U.S. patent application number 14/634221 was filed with the patent office on 2016-01-21 for enhanced bimatoprost ophthalmic solution.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to CHIN-MING CHANG, JAMES N. CHANG, JOAN-EN CHANG-LIN, R. SCOTT JORDAN, RHETT M. SCHIFFMAN.
Application Number | 20160015717 14/634221 |
Document ID | / |
Family ID | 42104590 |
Filed Date | 2016-01-21 |
United States Patent
Application |
20160015717 |
Kind Code |
A1 |
CHANG; CHIN-MING ; et
al. |
January 21, 2016 |
ENHANCED BIMATOPROST OPHTHALMIC SOLUTION
Abstract
A composition comprising from 0.005% to 0.02% bimatoprost by
weight and from 100 ppm to 250 ppm benzalkonium chloride, wherein
said composition is an aqueous liquid which is formulated for
ophthalmic administration is disclosed herein. A method which is
useful in treating glaucoma or ocular hypertension related thereto
is also disclosed herein.
Inventors: |
CHANG; CHIN-MING; (TUSTIN,
CA) ; CHANG; JAMES N.; (NEWPORT BEACH, CA) ;
SCHIFFMAN; RHETT M.; (LAGUNA BEACH, CA) ; JORDAN; R.
SCOTT; (TRABUCO CANYON, CA) ; CHANG-LIN; JOAN-EN;
(TUSTIN, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
42104590 |
Appl. No.: |
14/634221 |
Filed: |
February 27, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13254543 |
Apr 16, 2012 |
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PCT/US10/26151 |
Mar 4, 2010 |
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14634221 |
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12351383 |
Jan 9, 2009 |
8338479 |
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13254543 |
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11083261 |
Mar 16, 2005 |
7851504 |
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12351383 |
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61157225 |
Mar 4, 2009 |
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Current U.S.
Class: |
514/622 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 9/08 20130101; A61K 31/14 20130101; A61K 31/164 20130101; A61K
47/186 20130101; A61K 9/0048 20130101; A61K 31/5575 20130101; A61K
47/02 20130101; A61P 27/02 20180101; A61P 27/06 20180101; A61K
31/14 20130101; A61K 2300/00 20130101; A61K 31/5575 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/5575 20060101
A61K031/5575; A61K 9/00 20060101 A61K009/00; A61K 47/18 20060101
A61K047/18 |
Claims
1. A composition comprising from 0.005% to 0.02% bimatoprost by
weight and from 100 ppm to 250 ppm benzalkonium chloride, wherein
said composition is an aqueous liquid which is formulated for
ophthalmic administration.
2. The composition of claim 1 which further comprises an effective
amount of EDTA.
3. The composition of claim 2 wherein the concentration of
benzalkonium chloride is from 150 ppm to 200 ppm.
4. The composition of claim 3 having a pH of 7.4 which consists
essentially of 0.0125% bimatoprost, 200 ppm benzalkonium chloride,
from 0 to 0.03% EDTA, a phosphate buffer, NaCl, and water.
5. The composition of claim 1 wherein the concentration of
bimatoprost is from 0.005% w/v to 0.015% w/v.
6. The composition of claim 5 wherein the concentration of
bimatoprost is from 0.0125% w/v to 0.015% w/v.
7. The composition of claim 6 wherein the concentration of
benzalkonium chloride is from 100 ppm to 150 ppm.
8. The composition of claim 7 wherein the concentration of
benzalkonium chloride is 100 ppm.
9. The composition of claim 6 which further comprises an effective
amount of EDTA.
10. The composition of claim 9 having a pH of 7.4 which comprises
0.015% bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03%
EDTA, a phosphate buffer, and NaCl.
11. The composition of claim 10 having a pH of 7.4 which consists
of 0.015% bimatoprost, 200 ppm benzalkonium chloride, from 0 to
0.03% EDTA, a phosphate buffer, NaCl, and water.
12. A method comprising administering to a mammal suffering from
glaucoma or intraocular hypertension a composition comprising from
0.005% to 0.125% bimatoprost by weight and from 100 ppm to 250 ppm
benzalkonium chloride.
