COMPOSITIONS FOR TREATMENT OF GLAUCOMA COMPRISING PILOCARPINE AND A BETA-BLOCKER

Abstract: Compositions for controlling glaucoma and ocular hypertension are disclosed. These compositions comprise pilocarpine, a beta-blocker such as betaxolol, an ion exchange resin and a polyanionic polymer such as carbomers.

Description: C0MP0SITI0NS FOR TREATMENT OF GLAUCOMA COMPRISING PILOCARPINE AND A BETA-BLOCKER This invention is directed to compositions which are useful for the treatment of glaucoma and ocular hypertension. BACKGROUND OF THE INVENTION European Patent No. 253 717 discloses ophthalmic formulations containing combinations of specific beta adrenergic receptor antagonists (beta-bloc ers) and pilocarpine for the treatment of elevated intraocular pressure in patients refractory to treatment with beta-blockers alone. The patent discloses a beta-blocker concentration of 0.5 to 1.0 weight/volume percent (wt./v.%) and a pilocarpine concentration of 2 to 4 wt./v.%. The claimed formulation is made by combining lyophilized pilocarpine hydrochloride and a solution of an ophthalmic beta-blocker. A product known as Normoglaucon has been sold in Germany. The product contains 2% pilocarpine and 0.1 % metipranolol. U.S. Patent No. 4,474,751 discloses an ophthalmic drug delivery system using selected polymers which use the body temperature and pH to induce liquid to gel transition of the polymers. The patent discloses an extensive list of drugs which can be administered by the system, including a combination of timoloi or R-timolol with pilocarpine. The specific examples do not describe any formulations of any drug combinations. SUMMARY OF THE INVENTION The present invention is directed to formulations for treating glaucoma and/or ocular hypertension in mammals, including humans. The formulations contain a combination of a beta-blocker, pilocarpine, a cation exchange resin, and a polyanionic polymer. The invention is also directed to methods for treating glaucoma and/or ocular hypertension by topical administration of the formulations to the eye. DESCRIPTION OF THE PREFERRED EMBODIMENTS Many people suffering from glaucoma or ocular hypertension cannot control their elevated intraocular pressure (IOP) using beta-blockers alone. It is known that in many instances control can be gained by using an additional drug known to reduce intraocular pressure, such as pilocarpine, in combination with a beta-blocker. Pilocarpine is a cholinergic agonist that has been used for a long time to reduce intraocular pressure associated with glaucoma and ocular hypertension. While it is known to be relatively safe and effective, it does cause side effects, such as ocular discomfort, headache, and blurred vision. These side effects are uncomfortable for the patient and contribute to poor patient compliance. The present invention provides a formulation which is useful to those people requiring two drugs to control the elevated intraocular pressure associated with their glaucoma and/or ocular hypertension with a significant reduction in side effects. The formulations of the present invention are believed to have the following advantages over known formulations: better patient compliance due to decreased side effects and by alleviating the need for two separate medications with different dosing regimens, better bioavailabiiity of pilocarpine due to improved suspension properties, and reduced side effects. The formulation of the present formulation contains about 0.1 to 1.0 weight/volume % (wt.A/ol.%) beta-blocker; about 0.25 to 10.0 wt./vol.% pilocarpine; about 0.05 to 10 wt./vol.% pharmaceutically acceptable ion exchange resin and about 0.01 to 5.0 wt./vol.