AU2007254671B2 - Combination of brimonidine and timolol for topical ophthalmic use - Google Patents

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title ""Combination of brimonidine and timolol for topical ophthalmic use"" The following statement is a full description of this invention, including the best method of performing it known to me/us:- P:\WPDOCSCRN\XJ\Spc\20331335 spcM Ist SPA do-9/10/209 COMBINATION OF BRIMONIDINE AND TIMOLOL FOR TOPICAL OPHTHALMIC USE BACKGROUND OF THE INVENTION 5 This invention relates to the topical ophthalmic use of brimonidine in combination with timolol when indicated for treatment of glaucoma or ocular hypertension. Such combinations or formulations are available for separate use in the ophthalmic art and have been combined in serial application during the course of treatment of glaucoma. However, 10 there are concerns and expressed reservations in the ophthalmic community about patient compliance when the patient is required to administer separate medications to treat a singe disease or condition such as glaucoma. There is, moreover, a long felt need for an effective and safe topical ophthalmic pharmaceutical composition including brimonidine and timolol which has increased stability and requires a lower effective concentration of 15 preservative as compared to the individual agents taken alone. Finally, there is a need to increase the efficacy of many topical ophthalmic agents, without increasing the systemic concentration of such topical agents, since it is well known that many of such topically applied ophthalmic agents cause systemic side effects, e.g. drowsiness, heart effects, etc. Unexpectedly it has been discovered that brimonidine in combination with timolol meets 20 these criteria. Brimonidine is disclosed in U.S. Patent 3,890,319. The use of brimonidine for providing neuroprotection to the eye is disclosed in U.S. Patents 5,856,329; 6,194,415 and 6,248,741. Timolol, as an ophthalmic drug, is disclosed in U.S. Patents 4,195,085 and 25 4,861,760. Summary of the invention A first aspect of the invention provides an ophthalmic pharmaceutical composition useful in the treatment of glaucoma or ocular hypertension comprising an effective amount of brimonidine and an effective amount of timolol in a pharmaceutically acceptable carrier. 30 A second aspect of the invention provides a method of treating glaucoma which comprises administering a therapeutically effective amount of a composition as defined in P \WPDOCS\CRN\)XJSpc\2011I1335 spec I SPA doc-9/10/2(09 -2 the first aspect to the affected eye. A third aspect of the invention provides a method of lowering intraocular pressure which comprises administering a therapeutically effective amount of a composition as defined in the first aspect to the affected eye. 5 A fourth aspect of the invention provides an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for lowering intraocular pressure and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for lowering intraocular pressure and wherein said 10 pharmaceutical agent comprises effective amount of brimonidine and an effective amount of timolol. A fifth aspect of the invention provides a method of reducing intraocular pressure comprising administering a composition as defined in the first aspect to a mammal in need thereof. 15 DESCRIPTION OF THE INVENTION Brimonidine is an alpha adrenergic agonist represented by the following formula: HN NH COOH BrI Br H-C-OH N ~ NI N~ N~ HO-C-H COOH 20 The chemical name for brimonidine is 5-Bromo-6-(2 imidazolindinylideneamino)quinoxaline L-tartrate. Timolol is a beta adrenergic agent represented by the following formula: 25 P XWP1)OCS'CRNUJXM~PcQM3l115 spc, I v SPA dM 'I .!w2') -2A S NH 3 C

