Pharmaceutical compositions containing bimatoprost, brimonidine, and etimolol, used to lower intraocular pressure.

Abstract

Disclosed herein are compositions for lowering intraocular pressure (IOP) of an eye comprising a combination of the IOP -lowering agents bimatoprost, brimonidine, and timolol. Further disclosed are methods for reducing IOP in the eye of a subject.

Description

Descriptive Report of the Invention Patent for “PHARMACEUTICAL COMPOSITIONS CONTAINING BIMATOPROST, BRIMONIDINE AND TIMOLOL AND USE TO LOWER INTRAOCULAR PRESSURE” CROSS-REFERENCE TO RELATED APPLICATION This application claims priority over U.S. Provisional Application No. 61 / 288,936, filed December 22, 2009, and U.S. Provisional Application No. 61 / 361,749, filed July 6, 2010, which are incorporated herein by reference in their entirety. FIELD The achievements disclosed herein provide compositions and methods that lower intraocular pressure. The compositions and methods disclosed herein include bimatoprost, brimonidine, and timolol, and combinations thereof, and are particularly suitable for patients requiring maximal medical therapy to lower intraocular pressure and for the treatment of glaucoma. BACKGROUND Numerous eye disorders or conditions lead to an increase in intraocular pressure (IOP). For example, post-surgical or post-laser trabeculectomy, ocular hypertensive episodes, and glaucoma can all result in increased IOP. Based on its etiology, glaucoma has been classified as primary or secondary. Primary glaucoma, also known as congenital glaucoma, can occur in the absence of other ocular conditions. The causes of primary glaucoma are unknown. It is known, however, that the increased IPO in primary glaucoma is due to obstruction of aqueous humor outflow from the eye. In chronic open-angle primary glaucoma, the anterior chamber and its anatomical structures appear normal, but drainage of aqueous humor is impeded. In acute or chronic closed-angle primary glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of Schlemm's canal. Pupil dilation may also push the iris root forward against the angle, producing pupillary block that precipitates an acute arachnoid hemorrhage. Additionally, eyes with anterior chamber angles Petition 870260074611, dated 07 / 27 / 2026, page 14 / 20 2 / 26 anterior against the angle, to produce pupillary block that precipitates an acute arachnoid flare. Additionally, eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of varying degrees of severity.

[005] Secondary glaucoma results from another pre-existing eye disease, such as, but not limited to, uveitis, intraocular tumor, enlarged cataract, central retinal vein occlusion, eye trauma, surgical procedures, and intraocular hemorrhage. Consequently, any interference with the outflow of aqueous humor from the posterior chamber into the anterior chamber and, subsequently, into Schlemm's canal, can lead to secondary glaucoma.

[006] Considering all types of glaucoma together, this eye disorder occurs in about 2% of all people over the age of 40. Unfortunately, glaucoma can be asymptomatic for years before progressing to rapid vision loss.

[007] In cases where surgery is not indicated, topical β-adrenoreceptor antagonists have traditionally been the drugs of choice for glaucoma treatment. Certain eicosanoids and their derivatives have also been reported to possess ocular hypotensive activity and have been recommended for use in glaucoma control. Eicosanoids and their derivatives include numerous biologically important compounds, such as prostaglandins and their derivatives. While prostaglandins were previously associated with potent ocular hypertensives, evidence has accumulated that some prostaglandins are highly effective hypotensive agents suitable for long-term medical control of glaucoma.

[008] Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula: Petition 870190042377, dated 06 / 05 / 2019, page 13 / 50 3 / 26

[009] Prostaglandins in particularly useful hypotensive agents include PGF2α, PGF1α, PGE2α, and certain lipid-soluble esters, such as C1 to C5 alkyl esters, for example, 1-isopropyl ester, of such compounds. Many patients who need to lower their intraocular pressure are on fixed combination therapies, such as COMBIGAN® and GANFORT®. However, for some patients, combination therapies are not sufficient to lower intraocular pressure and triple combination therapy is required. The combined effect is expected to potentially result in further IOP reduction in patients with open-angle glaucoma, or ocular hypertension, who are not well controlled on the 2 IOP-lowering agents. SUMMARY

[010] The embodiments disclosed herein relate to enhanced medical therapy for patients with increased intraocular pressure (IOP) using a combination of IOP-lowering agents. In particular, the embodiments disclosed herein contain a triple combination of IOP-lowering agents for use by patients with increased IOP providing superior efficacy while maintaining safety and tolerability. In certain embodiments, the patient or individual is human.

