USE OF KETOTIFEN AS OPHTHALMIC AGENT

Abstract: The present invention is related to the use of an ophthalmic composition comprising ketotifen in the preparation of an eye medicament for the treatment allergic conjunctivitis of contact lens wearers.

Description: SE OF KETOTIFEN AS OPHTHALMIC AGENT This invention is directed to the use of an ophthalmic composition comprising a pharmaceutically active agent, in particular ketotifen as an active agent in connection with contact lens, in particular soft contact lens. Prior art teaches that patients who use topical ophthalmic medications and wear soft contact lens must remove their lenses before drop instillation to prevent absorption of the medication into the lenses (Christensen et al., CLAO Journal, 1998, 227-231 ). If said contact lens is not removed and said medicament is administered repeatedly, an accumulation of said absorbed medicament is presumed, which might typically cause ocular irritation, hypersensitivity, keratitis and the like. It has now surprisingly found, that a composition comprising ketotifen or a pharmaceutically acceptable salt thereof, in particular in a concentration of from 0.01 to 0.05 %, is compatible with soft contact lens. Consequently, patients do not have to remove their lens when they are in need of said medication. An object of the present invention is therefore the use of ketotifen or a pharmaceutically acceptable salt thereof in the preparation of an eye medicament to treat allergic conjunctivitis in a patient wearing soft contact lens. A pharmaceutically acceptable ketotifen salt is preferably ketotifen fumarate. The concentration of a ketotifen salt is preferably 0.005 to 0.05 %, more preferred 0.01 to 0.03%, and highly preferred 0.025 %. An addressed composition further comprises a non-ionic tonicity agent and is preferably glycerol. The non-ionic tonicity agent is preferably present in an amount such that the total tonicity of the composition has an osmolarity in the range of 230 to 260 milliosmoles, more preferred to 235 to 255 milliosmoles. If glycerol is used, the concentration of glycerol is preferably in the range of 1.5 to 2.5 %. A preservative may be present, in particular for multi-dose units, but it is routinely not present in single dose units. Such single dose units are in particular preferred in the context with the present invention. If a preservative is present, a preferred preservative is benzalkonium chloride. Typically the amount of the preservative is 0.005 to 0.02 %, more preferred 0.01 %. An acid or base may be used in small amounts, such as 0.05 to 0.1 %, for adjusting the pH of such solution. Preferred is for example the use of small amounts of sodium hydroxide 1 N, e.g. 0.075 %. The pH of an addressed composition is adjusted to weak acidity for optimization of stability and tolerability, and said pH of weak acidity is understood to mean preferably a pH of 4.4 to 5.8, more preferably a pH of 5 to 5.5, and most preferably a pH of 5.3. A preferred composition of this invention comprises ketotifen fumarate, in a concentration of 0.01 to 0.04 %, glycerol in a concentration of 2 to 2.5 %, optionally benzalkonium chloride in an amount of 0.005 to 0.02 %, sodium hydroxide, and water. An even more preferred composition comprises ketotifen fumarate, in a concentration of 0.025 %, glycerol in a concentration of 2.125 %, optionally benzalkonium chloride in an amount of 0.01 %, sodium hydroxide, and water. The ophthalmic compositions mentioned above are useful as eye drops, in particular as unpreserved single dose units. Said eye drops do have a high therapeutic value because they can be used for the treatment and the temporary prevention of itching of the eye due to allergic conjunctivitis, and they can be used for the treatment and prevention of signs and symptoms of seasonal allergic conjunctivitis. Their therapeutic utility has now been greatly improved by the findings of the present invention, which clearly indicate that ketotifen is not significantly absorbed in soft contact lens and is therefore compatible with soft contact lens. Soft contact lenses are typically classified both by their water content and the ionic nature of the polymer. Soft contact lenses contain typically of from 1 to 85 % water, preferably of from 5 to 60% water and in particular of from 25 - 55% water. A particular generic class of soft contact lens material is called "filcon". Typical examples of a filcon material are nelfilcon, etafilcon, alfafilcon and vifilcon. Accordingly, within the scope of the present invention, the term soft contact lens is preferably referring to a filcon material, more preferably to nelfilcon, etafilcon, alfafilcon and vifilcon material, and most preferably to a nelfilcon material. Another object of the present invention is a method to treat allergic conjunctivitis in a patient wearing soft contact lens, which method comprises the direct administration of an aqueous eye drop preparation comprising ketotifen or a pharmaceutically active salt thereof, characterized in that said ketotifen is not significantly absorbed in said soft contact lens. An ophthalmic composition of the present invention may be manufactured by mixing the ingredients, and packaging the resulting mixture, both as known in the art. Sterilization of the composition and the primary package can be effected e.g. by gamma irradiation, by ethyleneoxide treatment, by electron beam, by autoclaving or by steam sterilization. Typical examples are mentioned infra but are not deemed to restrict the scope of the utility of the present invention. Example 1 : Multidose Units: Ketotifen fumarate 0.25 mg (0.025 %) Benzalkonium chloride 0.10 mg (0.010 %) Glycerol 100 % 21.25 mg (2.125 %) Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %) Water for injection ad ad 1.0 ml Example 2: Single dose Units: Ketotifen fumarate 0.25 mg (0.025 %) Glycerol 100 % 21.25 mg (2.125 %) Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %) Water for injection ad ad 1.0 ml

Claims: Claims 1. Use of ketotifen or a pharmaceutically acceptable salt thereof in the preparation of an eye medicament to treat allergic conjunctivitis in a patient wearing soft contact lens. 2. Use of claim 1 wherein the ketotifen salt is ketotifen fumarate. 3. Use of claim 1 wherein the concentration of the ketotifen salt is 0.005 to 0.05 %, more preferred 0.01 to 0.03%, and highly preferred 0.025 %. 4. Use of claim 1 wherein said eye medicament further comprises a non-ionic tonicity agent, said tonicity agent being preferably glycerol. 5. Use of claim 1 wherein said eye medicament further comprises a preservative. 6. Use of claim 1 wherein said eye medicament comprises no preservative. 7. Use of claim 1 wherein said eye medicament comprises: Ketotifen fumarate 0.25 mg (0.025 %), Benzalkonium chloride 0.10 mg (0.010 %), Glycerol 100 % 21.25 mg (2.125 %), Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %), Water for injection ad ad 1.0 ml. 8. Use of claim 1 wherein said eye medicament comprises: Ketotifen fumarate 0.25 mg (0.025 %), Glycerol 100 % 21.25 mg (2.125 %), Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %), Water for injection ad ad 1.0 ml. 9. Method to treat allergic conjunctivitis in a patient wearing soft contact lens, which method comprises the direct administration of an aqueous eye drop preparation comprising ketotifen or a pharmaceutically active salt thereof, characterized in that said ketotifen is not significantly absorbed in said soft contact lens. 10. Method of claim 9, wherein said allergic conjunctivitis is seasonal allergic conjunctivitis and wherein said ketotifen is preferably a non-preserved composition.

Inventors: FETZ ANDREA, TRIMMING JULIAN, FETZ, ANDREA, TRIMMING, JULIAN
Applicants: FETZ ANDREA, NOVARTIS AG, NOVARTIS ERFIND VERWALT GMBH, TRIMMING JULIAN, FETZ, ANDREA, NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.H., TRIMMING, JULIAN
Application year: 2000
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P27, C07D409