CH

3 N

CH

3 H OH o< 0 HO N 0 ., 3 Brimonidine is available from Allergan, Inc., Irvine, California as an ophthalmic pharmaceutical product having the name Alphagan@. Timolol is available from various sources, including Merck Co., Rahway, New s Jersey. The compositions of the present invention are administered topically. The dosage is 0.001 to 1.0, e.g. mg/per eye BID; wherein the cited mass figures represent the sum of the two components, brimonidine and timolol. The compositions of the present invention can be administered as solutions in a suitable 10 ophthalmic vehicle. In forming compositions for topical administration, the mixtures are preferably formulated as 0.01 to 0.5 percent by weight brimonidine and 0.1 to 1.0 percent by weight timolol solution in water at a pH of 4.5 to 8.0, e.g. about 6.9. While the precise regimen is left to the discretion of the clinician, it is 15 recommended that the solution be topically applied by placing one drop in each eye two times a day. Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention include preservatives, co-solvents and viscosity building agents. 20 Antimicrobial Preservative: Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl 25 paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. In the prior art ophthalmic products, typically such preservatives are employed at a level of from 0.004% to 0.02%. In the compositions of the present application the preservative, preferably benzalkonium chloride, may be employed at a level of from 0.001% to less than 4 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzalkonium chloride of 0.005% is sufficient to preserve the compositions of the present invention from microbial attack. This concentration may be advantageously compared to the requirement of 0.01% s benzalkonium chloride to preserve timolol in the individual, commercially-available ophthalmic products. Moreover, it has been found that adequate lowering of intraocular pressure has been obtained when administering the compositions of this invention twice a day as compared to the FDA-approved regimen wherein brimonidine ophthalmic solution, i.e. Alphagan@ ophthalmic io solution is administered three times a day and timolol ophthalmic solution, i.e. Timoptic® ophthalmic solution is administered twice a day. This results in the exposure of the patient to 67% and 50% of benzalkonium chloride, with the compositions of this invention, as compared to the administration of Alphagan@ and Timoptic@, respectively. In FDA-approved adjunctive therapy, wherein 15 Alphagan@ and Timoptic@ are serially administered, the patient is exposed to almost three times the concentration of benzalkonium chloride as compared to the administration of the compositions of this invention twice a day. (It is noted that it is known that benzalkonium chloride at high concentrations is cytotoxic. Therefore, minimizing the patient's exposure to benzalkonium chloride, while 20 providing the preservative effects afforded by benzalkonium chloride, is clearly desirable.) Co-Solvents: 25 The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such cosolvents include polysorbate 20, 60, and 80, Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known to those skilled in the art. Typically such co-solvents are employed at a level of from 0.01 % to 2% by weight.

5 Viscosity Agents: Viscosity increased above that of simple aqueous solutions may be desirable s to increase ocular absorption of the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity building agents include as examples polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl 10 methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight. The present invention further comprises an article of manufacture comprising packaging material and a pharmaceutical agent contained within said is packaging material, wherein the phannaceutical agent is therapeutically effective for lowering intraocular pressure and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for lowering intraocular pressure and wherein said pharmaceutical agent comprises an effective amount of brimonidine and an effective amount of timolol. 20 The following example is a representative pharmaceutical composition of the invention for topical use when indicated for treating glaucoma. EXAMPLE I The combination of active pharmaceutical ingredients is as follows: Brimondine Tartrate 0.20 %(w/v) and Timolol Maleate 0.68 %(w/v) 25 (Equivalent to 0.50 %(w/v) timolol) The Brimonidine-Timolol combination formulation presented in the Table, below, is a sterile, preserved, aqueous solution. The formulation vehicle is based upon a timolol ophthalmic solution which contains an isotonic phosphate buffer 6 system at pH 6.9. The formulation preservative is benzalalkonium chloride (BAK) at a concentration of 0.005 %(w/v) (50 ppm). The formulation passes regulatory required preservative efficacy testing (PET) criteria for USP (United States Pharmacopoeia) and EP (European Pharmacopoeia-A and -B over 24 months. 5 Table Brimomdine Tartrate Active 0.2 Timolol Maleate, EP Active 0.681 Benzalkonum Chloride, NF, EP Preservative 0.005 Sodium Phosphate, monobasic monobydrate, USP Buffer 0.43 Sodium Phosphate, dibasic beptahydrate, USP Buffer 2.15 Sodium Hydroxide, NF pH adjust Adjust pH to 6.9 Hydrochloric Acid, NF pH adjust Adjust pH to 6.9 Purified Water, USP, EP Solvent q.s. ad 'Equivalent to 0.5 %(w/v) Timolol, free base The pharmaceutical composition of Example I is used in the clinical study 10 reported below. EXAMPLE II Objectives: To compare the safety and efficacy of twice-daily dosed brimonidine tartrate 15 0.2%/timolol 0.5% ophthalmic solution combination (henceforth referred to as Combination) with that of twice-daily dosed timolol ophthalmic solution 0.5% (henceforth referred to as Timolol) and three-times-daily dosed ALPHAGAN* (brimonidine tartrate ophthalmic solution) 0.2% (henceforth referred to as Brimonidine) administered for three months (plus 9-month masked extension) in 20 patients with glaucoma or ocular hypertension.

