Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-03-23
2001-01-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06180673
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a corneal subepithelial opacity (haze) inhibitor which comprises as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid (generic name: Tranilast) represented by the formula:
or a pharmaceutically acceptable salt thereof.
More particularly, the present invention relates to an inhibitor of corneal subepithelial opacity (haze) caused by an injury to the cornea, which inhibitor comprises as the active ingredient Tranilast or a pharmaceutically acceptable salt thereof.
In the present invention, examples of an injury to the cornea include, a wound occuring during refractive surgery such as keratectomy and radial keratotomy, an external wound, other physical injuries to the cornea and the like.
BACKGROUND OF THE INVENTION
In the ophthalmic field, refractive surgery such as keratectomy and radial keratotomy has recently received public attention. The surgical treatment to correct vision is extremely useful in that permanent vision correction can be realized in comparison with conventional correction methods using compensating lenses such as eye glasses and contact lenses.
Radial keratotomy (RK) is a surgical treatment which involves the placement of radial incisions extending outwardly from the center of the cornea with a surgical knife. In general, the number of incision lines is in the range of 4-12 and the depth of the cutting is about 90 to 95% of the corneal thickness. However, when performing this procedure, it is very difficult to place the cuts uniformly. Corneal degeneration after the surgery has become a problem. Accordingly, to solve the above problems found in keratotomy using a surgical knife, keratectomy using a laser was designed.
Keratectomy using an excimer laser can be divided into photo refractive keratectomy (PRK) and phototherapeutic keratectomy (PTK). As an example of keratectomy for either procedure, optical keratectomy using an ultraviolet laser having a wavelength about 193 nm can be illustrated. Hundreds of thousands of patients have already undergone excimer laser treatment all over the world. In the United States of America, this procedure for curing myopia received FDA approval in October of 1995. Photorefractive keratectomy is employed for curing or improving paropsia, for example, correcting ametropia such as myopia, hyperopia and astigmatism. Phototherapeutic keratectomy is useful for treating opacity regions in the corneal surface associated with corneal degeneration etc.
However, because these surgical methods involve incision or excision of the cornea, in almost all cases corneal subepithelial opacity (haze) will occur at the site of incision or laser application during the wound-healing stage. Especially, because keratectomy involves removal of the central corneal epithelium, there is a serious problem that corneal subepithelial opacity (haze) after the surgery leads to visual dysfunction such as lower vision, glare and regression. However, the mechanism of corneal subepithelial opacity (haze) has not yet been clearly elucidated. In general, corneal subepithelial opacity (haze) is usually transitory. Namely, corneal subepithelial opacity (haze) is not observed immediately after the surgery and occurs from 2 weeks to 1 month after the surgery, i.e., the time that the corneal epithelium has nearly rehealed. Subsequently, the opacity peaks in 2-3 months after the surgery and disappears generally at about 6 months to 1 year after the surgery. Occasionally, the cornea is not completely cured and the opacity remains.
At the present time, on the hypothesis that collagen accumulation plays more than a small part in corneal subepithelial opacity (haze) after excimer laser application, eye drops containing a steroid which has inhibitory activities on fibroblast cell proliferation and collagen accumulation and which is used for the treatment of keloid etc., have been used as therapeutic agents for curing corneal subepithelial opacity (haze). However, it has been reported that steroids delay rehealing of the corneal epithelium because of uncertain effects and that side effects such as glaucoma occur occasionally. Furthermore, it has been reported that instillation on the eyes of fluorouracil, an anticancer medicine, and heparin, an anticoagulant, had no therapeutic effect. Thus, corneal subepithelial opacity (haze) occurs in the eye, which is distinctive and is greatly different from the other organs and tissues. Therefore, corneal subepithelial opacity (haze) differs from diseases occurring in other organs and as such therapeutic agents capable of effectively treating diseases which result in cell proliferation or collagen accumulation do not show favorable effects on corneal subepithelial opacity (haze). Hence, satisfactory corneal subepithelial opacity (haze) inhibitors have not yet been developed.
Accordingly, development of inhibitors of corneal subepithelial opacity (haze) caused by an injury to the cornea has been desired for accelerating the healing of a wound such as occurs after keratectomy using an excimer laser etc. or radial keratotomy, or of external wound or other physical injury and for improving visual dysfunction such as lower vision.
Tranilast has been widely used as an internal medicine or in eye drops for the treatment of allergic disorders such as bronchial asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis, and cutaneous disorders such as keloid and hypertrophic scar. For example, it has been known that Tranilast has inhibitory activities on chemical mediator release caused by an allergic reaction, excessive collagen accumulation by fibroblast cells in cutaneous tissues and excessive proliferation of smooth muscle cells in coronary artery vessels.
However, it is not known that Tranilast suppresses corneal subepithelial opacity (haze) such as caused by an injury to the cornea.
SUMMARY OF THE INVENTION
The present invention relates to a corneal subepithelial opacity (haze) inhibitor which comprises as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula:
or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention or treatment of corneal subepithelial opacity (haze) which comprises administering N-(3,4-dimethoxycinnamoyl)-anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of corneal subepithelial opacity (haze)
Furthermore, the present invention relates to a use of N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the above formula (I) or a pharmaceutically acceptable salt thereof as a corneal subepithelial opacity (haze) inhibitor.
REFERENCES:
patent: 5223639 (1993-06-01), Satou
patent: 5356620 (1994-10-01), Yammamoto et al.
Iwaki Yoichi
Okamoto Susumu
Sakai Tatsuro
Tobari Ikuo
Frenkel Stuart D.
Henley III Raymond
Kissei Pharmaceutical Co. Ltd.
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