CA2440764C

CA2440764C - Combination of brimonidine and timolol for topical ophthalmic use

Info

Publication number: CA2440764C
Application number: CA002440764A
Authority: CA
Inventors: Chin-Ming Chang; Gary J. Beck; Cynthia C. Pratt; Amy L. Batoosingh
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 2002-04-19
Filing date: 2003-04-09
Publication date: 2005-10-25
Anticipated expiration: 2023-04-09
Also published as: CN100558364C; TW200402296A; TWI351959B; CY1114048T1; CN101664414A; US8748425B2; US20030199509A1; NO20044450L; EP1496912B9; US9907802B1; NO326579B1; US7030149B2; EP1496912A1; WO2003088973A1; US20160303119A1; BR0302584A; US20130116255A1; US20120184551A1; EP2241319A1; US20030199507A1

Abstract

Disclosed are pharmaceutical compositions comprising brimondine and timolol for topical ophthalmic delivery and a method of treatment comprising administering said composition when indicated for glaucoma and associated conditions such as elevated intraocular pressure in the eyes of humans.

Description

'~i Docket No. 17501 (AP) COMBINATION OF BRIMONIDIN'E AND TIMOLOL FOR
TOPICAL OPkITHALMIC USE
s BACKGROUND OF THE INVENTION
This invention relates to the topical ophthalmic use of brimonidine in combination with timoiol when indicated for treatment of glaucoma or ocular io hypertension. Such combinations or formulations are available for separate use in the ophthahxiic art and have been combined in serial application during the course of treatment of glaucoma. However, there are concerns and expressed reservations in the ophthatanic community about patient compliance when the patient is required to administer separate medications to treat a single disease or candition such as z s 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 preservative as eorz~pared to the individual agents taken alone. Finally, there is a need to increase the efficacy of many topical ophthalinic agents, without increasing the systemic a o concentration of such topical agents, since it is well known that many of such topically applied ophthalmic agents cause systemiic side effects, e.g.
drowsiness, heart effects, etc. Unexpectedly it has been discovered that brimonidine in cornbxnation with timolol meets these critezia.
Brimanidine is disclosed in U.S. Patent 3,89fl,319. The use of brimonidine

2 s for providing neuroprotection to the eye is disclosed in U.S. Patents 5,856,329;
6,194,415 and 6,Z~18,?41.
Timolol, as an ophthalmic drug, is disclosed in U.S. Patents 4,195,U8S and 4,851,760.

DESCRIPTION OF TH.'S 1~IVENTION
Briznonidine is an alpha adrenergic agonist represented by the following formula:
f~ cooH
H-- i -4H
N N HO- ~ ---H
cooH
y,- .-N
z o The chemical name for brimonidine is 5-Bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate.
Timolol is a beta adrenergic agent represented by the following formexla:
HOC
CHI
S N
H ~3 N \ a ~'~'~oH ~° ~o H /\
O HO
N

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 Bm; 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 io 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 is 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.
s o 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 2 s 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 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzallconium chloride of 0.005% is suihcient to preserve the compositions of the present invention from microbial attack. This concentration may be advantageously compared to the requirement of 0.01%
s benzallconium 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~ ophthalinic io solution is administered three times a day and timolol ophthalmic solution, i.e.
Timoptic~ ophthalinic 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 i5 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 benzaIkonium chloride, while 2 o providing the preservative effects afforded by benzalkonium chloride, is clearly desirable.) Co-Solvents:
2 s 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 lrnown to those skilled in the art. Typically such co-solvents are employed at a level of from 0.01 % to 2% by weight.
* Trade-mark V1SCOSItY_ 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 io 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 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 an effective amount of brimonidine and an effective amount of timolol.
2 o 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:
Brimonidine Tartrate 0.20 %(w/v) and Timolol Maleate 0.68 %(w/v) 2s (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 w 6 system at pH 6.9. The formulation preservative is benzalallconium 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.
s Table K y-.,,, ~ _j ,"w.~ .~~ S- .r ~~,,~~,, .L~'s ' ;yr .' J ~ .. 1~ y a,v ~4.~r~ .y 3 ~~"~'.. yrJ - .~V~~.; v sa~~.~ ~. .
.,,~,.,..,.,~,~~t.,- , .,i, f ..:wy~'.aa~s'~-rep!~PI~'~~Y'k..~-~'.r.A~':"~~
s "y.. a :J:'~.".' Brimoni~ue Tartratc Active 0.2 Timolol Mateate, EP Active fl.hg1 B~nzalkonium Chloride, NF, FP Preservative0.005 Sodium PlZOSphate, monobasic monohydrate,Buffer 0.43 USP