Methodology: Structure: multicenter, double-masked, randomized, parallel-group, active control Randomization: patients were randomized to one of the 3 masked treatment groups (Combination, Brimonidine or Timolol) based on an even allocation at each site s Visit Schedule: prestudy, baseline (day 0), week 2, week 6, month 3, month 6, month 9, and month 12 Number of Patients (Planned and Analyzed): 560 planned to enroll; 586 enrolled (Combination = 193, Brimonidine = 196, Timolol = 197); 502 completed. Mean (range) age: 62.4 (23 to 87) years; 46.1% 10 (270/586) males, 53.9% (316/586) females. Diagnosis and Main Criteria for Inclusion: Diagnosis: ocular hypertension, chronic open-angle glaucoma, chronic angle closure glaucoma with patent iridotomy, pseudoexfoliative glaucoma or pigmentary glaucoma and requiring bilateral treatment. is Key Inclusion Cnteria: 18 years, day 0 (post-washout) intraocular pressure (IOP) 22 mm Hg and 5 34 mm Hg in each eye and asymmetry of IOP 5 nmm Hg, best corrected Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity equivalent to a Snellen score of 20/100 or better in each eye. Key Exclusion Criteria: uncontrolled systemic disease, abnormally low or high 20 blood pressure or pulse rate for age or contraindication to beta-adrenoceptor antagonist therapy, anticipated alteration of existing chronic therapy with agents which could have a substantial effect on IOP, contraindication to brimonidine therapy, allergy or sensitivity to any of the study medication ingredients, anticipated wearing of contact lenses during the study, laser surgery, intraocular filtering 25 surgery or any other ocular surgery within the past 3 months, or required chronic use of other ocular medications during the study (intermittent use of artificial tear product was allowed). Test Product, Dose and Mode of Administration, Batch Number: Brimonidine tartrate 0.2%/timolol 0.5% combination ophthalmic solution one drop 8 (-35 piL) instilled in each eye BID in the morning and evening; and vehicle of the Combination ophthalmic solution, one drop (-35 pL) instilled in each eye once daily (QD) in the afternoon (for masking purposes). Duration of Treatment: 3 months (with a 9-month masked extension) 5 Reference Therapy, Dose and Mode of Administration, Batch Number: Active control ALPHAGAN* (brimonidine tartrate ophthalmic solution) 0.2%, one drop (-35 iL) instilled in each eye TID in the morning, afternoon, and evening. Active control timolol ophthalmic solution 0.5%, one drop (-35 pL) instilled in each eye BID in the morning and evening; and vehicle of the Combination 10 ophthalmic solution, one drop (-35 p.L) instilled in each eye once daily (QD) in the afternoon (for masking purposes). Criteria for Evaluation: Efficacy: IOP (hours 0, 2, 7, and 9), patient satisfaction questionnaire, patient comfort of 15 study medication questionnaire, pharmacoeconomic evaluation by investigator Safety: Adverse events (AE), biornicroscopy, visual acuity (VA), visual field, ophthalmoscopy, cup/disc ratio, heart rate, blood pressure, hematology, serum chemistry, urinalysis and pregnancy test. 20 Other: Quantitation of plasma brimonidine and timolol concentrations (at selected sites), resource utilization (to be reported upon completion of the 1 year study). Statistical Methods: All data were summarized with descriptive statistics, frequency tables, and/or data 25 listings. Safety analyses included all patients who received at least I dose of study medication. Analyses were performed for the primary efficacy variable IOP using 9 the intent-to-treat (ITT) population with last observation carried forward (LOCF), and the per protocol population with observed cases. Ordinal categorical variables were analyzed by the Wilcoxon rank-sum test. Nominal categorical variables were analyzed using Fisher's exact or Pearson's 5 chi-square tests. Within-group changes from baseline for categorical variables were analyzed using the Wilcoxon signed-rank test. Continuous variables (eg, IOP) were analyzed using analysis of variance (ANOVA). Within-group changes from baseline for continuous variables were analyzed using paired t-tests. A 2-way ANOVA model