[011] Bimatoprost is a potent ocular hypotensive agent (Cantor, 2001; Sherwood et al, 2001). It is a synthetic prostamide, structurally related to prostaglandin F2α (PGF2α), which selectively mimics the effects of biosynthesized substances called prostamides.

[012] Bimatoprost reduces IOP in humans by increasing the outflow of aqueous humor through the trabecular meshwork and enhances uveospatial outflow. Petition 870190042377, dated 06 / 05 / 2019, page 14 / 50 4 / 26 clerical (Brubaker et al, 2001).

[013] Brimonidine tartrate is an alpha-2 adrenergic receptor agonist that is 1000 times more selective for the alpha-2 adrenoreceptor than the alpha-1 adrenoreceptor (Munk et al, 1994). Brimonidine tartrate has been shown to lower IOP by increasing uveoscleral outflow and reducing aqueous humor formation (Report BIO-94-012; Serie et al, 1991). Timolol is a non-selective beta-1 and beta-2 adrenergic receptor blocking agent. Timolol lowers IOP by reducing aqueous humor formation (Coakes and Brubaker, 1978; Yablonski et al, 1978).

[014] According to the various embodiments, the compositions contain bimatoprost, brimonidine, and timolol. In another embodiment, brimonidine is a salt thereof, such as brimonidine tartrate, and timolol is a salt thereof, such as timolol maleate. In another embodiment, the compositions additionally contain dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the compositions additionally contain benzalkonium chloride.

[015] In another embodiment, the compositions contain 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, and 0.683% w / v timolol maleate. In this combination, both brimonidine tartrate and timolol maleate are at concentrations and regimens that are approved for the individual components. Bimatoprost in this combination, however, is at 0.01%, which is less than the approved concentration of 0.03%.

[016] In yet another embodiment, the compositions additionally contain 1.5% w / v of dibasic sodium phosphate heptahydrate, 0.025% w / v of citric acid monohydrate, and 0.35% w / v of sodium chloride. In yet another embodiment, the compositions additionally contain 0.005% w / v of benzalkonium chloride.

[017] In another embodiment, the composition consists essentially of bimatoprost, brimonidine, and timolol. In another embodiment, brimonidine is a salt Petition 870190042377, dated 06 / 05 / 2019, p. 15 / 50 5 / 26 of this, as brimonidine tartrate, and timolol is a salt thereof, as is timolol maleate. In yet another embodiment, the compositions additionally consist essentially of dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the compositions additionally consist essentially of benzalkonium chloride.

[018] In another embodiment, the compositions consist essentially of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, and 0.68% w / v timolol maleate. In another embodiment, the compositions further consist essentially of 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, sodium hydroxide, in an aqueous vehicle. In yet another embodiment, the compositions further consist essentially of 0.005% w / v benzalkonium chloride.

[019] In another embodiment, the compositions consist of bimatoprost, brimonidine, timolol, dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride and sodium hydroxide in an aqueous vehicle. In another embodiment, brimonidine is a salt thereof, such as brimonidine tartrate, and timolol is a salt thereof, such as timolol maleate. In yet another embodiment, the compositions additionally consist of benzalkonium chloride.

[020] In another embodiment, the compositions consist of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, and 0.68% w / v timolol maleate, 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, sodium hydroxide, and water. In yet another embodiment, the compositions additionally consist of 0.005% w / v benzalkonium chloride.

[021] In certain embodiments revealed here, the compositions do not contain, consist of, or consist essentially of components other than bimate. Petition 870190042377, dated 06 / 05 / 2019, page 16 / 50 6 / 26 prosta, brimonidine, timolol, dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride, benzalkonium chloride and sodium hydroxide in an aqueous vehicle.