13. The composition of claim 12 comprising from 0.001% to 0.15%
EDTA.
14. The composition of claim 13 comprising from 0.01% to 0.1%
EDTA.
15. The composition of claim 14 comprising from 0.01% to 0.05%
EDTA.
16. The composition of claim 12 comprising from 150 to 250 ppm
BAK.
17. The composition of claim 12 comprising 0.0125% bimatprost.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/254,543, filed Apr. 16, 2012, which is a
U.S. National Stage Application under 35 U.S.C. .sctn.371 of PCT
Application No. PCT/US10/26151, filed Mar. 4, 2010, which claims
the benefit of U.S. Provisional Patent Application Ser. No.
61/157,225, filed on Mar. 4, 2009, and is also a continuation in
part to U.S. patent application Ser. No. 12/351,383, filed Jan. 9,
2009, now U.S. Pat. No. 8,338,479, issued Dec. 25, 2012, which is a
Continuation of U.S. patent application Ser. No. 11/083,261, filed
Mar. 16, 2005, now U.S. Pat. No. 7,851,504, issued Dec. 14, 2010,
each of which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] This invention relates to pharmaceutical compositions
comprising bimatoprost.
BACKGROUND OF THE INVENTION
Description of Related Art
[0003] Bimatoprost, shown below, is a prostamide marketed
commercially for the treatment of glaucoma and ocular
hypertension.
##STR00001##
[0004] Benzalkonium chloride (BAK) is a preservative used in many
commercial ophthalmic products to prevent microbial contamination
in multi-use products. The commercial eye drops (Bimatoprost,
Allergan, Inc., Irvine, Calif.) contain 0.03% bimatoprost and
0.005% BAK. Although no other prostamides are currently marketed
for the treatment of glaucoma, several prostaglandin analogs are
commercially available which use BAK as a preservative. These
include latanoprost (Xalatan), travoprost (Travatan), and
unoprostone isopropyl (Rescula), which require significantly more
BAK, from 150-200 ppm, to meet antimicrobial effectiveness tests in
the United States and Europe.
[0005] U.S. Pat. No. 6,596,765 B2 discloses a composition
comprising 0.005% or 0.0005% latanoprost and 0.2 mg/mL BAK.
[0006] U.S. Pat. No. 6,646,001 B2 discloses compositions comprising
0.03% bimatoprost and 0.01% BAK or "0.01%+5% excess" BAK.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0007] FIG. 1 is a plot showing the aqueous humor concentration of
the parent acid of bimatoprost after topical administration of
several formulations.
[0008] FIG. 2 is a plot showing the membrane permeability of
bimatoprost in several different formulations.
DETAILED DESCRIPTION OF THE INVENTION
[0009] Composition comprising from 0.005% to 0.02% bimatoprost by
weight and from 100 ppm to 250 ppm benzalkonium chloride are
disclosed, wherein said composition is an aqueous liquid which is
formulated for ophthalmic administration. Methods which are useful
in treating glaucoma or ocular hypertension related thereto are
also disclosed herein.
[0010] An aqueous liquid which is formulated for ophthalmic
administration is formulated such that it can be administered
topically to the eye. The comfort should be maximized as much as
possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort.
[0011] In certain compositions, the concentration of bimatoprost is
from 0.005% to 0.02% w/v. In other compositions the concentration
of bimatoprost is from 0.01% to 0.02%. In other compositions, the
concentration is 0.0125% or 0.015% bimatoprost.
[0012] In certain compositions the concentration of BAK is from 50
ppm to 200 ppm. In other compositions the concentration of BAK is
from 100 ppm to 200 ppm. In other compositions the concentration of
BAK is from 150 ppm to 250 ppm.
[0013] In ophthalmic compositions, a chelating agent may be used to
enhance preservative effectiveness. Suitable chelating agents are
those known in the art, and, while not intending to be limiting,
edetate salts (EDTA) are useful chelating agents.
[0014] In certain compositions, concentration of EDTA is at least
0.001%. In other compositions, the concentration of EDTA is at
least 0.01%. In other compositions, the concentration of EDTA is
0.15% or less. In other compositions, the concentration of EDTA is
0.1% or less. In other compositions, the concentration of EDTA is
0.05% or less.
