U.S. patent application number 13/727106 was filed with the patent office on 2013-05-09 for combination of brimonidine and timolol for topical ophthalmic use.
This patent application is currently assigned to ALLERGAN, INC.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Amy L. Batoosingh, Gary J. Beck, Chin-Ming Chang, Cynthia C. Pratt.
Application Number | 20130116255 13/727106 |
Document ID | / |
Family ID | 29215107 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116255 |
Kind Code |
A1 |
Chang; Chin-Ming ; et
al. |
May 9, 2013 |
COMBINATION OF BRIMONIDINE AND TIMOLOL FOR TOPICAL OPHTHALMIC
USE
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.
Inventors: |
Chang; Chin-Ming; (Tustin,
CA) ; Beck; Gary J.; (Fullerton, CA) ; Pratt;
Cynthia C.; (Mission Viejo, CA) ; Batoosingh; Amy
L.; (Mission Viejo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc.; |
Irvine |
CA |
US |
|
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
29215107 |
Appl. No.: |
13/727106 |
Filed: |
December 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13308507 |
Nov 30, 2011 |
8354409 |
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13727106 |
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11946828 |
Nov 28, 2007 |
8133890 |
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13308507 |
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10685941 |
Oct 14, 2003 |
7320976 |
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11946828 |
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10126790 |
Apr 19, 2002 |
7030149 |
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10685941 |
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Current U.S.
Class: |
514/236.2 |
Current CPC
Class: |
A61P 27/00 20180101;
A61P 27/02 20180101; A61K 9/08 20130101; A61K 9/0048 20130101; A61P
27/04 20180101; A61K 31/4168 20130101; A61K 47/02 20130101; A61K
31/498 20130101; A61K 45/06 20130101; A61K 31/5377 20130101; A61P
27/06 20180101; A61K 31/535 20130101 |
Class at
Publication: |
514/236.2 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 31/5377 20060101 A61K031/5377 |
Claims
1. A pharmaceutical composition comprising: brimonidine at a
concentration of 0.2% w/v, and timolol at a concentration of 0.5%
w/v in a single composition, wherein the composition is sterile and
is suitable for topical ophthalmic use.
2. The composition of claim 1, further comprising a phosphate
buffer.
3. The composition of claim 2, further comprising about 0.005%
benzalkonium chloride.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is continuation of U.S. patent
application Ser. No. 13/308,507, filed Nov. 30, 2011, which is a
continuation of U.S. patent application Ser. No. 11/946,828, filed
Nov. 28, 2007, now U.S. Pat. No. 8,133,890, issued Mar. 13, 2012,
which is a continuation of U.S. patent application Ser. No.
10/685,941, filed Oct. 14, 2003, now U.S. Pat. No. 7,320,976,
issued Jan. 22, 2008, which is a continuation of U.S. patent
application Ser. No. 10/126,790, filed on Apr. 19, 2002, now U.S.
Pat. No. 7,030,149, issued Apr. 18, 2006, the disclosures of which
are hereby incorporated in their entirety herein by reference.
BACKGROUND
[0002] 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, 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 single 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 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 these criteria.
[0003] Brimonidine is disclosed in U.S. Pat. No. 3,890,319. The use
of brimonidine for providing neuroprotection to the eye is
disclosed in U.S. Pat. Nos. 5,856,329; 6,194,415 and 6,248,741.
[0004] Timolol, as an ophthalmic drug, is disclosed in U.S. Pat.
Nos. 4,195,085 and 4,861,760.
DESCRIPTION OF THE INVENTION
[0005] Brimonidine is an alpha adrenergic agonist represented by
the following formula:
##STR00001##
[0006] The chemical name for brimonidine is
5-Bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate.
[0007] Timolol is a beta adrenergic agent represented by the
following formula:
##STR00002##
[0008] Brimonidine is available from Allergan, Inc., Irvine, Calif.
as an ophthalmic pharmaceutical product having the name
Alphagan.RTM..
Timolol is available from various sources, including Merck Co.,
Rahway, N.J.
[0009] 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 ophthalmic
vehicle.
[0010] 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
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.
Antimicrobial Preservative:
[0011] 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 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 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% 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.RTM. ophthalmic
solution is administered three times a day and timolol ophthalmic
solution, i.e. Timoptic.RTM. 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.RTM. and
Timoptic.RTM., respectively. In FDA-approved adjunctive therapy,
wherein Alphagan.RTM. and Timoptic.RTM. 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 providing the preservative effects
afforded by benzalkonium chloride, is clearly desirable.)
Co-Solvents:
[0012] 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.