with factors for treatment and investigator was used for 10 the analysis of IOP. Comparisons were made between the Combination and each of the 2 monotherapies in a pairwise fashion using contrasts from the ANOVA model, with the same error term. A separate ANOVA model was employed at each hour/visit measurement of IOP. Each of the 2 null hypotheses (Combination versus Timolol and Combination versus Brimonidine) was tested at the 0.05 significance 15 level. Point estimates of the mean treatment differences, as well as 2-sided 95% confidence intervals (CI) of the difference, were provided at each timepoint. Summary - Conclusions: Efficacy: At baseline, mean values of diurnal IOP ranged from 22.2 mm Hg to 24.9 mm Hg 20 in the Combination group, 22.5 mm Hg to 25.0 mm Hg in the Brimonidine group, and 22.3 mm Hg to 24.8 mm Hg in the Timolol group. There were no statistically significant differences between treatment groups. Mean changes from baseline diurnal IOP at week 2, week 6 and month 3 ranged from: 25 -5.2 to -7.9 mm Hg in the Combination group -3.5 to -5.7 mm Hg in the Brimonidine group -4.5 to -6.4 mm Hg in the Timolol group 10 The mean decreases from baseline diurnal JOP were statistically significant within each treatment group at each follow-up timepoint (p < 0.001). The mean decrease from baseline diurnal IOP was statistically significantly greater with Combination than with Brimonidine at hours 0, 2, and 7 at all follow-up visits 5 (p <0.001). In addition, clinically significant differences of more than 1.5 mm Hg in mean change from baseline lOP favoring Combination over Brimonidine were seen at hours 0, 2, and 7 at all follow-up visits. At hour 9, the decreases from baseline diurnal IOP were greater for the Combination group than the Brimonidine group at all follow-up visits, although the differences were not statistically 10 significant (p 0.104). The mean decrease from baseline diurnal IOP was statistically significantly greater with Combination than with Timolol at hours 0, 2, 7 and 9 at all follow-up visits (p 0.041). In addition, clinically significant differences of more than 1.5 mm Hg in mean change from baseline IOP favoring Combination over Timolol were seen at is week 2 (hours 0, 2, and 7), week 6 (hours 2 and 7), and month 3 (hours 0 and 2). Mean values of diurnal IOP at week 2, week 6 and month 3 ranged from: 15.9 to 18.1 mm Hg in the Combination group 17.4 to 21.5 mm Hg in the Brimonidine group 17.5 to 18.9 mm Hg in the Timolol group Mean values of diurnal IOP were statistically significantly less with Combination than with Brimonidine at hours 0, 2, and 7 at all follow-up visits (p < 0.001) and at hour 9 at week 6 and month 3 (p 0.011). The mean values of lOP at hour 9 at week 2 were lower for the Combination group than the Brimonidine group, 5 although the difference was not statistically significant (p = 0.205). In addition, clinically significant differences of more than 1.5 mm Hg in mean lOP favoring Combination over Brimonidine were seen at hours 0, 2, and 7 at all follow-up visits and at hour 9 at month 3. Mean values of diurnal IOP were statistically significantly less with Combination 10 than with Timolol at hour 0 at week 2 and month 3; and at hours 2, 7 and 9 at all follow-up visits (p 0.050). The mean values of IOP at hour 0, week 6, were lower for the Combination group than the Timolol group, although the difference was not statistically significant (p = 0.102). In addition, clinically significant differences of more than 1.5 mm Hg in mean IOP favoring Combination over Timolol were seen i5 at week 2 (hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and month 3 (hours 2 and 9). At the month 3 or exit visit, a statistically significantly greater "yes" response to the Investigator Pharmacoeconomic Evaluation was recorded for patients receiving Combination (91.1%, 173/190) than for patients receiving Brimonidine 20 (73.4%, 141/192, p <0.001). A "yes" response was recorded for 92.7% (179/193) of patients receiving Timolol. There were no statistically significant differences in the change from baseline in treatment comfort between Combination and each of the monotherapy groups.

