AU2011211356B2 - Enhanced bimatoprost ophthalmic solution - Google Patents

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. C:\NRPonb\DCC\TZM\38051 17_I.DOC - 9/8/11

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Enhanced bimatoprost ophthalmic solution The following statement is a full description of this invention, including the best method of performing it known to me: P/00/01 5951i WO 2006/101839 PCT/US2006/009124 1 ENHANCED BIMATOPROST OPHTHALMIC SOLUTION By Inventors Chin-Ming Chang, James N. Chang, Rhett M. Schiffman, R. Scott Jordan, 5 and Joan-En Chang-Lin FIELD OF THE INVENTION This invention relates to pharmaceutical compositions comprising 10 bimatoprost. BACKGROUND OF THE INVENTION Description of Related Art 15 Bimatoprost, shown below, is a prostamide marketed commercially for the treatment of glaucoma and ocular hypertension.

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2 H, H. 0 HoN H HOH Formula 1 20 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, CA) contain 0.03% bimatoprost and 0.005% BAK. Although no other prostamides are 25 currently marketed for the treatment of glaucoma, several prostaglandin analogs H:JXAlnterwoven\NRPorbI\DCC\JXA\6309808.,doc-7/05/2014 2 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. 5 United States Patent No. 6,596,765 B2 discloses a composition comprising 0.005% or 0.0005% latanoprost and 0.2 mg/mL BAK. United States Patent No. 6,646,001 B2 discloses compositions comprising 0.03% bimatoprost and 0.01% BAK or "0.01% + 5% excess" BAK. 10 SUMMARY OF THE INVENTION A first aspect of the invention provides a composition for the treatment of elevated intraocular pressure, the composition comprising about 0.01% w/v bimatoprost, about 200 ppm benzalkonium chloride, at least one buffer and having a pH value of about 7.3, 15 wherein said composition is an aqueous liquid which is formulated for ophthalmic administration. A second aspect of the invention provides a method for treating glaucoma or intraocular hypertension in a mammal, the method comprising administering to the mammal a composition comprising about 0.0 1% w/v bimatoprost by weight, about 200 20 ppm benzalkonium chloride, and sodium phosphate dibasic, wherein the composition has a pH of about 7.3. A third aspect of the invention provides a method for treating glaucoma or intraocular hypertension in a mammal, the method comprising administering to the mammal a composition as defined in the first aspect. 25 A fourth aspect of the invention provides a use of a composition as defined in the first aspect for the manufacture of a medicament for treating glaucoma or intraocular hypertension in a mammal. BRIEF DESCRIPTION OF THE DRAWING FIGURES 30 Figure 1 is a plot showing the aqueous humor concentration of the parent acid of bimatoprost after topical administration of several formulations.

H:\JXJ\Incnvoven\NRPorbI\DCC\JX\6309808_Ldoc-7/05/2014 2a Figure 2 is a plot showing the membrane permeability of bimatoprost in several different formulations. DETAILED DESCRIPTION OF THE INVENTION 5 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 10 thereto is 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. 15 In certain compositions the concentration of bimatoprost is from 0.01% to 0.02%. In other compositions the concentration of bimatoprost is from 0.015% to 0.02%.

WO 2006/101839 PCT/US2006/009124 3 In certain compositions the concentration of BAK is from 150 ppm to 200 ppm. In other compositions the concentration of BAK is from 150 ppm to 200 ppm. In other compositions the concentration of BAK is from 150 ppm to 250 ppm. 5 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 10 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. Certain compositions comprise from 150 to 250 ppm BAK and an 15 effective amount of EDTA. 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-S 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. 20 Another commonly used excipient in ophthalmic compositions is a viscosity-enhancing, 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 25 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 30 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 WO 2006/101839 PCT/US2006/009124 4 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 5 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 0.0 1% bimatoprost, 10 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer, NaCl, and water. The best mode of making and using the present invention are described in the following examples. These examples are given only to provide direction and guidance in how to make and use the invention, and are not intended to limit the 15 scope of the invention in any way. 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 0.015% Bimatoprost, 0.02% 20 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, 25 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 30 the pH is 7.3. Another embodiment consists essentially of 0.01% Bimatoprost, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, WO 2006/101839 PCT/US2006/009124 5 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, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 5 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, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and 10 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. 15 Another embodiment consists of 0.01% Bimatoprost, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.0 14% Citric Acid, Monohydrate, 0.8 1% Sodium Chloride, and water, wherein the pH is 7.3. Another embodiment consists of 0.015% Bimatoprost, 0.02% 20 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 0.0 15% Bimatoprost, 0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 25 0.0 14% Citric Acid, Monohydrate, 0.8 1% Sodium Chloride, 0.03%, EDTA, and water, wherein the pH is 7.3. Another embodiment consists of 0.02% Bimatoprost, 0.02% Benzalkonium Chloride, 0.26S% Sodium Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water, wherein 30 the pH is 7.3. Another embodiment comprises 0.0125% bimatoprost, 0.02% benzalkonium chloride, 0.268% sodium phosphate dibasic heptahydrate, WO 2006/101839 PCTIUS2006/009124 6 0.014% citric acid monohydrate, 0.8 1% sodium chloride, sufficient sodium hydride and/or hydrochloric acid to adjust the pH to 7.3, and water. Another embodiment consists essentially of 0.0 125% bimatoprost, 0.02% benzalkonium chloride, 0.268% sodium phosphate dibasic heptahydrate, 5 0.014% citric acid monohydrate, 0.81% sodium chloride, sufficient sodium hydride and/or hydrochloric acid to adjust the pH to 7.3, and water. Another embodiment consists of 0.0125% bimatoprost, 0.02% benzalkonium chloride, 0.268% sodium phosphate dibasic heptahydrate, 0.014% citric acid monohydrate, 0.81% sodium chloride, sufficient sodium 10 hydride and/or hydrochloric acid to adjust the pH to 7.3, and water. 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 15 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 Formulation 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 20 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 tL eyedrop bilaterally and aqueous humor samples were collected (n=3 animals with 6 eyes per 25 formulation) at 60 min postdose. Two rabbits (4 eyes) remained untreated to serve as pre-dose bioanalytical controls. Bimatoprost and its parent carboxylic WO 2006/101839 PCT/US2006/009124 7 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 5 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 Figure 1 and Table 2 below. Table 2 Formulation Aqueous Humor' (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 i 3.3* 10 a Mean ± SD. Per formulation, N=3 rabbits (6 eyes). * Statistically different (p<0.0 5 ) 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 15 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 20 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, 25 0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3 in qs WO 2006/101839 PCT/US2006/009124 8 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 Formulation 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) 1. 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 5 Example 4 The effect of benzalkonium chloride (BAK) and ethylenediaminetetraacetic acid (EDTA) on bimatoprost permeability across primary culture of rabbit corneal epithelial cell layers (RCECL). Corneal 10 epithelial cells were harvested from New Zealand White rabbits and cultured on TranswelTM 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 15 cultures; n=3-4 per culture) and the cells were incubated at 37*C. At 30, 60, 90 and 120 minutes postdose, 200 tL 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. 20 The results are presented in Figure 2.

