Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-29
2002-11-05
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259500, C514S912000
Reexamination Certificate
active
06476039
ABSTRACT:
TECHNICAL FIELD
This invention relates to ophthalmic compositions, in particular, those for treatment of corneal lesions, those for treatment of deteriorated corneal esthesia, those for treatment of dry eye syndrome, and those for treatment of hypolacrimation.
PRIOR ART
Corneal lesions are caused by defects in the corneal tissue. Defects in the epithelium generally give rise to subjective symptoms including foreign body sensation, eye pain, photophobia, tear secretion, etc. Defects in the corneal tissue are called epithalaxia or erosion when they are restricted only in the epithelium, and corneal ulcer when they extend from the Bowman's membrane to the parenchyma.
There are various possible factors involved in corneal lesions, including pathological factors such as diabetes, inflammation, allergy, microorganisms (virus, bacteria, fungi, etc.) etc., chemical factors such as cytotoxicity by chemicals, caustic effect by acids or alkalis, etc., and physical factors such as dryness (dry eye syndrome, etc.) and trauma due to foreign bodies (contact lens, etc.), burn, etc. It has recently been reported that antiseptics contained in eye drops such as benzalkonium chloride and chlorobutanol, antibiotics of the aminoglycoside series, non-steroidal antiphlogistics, IDU, pimaricin, etc. impair the corneal epithelium.
Various treatments have been attempted depending on the site affected and the severity of the corneal lesion. In addition to physical treatments such as instillation of antibiotic-containing ointment plus pressure eye-patch treatment, use of therapeutic soft contact lens, and corneal superficial puncture, instillation of fibronectin, hyaluronic acid, or a high osmotic agent is currently employed. From the viewpoint of treatment of diabetic complications, it has been reported that aldose reductase inhibitors are effective in treatment of diabetic corneal lesions. However, for example in cases where the symptoms have become aggravated so that the keratoepithelium becomes detached from the corneal parenchyma, satisfactory recovery cannot be attained at present with any of the treatments described above. Thus the treatments desired are those effective even in considerably progressive corneal lesions where the epithelium has been detached or defected.
The cornea is one of the most sensitive tissues on the body surface, and sensory nerve endings are distributed all over the cornea. Therefore when the corneal esthesia remains normal, the patient can notice the pain due to pathological conditions or lesions in cornea. When the corneal esthesia is deteriorated, however, no subjective symptoms are noticed and this promotes to further aggravation of the corneal lesions.
Factors that are known to deteriorate corneal esthesia include aging, diseases (corneal herpes, diabetes, etc.), use of contact lens, and ophthalmologic surgery (surgery for cataract, corneal transplantation, surgery for retinal detachment, etc.). Not only for treatment but also for prevention of progress of the pathological conditions, treatments that may normalize the subjective symptoms of the patients, i.e. agents that may improve the deteriorated corneal esthesia due to various diseases are being desired.
One of the opthalmologic symptoms that became lately the center of wide interest is dry eye syndrome. Dry eye syndrome is defined as “the condition where the tear quantity has been decreased or tear quality has become abnormal, irrespective of whether the keratoconjunctival lesion is present or absent” (Yamada, N., et al., Folia Ophthalmol. Jpn., 43, 1289-1293 (1992)), including dry eye syndrome noted in diseases such as hypolacrimation, alacrima, xerophthalmia, Sjögren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis, diabetes, etc. dry eye syndrome noted after surgery for cataract, or accompanied with allergic conjunctivitis, etc., and dry eye syndrome observed in hypolacrimation due to increased VDT (visual display terminal) tasks or dry air in an air-conditioned room.
There are various causes of dry eye syndrome some of which remain unidentified. Dry eye syndrome is treated only by administration of artificial tears for increase of the quantity of tear retained within the conjunctival sac to relieve the subjective symptoms, or by prevention of eyes from drying. It has been desired that substances capable of bringing about satisfactory treatment including improvement of hypolacrimation are provided.
Tear secretion is classified into basal tear secretion and reflex tear secretion. Basal tear secretion means tear secretion under ordinary conditions with the eyelid open, being considered to be mainly from the accessory lacrimal glands (Krause gland, Wolfring gland, etc.). On the other hand, reflex tear secretion means tear secretion in the presence of some stimulation to the keratoconjunctival surface, nasal mucosa, etc. or accompanied with mental changes such as grief and joy. It is considered to be from the main lacrimal gland. Therefore improvement of decreased basal tear secretion, i.e. tear secretion under ordinary conditions with the eyelid open, is particularly important as judged from the symptoms of dry eye syndrome.
DISCLOSURE OF THE INVENTION
This invention intends to solve the problems described above, and one of the objectives is to provide ophthalmic compositions effective in treatment of at least one disease selected among corneal lesion, deteriorated corneal esthesia, dry eye syndrome, and hypolacrimation.
The inventors have eventually found as the result of their researches that the compounds represented by the general formula (I):
wherein, A and B are independently lower alkylene, and X, Y, and Z are independently halogen, are excellent improvement of diabetic corneal lesion and deteriorated corneal esthesia.
The inventors have also found that the compounds capable of inhibiting aldose reductase including the compounds represented by the above-mentioned general formula (I) are excellent in improvement not only of diabetic corneal lesion but also of non-diabetic corneal lesions, and that the compounds are excellent in improvement of dry eye syndrome, especially hypolacrimation including diminished basal tear secretion. Thus, they completed this invention.
The invention is explained in detail in the following.
(1) An ophthalmic composition for treatment of diabetic corneal lesion and/or for treatment of deteriorated corneal esthesia of which comprises, as an active ingredient, a compound represented by the general formula (I):
wherein, A and B are independently lower alkylene and X, Y, and Z are independently halogen (named the compound hereinafter), or a pharmacologically acceptable salt thereof.
(2) The ophthalmic composition described in (1) wherein in the general formula (I) A and B are independently methylene, X is chlorine, Y is bromine, and Z is fluorine atom.
(3) The ophthalmic composition described in (1) or (2) that are used for treatment of diabetic corneal lesion.
(4) The ophthalmic composition described in (1) or (2) that are used for treatment of deteriorated corneal esthesia.
(5) The ophthalmic composition described in any of (1) to (4) that are in the form of preparations for eye local administration.
(6) An ophthalmic composition for treatment of non-diabetic corneal lesions which comprises, as an active ingredient, an aldose reductase inhibitor.
(7) An ophthalmic composition for treatment of dry eye syndrome, which comprises, as an active ingredient, an aldose reductase inhibitor.
(8) An ophthalmic composition for treatment of hypolacrimation, which comprises, as an active ingredient, an aldose reductase inhibitor.
(9) The ophthalmic composition described in any of (6) to (8), wherein the aldose reductase inhibitor is a compound represented by the general formula (I):
wherein A and B are independently lower alkylene, and X, Y, and Z are independently halogen, or a pharmacologically acceptable salt thereof.
(10) The ophthalmic composition described in (9), wherein A and B are methylene, X is chlorine, Y
Kato Ichie
Ueno Ryuji
Fay Zohreh
R-Tech Ueno Ltd.
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