Preservative free brimonidine and timolol solutions

This Application is a national phase application under 35 U.S.C. § 371 of PCT Patent Application No. PCT/US11/45656, which claims priority to U.S. Provisional Patent Application Ser. No. 61/368,681, which was filed on Jul. 29, 2010, both of which are incorporated herein by reference in their entirety.

The present application is directed to preservative-free formulations of brimonidine and timolol.

Brimonidine tartrate is a selective and potent alpha-2 adrenergic agonist. Brimonidine lowers intraocular pressure by reducing aqueous humor production and increasing uveoscleral outflow. Timolol maleate is a non-selective beta adrenergic receptor blocking agent. Currently marketed brimonidine and timolol combination ophthalmic solution with preservative is indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP.

Use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease. Management of open angle glaucoma and ocular hypertension require long term treatment with eye drops containing preservatives. Symptoms and signs of ocular surface disease such as ocular surface breakdown, irritation, burning, foreign body sensation, dryness, inadequate quantity of tears, etc. are prevalent in a large proportion of patients with open angle glaucoma and ocular hypertension.

Compared to eye drops preserved with benzalkonium chloride, preservative-free eye drops induce significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, hyperemia, foreign body sensation, stinging or burning, and dry eye sensation.

Patients experiencing hypersensitivity reactions with benzalkonium chloride cannot use a commercial brimonidine and timolol products containing benzalkonium chloride which is preserved even with 0.005% w/v benzalkonium chloride. Benzalkonium chloride also may be absorbed by the soft contact lenses therefore patients wearing soft contact lenses are advised to remove lenses prior to administration and wait at least 15 minutes before reinserting them.

The present invention is directed to a brimonidine and timolol solutions without benzalkonium chloride or other preservatives which will be superior from a safety & tolerability standpoint while maintaining and/or improving its efficacy of IOP lowering and be available for use by patients hypersensitive to benzalkonium chloride and be convenient for patients wearing soft contact lenses.

Brimonidine and timolol ophthalmic solution without preservative is a clear, greenish-yellow, isotonic, sterile solution. The drug product contains brimonidine and timolol as the active ingredients. The inactive ingredients are tonicity and buffer agents, and purified water. Suitable buffers such as sodium phosphate dibasic heptahydrate and citric acid monohydrate and suitable tonicity agents such as sodium chloride may be included. The final solution would be an aqueous solution having a pH value within the range of about 6.5 to about 7.3, preferably 6.9 and osmolality in range of 260-220 mOsmol/kg.

The compositions of the present invention may be generally made according to the teachings of U.S. Pat. No. 7,323,463 which is hereby incorporated by reference in its entirety.

Certain embodiments of the present invention are described below:

1) A preservative free brimonidine and timolol composition for lowering intraocular pressure in a human patient comprising the following formulation: about 0.2% w/v brimonidine; about 0.5% w/v timolol; about 2.15% w/v sodium phosphate dibasic heptahydrate; water and at a pH of about 6.9. 2) A preservative free brimonidine and timolol composition for lowering intraocular pressure in a human patient comprising the following formulation: 0.2% w/v brimonidine; 0.5% w/v timolol; about 2.15% w/v sodium phosphate dibasic heptahydrate; hydrochloric acid, sodium hydroxide, and water and at a pH of about 6.9. 3) The preservative free composition of paragraphs 1-2 wherein the timolol is timolol maleate at 0.68% w/v and brimonidine is brimonidine tartrate. 4) A composition as described in Table 1. 5) The composition of any of paragraphs 1-4 wherein the composition is a solution and is useful for treating glaucoma. 6) The composition of any of paragraphs 1-4 wherein the composition is a solution and is contained in a unit dose kit form. 7) The composition of any of paragraphs 1-4 wherein the composition is applied at least once a day. 8) The composition of paragraph 2 wherein the composition is applied twice a day. 9) The composition of paragraphs 1 or 2 wherein the composition has greater bioavailability of brimonidine and timolol in the eye of the patient with fewer side-effects than brimonidine and timolol preserved with benzalkonium chloride. 10) The composition of paragraphs 1 and 2 wherein the composition is contained in a multi-dose vial which has anti-preservative properties such as metal-ions imbedded in its dispensing tip. 11) The composition of paragraph 12 wherein the metal ions are silver ions.

A brimonidine and timolol ophthalmic formulation of the present invention without preservative is shown in Table-1.

The present invention is directed to formulations of brimonidine and timolol without benzalkoinium benzalkonium chloride as a preservative. As a result of the removal of benzalkonium chloride, the present invention results in the same or greater bioavailability of the active ingredients bimatoprost and timolol in the eye without the unwanted side-effects associated with the preservative benzalkonium chloride which will improve efficacy of the product in lowering IOP per dosage unit, superior patient compliance and with fewer side-effects such as hyperemia. Other side effects which may be avoided include asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance.