Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-11-14
2003-05-27
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S652000, C514S912000
Reexamination Certificate
active
06569903
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an ophthalmic composition containing a selective adrenergic &bgr;
2
receptor agonist.
BACKGROUND ART
Tear film covers the ocular surface, consisting of the cornea and conjunctiva, to keep it moisturized and protect it from drying. At the same time, tears function as a transparent optical transmissive liquid that maintains the corneal surface flat and smooth for the clear viewing of images. Tears also contain a large number of ingredients such as antibodies that prevent infections by viruses, bacteria, etc. Furthermore, tears play a role in washing away foreign substances which happen to get into eyes as well as cellular wastes derived from the cornea and conjunctiva. In addition, tears serve as a supply source of oxygen, moisture and nutrients for the cornea, which is an avascular tissue, and actively contribute to the healing of eye wounds, serving as a source of various biologically active substances at the time of keratoconjunctival disorders (corneal and conjunctival injuries) (Ocular Surface no Shindan to Chiryou (Diagnosis and Treatment of Ocular Surface), 24-30 (1993)).
Methods known in the art for treating hypolacrimia, xerophthalmia, dry eye, keratoconjunctivitis sicca, and such, which are all accompanied with the aberrant tear secretion, involve externally supplementing natural tears in shortage with artificial tears, and prolonging the retention time of artificial tears in the conjunctival sac by combining the artificial tears with viscous materials and such. However, since the actual tears contain a variety of biologically active substances as described above which contribute to the homeostasis and functional restoration (healing of injuries) of ocular surface, the mere moisture replenishment with artificial tears and such is insufficient to act as substitute for the role of natural tears. Therefore, there has been a strong demand for drugs capable of quantitatively as well as qualitatively improving tear secretion (Atarashii Ganka (New Ophthalmology), 14, 1631-1636 (1997)).
Promotion of tear secretion by isoproterenol, a &bgr; adrenergic receptor agonist, has been hitherto reported (Invest. Ophthalmol. Vis. Sci., 20, 110-116 (1981)). There exist two subtypes, &bgr;
1
and &bgr;
2
, for the &bgr; adrenergic receptors, &bgr;
1
being distributed mainly in the heart while &bgr;
2
is predominantly in the smooth and skeletal muscles. Since isoproterenol is a nonselective &bgr; adrenergic receptor agonist which strongly acts on either &bgr;
1
or &bgr;
2
receptor, it acts on the heart, wherein the &bgr;
1
adrenergic receptor is abundant, often causing unfavorable side effects on the cardiovascular system, specifically inducing an increase in the heart rate and an enhancement of heart contractile force. Thus, administration of a nonselective &bgr; adrenergic receptor agonist as a bronchodilator is often accompanied with side effects on the cardiovascular system. In light of its unfavorable side effects, isoproterenol, a tear secretion promoting agent, is difficult to use as a tear secretion improving agent.
Research aiming at reducing side effects and prolonging actions of &bgr; adrenergic receptor agonists, focusing on the organ distribution of &bgr; adrenergic receptor subtypes, has been ongoing. In recent years, drugs having a high selectivity to the &bgr;
2
adrenergic receptor with a low cardiac distribution, so-called selective &bgr;
2
adrenergic receptor agonists, have been developed among &bgr; adrenergic receptor agonists. Since selective &bgr;
2
adrenergic receptor agonists directly act on &bgr;
2
adrenergic receptors in smooth muscles to dilate bronchus and blood vessels, and also relax uterus, and such, they are applied to the treatment of bronchial asthma, threatened abortion, etc. Drugs of this type are inert to cardiovascular systems in therapeutic doses, expressing no action to increase the heart rate and/or to enhance heart contractile force. However, there has been no report on actions of these selective &bgr;
2
adrenergic receptor agonists concerning the promotion of tear secretion, increase in protein concentration in tears, and the treatment of keratoconjunctival and xerophthalmic disorders.
DISCLOSURE OF THE INVENTION
It is an object of this invention to provide an ophthalmic composition with as low side effects on the heart as possible, more specifically, to provide a composition whose side effects on the heart are sufficiently suppressed and which is capable of promoting tear secretion. It is another object of this invention to provide a composition which is able to increase protein concentration secreted in tears.
Present inventors proposed that compounds that promote tear secretion and, moreover promote secretion of tear proteins, which function as biologically active substance in particular, would be useful for the treatment of xerophthalmic and keratoconjunctival disorders. Further, they have selected the &bgr; adrenergic receptor agonist as candidate compound for drugs having the activity to promote tear secretion. To develop drugs to improve tear secretion targeting the &bgr; adrenergic receptor, it is necessary to avoid side effects thereof on the heart. To solve these problems, present inventors paid attention to the distribution of &bgr; adrenergic receptor subtypes in the lacrimal gland and heart. That is, more &bgr;
1
adrenergic receptors are distributed in the heart, while more &bgr;
2
adrenergic receptors in the lacrimal gland. Present inventors proposed to avoid side effects on the heart by utilizing the difference in &bgr; adrenergic receptor subtypes in both tissues, and discovered that agents that improve tear secretion with less side effect on the heart could be provided by utilizing &bgr; adrenergic receptor agonists having a high selectivity for the &bgr;
2
adrenergic receptor. Furthermore, they confirmed that &bgr;
2
adrenergic receptor agonists, in addition to promoting tear secretion level, acted to increase the protein concentration in tears, thereby accomplishing this invention. That is, the present invention relates to the following compositions, methods for improving tear secretion using such compounds, and methods for suppressing their side effects.
[1] A composition for treating and/or preventing diseases due to xerophthalmic and/or keratoconjunctival disorders, said composition comprising a selective &bgr;
2
adrenergic receptor agonist as an active ingredient.
[2] A composition for treating and/or preventing at least one disease selected from the group consisting of keratoconjunctivitis sicca, lacrimal hyposecretion, xerophthalmia, dry eye, age-related xerophthalmia, Stevens-Johnson syndrome, corneal epithelial disorder, corneal epithelial detachment and keratoconjunctival ulcer, said composition comprising a selective &bgr;
2
adrenergic receptor agonist as an active ingredient.
[3] The composition of [1] or [2], wherein the selectivity of the selective &bgr;
2
adrenergic receptor agonist to the &bgr;
2
adrenergic receptor is not less than ten times the selectivity to the &bgr;
2
adrenergic receptor of isoproterenol.
[4] The composition of any one of [1] to [3], wherein said selective &bgr;
2
adrenergic receptor agonist is one or more compounds selected from the group consisting of clenbuterol, fenoterol, procaterol, salbutamol, salmeterol, hexoprenaline, pirbuterol, mabuterol, bambuterol, formoterol, meluadrine, tulobuterol, levosalbutamol, and their salts.
[5] The composition of any one of [1] to [4], wherein said composition is a pharmaceutical preparation formulated for oral administration.
[6] The composition of any one of [1] to [4], wherein said composition is a pharmaceutical preparation formulated for parenteral administration.
[7] The composition of [6], wherein said pharmaceutical preparation formulated for parenteral administration is an eye drop (an ophthalmic solution) or an eye o
Akagi Yukie
Hirotsu Ichiro
Honma Yoichi
Matsushita Nobutoshi
Fay Zohreh
Fish & Richardson P.C.
Rohto Pharmaceutical Co. Ltd.
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