[0015] As is known in the art, buffers are commonly used to adjust
the pH to a desirable range for ophthalmic use. Generally, a pH of
around 6-8 is desired, and in certain compositions a pH of 7.4 is
desired. Many buffers including salts of inorganic acids such as
phosphate, borate, and sulfate are known.
[0016] Another commonly used excipient in ophthalmic compositions
is a viscosity-enhancing agent, or a thickening agent. Thickening
agents are used for a variety of reasons, ranging from improving
the form of the formulation for convenient administration to
improving the contact with the eye to improve bioavailability. The
viscosity-enhancing agent may comprise a polymer containing
hydrophilic groups such as monosaccharides, polysaccharides,
ethylene oxide groups, hydroxyl groups, carboxylic acids or other
charged functional groups. While not intending to limit the scope
of the invention, some examples of useful viscosity-enhancing
agents are sodium carboxymethylcellulose,
hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, and
polyethylene glycol.
[0017] In ophthalmic solutions, tonicity agents often are used to
adjust the composition of the formulation to the desired isotonic
range. Tonicity agents are well known in the art and some examples
include glycerin, mannitol, sorbitol, sodium chloride, and other
electrolytes.
[0018] One composition has a pH of 7.4 and consists essentially of
0.015% bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03%
EDTA, a phosphate buffer, NaCl, and water.
[0019] Another composition has a pH of 7.4 and comprises 0.02%
bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a
phosphate buffer, NaCl, and water.
[0020] Another composition has a pH of 7.4 and consists of 0.01%
bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a
phosphate buffer, NaCl, and water.
[0021] One embodiment comprises 0.01% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0022] Another embodiment comprises 0.0125% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0023] Another embodiment comprises 0.015% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, 0.03%, EDTA, and water, wherein the pH is 7.3.
[0024] Another embodiment comprises 0.02% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0025] Another embodiment comprises 0.005% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0026] Another embodiment consists essentially of 0.015%
Bimatoprost, 0.01%-0.02% Benzalkonium Chloride, 0.268% Sodium
Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid, Monohydrate,
0.81% Sodium Chloride, and water, wherein the pH is 7.3.
[0027] Another embodiment consists of 0.015% Bimatoprost,
0.01%-0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, 0.03%, EDTA, and water, wherein the pH is 7.3.
[0028] Another embodiment consists essentially of 0.02%
Bimatoprost, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate
Dibasic, Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81%
Sodium Chloride, and water, wherein the pH is 7.3.
[0029] Another embodiment consists of 0.0125% Bimatoprost,
0.01%-0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0030] Another embodiment consists of 0.015% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, and water, wherein the pH is 7.3.
[0031] Another embodiment consists of 0.015% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, 0.03%, EDTA, and water, wherein the pH is 7.3.
[0032] Another embodiment consists of 0.02% Bimatoprost, 0.02%
Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,
Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium
Chloride, EDTA and water, wherein the pH is 7.3.
[0033] One embodiment of the present invention is shown in the
Table below:
TABLE-US-00001 Concentration Concentration Reference of Component
(% w/v) (mg/mL) Quality Standard Function Bimatoprost 0.01 0.1
In-house standard Drug Substance Benzalconium Chloride.sup.a 0.02
0.2 NF/Ph Eur Preservative Dibasic Sodium Phosphate 0.268 2.68 USP
Buffering Agent Heptahydrase Citric Acid Monohydrase 0.014 0.14
USP/Ph Eur Buffering Agent Sodium Chloride 0.81 8.1 USP/Ph Eur
Tonicity Agent Hydrochloric Acid.sup.b Adjust pH to 7.3 NF/Ph Eur
PH Adjuster Sodium Hydroxide.sup.b NF/Ph Eur pH Adjuster Purified
Water q.s. ad 100 q.s. ad 1 mL USP/Ph Eur Vehicle
EXAMPLE 1
[0034] Formulations containing 0.268% sodium phosphate dibasic
heptahydrate, 0.014% citric acid, 0.83% sodium chloride, with the
pH adjusted to 7.3 in qs water, and the amounts of bimatoprost,
BAK, and EDTA listed in Table 1 below were prepared by conventional
methods well known in the art.
