# Patent

## Title
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.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This is a national stage application under 35 U.S.C. §371 of PCT patent application PCT/US10/26151, filed on Mar. 4, 2010, which claims the benefit of U.S. Provisional Patent Application 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.


FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions comprising bimatoprost.
BACKGROUND OF THE INVENTION
Description of Related Art
Bimatoprost, shown below, is a prostamide marketed commercially for the treatment of glaucoma and ocular hypertension.




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.
U.S. Pat. No. 6,596,765 B2 discloses a composition comprising 0.005% or 0.0005% latanoprost and 0.2 mg/mL BAK.
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
FIG. 1 is a plot showing the aqueous humor concentration of the parent acid of bimatoprost after topical administration of several formulations.
FIG. 2 is a plot showing the membrane permeability of bimatoprost in several different formulations.



DETAILED DESCRIPTION OF THE INVENTION
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
One embodiment of the present invention is shown in the Table below:















Concentration
Concentration
Reference of



Component
(% w/v)
(mg/mL)
Quality Standard
Function



















Bimatoprost
0.01
0.1
In-house standard
Drug Substance


Benzalkonium Chloridea
0.02
0.2
NF/Ph Eur
Preservative


Dibasic Sodium Phosphate
0.268
2.68
USP
Buffering Agent


Heptahydrate






Citric Acid Monohydrate
0.014
0.14
USP/Ph Eur
Buffering Agent


Sodium Chloride
0.81
8.1
USP/Ph Eur
Tonicity Agent










Hydrochloric Acidb
Adjust pH to 7.3
NF/Ph Eur
pH Adjuster


Sodium Hydroxideb

NF/Ph Eur
pH Adjuster











Purified Water
q.s. ad 100
q.s. ad 1 mL
USP/Ph Eur
Vehicle









Example 1
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 1









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
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 μL 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.
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 2






Aqueous 


Formulations
Humora (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*





aMean ± SD. Per formulation, N = 3 rabbits (6 eyes).


*Statistically different (p < 0.05) compared to 0.03% Bimatoprost






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).
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
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 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
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 TranswellTM filters until confluency (Day 5). For the transport experiment, cells were first equilibrated in transport buffer for 1 hour at 37° 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 TranswellTM (2 cultures; n=3-4 per culture) and the cells were incubated at 37° C. At 30, 60, 90 and 120 minutes postdose, 200 μL 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
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
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®) 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® (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.
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 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 mm Hg)
(>25 mm Hg)
(>25 mm Hg)
(≦25 mm Hg)
(≦25 mm Hg)
(≦25 mm Hg)


CCT Thin
CCT Average
CCT Thick
CCT Thin
CCT Average
CCT Thick


(<555 μm)
(555-600 μm)
(>600 μm)
(<555 μm)
(555-600 μm)
(>600 μm)









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®) 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.
At baseline, no statistically significant differences in mean IOP were observed between each of the investigational treatments and LUMIGAN®. 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®: 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®. Bim 0.01% was equivalent to LUMIGAN® for mean IOP. For the comparison of Bim 0.01% with LUMIGAN®, 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®, 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)
At baseline, no statistically significant differences in mean IOP were observed between each of the investigational treatments and LUMIGAN®. 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®: 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®.
For the comparison of both Bim 0.01% and Bim 0.0125% with LUMIGAN®, 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® 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).
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.
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®.
LUMIGAN® (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®. 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® demonstrated that Bim 0.01% (200 ppm BAK) had superior safety and similar efficacy to LUMIGAN® (192024-030). In the same study, Bim 0.015% (200 ppm BAK) also showed comparable efficacy to LUMIGAN® 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%.
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.
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® 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®. 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®, 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.
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®. For the comparison of both Bim 0.01% and Bim 0.0125% with LUMIGAN®, 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® 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.
Secondary non-inferiority analyses showed Bim 0.01% to be non-inferior to LUMIGAN® 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®. 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®, 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®, 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.
The safety results showed an overall improved safety profile for Bim 0.01% and Bim 0.0125% compared with LUMIGAN®. An improved macroscopic hyperaemia safety profile was observed in the Bim 0.01% and Bim 0.0125% groups compared with the LUMIGAN® 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® in the severity of macroscopic hyperaemia over the 12 month follow-up; the improvement over LUMIGAN® ranged from 20-30% in the mean peak change from baseline of severity (p=0.01).
Biomicroscopic examinations supported these observations. An increased severity of conjunctival hyperaemia was more commonly noted with LUMIGAN® (49.2%) than with Bim 0.01% (41.1%) or Bim 0.0125% (35.1%), and the LUMIGAN® 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®, 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®. These are reassuring findings given the 4-fold increase of BAK in the new formulation.
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® 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® 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® (41.2%) groups compared with the Bim 0.0125% (36.7%) group.
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
The 12-month results demonstrate equivalence of efficacy between the new formulation of bimatoprost (Bim 0.01%, BAK 200 ppm) and LUMIGAN® (Bim 0.03%, BAK 50 ppm) at all timepoints for mean IOP, and non-inferiority to LUMIGAN® at 15/17 timepoints for mean change from baseline IOP. Compared with LUMIGAN®, 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.

## Claims

1. A first ophthalmic composition for the treatment of glaucoma or elevated intraocular pressure comprising about 0.01% w/v bimatoprost, about 200 ppm benzalkonium chloride, about 0.268% w/v dibasic sodium phosphate heptahydrate, about 0.014% w/v citric acid monohydrate, about 0.81% w/v sodium chloride, and water, wherein administration thereof results in a lower incidence of one or more adverse events as compared to the administration of a second ophthalmic composition comprising 0.03% w/v bimatoprost and 50 ppm benzalkonium chloride, and wherein the one or more adverse events are selected from the group consisting of macroscopic hyperemia, conjunctival hyperemia, corneal abnormalities, and punctate keratitis.

2. The composition of claim 1 wherein the concentration of benzalkonium chloride is 200 ppm.

3. The composition of claim 2 having a pH of 7.3 which consists essentially of 0.01% w/v bimatoprost, 200 ppm benzalkonium chloride, 0.268% w/v dibasic sodium phosphate heptahydrate, 0.014% w/v citric acid monohydrate, 0.81% w/v sodium chloride, one or more selected from the group of sodium hydroxide and hydrochloric acid, and water.

4. A method comprising administering to a mammal suffering from glaucoma or intraocular hypertension the composition of claim 1.

5. The composition of claim 1 or 3, wherein the adverse event is macroscopic hyperemia.

6. The composition of claim 1 or 3, wherein the adverse event is conjunctival hyperemia.

7. The composition of claim 1 or 3, wherein the adverse event is corneal abnormalities.

8. The composition of claim 1 or 3, wherein the adverse event is punctate keratitis.