[022] The embodiments disclosed herein also include methods of reducing IOP by administering compositions containing bimatoprost, brimonidine, and timolol. In another embodiment, brimonidine is a salt thereof, such as brimonidine tartrate, and timolol is a salt thereof, such as timolol maleate. In yet another embodiment, the administered compositions additionally contain dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the administered compositions additionally contain benzalkonium chloride.

[023] In another embodiment, the method of lowering IOP includes administering compositions containing 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, and 0.68% w / v timolol maleate. In yet another embodiment, the administered compositions additionally contain 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, sodium hydroxide, in an aqueous vehicle. In yet another embodiment, the administered compositions additionally contain 0.005% w / v benzalkonium chloride.

[024] The realizations disclosed herein also include methods of reducing IOP through the administration of the compositions described herein to individuals or patients. In certain embodiments, the compositions described herein are administered to human subjects.

[025] The realizations disclosed herein also include methods of reducing IOP through the administration of compositions consisting essentially of bimatoprost, brimonidine, and timolol. In another embodiment, brimonidine is a salt thereof, such as brimonidine tartrate, and timolol is a salt thereof, such as maleate. Petition 870190042377, dated 06 / 05 / 2019, p. 17 / 50 7 / 26 of timolol. In yet another embodiment, the additionally administered compositions consist essentially of dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the additionally administered compositions consist essentially of benzalkonium chloride.

[026] In another embodiment, the method of lowering IOP includes administering compositions consisting essentially of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, and 0.68% w / v timolol maleate. In yet another embodiment, the compositions administered additionally consist essentially of 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the compositions administered additionally consist essentially of 0.005% w / v benzalkonium chloride.

[027] The embodiments disclosed herein also include methods of reducing IOP by administering compositions consisting of bimatoprost, brimonidine, timolol, dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous vehicle. In another embodiment, brimonidine is the salt, brimonidine tartrate, and timolol is the salt, timolol maleate. In yet another embodiment, the compositions administered additionally consist of benzalkonium chloride.

[028] In another embodiment, the method of lowering IOP includes administering compositions consisting of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, and sodium hydroxide in an aqueous vehicle. In yet another embodiment, the compositions administered additionally consist of 0.005% w / v benzalkonium chloride. Petition 870190042377, dated 06 / 05 / 2019, p. 18 / 50 8 / 26 DEFINITION OF TERMS

[029] For the purposes of this description, treat, treating, treatment, or therapy refers to the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, mitigation, or treatment of disease or condition.

[030] A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any additional harmful or inconvenient effects to the individual to whom it is administered and in the context in which it is administered compared to the parent compound. A pharmaceutically acceptable salt also refers to any salt that can form in vivo as a result of the administration of an acid, another salt, or a prodrug that is converted into an acid or salt.

[031] Pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases. The salt may comprise a mono- or polyvalent ion. Of particular interest are the inorganic ions of lithium, sodium, potassium, calcium, and magnesium. Organic salts may be produced with amines, particularly ammonium salts, such as mono-, di-, and trialkyl amines or ethanolamines. Salts may also be formed with caffeine, tromethamine, and similar molecules. Hydrochloric acid, or some other pharmaceutically acceptable acid, may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.

[032] A prodrug is a compound that is converted to a therapeutically active compound after administration, and the term should be interpreted broadly here as is generally understood by one skilled in the art. While not intending to limit the scope of this disclosure, the conversion may occur by hydrolysis of an ester group, or some other biologically unstable group. Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted. Prodrugs Petition 870190042377, dated 06 / 05 / 2019, page 19 / 50 9 / 26 of the ester forms of the compounds disclosed herein are specifically contemplated. An ester may be derived from a carboxylic acid of Cl (i.e., the terminal carboxylic acid of a natural prostaglandin), or an ester may be derived from a carboxylic acid functional group elsewhere in the molecule, such as on a phenyl ring. While not intended to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester. The term alkyl has the meaning generally understood by those skilled in the art, and refers to linear, branched, or cyclic alkyl moieties. C1-6 alkyl esters are particularly useful, where the alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbon atoms, etc. DESCRIPTION