TABLE-US-00002 TABLE 1 Formulations 1. 0.03% Bimatoprost (50 ppm
BAK) Control 2. 0.03% Bimatoprost - 200 ppm BAK 3. 0.03%
Bimatoprost - 0.015% TPGS (no preservative) 4. 0.03% Bimatoprost -
0.2% TPGS (no preservative) 5. 0.03% Bimatoprost - 0.4% TPGS (no
preservative) 6. 0.03% Bimatoprost - 1.0% TPGS (no
preservative)
EXAMPLE 2
[0035] Studies were carried out to determine the effect of
benzalkonium chloride (BAK) and d-alpha tocopheryl polyethylene
glycol 1000 succinate (TPGS) on ocular absorption of bimatoprost in
vivo. For the in vivo study, eighteen female rabbits were given a
single 28 .mu.L eyedrop bilaterally and aqueous humor samples were
collected (n=3 animals with 6 eyes per formulation) at 60 min
postdose. Two rabbits (4 eyes) remained untreated to serve as
pre-dose bioanalytical controls. Bimatoprost and its parent
carboxylic acid extracted from aqueous humor and in vitro samples
were analyzed by a liquid chromatography tandem mass spectrometry
(LC-MS/MS) method with a quantitation range of 0.25-60 ng/mL.
[0036] Due to extensive metabolism of bimatoprost in rabbit eyes,
its parent acid was used as a surrogate for determining ocular
absorption of bimatoprost. Concentration of the acid in rabbit
aqueous humor following single dose of 6 different bimatoprost
formulations are summarized in FIG. 1 and Table 2 below.
TABLE-US-00003 TABLE 2 Aqueous Formulations Humor.sup.a (ng/mL) 1.
0.03% Bimatoprost (50 ppm BAK) Control 51.0 .+-. 9.4 2. 0.03%
Bimatoprost - 200 ppm BAK 87.2 .+-. 19.0* 3. 0.03% Bimatoprost -
0.015% TPGS (no 26.1 .+-. 3.3* preservative) 4. 0.03% Bimatoprost -
0.2% TPGS (no preservative) 22.9 .+-. 3.2* 5. 0.03% Bimatoprost -
0.4% TPGS (no preservative) 19.3 .+-. 5.6* 6. 0.03% Bimatoprost -
1.0% TPGS (no preservative) 15.4 .+-. 3.3* .sup.aMean .+-. SD. Per
formulation, N = 3 rabbits (6 eyes). *Statistically different (p
< 0.05) compared to 0.03% Bimatoprost
[0037] Test formulations containing 0.015%, 0.2%, 0.4% and 1.0%
TPGS resulted in a lower aqueous humor carboxylic acid
concentration compared to Bimatoprost by 52%, 59%, 62% and 72%,
respectively. In contrast, 0.03% Bimatoprost containing 200 ppm BAK
resulted in 57% higher aqueous humor AGN 191522 concentration
compared to Bimatoprost (50 ppm BAK).
[0038] While not intending to limit the scope of the invention in
any way, or be bound by theory, compared to the Bimatoprost
control, formulations containing TPGS resulted in decrease
bimatoprost permeability. In contrast, formulations with higher BAK
resulted in higher permeability.
EXAMPLE 3
[0039] Formulations containing 0.268% sodium phosphate dibasic
heptahydrate, 0.014% citric acid, 0.83% sodium chloride, with the
pH adjusted to 7.3 in qs water, and the amounts of bimatoprost,
BAK, and EDTA listed in Table 3 below were prepared by conventional
methods well known in the art.