Sodium Phosphate, dibasic heptalxydrate,Buffer 2.15 USP

Sodium Hydroxide, NF pH adjust Adjust pH to 6.9 1-Iydrochlozic Acid, NF pH adjust Adjust pH to 6.9 Purified Water, USP, EP Solvent d_s. ad 'Equivalent to 0.5 %(wlv) Timolol, free base 'The pharmaceutical composition of Example I is used in the clinical study a. o reported below.
EXAMPI<.E II( Objectives:
'T"'o compare the safety and ef~cacy of twice-daily dosed bri~monidine tartrate ~ s 0.2%Itiznolol 0.5°/'0 ophthalmic solution combination (henceforth referred to as Combination) with that of twice-daily dosed timolol ophthalmic solution U.S%
(henceforth referred to as Timolol) and three-times-daily dosed ALPH.AGAN~
(brinnonidine tartrate ophthalmic solution) 0.2% (henceforth refet~ed to as Brimonidine) administered for three months (plus 9-month masked extension) in 2 o 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 1 Z
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 io (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 Criteria: >_ 18 years, day 0 (post-washout) intraocular pressure (IOP) >_ 22 mm Hg and S 34 mm Hg in each eye and asymmetry of IOP <_ S mm 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 2 o 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 is 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 a {~35 ~L) 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 tlae afternoon (for masking purposes).
Duration of Treatment: 3 months (with a 9-month masked extension) s . Reference Therapy, Aose and Mode of Administration, Batch Number:
Active control ALPHAGAN~ (brimonidine tartrate ophthalmic solution) 0.2%, one ~~ drop (~-35 pL) instilled in each eye TID in the morning, afternoon, and evening.
.~ Active control timoIol ophthalmic solution 0.5%, one dmp ( 35 N.L,) instilled in each eye BlI3 in the morning and evening; and vehicle of the Combination 20 ophthalmic solution, one drop (--35 p,L) instilled in each eye once daily (QD) in the afternoon (for masking purposes).
Criteria for Evacuation:
Ef~cacy:
rOP (hours 0, 2, 7, and 9), patient satisfaction questionnaire, patient comfort of is study medication questionnaire, phazTnacoeconomic evaluation by investigator Saferi:.
Adverse events {A.B), biomieroscopy, visual acuity (VA), visual field, ophthalmoscopy, cup/disc ratio, heart rate, blood pressure, hexrxatology, serum chemistry, urinalysis and pregnancy test.
z o Other:
Quantitatian ofplasma brimonidine and timolol concentrations (at selected sites), resource utilization (to be reported upon completion of the 1 year study).
Statistical Methods:
Alt data were summarized with descriptive statistics, frequency tables, andlor data 2 s listings. Safety analyses included all patients who received at least 1 dose of study medication. Analyses were performed for the primary efficacy variable IOP
using 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 WiIcoxon rank-sum test.
- Norr~inai categorical variables were analyzed using Fisher's exact or Pearson's s 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 io the ana3y~ of TOP. Comparisons were made between the Combination and each of the 2 monotherapies in a pairwise fashion using contrasts fton~z the ANOVA
tnodet, with the same error term, A separate ANOVA model was employed at each hourlvisii measurement of IMP. Each of the 2 null hypotheses (Combination versus Timolol and Combination versus Brimonidine) was tested at the 0.05 significance s level. Point estimates of the mean treatment differences, as well as 2-sided 95%
confidence intervals (Cl~ 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 ~-ig z o in the Combination group, 22.5 mm Hg to 25.0 mm Hg in the Brimonidine group, and 22.3 tnm Hg to 24.8 mm Hg in the Timolol group. There were no statistically signif cant differences between treatment groups.
rl Ivlean changes from baseline diurnal IOP at week 2, week 6 and month 3 ranged tom:
-S.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 The mean decreases from baseline diurnal IOP were statistically significant witlxin 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 aU follow-up visits s (p < 0.001 ). In addition, clinically significant di~~erences of more than 1.5 rtum Hg in mean change from baseline IOP favoring Combination over Brirnonidine were . seen at hours 0, 2, and 7 at all follow-up visits. At hour 9, the decreases from Haseline diurnal IOP were greater for the Combination group than the Brimorudine group at all follow-up visits, although the differences were not statistically i o ..- significant (p ? o.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 . ~ < 0_041). In addition, clinically significant differences of more than L5 mm Hg v in mean change from baseline TOP favoring Combination over 'I~molol were seen at ~.s " 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 inn the Combination group 17.4 to 2 i .5 mm Hg in the Brimonidine group 17.5 to 18.9 mm Hg in the TimoloI group .. , ~ 3.1 .
. Mean values of diurnal IOP were statistically significantly Less with Combination than with Brimonidane at hours 0, 2, and 7 at aII follow-up visits (p c 0.001 ) and at .~ hour 9 at week 6 and month 3 (p S 0.011). The mean values of IpP at hour 9 at week 2 were lower for the Combination group than the Brinr~onidine group, s although the difference was not statistically significant (p - 0.205). In addition, clinically significant di$erences of more than 1.5 mm Hg in mean IOP favoring Combination over Erimonidine were seen at hours 0, 2, and 7 at all follow-up visits and at hour 9 at month 3.
lViean values of diurnal IOP were statistically significantly less with Combination zo ' than with Tiznolol at hour 0 at week 2 and month 3; and at hours 2, 7 and 9 at all follow-up visits (p S 0.050). The mean values of ZOP at hour 0, week 6, were lower far the Combination group than the Timolol group, althau~ the difference was not statistically significant (p = 0.102). In addition, clinically significant differences of more than I .5 mm Hg in mean IOP favoring Combination over Timolol were seen i s at week 2 (hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and xnonth 3 (hours 2 and 9).
At the month 3 ox exit visit, a statistically significantly greater "yes"
response to the Investigator Pharmacoecanomic Evaluation was recorded fax patients receiving Combination (91.1 %, 1731190) than for patients receiving Brimonidine 20 , (73.4°/a, 141/192, p <0.001). A "yes" response was recorded for 92.7% (1791193) 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.

