MEDICAMENTS FOR TREATMENT OF OCULAR INFLAMMATION

Abstract: The use of a compound of formula (I) wherein: X represents H or halogen; Y represents H₂, H(OH), H(Acyl) or O; R¹ represents H, CH₃ or a halogen atom; R² represents alkyl having 1-4 carbon atoms; R³ represents H, OAcyl, Oalkyl, and CH₃; R⁴ represents H and alkyl having 1-4 carbon atoms; and C₁-C₂ and C₆-C₇ are either a saturated or an unsaturated bond, is described for the manufacture of a medicament for treatment of ocular inflammation.

Description: The present invention relates to the treatment of ophthalmic inflammatory disorders with a class of steroids which does not adversely affect intraocular pressure. Anti-inflammatory steroids, such as, hydrocortisone, prednisolone, dexamethasone and fluorometholone, are very useful in controlling a wide range of ophthalmic inflammatory conditions. However, this indication is not without risk of an induced side effect associated with the chronic use of these compounds. This side effect may be manifested by a rise in intraocular pressure (IOP) in steroid responders. The above-described manifestations can generally be tolerated in most patients over a relatively short treatment period, such as, four to six weeks or less. However, the increase in IOP caused by these compounds is generally unacceptable over extended periods of treatment, such as one to twelve months or more. The increased intraocular pressure associated with the short-term use of these compounds may also be unacceptable in certain patients, such as, patients already suffering from an elevated IOP (e.g., glaucoma patients). Therefore, a need exists for anti-inflammatory compounds suitable for ophthalmic use which do not cause any significant increase in IOP, and for a method of treating ophthalmic inflammatory disorders utilizing such compounds. There is also known from Rote Liste 1985, with reference to entry No. 67059 Ophtocortin® Medryson, that 11 β-hydroxy-6 α methyl-4-pregnen-3,20-dione and its salts are useful as anti-inflammatory agents for opthamalogical use. These compounds are further described in U.S. Patent 2,968,655. A principal object of the present invention is the provision of pharmaceutical compositions and methods of using such compositions in treating ophthalmic inflammatory disorders which does not result in any significant increase in IOP, or in fact stabilizes or lowers IOP; wherein the method comprises applying said compositions comprising an effective amount of a steroid of Structure (I), below, to the affected eye(s) when indicated for the relief of inflammation: wherein: X = H or halogen; Y = H₂, H(OH), H(OAcyl) or O; R¹ = H, CH₃ or halogen; R² = alkyl having 1-4 carbon atoms; R³ = H, Oacyl, Oalkyl, or CH₃; R⁴ = H or alkyl having 1-4 carbon atoms; and C₆-C₇ is a saturated or an unsaturated bond. The invention thus provides use of a compound of the general formula (I) for the manufacture of a medicament for treatment of ocular inflammation. The compounds (I) are disclosed, among others, in U.S. Patent 3,947,478, which also discloses their anti-inflammatory dermatological utility. While the anti-inflammatory utility of these compounds as dermatologicals is known, there is no disclosure indicating ophthalmic utility, i.e., that the compounds of formula (I) have anti-inflammatory activity in the eye and that their use does not adversely affect IOP. In this regard the art has long searched for a steroid or class of steroids which would meet the following features of the steroids of formula (I): 1) ophthalmic anti-inflammatory activity; 2) capable of topical delivery; and 3) does not raise IOP. The following species member of the genus defined by formula (I) is especially preferred: The compounds of formula (I) may be incorporated into various types of ophthalmic formulations for delivery to the eye. For example, these compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride and water to form an aqueous, sterile ophthalmic suspension. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulation may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of Carbopol -940 (a carboxy vinyl polymer available from the B. F. Goodrich Company) according to published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated. The specific type of formulation selected will depend on various factors, such as, the type of inflammation being treated (e.g., internal or external), and dosage frequency. Ophthalmic suspensions, ointments and gels are the preferred dosage forms. The compounds will normally be contained in these formulations in an amount of 0.05% to 2.0% by weight. Thus, for topical presentation these formulations would be delivered in modest excess to the surface of the eye 1-3 times/day depending upon the discretion of the clinician. While preservatives are normally recommended for multidose containers, their presence is not critical. Pharmceutical compositions of the present invention designed for single use do not require any preservative. Intracameral delivery is also contemplated by the present invention, for example, during surgery. Typically, such intracameral formulations would contain from 0.0001% to 0.05% by weight of one or more compounds of Structure (I) in an aqueous vehicle, for example, a dispersion in HEALON (Pharmacia). Details of the use of such compositions delivered intracamerally by injection or during surgery, would be left to the discretion of the clinician and would be indicated to combat internal uveal tract inflammations. Example 1 The formulations set out below illustrate the dosage forms which may be utilized in the present invention. In these formulations, the term "steroid" represents any of the above-described compounds of Structure (I), specifically including the compound of Structure (Ia). The treatment method of the present invention comprises applying an anti-inflammatory effective amount of a compound of Structure (I) to the affected ocular tissue when indicated for the relief of inflammation. The dosage regimen utilized will depend on various factors, such as, the severity of the inflammation and the duration of action of the particular formulation utilized. In general, the above-described formulations may be topically applied, for example, as drops to the upper globe, or as a 0.5-1 cm strip of ointment or gel to the lower conjunctival sac of the eye. Suspensions will generally be applied 2 to 4 times daily, while ointments or gels will generally be applied once or twice daily. The application of sustained release formulations (e.g., polymer based gels) once daily at bedtime will be preferred in some conditions. The above-described formulations are useful in treating virtually any type of ocular inflammation. These formulations are especially useful in the treatment of ocular inflammation in patients who are predisposed to experiencing elevated intraocular pressure when treated with a conventional steroid compound; this class of patients, which is estimated as constituting approximately 5% of the general population, is referred to as "steroid responders." The formulations also have special value in treating ocular inflammation in patients suffering from open-angle glaucoma, since it has been estimated that approximately 92% of these patients experience a large increase in intraocular pressure after chronic (i.e., 6 to 8 weeks) steroid therapy. Finally, the formulations also find special use in treating the inflamed ocular tissue of patients who are predisposed to open-angle glaucoma or ocular hypertension. The present invention has been described above in connection with certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto. The invention is only limited by the claims which follow.

Claims: Use of a compound of the general formula (I): wherein: X represents H or halogen; Y represents H₂, H(OH), H(OAcyl) or O; R¹ represents H, CH₃ or a halogen atom; R² represents alkyl having 1-4 carbon atoms; R³ represents H, OAcyl, Oalkyl, or CH₃; R⁴ represents H and alkyl having 1-4 carbon atoms; and C₆-C₇ is either a saturated or an unsaturated bond, for the manufacture of a medicament for treatment of ocular inflammation. Use according to claim 1, wherein the compound of general formula (I) is: Use according to claim 1 or 2, wherein the manufacture comprises combining a compound of general formula (I) with one or more of ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers and sodium chloride together with water to form an aqueous sterile ophthalmic suspension. Use according to claim 1 or 2, wherein the manufacture comprises combining a compound of general formula (I) with a preservative in an appropriate vehicle to form a sterile ophthalmic ointment. Use according to claim 1 or 2, wherein the manufacture comprises suspending a compound of general formula (I) in a hydrophilic base, optionally incorporating one or more preservatives and tonicity agents. Use according to any of claims 1 to 5, wherein the compound of general formula (I) is contained in the medicament in an amount of from 0.05% to 2.0% by weight.

Inventors: BOLTRALIK, JOHN J.
Applicants: ALCON LABORATORIES INC
Application year: 1987
Main classification: A61K31
IPC codes: A61K31