TABLE-US-00004 TABLE 3 Formulations A. 0.03% Bimatoprost (50 ppm
BAK) - Control B. 0.015% Bimatoprost (50 ppm BAK) C. 0.015%
Bimatoprost (50 ppm BAK) 0.03% EDTA D. 0.015% Bimatoprost (200 ppm
BAK) E. 0.015% Bimatoprost (200 ppm BAK) 0.03% EDTA F. 0.015%
Bimatoprost (50 ppm BAK) 0.015% EDTA G. 0.015% Bimatoprost (200 ppm
BAK) 0.015% EDTA H. 0.015% Bimatoprost (125 ppm BAK) I. 0.015%
Bimatoprost (125 ppm BAK) 0.03% EDTA J. 0.015% Bimatoprost (125 ppm
BAK) 0.015% EDTA K. 0.015% Bimatoprost (150 ppm BAK) L. 0.015%
Bimatoprost (150 ppm BAK) 0.1% EDTA M. 0.015% Bimatoprost N. 0.03%
Bimatoprost
EXAMPLE 4
[0040] The effect of benzalkonium chloride (BAK) and ethylene
diaminetetraacetic acid (EDTA) on bimatoprost permeability across
primary culture of rabbit corneal epithelial cell layers (RCECL)
was studied. Corneal epithelial cells were harvested from New
Zealand White rabbits and cultured on Transwell.TM. filters until
confluency (Day 5). For the transport experiment, cells were first
equilibrated in transport buffer for 1 hour at 37.degree. C. Dosing
solution containing 0.015% or 0.03% bimatoprost with varying
concentrations of BAK and EDTA was then applied to the apical
compartment of the Transwell.TM. (2 cultures; n=3-4 per culture)
and the cells were incubated at 37.degree. C. At 30, 60, 90 and 120
minutes postdose, 200 .mu.L samples were taken from the basolateral
chamber for apical to basolateral (AB) transport. The samples were
analyzed by a liquid chromatography tandem mass spectrometry
(LC-MS/MS) method with quantitation range of 1-600 ng/mL. The
results are presented in FIG. 2.
EXAMPLE 5
[0041] A drop of formulation J (see Table 3) is administered once
daily topically to the eye of a person suffering from glaucoma.
After a few hours, intraocular pressure drops more and less
hyperemia is observed than would be observed for formulation A.
Lowered intraocular pressure persists for as long as the treatment
continues.
EXAMPLE 6
[0042] Human patients were instructed to instill 1 drop of the
study medication (Bimatoprost 0.01% ophthalmic solution,
Bimatoprost 0.0125% ophthalmic solution or Bimatoprost 0.03%
ophthalmic solution (LUMIGAN.RTM.) in each eye once-daily in the
evening. Bimatoprost 0.01% ophthalmic solution contained
bimatoprost 0.01%, benzalkonium chloride (BAK) 200 ppm, sodium
phosphate dibasic heptahydrate, citric acid, sodium chloride,
sodium hydroxide, hydrochloric acid, and purified water.
Bimatoprost 0.0125% ophthalmic solution contained bimatoprost
0.0125%, BAK 200 ppm, sodium phosphate dibasic heptahydrate, citric
acid, sodium chloride, sodium hydroxide, hydrochloric acid, and
purified water. Bimatoprost 0.03% ophthalmic solution (LUMIGAN.RTM.
(bimatoprost ophthalmic solution) 0.03% contained bimatoprost
0.03%, BAK 50 ppm, sodium phosphate dibasic heptahydrate, citric
acid, sodium chloride, sodium hydroxide, hydrochloric acid, and
purified water.
[0043] Prior to initiation of study treatment, each patient who
qualified for entry was assigned a study patient number that was
used on all patient documentation. Within the series of patient
numbers provided to the site, numbers were assigned in ascending
order without omissions. Patients were assigned a treatment group
based on a central randomisation schedule stratified by baseline
(Day 0, Hour 0) IOP and prestudy CCT. Patients were placed into 1
of 6 strata as follows:
TABLE-US-00005 TABLE 4 Stratum 1 Stratum 2 Stratum 3 Stratum 4
Stratum 5 Stratum 6 IOP High IOP High IOP High IOP Low IOP Low IOP
Low (>25 mmHg) (>25 mmHg) (>25 mmHg) (.ltoreq.25 mmHg)
(.ltoreq.25 mmHg) (.ltoreq.25 mmHg) CCT Thin CCT Average CCT Thick
CCT Thin CCT Average CCT Thick (<55 .mu.m) (555-600 .mu.m)
(>600 .mu.m) (<555 .mu.m) (555-600 .mu.m) (>600 .mu.m)
[0044] Within each stratum, a patient was assigned through the
automated Interactive Voice Response System/Interactive Web
Response System (IVRS/IWRS) to either Bim 0.01%, Bim 0.0125%, or
Bim 0.03% (LUMIGAN.RTM.) once-daily in an even allocation (1:1:1)
according to the schedule of randomization numbers prepared by
Allergan. The automated IVRS/IWRS was used to manage the
randomization and treatment assignment, and sites dispensed
medication according to this system.