A
,~;f iz 'T.'reatx~nent satisfaction was better than baseline far a statistically significantly greater percentage of patients in the Combination goup (23.4%, 3b/154) than in the Brimonidine group ( 13.2%, 20/1 S 1, p = 0.005). A total of 19.9% (301151 ) of patients in the 'fimolol group reported better treatment satisfaction than baseline.
s Safety:
Through month 3 of the study, 53.4% (103/I93) of patients in the Combination group, b1.7% ( l21/19C) of the Brimon~idine group, and 50.8% (100/I97) of the Timolol group experienced one or mox-e adverse events, regardless of causality.
~ The incidences of oral dryness, eye pruritus, foreign body sensation and s o con~unctival folliculosis were statistically sigizificantly lower with the Combination than with Brimonidine (p S 0.034), while burning and stinging were statistically significantly higher with the Combination than with Brimanidine (p < 0.028}.
There were no statistically significant differences in adverse events between the Combination and Timolol, except far a statistically significantly highex incidence of is eye discharge with the Combination (2.b%, 51193) compared to Timolol (0%, 0!297; p ~ 0.029). The most frequently reported adverse events (> 3% in any treatment group) were as follows, tabulated by descending order in the Combination group:

CombinationBrimonidineTimolol Preferred Term N =193 N =196 N =197 burning sensation 23 (11.9%)11 ( 5.6%) 25 (12.7%) in eye conjunctiva) hyperemia16 ( 8.3%)23 (11.7%) 11 ( 5.6%) stinging sensation13 ( 6.7%)4 ( 2.0%) 11 ( 5.6%) eye infection (body 11 ( 5.7%)6 ( 3.1 8 ( 4.1 as a %) %) whole) visual disturbance6 ( 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 conjunctivitis3 ( 1.6%) 7 ( 3.6%) 0 ( 0.0%) asthenia 3 ( 1.6%) 6 ( 3.1%) 1 ( 0.5%) foreign body sensation2 ( 1.0%) I O ( 5.1 5 ( 2.5%) %) conjunctiva) folliculosis2 ( 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/I97) 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 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 s hematology, chemistry, or urinalysis parameter. Statistically significant (p 5 0.048) within-group changes finm baseline were found, but were small and not clinically relevant.
Small but statistically significant (p < 0.001) mean reductions in heart rate ranging from -2.1 to -3.7 bpm were seen with the Combination, similar to Timolol.
Small to 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 conjunctiva) erythema and conjunctiva) 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 S pg/mL). Plasma brimonidine and timolol concentrations were not quantifiable in all but 1 sample on day 0, hour 0 for both Combination and the 2 s monotherapy treatment groups.
In the Combination group, mean t standard deviation (SD) plasma brimonidine concentrations 1 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 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 t 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 t 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. Brimonidine concentrations were 39%, 34% and 39% lower in the Combination group than in the monotherapy group to 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 is concentrations were 49%, 32%, and 21% lower in the combination group than in the monotherapy group at week 2, month 3, and month 1 Z, 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 2o the Combination group. The plasma dmolol 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]).
2s Plasma brimonidine concentration in the elderly group was not significantly different from in the young group for the combined data from both the combination and Brimonidine treatment groups (p-value=0.1323). However, plasma timolol concentration in the young group was significantly lower than in the elderly group