12 Treatment satisfaction was better than baseline for a statistically significantly greater percentage of patients in the Combination group (23.4%, 36/154) than in the Brimonidine group (13.2%, 20/151, p = 0.005). A total of 19.9% (30/15 1) of patients in the Timolol group reported better treatment satisfaction than baseline. s Safety: Through month 3 of the study, 53.4% (103/193) of patients in the Combination group, 61.7% (121/196) of the Bnimonidine group, and 50.8% (100/197) of the Timolol group experienced one or more adverse events, regardless of causality. The incidences of oral dryness, eye pruritus, foreign body sensation and 10 conjunctival folliculosis were statistically significantly lower with the Combination than with Brimonidine (p 5 0.034), while burning and stinging were statistically significantly higher with the Combination than with Brimonidine (p 0.028). There were no statistically significant differences in adverse events between the Combination and Timolol, except for a statistically significantly higher incidence of 15 eye discharge with the Combination (2.6%, 5/193) compared to Timolol (0%, 0/197; p = 0.029). The most frequently reported adver-se events (> 3% in any treatment group) were as follows, tabulated by descending order in the Combination group: 13 Combination Brimoridine Timolol PreferredTerm N=193 N=196 N=197 burning sensation in eye 23 (11.9%) 11 (5.6%) 25 (12.7%) conjunctival hyperemia 16(8.3%) 23 (11.7%) 11 ( 5.6%) stinging sensation eye 13 (6.7%) 4 ( 2.0%) 11 ( 5.6%) infection (body as a 11 ( 5.7%) 6(3.1%) 8(4.1%) whole) visual disturbance 6(3.1%) 11 (5.6%) 3 (1.5%) epiphora 5 (2.6%) 8(4.1%) 3 (1.5%) oral dryness 4(2.1%) 19(9.7%) 1 (0.5%) eye pruritus 3( 1.6%) 13(6.6%) 3 ( 1.5%) allergic conjunctivitis 3 ( 1.6%) 7 (3.6%) 0 (0.0%) asthenia 3 ( 1.6%) 6(3.1%) 1 (0.5%) foreign body sensation 2 ( 1.0%) 10(5.1%) 5 (2.5%) conjunctival folliculosis 2 ( 1.0%) 9(4.6%) 1 (0.5%) somnolence 2 ( 1.0%) 7 ( 3.6%) 0 ( 0.0%) Adverse events led to the discontinuation of 3.6% (7/193) of patients in the Combination group, similar to 3.0% (6/197) of patients in the Timolol group, and statistically significantly less than 14.3% (28/196) of patients in the Brimonidine s group (p < 0.001). Serious adverse events were reported for 1.0% (2/193) of patients in the Combination group, 2.0% (4/196) of patients in the Brimonidine group, and 2.0% (4/197) of patients in the Timolol group. Two patients receiving Timolol had 4 serious adverse events (emphysema in one patient; nausea, sweating, and tachycardia in the other patient) which were considered possibly related to the 14 study drug. There was 1 death in the Brimonidine group, possibly due to complications from cardiac surgery, and not related to study drug. There were no clinically relevant differences between the Combination and either of the individual components in the mean change from baseline to month 3 for any 5 hematology, chemistry, or urinalysis parameter. Statistically significant (p 5 0.048) within-group changes from baseline were found, but were small and not clinically relevant. Small but statistically significant (p 5 0.001) mean reductions in heart rate ranging from -2.1 to -3.7 bpm were seen with the Combination, similar to Timolol. Small 10 but statistically significant (p 0.003) mean reductions in blood pressure at hour 2 (postdose) were seen with the Combination, similar to Brimonidine. These small changes in mean heart rate and blood pressure were associated with clinical symptoms in only a few patients. Increases from baseline in the severity of conjunctival erythema and conjunctival is follicles on biomicroscopy were statistically significantly less with the Combination than with Brimonidine (p 5 0.011). The majority of