[0045] At baseline, no statistically significant differences in
mean IOP were observed between each of the investigational
treatments and LUMIGAN.RTM.. At Hours 0, 4 and 8, respectively,
mean IOP (mm Hg) was [Bim 0.01%: 25.1, 23.0, 22.3; Bim 0.0125%:
25.1, 23.0, 22.4; LUMIGAN.RTM.: 25.0, 23.2, 22.3]. Mean IOP at
follow-up ranged from 16.4 to 17.9 mm Hg for Bim 0.01%, 16.6 to
18.3 mm Hg for Bim 0.0125%, and 16.1 to 17.8 mm Hg for
LUMIGAN.RTM.. Bim 0.01% was equivalent to LUMIGAN.RTM. for mean
IOP. For the comparison of Bim 0.01% with LUMIGAN.RTM., at 17/17
timepoints, the CIs (95% or 97.5% according to the Hochberg
procedure) of the between-treatment difference were within .+-.1.50
mm Hg and at 9/17 timepoints were within .+-.1.00 mm Hg. For the
comparison of Bim 0.0125% with LUMIGAN.RTM., at 16/17 timepoints,
the CIs (95% or 97.5% according to the Hochberg procedure) of the
between-treatment difference were within .+-.1.50 mm Hg, at 2/17
timepoints were within .+-.1.00 mm Hg, and at 9/17 timepoints were
within .+-.1.16 mm Hg.
Mean Change from Baseline IOP (Non-Inferiority/Superiority at 1.50
mm Hg Margin)
[0046] At baseline, no statistically significant differences in
mean IOP were observed between each of the investigational
treatments and LUMIGAN.RTM.. At Hours 0, 4 and 8, respectively,
mean IOP was [Bim 0.01%: 25.1, 23.0 and 22.3 mm Hg; Bim 0.0125%:
25.1, 23.0, 22.4 mm Hg; LUMIGAN.RTM.: 25.0, 23.2, 22.3 mm Hg]. All
treatments studied showed statistically and clinically significant
mean decreases from baseline IOP at all follow-up timepoints
(p<0.001). Mean changes from baseline IOP ranged from -5.2 to
-7.8 mm Hg for Bim 0.01%, -5.2 to -7.5 mm Hg for Bim 0.0125%, and
-5.6 to -8.0 mm Hg for LUMIGAN.RTM..
[0047] For the comparison of both Bim 0.01% and Bim 0.0125% with
LUMIGAN.RTM., at 15/17 timepoints, the upper limit of the 95% CI of
the between-treatment difference was within the 1.50 mm Hg
margin.
[0048] For 2 timepoints (Week 2/Hour 4, Month 6/Hour 4) the upper
limit was >1.50 mm Hg favouring LUMIGAN.RTM. over Bim 0.01%
(1.70 mm Hg; 1.53 mm Hg, respectively) and Bim 0.0125% (1.67 mm Hg;
1.75 mm Hg, respectively).
[0049] Bim 0.01% has an acceptable long-term safety profile with no
areas of particular concern when administered once-daily for up to
12 months.
[0050] Bim 0.01% demonstrated an improved safety profile with a
statistically significantly lower incidence of overall adverse
events (p=0.010), ocular adverse events (p=0.005), overall
treatment-related adverse events (p=0.016), and ocular
treatment-related adverse events (p=0.016) when compared with
LUMIGAN.RTM..