H:UXJxntenvoven\NRPoribl\DCCJX\6309808_.doc-7/05/2014 9 Example 5 A drop of formulation J is administered once daily topically to the eye of a person suffering from glaucoma. After a few hours, intraocular pressure drops more and less 5 hyperemia is observed than would be observed for formulation A. Lowered intraocular pressure persists for as long as the treatment continues. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or 10 "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as, an 15 acknowledgement or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (16)

1. A composition for the treatment of elevated intraocular pressure, the composition comprising about 0.01% w/v bimatoprost, about 200 ppm benzalkonium chloride, at least 5 one buffer and having a pH value of about 7.3, wherein said composition is an aqueous liquid which is formulated for ophthalmic administration.

2. The composition of claim 1, consisting essentially of about 0.01% w/v bimatoprost, about 200 ppm benzalkonium chloride, a phosphate buffer, NaCl, citric acid monohydrate 10 and water.

3. The composition of claim 1, having a pH of about 7.3 which comprises about 0.0 1% w/v bimatoprost, about 200 ppm benzalkonium chloride, 0.0 14% w/v citric acid monohydrate, a phosphate buffer, and NaCl. 15

4. The composition of claim 1, consisting essentially of about 0.01% w/v bimatoprost, about 200 ppm benzalkonium chloride, a phosphate buffer, NaCl, and water.

5. The composition of claim 1, comprising about 0.01% w/v bimatoprost, about 20 200 ppm benzalkonium chloride, about 0.26% sodium phosphate dibasic heptahydrate, about 0.014% citric acid monohydrate, about 0.8% NaCl, sufficient sodium hydride and/or hydrochloric acid to adjust the pH to about 7.3, and water.

6. The composition of any one of claims 1 to 5, further comprising an effective 25 amount of EDTA.

7. The composition of any one of claims I to 6, wherein the concentration of benzalkonium chloride is 200 ppm. 30

8. The composition of any one of claims I to 7, wherein the concentration of bimatoprost is 0.01% w/v. H:\JXJ\Intenvoven\NRPortbl\DCCJXJ\6309808_l.doc-7/05/2014 11

9. The composition of claim 2, wherein the concentration of citric acid monohydrate is about 0.0 14% w/v.

10. A method for treating glaucoma or intraocular hypertension in a mammal, the 5 method comprising administering to the mammal a composition comprising about 0.01% w/v bimatoprost by weight, about 200 ppm benzalkonium chloride, and sodium phosphate dibasic, wherein the composition has a pH of about 7.3.

11. The method of claim 10, wherein the composition comprises 0.01% w/v 10 bimatoprost.

12. The method of claim 10, wherein the composition consists essentially of about 0.01% w/v bimatoprost. 15

13. The method of claim 10, wherein the composition consists of 0.01% w/v bimatoprost.

14. The method of any one of claims 10 to 13, wherein the composition further comprises citric acid monohydrate, about 0.8% NaCl, sufficient sodium hydride to adjust 20 the pH value to about 7.3 and water.

15. A method for treating glaucoma or intraocular hypertension in a mammal, the method comprising administering to the mammal a composition of any one of claims 1 to 9. 25 16. Use of a composition of any one of claims 1 to 9 for the manufacture of a medicament for treating glaucoma or intraocular hypertension in a mammal.

16. A composition according to claim 1, substantially as hereinbefore described with reference to the Examples but excluding the comparative Examples.