Viscosity Agents:
[0013] Viscosity increased above that of simple aqueous solutions
may be desirable 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 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.
[0014] The present invention further comprises 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 an effective amount of brimonidine and an effective
amount of timolol.
[0015] The following example is a representative pharmaceutical
composition of the invention for topical use when indicated for
treating glaucoma.
Example I
[0016] The combination of active pharmaceutical ingredients is as
follows:
Brimonidine Tartrate 0.20% (w/v) and Timolol Maleate 0.68% (w/v)
(Equivalent to 0.505 (w/v) timolol)
[0017] 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 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.
TABLE-US-00001 TABLE Concentration, Ingredient Function % (w/v)
Brimonidine Tartrate Active 0.2 Timolol Maleate, EP Active
0.68.sup.1 Benzalkonium Chloride, NF, EP Preservative 0.005 Sodium
Phosphate, monobasic Buffer 0.43 monohydrate, USP Sodium Phosphate,
dibasic Buffer 2.15 heptahydrate, USP 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 .sup.1Equivalent to
0.5% (w/v) Timolol, free base
[0018] The pharmaceutical composition of Example I is used in the
clinical study reported below.
Example II
Objectives:
[0019] To compare the safety and efficacy of twice-daily dosed
brimonidine tartrate 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.RTM.
(brimonidine tartrate ophthalmic solution) 0.2% (henceforth
referred to as Brimonidine) administered for three months (plus
9-month masked extension) in patients with glaucoma or ocular
hypertension.
Methodology:
[0020] Structure: multicenter, double-masked, randomized,
parallel-group, active control;
[0021] Randomization: patients were randomized to one of the 3
masked treatment groups (Combination, Brimonidine or Timolol) based
on an even allocation at each site;
[0022] 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):
[0023] 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% (270/586) males, 53.9% (316/586)
females.
Diagnosis and Main Criteria for Inclusion:
[0024] Diagnosis: ocular hypertension, chronic open-angle glaucoma,
chronic angle-closure glaucoma with patent iridotomy,
pseudoexfoliative glaucoma or pigmentary glaucoma and requiring
bilateral treatment;
[0025] Key Inclusion Criteria: 18 years, day 0 (post-washout)
intraocular pressure (IOP).gtoreq.22 mm Hg and .ltoreq.34 mm Hg in
each eye and asymmetry of IOP.ltoreq.5 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;
[0026] Key Exclusion Criteria: uncontrolled systemic disease,
abnormally low or high 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 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:
[0027] Brimonidine tartrate 0.2%/timolol 0.5% combination
ophthalmic solution one drop (.about.35 .mu.L) instilled in each
eye BID in the morning and evening; and vehicle of the Combination
ophthalmic solution, one drop (.about.35 .mu.L) instilled in each
eye once daily (QD) in the afternoon (for masking purposes).
[0028] Duration of Treatment: 3 months (with a 9-month masked
extension).
Reference Therapy, Dose and Mode of Administration, Batch
Number:
[0029] Active control ALPHAGAN.RTM. (brimonidine tartrate
ophthalmic solution) 0.2%, one drop (.about.35 .mu.L) instilled in
each eye TID in the morning, afternoon, and evening.
[0030] Active control timolol ophthalmic solution 0.5%, one drop
(.about.35 .mu.L) instilled in each eye BID in the morning and
evening; and vehicle of the Combination ophthalmic solution, one
drop (.about.35 .mu.L) instilled in each eye once daily (QD) in the
afternoon (for masking purposes).
Criteria for Evaluation:
[0031] Efficacy: IOP (hours 0, 2, 7, and 9), patient satisfaction
questionnaire, patient comfort of study medication questionnaire,
pharmacoeconomic evaluation by investigator;
[0032] Safety: Adverse events (AE), biomicroscopy, visual acuity
(VA), visual field, ophthalmoscopy, cup/disc ratio, heart rate,
blood pressure, hematology, serum chemistry, urinalysis and
pregnancy test;
[0033] 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:
[0034] All data were summarized with descriptive statistics,
frequency tables, and/or data 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.
[0035] Ordinal categorical variables were analyzed by the Wilcoxon
rank-sum test. Nominal categorical variables were analyzed using
Fisher's exact or Pearson'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.
[0036] A 2-way ANOVA model with factors for treatment and
investigator was used for 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 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
[0037] Efficacy: At baseline, mean values of diurnal IOP ranged
from 22.2 mm Hg to 24.9 mm Hg 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.