[0051] LUMIGAN.RTM. (0.03% bimatoprost in 50 ppm BAK) has been
shown to be both an effective and safe topical IOP-lowering
medication. This 12-month study was designed to confirm that
IOP-lowering efficacy can be maintained and the safety profile
improved by lowering the concentration of the active ingredient and
changing the formulation. This was achieved by increasing the
concentration of the preservative BAK from 50 ppm to 200 ppm to
ensure comparable ocular exposure to that achieved by LUMIGAN.RTM..
Two formulations of bimatoprost (Bim 0.01% and Bim 0.0125%, 200 ppm
BAK) were selected for evaluation in this study. A previous
paired-eye study of 4 formulations and LUMIGAN.RTM. demonstrated
that Bim 0.01% (200 ppm BAK) had superior safety and similar
efficacy to LUMIGAN.RTM. (192024-030). In the same study, Bim
0.015% (200 ppm BAK) also showed comparable efficacy to
LUMIGAN.RTM. but had a similar incidence of ocular adverse events.
For the purposes of the present phase 3 study, in addition to Bim
0.01%, a concentration of bimatoprost between 0.01% and 0.015% was
chosen for investigation--bimatoprost 0.0125%.
[0052] Two primary endpoints were evaluated in this 12 month study.
For US regulatory purposes, the primary efficacy endpoint was mean
IOP at all timepoints up to and including the month 3 visit
assessed using an equivalence analysis. For EU regulatory purposes,
the primary endpoint was mean change from baseline IOP analysed
using a strategy of non-inferiority and superiority.
[0053] All treatments in this study were effective in lowering IOP
at all follow-up timepoints (p<0.001). Mean IOP ranged from 16.4
to 17.9 mm Hg for Bim 0.01%, 16.6 to 18.3 mm Hg for Bim 0.0125%,
and 16.1 to 17.8 mm Hg for LUMIGAN.RTM. over all post-baseline
timepoints. The primary analysis for US regulatory purposes at 3
months showed that the new formulation, Bim 0.01%, was equivalent
in efficacy to LUMIGAN.RTM.. The 12 month results demonstrate that
Bim 0.01% continues to meet the definition of equivalence. The 95%
and 97.5% confidence intervals (CIs) of the between-treatment
difference in mean IOP were within .+-.1.50 mm Hg at all (17/17)
post-baseline timepoints and within .+-.1.00 mm Hg at 9/17
post-baseline timepoints. For the comparison of Bim 0.0125% with
LUMIGAN.RTM., at 16/17 timepoints, the 95% and 97.5% CIs of the
between-treatment difference were within .+-.1.50 mm Hg, at 2/17
timepoints were within .+-.1.00 mm Hg, and at 9/17 timepoints were
within .+-.1.16 mm Hg.
[0054] Mean change from baseline IOP was analysed for EU regulatory
purposes. From comparable baseline IOP, mean IOP changes from
baseline ranged from -5.2 to -7.8 mm Hg for Bim 0.01%, -5.2 to -7.5
mm Hg for Bim 0.0125%, and -5.6 to -8.0 mm Hg for LUMIGAN.RTM.. For
the comparison of both Bim 0.01% and Bim 0.0125% with LUMIGAN.RTM.,
at 15/17 timepoints, the upper limit of the 95% CI of the
between-treatment difference was within the 1.50 mm Hg margin. For
2 timepoints (Week 2/Hour 4, Month 6/Hour 4) the upper limit was
>1.50 mm Hg favouring LUMIGAN.RTM. over Bim 0.01% (1.70 mm Hg,
1.53 mm Hg, respectively) and Bim 0.0125% (1.67 mm Hg, 1.75 mm Hg,
respectively). The PP analyses gave similar results to the ITT
analyses.
