Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-04
2002-04-30
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000
Reexamination Certificate
active
06380198
ABSTRACT:
This Application is a 371 of PCT/IT98/00266, filed on Oct. 6, 1998.
SPECIFICATION
The present invention concerns the use of flunarizine for the topical treatment of glaucoma. More specifically, this invention relates to the use of flunarizine, a calcium channel blocking agent known and employed as cerebral and peripheral vasodilator, in a new indication as an antiglaucoma agent for topical ophthalmic treatment.
As it is known, glaucoma is a pathological ophthalmic condition the underlying causes of which are not well understood at present. This condition is usually shown by a progressive increase of the intraocular pressure, leading to severe impairment of the eye structures, in particular to damage to the optic nerve disc and to decrease in the visual field, finally resulting in optic atrophy. The disease is generally connected to an insufficient outflow of aqueous humour from the eye, although other causes, such as, e.g., the production of aqueous humour and the episcleral veins pressure, take part in the regulation of the intraocular pressure.
The rationale of the pharmacological therapy presently in use is to lower the intraocular pressure. The drugs currently used to that aim, divided into classes according to their mechanism of action, are beta-blockers (such as timolol, betaxolol, levobunolol), sympathomimetics (such as epinephrine and dipivephrine), parasympathomimetics or miotics (such as pilocarpine and acetylcholine) and carbonic anhydrase inhibitors (such as acetazolamide and dichlorphenamide). Besides the foregoing drugs well established in use, the search for agents having less side effects and longer lasting activity has lead to evaluate, more recently, the possibility of using for the treatment of glaucoma another class of drugs, i.e. the calcium blocking agents. The latter, also known as “calcium entry blockers” or “calcium antagonists”, are currently used as vasodilators and in the treatment of cardiac affections. For such indications, the most widespread calcium antagonists are, e.g., nifedipine, diltiazem and verapamil.
The role of calcium in the dynamics of aqueous humour and in the control of intraocular pressure has not yet been entirely clarified, although it is known that the production and the outflow of aqueous are modulated also by calcium. As concerns the formation of aqueous, it is to be noted, firstly, that the hydrostatic component due to the arterial pressure and to the pressure of the vessels feeding the ciliary body is calcium-dependent, as it is confirmed by the known systemic vascular action of calcium antagonists. Further, the osmotic pressure due to ionic secretion at the level of the non-pigmented ciliary epithelium is likely to be modulated by calcium, as hypothesised by Abelson et al. (Abelson M. B., Gilbert C. M., Smith L. M., Sustained reduction of intraocular pressure in humans with the calcium channel blocker verapamil, Am. J. Ophthamol. 105; 155 (1988)).
As far as the outflow of the aqueous humour is concerned, calcium ions play a direct role in modulating the pressure of episcleral veins, and some studies suggest that calcium influences the outflow capacity, by maintaining the structural integrity of the trabecuale and of the exterior wall of the Schlemm's canal.
In spite of the foregoing suggestions several experimental works, both on animal models and clinical, and involving both systemic and topical administration, reported contradictory results about the activity of calcium channel blockers in the therapy of glaucoma. For instance, Monica et al. (Monica M. L., Hesse R. J., Messerli F. H., The effect of a calcium-channel blocking agent on intraocular pressure, Am. J. Ophthalmol. 96, 814 (1983)) reports that the oral administration of nitrendipine to patients with moderate hypertension but with normal intraocular pressure slightly lowered the latter, while Beatty and co-workers (Beatty J. F., Krupin T., Nichols P. F., Elevation of intraocular pressure by calcium-channel blockers, Arch. Ophthalmol. 102; 1072, (1984)) did not evidence any effect upon oral administration of verapamil to rabbits, and did even report an increase in the intraocular pressure upon topical administration. More recently, for instance, Payene and coworkers (Payene, L. J., Slagle T. M., Cheeks L. T., Effect of calcium-channel blockers on intraocular pressure, Ophthalmic Res. 22; 337, (1990)) obtained a reduction in the intraocular pressure upon systemic administration of verapamil or nifedipine to rabbits, but did not detect any significant effect upon topical administration of the same agents or of diltiazem by the topical route.
In general, however, at least as far as verapamil is concerned, it may be said that the administration of this drug to man normally results in a reduction of the intraocular pressure. A more consistent reduction upon topical administration has been explained, in particular, by a work of Ettl et al. (Ettl A., Daxer A., Hoffmann U., Calcium channel blockers in the management of low-tension and open-angle glaucoma, Am. J. Ophthalmol. 116; 778, (1993)). These authors have detected, in the rabbit eye, verapamil levels 200 times higher than the levels obtainable by systemic administration.
Accordingly, the use of verapamil in the treatment of ocular hypertension is the object of the international PCT application No. WO 92/07563, filed by Abelson (i.e., the first author cited above) et al. A later publication in the name of the same author is the international application No. WO 96/03986, concerning the treatment of a particular form of glaucoma, referred to as low-tension glaucoma. This pathology is characterised by an intraocular pressure which is almost normal, in spite of the fact that all of the other symptoms of glaucoma are present. In the latter document the therapeutic proposal is generically extended to all calcium-antagonists, many representatives of which are mentioned in a preliminary list. However, the only example of active agent disclosed in the document and supported by experimental data is verapamil.
Another calcium blocking agent that was specifically proposed for use, in a patent document, in the treatment of intraocular hypertension is diltiazem (French patent No. 2593395, published in 1987), while a list of more than one hundred calcium antagonists is presented in the international PCT application No. WO 93/23082. The latter concerns, for use in the treatment of glaucoma, a combination of a compound which lowers the intraocular pressure (i.e., a conventional antiglaucoma agent) and a calcium channel blocking agent. The disclosure does not contain any specific example of preferred combination, nor any experimental detail regarding the activity of any combination.
Some experimental trials on verapamil also allowed to ascertain that the ophthalmic use of the said agent causes an undesirable swelling of the cornea. (Green K., Cheeks L., Hull D. S., Effects of calcium channel blockers on rabbit corneal endothelial function, Curr. Eye Res. 13; 401-408, (1994)). This is particularly critical if one considers the use for the treatment of a chronic condition as is, actually, glaucoma.
Although the entire class of calcium antagonists has already been considered for its potential use in the treatment of glaucoma, there does not seem to have been evidenced the particular activity, against this type of pathologies, of a specific agent belonging to the said class, i.e. flunarizine. It has now been found, and it is the subject-matter of this invention, that the specific calcium antagonist flunarizine, when administered through the topical ocular route, is able to lower the intraocular pressure in a surprisingly more marked way than the other calcium antagonists so far proposed and tested for the therapy of glaucoma.
Within the frame of the studies connected with this invention, it has also been found that some known receptors, referred to as a receptors, are localised in the ocular region, in particular in the ciliary body and in the iris, and that some specific “ligands”, having a &sgr;-agonist activity, significantly lowe
Fay Zohreh
Hedman & Costigan ,P.C.
Laboratoire Medidom S.A.
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