patients in each treatment group showed less than a 2-line change from baseline visual acuity. There were no significant between-group differences for changes in visual fields or cup/disc ratio. Pharmacokinetics: 20 Blood samples were available for 55 patients in the Combination group, 49 patients in the Brimonidine group, and 54 patients in the Timolol group. All samples were assayed for both brimonidine (lower limit of quantitation [LLOQ] 5 pg/mL) and timolol (LLOQ 5 pg/mL). Plasma brimonidine and timolol concentrations were not quantifiable in all but I sample on day 0, hour 0 for both Combination and the 25 monotherapy treatment groups. In the Combination group, mean ± standard deviation (SD) plasma brimonidine concentrations I hour postdose at week 2 and month 3 were 49.7 ± 36.1 and 52.8 ± 46.7 pg/mL, respectively. In the Brimonidine group, mean ± SD plasma 15 brimonidine concentrations at week 2 and month 3 were 81.0 ± 63.8 and 78.6 48.9 pg/mL, respectively. In the Combination group, mean ± SD plasma timolol concentrations at week 2 and month 3 were 0.499 ± 0.327 and 0.586 0.580 ng/mL, respectively. In the Timolol group, mean ± SD plasma timolol s concentrations at week 2 and month 3.were 0.950 ± 0.709 and 0.873 0.516 ng/mL, respectively. Plasma brimonidine and timolol concentrations 1 hour postdose were steady and did not increase over the 3-month study duration. Bnmonidine concentrations were 39%, 34% and 39% lower in the Combination group than in the monotherapy group io at week 2 (p = 0.004), month 3 (p = 0.013), and month 12, respectively. Timolol concentrations were 47% and 33% lower in the Combination group than in the monotherapy group at week 2 (p < 0.001) and month 3 (p = 0.011), respectively. Timolol concentrations were also significantly lower in the combination treatment group than in the Timolol monotherapy treatment group (p=0.0006). Timolol 15 concentrations were 49%, 32%, and 21% lower in the combination group than in the monotherapy group at week 2, month 3, and month 12, respectively. The plasma brimonidine concentration in males was statistically significantly lower than in females for the Brimonidine group (37% lower at week 2 [p = 0.034] and 37% lower at month 3 [p = 0.017]); the difference was not statistically significant in 20 the Combination group. The plasma timolol concentration in males was statistically significantly lower than in females for both the Combination group (not statistically significant at week 2; 52% lower at month 3 [p = 0.012]) and the Timolol group (45% lower at week 2 [p = 0.006] and 39% lower at month 3 [p = 0.003]). 25 Plasma bnmonidine concentration in the elderly group was not significantly different from in the young group for the combined data from both the combination and Bnmonidine treatment groups (p-value=0.1323). However, plasma timolol concentration in the young group was significantly lower than in the elderly group - 16 for combined data from both the combination and the Timolol treatment groups (p value=0.0005). Conclusions: The Combination treatment (bnmonidine tartrate 0.2%.htimolol 0.5%) administered 5 BID for 3 months was superior to Timolol (timolol 0.5%) BID and Bnimoruidine (bimonidine tartrate 0.2%) TID in lowering the elevated IOP of patients with glaucoma or ocular hypertension. The Combination admiruistered BID demonstrated a favorable safety profile that was comparable to Timolol BID and better than Brimonidine TID with regard to the incidence of adverse events and 10 discontinuations due to adverse events. The invention has been described herein by reference to 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. 15 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 20 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (20)