[0038] Mean changes from baseline diurnal IOP at week 2, week 6 and
month 3 ranged from:
[0039] -5.2 to -7.9 mm Hg in the Combination group
[0040] -3.5 to -5.7 mm Hg in the Brimonidine group
[0041] -4.5 to -6.4 mm Hg in the Timolol group
[0042] The mean decreases from baseline diurnal IOP were
statistically significant within each treatment group at each
follow-up timepoint (p<0.001).
[0043] 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
(p<0.001). In addition, clinically significant differences of
more than 1.5 mm Hg in mean change from baseline IOP 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 significant (p.gtoreq.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.ltoreq.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 week 2
(hours 0, 2, and 7), week 6 (hours 2 and 7), and month 3 (hours 0
and 2).
[0044] Mean values of diurnal IOP at week 2, week 6 and month 3
ranged from:
[0045] 15.9 to 18.1 mm Hg in the Combination group
[0046] 17.4 to 21.5 mm Hg in the Brimonidine group
[0047] 17.5 to 18.9 mm Hg in the Timolol group
[0048] 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.ltoreq.0.011). The mean values of IOP at hour 9 at week 2 were
lower for the Combination group than the Brimonidine group,
although the difference was not statistically significant
(p=0.205). In addition, clinically significant differences of more
than 1.5 mm Hg in mean IOP favoring Combination over Brimonidine
were seen at hours 0, 2, and 7 at all follow-up visits and at hour
9 at month 3.
[0049] Mean values of diurnal IOP were statistically significantly
less with Combination 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.ltoreq.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 at week 2
(hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and month 3 (hours
2 and 9).
[0050] 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 (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.
[0051] 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% (30/151) of patients in
the Timolol group reported better treatment satisfaction than
baseline.
Safety:
[0052] Through month 3 of the study, 53.4% (103/193) of patients in
the Combination group, 61.7% (121/196) of the Brimonidine 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 conjunctival
folliculosis were statistically significantly lower with the
Combination than with Brimonidine (p.ltoreq.0.034), while burning
and stinging were statistically significantly higher with the
Combination than with Brimonidine (p.ltoreq.0.028). There were no
statistically significant differences in adverse events between the
Combination and Timolol, except for a statistically significantly
higher incidence of eye discharge with the Combination (2.6%,
5/193) compared to Timolol (0%, 0/197; 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:
TABLE-US-00002 Combination Brimonidine Timolol Preferred Term N =
193 N = 196 N = 197 burning sensation in 23 (11.9%) 11 (5.6%) 25
(12.7%) eye conjunctival 16 (8.3%) 23 (11.7%) 11 (5.6%) hyperemia
stinging sensation 13 (6.7%) 4 (2.0%) 11 (5.6%) eye 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 2 (1.0%) 10 (5.1%) 5 (2.5%)
sensation conjunctival 2 (1.0%) 9 (4.6%) 1 (0.5%) folliculosis
somnolence 2 (1.0%) 7 (3.6%) 0 (0.0%)
[0053] 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 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.
[0054] 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 hematology, chemistry, or
urinalysis parameter. Statistically significant (p.ltoreq.0.048)
within-group changes from baseline were found, but were small and
not clinically relevant.
[0055] Small but statistically significant (p.ltoreq.0.001) mean
reductions in heart rate ranging from -2.1 to -3.7 bpm were seen
with the Combination, similar to Timolol. Small but statistically
significant (p.ltoreq.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.
[0056] Increases from baseline in the severity of conjunctival
erythema and conjunctival follicles on biomicroscopy were
statistically significantly less with the Combination than with
Brimonidine (p.ltoreq.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:
[0057] 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 1 sample on day 0,
hour 0 for both Combination and the monotherapy treatment
groups.
[0058] In the Combination group, mean.+-.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.+-.0.327 and
0.586.+-.0.580 ng/mL, respectively. In the Timolol group,
mean.+-.SD plasma timolol concentrations at week 2 and month 3 were
0.950.+-.0.709 and 0.873.+-.0.516 ng/mL, respectively.
[0059] 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 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.
[0060] Timolol concentrations were also significantly lower in the
combination treatment group than in the Timolol monotherapy
treatment group (p=0.0006). Timolol 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.
[0061] 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 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]).
[0062] 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
for combined data from both the combination and the Timolol
treatment groups (p-value=0.0005).
Conclusions:
[0063] The Combination treatment (brimonidine tartrate 0.2%/timolol
0.5%) administered BID for 3 months was superior to Timolol
(timolol 0.5%) BID and Brimonidine (brimonidine tartrate 0.2%) TID
in lowering the elevated IOP of patients with glaucoma or ocular
hypertension. The Combination administered 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 discontinuations due to adverse events.
[0064] 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.
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