline solution of pioglitazone hydrochloride (0.01%) was instilled into both eyes 6 times a day for 14 days (8 animals per group).

 In the control group, physiological saline was instilled into both eyes 6 times a day for 14 days (8 animals per group).

 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 improvement rate of corneal injury was calculated from the average value of the scores of the respective parts.

(Criteria)
0: Not dyed.

 1: Dyeing is sparse and each dot-like dyeing part is separated.

 2: The dyeing is moderate, and some of the dotted dyed portions are adjacent.

 3: Dyeing is dense and each dot-like dyeing part is adjacent.

(result)
Using the average score in the control group (saline) as a reference (improvement rate: 0%), the rosiglitazone (0.02%) ophthalmic group and the pioglitazone (0.01%) ophthalmic group according to the following formula The improvement rate was calculated. These are shown in Table 1. In addition, the average value of a score is an average of 8 cases each.

Improvement rate (%) = {(control)-(this compound)} / degree of failure × 100
Disability level = (control)-(normal eye)

(Discussion)
As is apparent from the results of the above pharmacological tests using rats, rosiglitazone and pioglitazone significantly improve corneal damage.

[Formulation example]
Representative preparation examples using rosiglitazone and pioglitazone are shown below.

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

  By changing the amount of rosiglitazone added, the concentrations were 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
Pioglitazone hydrochloride 100mg in 100ml
Sodium chloride 800mg
Disodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount

  By changing the addition amount of pioglitazone hydrochloride, the concentrations were 0.05% (w / v), 0.3% (w / v), 0.5% (w / v), 1.5% (w / v). v) 3% (w / v) eye drops can be prepared.

Formulation Example 3
Rosiglitazone 0.3g in 100g
Liquid paraffin 10.0g
White petrolatum

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

Claims (3)

5- [p- [2- (methyl-2-pyridylamino) ethoxy] benzyl] -2,4-thiazolidinedione, 5-[[4- [2- (5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl ] A therapeutic agent for keratoconjunctive disorder containing -2,4-thiazolidinedione or a salt thereof as an active ingredient. The therapeutic agent according to claim 1, wherein the keratoconjunctive disorder is dry eye, corneal ulcer, keratitis, or conjunctivitis. The therapeutic agent according to claim 1, wherein the dosage form is an eye drop or an eye ointment.