1. An ophthalmic pharmaceutical composition useful in the treatment of glaucoma or ocular hypertension comprising an effective amount of brimonidine and an effective 5 amount of timolol in a pharmaceutically acceptable carrier.

2. A composition according to claim 1, wherein the timolol is present as timolol free base. 10

3. A composition according to claim 1 or claim 2, wherein the concentration of brimonidine is 0.01 to 0.5 percent by weight and the concentration of timolol is 0.1 to 1.0 percent by weight.

4. A composition according to claim 3, wherein the concentration of brimonidine is 15 0.2 percent by weight and the concentration of the timolol is 0.5 percent by weight.

5. A method of treating glaucoma which comprises administering a therapeutically effective amount of a composition according to any one of claims I to 4 to the affected eye. 20

6. A method of lowering intraocular pressure which comprises administering a therapeutically effective amount of a composition according to any one of claims I to 4 to the affected eye. 25

7. An article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for lowering intraocular pressure and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for lowering intraocular pressure and wherein said pharmaceutical agent comprises effective 30 amount of brimonidine and an effective amount of timolol. P \WPDOCS\CRN\JXASpec2031 S33 clIms doc.l 2/Ifv2(09 - 18

8. The composition of claim 1, wherein the concentration of brimonidine is about 0.2 percent by weight, the concentration of timolol is about 0.5 percent by weight, and wherein the composition further comprises an effective amount of benzalkonium chloride to act as a preservative, and sodium phosphate. 5

9. The composition of claim 8, wherein the concentration of benzalkonium chloride is from about 0.001 percent to about 0.01 percent by weight.

10. The composition of claim 9 consisting essentially of about 0.2 percent 10 brimonidine by weight, about 0.5 percent timolol by weight, about.0.005 percent by weight benzalkonium chloride, about 0.43 percent by weight sodium phosphate monobasic monohydrate, about 2.15 percent by weight sodium phosphate dibasic heptahydrate, sufficient sodium hydroxide and/or hydrochloric acid to adjust the pH to about 6.9, and the remainder water. 15

11. The composition of claim 10 further comprising an effective amount of benzalkonium chloride to act as a preservative, and sodium phosphate.

12. The composition of claim I1 consisting essentially of about 0.0045 M 20 brimonidine, about 0.016 M timolol, about 0.005 percent by weight benzalkonium chloride, about 0.031 M sodium phosphate monobasic, about 0.080 M sodium phosphate dibasic, sufficient sodium hydroxide and/or hydrochloric acid to adjust the pH to about 6.9, and the remainder water. 25

13. A method of reducing intraocular pressure comprising administering a composition according to any one of claims I to 4 or 8 to 12 to a mammal in need thereof.

14. The method of claim 13, wherein the timolol in said composition is present as 30 timolol free base. P \WPDOCS\CRN\JXJ\Spec\2M331335 cIms doc.-12l(V2(X)9 - 19

15. The method of claim 13 or claim 14, wherein said composition further comprises an effective amount of benzalkonium chloride to act as a preservative, and sodium phosphate. 5

16. The method of claim 15, wherein said composition consists essentially of about 0.0045 M brimonodine, about 0.016 M timolol, about 0.005 percent by weight benzalkonium chloride, about 0.031 M sodium phosphate monobasic, about 0.080 M sodium phosphate dibasic, sufficient sodium hydroxide and/or hydrochloric acid to adjust the pH to about 6.9, and the remainder water. 10

17. The method of claim 17, wherein said composition consists essentially of about 0.2 percent brimonidine by weight, about 0.5 percent timolol by weight, about 0.005 percent by weight benzalkonium chloride, about 0.43 percent by weight sodium phosphate monobasic monohydrate, about 2.15 percent by weight sodium phosphate 15 dibasic heptahydrate, sufficient sodium hydroxide and/or hydrochloric acid to adjust the pH to about 6.9, and the remainder water.

18. The method of any one of claims 13 to 17, wherein the mammal is a human. 20

19. An ophthalmic pharmaceutical composition useful in the treatment of glaucoma or ocular hypertension according to claim 1, substantially as hereinbefore described with reference to the Examples.

20. A method of treating glaucoma according to claim 5, or a method of lowering 25 intraocular pressure according to claim 6, substantially as hereinbefore described with reference to the Examples.