% polyanionic polymer such as Carbomer 934P or 974P. Useful beta-blockers (e.g. betaxolol, timolol, befunolol, labetalol, propranolol, bupranolol, metaproiol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranoiol, celiprolol, azotinolol, diacetolol, acebutolol, atenolol, isoxaprolol), polyanionic polymers, and ion exchange resins of the invention are disclosed in U.S. Patent No. 4,911 ,920, from which this case descends, and which is incorporated herein by reference. Since both pilocarpine and most beta-blockers are basic compounds, they readily bind with strongly acidic ion exchange resins, such as poly(styrene-divinyl benzene) sulfonic acid. Upon administration to the eye, the pilocarpine and beta- blocker relatively slowly disassociate from the resin. Although the beta-blocker, betaxolol, alone has been formulated with an ion exchange resin and a polyanionic polymer resulting in a more comfortable formulation (Betoptic ® S, available from Alcon Laboratories, Inc.), it is unexpected that side effects associated with pilocarpine would be significantly reduced through use of the present formulation. The stability of pilocarpine in solution is limited at physiological pH. Therefore, the formulations of the present invention are prepared in two parts. As shown in the examples, the pilocarpine portion (Part I) is prepared at or below about pH 5. The beta-blocker portion (Part II) is prepared at about pH 8. Mixing of the two parts by the patient, doctor, or pharmacist is required before application to the eye. The reconstituted formulation is close to physiological pH and is stable for about one month at room temperature. The preferred reconstituted formulation contains 0.25% betaxolol base, 1.75% pilocarpine, 0.25% poly(styrene-divinyl benzene) sulfonic acid (Amberlite, Rohm & Haas), and 0.40% of Carbomer 934P (B.F. Goodrich). Betaxolol is a known compound, see U.S. Patent Nos. 4,252,984, 4,311 ,708, and . 4,342,783. The formulations of the present invention can be used to control glaucoma and ocular hypertension through topical administration to the eye one to four times daily according to the discretion of a skilled clinician. The following examples are representative of formulations of the present invention and are not meant to be limiting. EXAMPLE 1 PART 1 FORMULA INGREDIENTS PERCENT wt./vol. Pilocarpine Hydrochloride 8.75 Sodium Hydroxide and/or QS pH to 5.0 +/-0.2 Hydrochloric Acid Purified Water QS to 100 PART II FORMULA INGREDIENTS PERCENT wt./vol. Betaxolol Hydrochloride 0.35 * Poiy(Styrene-Divinyl Benzene) 0.313 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 934P 0.50 Boric Acid 0.10 Mannitol 2.20 Disodium Edetate 0.0125 Benzalkonium Chloride, Solution 0.0125 + 5% XS Sodium Hydroxide and/or QS pH to 8.0 +/-0.2 Hydrochloric Acid Purified Water QS to 100 Equivalent to 0.313% Betaxolol Base RECONSTITUTION OF PARTS I AND The product composition after reconstitution (1 mL of Part I, and 4 mL of Part II, is given below. The entire contents of Part I are transferred to the Part II container and mixed well for 60 seconds. Reconstituted Product INGREDIENTS PERCENT wt./vol. Betaxolol Hydrochloride, USP 0.28 * Pilocarpine Hydrochloride, USP 1 .75 Poly(Styrene-Divinyl Benzene) 0.25 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 934P, NF 0.40 Boric Acid, NF 0.08 Mannitol, USP, USP 1 .76 Disodium Edetate, USP 0.01 Benzalkonium Chloride, Solution, NF 0.01 + 5% XS Purified Water, USP 95 - 96 * Equivalent to 0.25% Betaxolol Base EXAMPLE 2 PART 1 FORMULA INGREDIENTS PERCENT wt./vol. Pilocarpine Hydrochloride 8.75 Sodium Hydroxide and/or QS pH to 5.0 +/-0.2 Hydrochloric Acid Purified Water QS to 100 PART II FORMULA INGREDIENTS PERCENT wt./vol. Betaxolol Hydrochloride 0.35 * Poly(Styrene-Divinyl Benzene) 0.313 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 974P 0.50 Boric Acid 0.10 Mannitol 2.20 Disodium Edetate 0.0125 Benzalkonium Chloride, Solution 0.0125 + 5% XS Sodium Hydroxide and/or QS pH to 8.0 +/-0.2 Hydrochloric Acid Hamposyl L 0.0375 Purified Water QS to 100 Equivalent to 0.313% Betaxolol Base RECONSTITUTION OF PARTS I AND II The product composition after reconstitution (1 mL of Part I, and 4 mL of Part II, is given below. The entire contents of Part I are transferred to the Part II container and mixed well for 60 seconds. Reconstituted Product INGREDIENTS PERCENT wt./vol. Betaxolol Hydrochloride, USP 0.28 * Pilocarpine Hydrochloride, USP 1 .75 Poly(Styrene-Divinyl Benzene) 0.25 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 974P, NF 0.40 Boric Acid, NF 0.08 Mannitol, USP, USP 1 .76 Disodium Edetate, USP 0.01 Benzalkonium Chloride, Solution, NF 0.01 + 5% XS Hamposyl L 0.03 Purified Water, USP 95 - 96 Equivalent to 0.25% Betaxolol Base EXAMPLE 3 Formulations containing different beta-blockers at