[0055] Secondary non-inferiority analyses showed Bim 0.01% to be
non-inferior to LUMIGAN.RTM. for mean IOP (in both the ITT and PP
populations), mean diurnal IOP and change from baseline mean
diurnal IOP. Bim 0.0125% did not meet the definition of
non-inferiority for mean IOP. In addition, the single secondary
analysis for the US regulatory review of mean diurnal IOP, showed
Bim 0.01% to be equivalent to LUMIGAN.RTM.. Bim 0.0125% did not
meet the definition of equivalence for this analysis. A sensitivity
analysis was performed on the PP population for US regulatory
purposes. For the comparison of Bim 0.01% with LUMIGAN.RTM., at
17/17 timepoints, the 95% CIs of the between-treatment difference
were within .+-.1.50 mm Hg, at 6/17 timepoints were within .+-.1.00
mm Hg, and at 9/17 timepoints were within .+-.1.11 mm Hg. For the
comparison of Bim 0.0125% with LUMIGAN.RTM., at 17/17 timepoints,
the 95% CIs of the between-treatment difference were within
.+-.1.50 mm Hg, at 4/17 timepoints were within .+-.1.00 mm Hg and
at 9/17 timepoints were within .+-.1.19 mm Hg.
[0056] The safety results showed an overall improved safety profile
for Bim 0.01% and Bim 0.0125% compared with LUMIGAN.RTM.. An
improved macroscopic hyperaemia safety profile was observed in the
Bim 0.01% and Bim 0.0125% groups compared with the LUMIGAN.RTM.
group as demonstrated by incidence of patients experiencing
worsening in severity, at least one clinically significant change
from baseline severity grade, peak severity changes from baseline
and also in mean peak severity. Bim 0.01% consistently showed a
superior profile to LUMIGAN.RTM. in the severity of macroscopic
hyperaemia over the 12 month follow-up; the improvement over
LUMIGAN.RTM. ranged from 20-30% in the mean peak change from
baseline of severity (p=0.01).
[0057] Biomicroscopic examinations supported these observations. An
increased severity of conjunctival hyperaemia was more commonly
noted with LUMIGAN.RTM. (49.2%) than with Bim 0.01% (41.1%) or Bim
0.0125% (35.1%), and the LUMIGAN.RTM. group had consistently more
patients with moderate/severe hyperaemia over the 12-month study
period. Overall, Bim 0.01% showed an improved ocular surface
tolerability compared with LUMIGAN.RTM., as demonstrated by the low
incidence of corneal abnormalities on the ocular surface. Punctate
keratitis occurred in only 5 patients (2.7%) receiving Bim 0.01%
compared with 11 patients (5.9%) receiving LUMIGAN.RTM.. These are
reassuring findings given the 4-fold increase of BAK in the new
formulation.
[0058] Overall adverse events, ocular adverse events, overall
treatment-related adverse events, and ocular treatment-related
adverse events were reported by a statistically significantly
smaller percentage of patients in the Bim 0.01% and Bim 0.0125%
groups compared with the LUMIGAN.RTM. group. No significant
differences were seen between the test formulations. The majority
of ocular adverse events and treatment-related adverse events were
mild in severity. Conjunctival hyperaemia was the most frequently
reported adverse event and was seen in a significantly smaller
percentage of patients in the Bim 0.0125% group (26.6%) compared
with the LUMIGAN.RTM. group (39.0%; p=0.010). The incidence of
conjunctival hyperaemia in the Bim 0.01% group was 31.4%. There
were no notable non-ocular adverse events and incidences were
slightly higher in the Bim 0.01% (43.2%) and LUMIGAN.RTM. (41.2%)
groups compared with the Bim 0.0125% (36.7%) group.
[0059] Patient's and physician's perceptions of all treatments were
positive. The vast majority would have been very/extremely willing
to use or prescribe the study treatment and most patients did not
experience any change in eye appearance. This is an important
finding as satisfaction with glaucoma medication is vital for
compliance and continuation of treatment.
CONCLUSIONS
[0060] The 12-month results demonstrate equivalence of efficacy
between the new formulation of bimatoprost (Bim 0.01%, BAK 200 ppm)
and LUMIGAN.RTM. (Bim 0.03%, BAK 50 ppm) at all timepoints for mean
IOP, and non-inferiority to LUMIGAN.RTM. at 15/17 timepoints for
mean change from baseline IOP. Compared with LUMIGAN.RTM., Bim
0.01% had significantly fewer adverse events (all causality and
treatment-related). Furthermore, patients randomised to Bim 0.01%
experienced less severe macroscopic hyperaemia, significantly fewer
ocular adverse events and significantly fewer discontinuations due
to ocular adverse events.
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