3.6 .., fox cam~ined data from both the combination and the Timolol treatment groups (-p-value=0.0005).
r Conclusions:
The Combination treatment (brimonidine tartrate 0.2%/timolol 0.5%) administered s B1D for 3 months was superior to Timolol (timolol 0.5%) BiD and Brimoni.dine (brirnonidine tartrate 0.2%) TID in lowering the elevated IOl' of patients with glaucoma or ocular hypertension. The Combination administered BI17 - d~onstrated a favorable safety profile that was comparable to Timolol BID
and better than Brimonidine TID with regard to the incidence of adverse eveats and io 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 tZ~e art, the invention is not to be considered as limited thereto.
~k r

Claims

Claims:

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

2. A composition according to Claim 1, wherein the amount of brimonidine is 0.01 to 0.5 percent by weight and the amount of timolol is 0.1 to 1.0 percent by weight.

3. A composition according to Claim 1, wherein the amount of brimonidine is 0.2 percent by weight and the amount of the timolol is 0.5 percent by weight.

4. A composition according to claim 1 further comprising from 0.001%
by weight to less than 0.01% by weight of benzalkonium chloride.

5. A composition according to claim 2 further comprising from 0.001%
by weight to less than 0.01% by weight of benzalkonium chloride.

6. A composition according to claim 3 further comprising from 0.001%
by weight to less than 0.01% by weight of benzalkonium chloride.

7. A packaging material containing a pharmaceutical agent for topical use, 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 an effective amount of brimonidine and an effective amount of timolol.

8. A packaging according to claim 7 wherein said effective amount of brimonidine is from 0.01 to 0.5 percent by weight and said effective amount of timolol is from 0.1 to 1.0 percent by weight.

9. A packaging according to claim 7 wherein said effective amount of brimonidine is 0.2 percent by weight and said effective amount of timolol is 0.5 percent by weight.

10. A packaging according to claim. 7 wherein said pharmaceutical agent further comprises from 0.001% by weight to less than 0.01%
by weight of benzalkonium chloride.

11. A packaging according to claim 10 comprising 0.005% by weight of benzalkonium chloride.

12. A packaging according to claim 8 further comprising 0.005% by weight of benzalkonium chloride.

13. A packaging according to claim 9 further comprising 0.005% by weight of benzalkonium chloride.

14. Topical use of a therapeutically effective amount of a composition according to claim 1 in an affected eye for treating glaucoma.

15. Topical use of a therapeutically effective amount of a composition according to claim 2 in an affected eye for treating glaucoma.

16. Topical use of a therapeutically effective amount of a composition according to claim 3 in an affected eye for treating glaucoma.

17. Topical use of a therapeutically effective amount of a composition according to claim 1 in an affected eye for lowering intraocular pressure.

18. Topical use of a therapeutically effective amount of a composition according to claim 2 in an affected eye for lowering intraocular pressure.

19. Topical use of a therapeutically effective amount of a composition according to claim 3 in an affected eye for lowering intraocular pressure.

20. Topical use of a therapeutically effective amount of a composition according to claim 4 in an affected eye for treating glaucoma.

21. Topical use of a therapeutically effective amount of a composition according to claim 5 in an affected eye for treating glaucoma.

22. Topical use of a therapeutically effective amount of a composition according to claim 6 in an affected eye for treating glaucoma.

23. Topical use of a therapeutically effective amount of a composition according to claim 4 in an affected eye for lowering intraocular pressure.

24. Topical use of a therapeutically effective amount of a composition according to claim 5 in an affected eye for lowering intraocular pressure.

25. Topical use of a therapeutically effective amount of a composition according to claim 6 in an affected eye for lowering intraocular pressure.