different concentrations and different concentrations of pilocarpine can be made by a person skilled in the art of making ophthalmic formulations. PART 1 FORMULA INGREDIENTS PERCENT wt./vol. Pilocarpine Hydrochloride 1 .25 to 50 Sodium Hydroxide and/or QS pH to 5.0 +/-0.2 Hydrochloric Acid Purified Water QS to 100 PART II FORMULA INGREDIENTS PERCENT wt./vol. Beta-blocker 0.125 to 1.252 ** Poly(Styrene-Divinyl Benzene) 0.125 to 1.252 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 934P 0.50 Boric Acid 0.10 Mannitol 2.20 Disodium Edetate 0.0125 Benzalkonium Chloride, Solution 0.0125 + 5% XS Sodium Hydroxide and/or QS pH to 8.0 +/-0.2 Hydrochloric Acid Purified Water QS to 100 * Equivalent to provide for 0.25 to 10.0 wt./vol. % upon reconstitution. ** Equivalent to provide for 0.1 to 1 .0 wt./vol. % upon reconstitution. RECONSTITUTION OF PARTS I AND II The product composition after reconstitution (1 mL of Part I, and 4 mL of Part II, is given below. The entire contents of Part I are transferred to the Part II container and mixed well for 60 seconds. Reconstituted Product INGREDIENTS PERCENT wt./vol. Beta-blocker 0.1 to 1 .0 Pilocarpine Hydrochloride 0.25 to 10.0 Poly(Styrene-Divinyl Benzene) 0.1 to 1 .0 Sulfonic Acid (Amberlite IRP-69 Hydrogen Form) Carbomer 934P, NF 0.40 Boric Acid, NF 0.08 Mannitol, USP, USP 1 .76 Disodium Edetate, USP 0.01 Benzalkonium Chloride, Solution, NF 0.01 + 5% XS Purified Water, USP 95 - 96

Claims: We Claim: 3 1. A topical ophthalmic composition for controlling glaucoma and/or ocular 4 hypertension comprising 0.1 to 1.0 wt./vol. % beta-blocker, 0.25 to 10.0 wt./vol. % 5 pilocarpine, 0.05 to 10.0 wt./vol. % ion exchange resin, and 0.01 to 5.0 wt./vol. % e polyanionic polymer. 7 8 2. The composition of Claim 1 wherein the beta-blocker is selected from the group 9 consisting of betaxolol, timolol, befunoiol, labetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotinolol, diacetolol, acebutolol, atenolol, isoxaprolol. 3. The composition of Claim 2 wherein the beta-blocker is betaxolol. 4. The composition of Claim 3 wherein the ion exchange resin in poly(styrene- divinyl benzene) sulfonic acid and the polyanionic polymer is Carbomer 934P. 5. The composition of Claim 4 wherein the betaxolol concentration is 0.25%, the pilocarpine concentration is 1.75%, the resin concentration is 0.25%, and the Carbomer 934P concentration is 0.40%. 6. The composition of Claim 3 wherein the ion exchange resin is poly(styrene- divinyl benzene) sulfonic acid and the polyanionic polymer is Carbomer 974P. 7. The composition of Claim 6 wherein the betaxolol concentration is 0.25%, the pilocarpine concentration is 1.75%, the resin concentration is 0.25%, and the Carbomer 974P concentration is 0.40%. 8. A method for controlling intraocular pressure by topically applying to the eye a composition which comprises 0.1 to 1.0 wt./vol. % beta-blocker, 0.25 to 10.0 wt./vol. % pilocarpine, 0.05 to 10.0 wt./vol. % ion exchange resin, and 0.01 to 5.0 wt./vol. % polyanionic polymer. 9. The method of Claim 8 wherein the beta-blocker is selected from the group consisting of betaxolol, timolol, befunolol, labetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotinolol, diacetolol, acebutolol, atenolol, isoxaprolol. 10. The method of Claim 9 wherein the beta-blocker is betaxolol. 11. The method of Claim 10 wherein the ion exchange resin is poly(styrene-divinyl benzene) sulfonic acid and the polyanionic polymer is Carbomer 934P. 12. The method of Claim 11 wherein the betaxolol concentration is 0.25%, the pilocarpine concentration is 1.75%, the resin concentration is 0.25%, and the Carbomer 934P concentration is 0.40%. 13. The method of Claim 10 wherein the ion exchange resin is poly(styrene-divinyl benzene) sulfonic acid and the polyanionic polymer is Carbomer 974P. 14. The method of Claim 13 wherein the betaxolol concentration is 0.25%, the pilocarpine concentration is 1.75%, the resin concentration is 0.25%, and the Carbomer 974P concentration is 0.40%.

Inventors: ALI YUSUF, JANI RAJNI, MCCARTY GEORGE R, ALI, YUSUF, JANI, RAJNI, MCCARTY, GEORGE, R.
Applicants: ALCON LAB INC, ALCON LABORATORIES, INC.
Application year: 1995
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47, A61P27