[033] In a series of United States patent applications transferred to Allergan, Inc., prostaglandin esters with increased hypotensive activity accompanied by substantially reduced side effects are described. U.S. Patent Application Serial No. 386,835 (filed July 27, 1989) refers to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF2α useful for lowering intraocular pressure (IOP). Intraocular pressure-reducing 15-acyl prostaglandins are disclosed in U.S. Patent Application Serial No. 357,394 (filed May 25, 1989). Similarly, 11,15-9,15- and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF2α, have ocular hypotensive activity. See U.S. Patent Application Serial No. 385,645 (filed July 27, 1990), now U.S. Patent No. 4,994,274; U.S. Patent Application No.Serial No. 584,370 (filed September 18, 1990), now U.S. Patent No. 5,028,624, which is a continuation of the application. Petition 870190042377, dated 06 / 05 / 2019, page 20 / 50 U.S. Patent No. 386,312 (filed July 27, 1989) and U.S. Patent Application No. 585,284 (filed September 18, 1990), now U.S. Patent No. 5,034,413, which is a continuation of U.S. Patent Application No. 385,834 (filed July 27, 1989). Each of these references is incorporated by reference herein in its entirety for its teachings regarding prostaglandin esters with ocular hypotensive activity.

[034] Compositions and methods for reducing IOP using a combination of at least three IOP-reducing agents, or pharmaceutical salts or prodrugs thereof, including bimatoprost, brimonidine, and timolol, are described. In certain embodiments, additional ingredients are added to the triple combination of bimatoprost, brimonidine, and timolol to make the composition more ophthalmically acceptable, including, without limitation, preservatives, buffers, tonicity adjusters, and surfactants. Additionally, various vehicles may be used in the disclosed embodiments. These compositions are useful in reducing IOP in patients with increased IOP, thereby, for example, preventing or delaying glaucoma in those with ocular hypertension, and further preventing and delaying vision loss in those with glaucoma.

[035] Without wishing to be bound by any particular theory, it is found that the prostamide analogue, bimatoprost (sold by Allergan, Inc. under the brand name LUMIGAN®), reduces IOP by increasing the outflow of aqueous humor from the eye. The chemical name bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1E,3S)-3hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and has a molecular weight of 415.58.

[036] Brimonidine, an α2-adrenergic receptor agonist, reduces the body's production of aqueous humor and increases the outflow of aqueous humor from the eye, resulting in a decrease in IOP. Brimonidine is available from Allergan, Inc. Petition 870190042377, dated 06 / 05 / 2019, page 21 / 50 11 / 26 as ALPAHAGAN®. The chemical name of brimonidine tartrate, a brimonidine salt, is 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate. Brimonidine has a molecular weight of 442.24 as the tartrate salt.

[037] Timolol, a non-selective β-adrenergic receptor blocking agent, reduces the body's aqueous humor production by blocking β receptors in the ciliary epithelium. In one embodiment, the timolol component contains an acid salt of timolol, and in another embodiment, it contains timolol maleate. The chemical name of timolol maleate is (-)-1-tert-butylamino)-3-[(4-morolino-1,2,5-thiodiazol3yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate has a molecular weight of 432.50. Timolol is commercially available from Merck as TIMOPTIC®.

[038] Preservatives that may be used in the pharmaceutical compositions of the present embodiments include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, and phenylmercury nitrate. Preservative-free compositions may be considered, in a non-limiting embodiment, for patients who experience hypersensitivity reactions to the preservatives listed above, or other preservatives not listed.

[039] Various buffers and pH adjusting media may be used provided that the resulting preparation is ophthalmically acceptable. Consequently, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may also be used to adjust the pH of these formulations as needed. The pH of the disclosed compositions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system.

[040] Tonicity adjusters may be added as needed and include, without limitation, glycerin, sorbitol, sodium chloride, potassium chloride, and mannitol, or any ophthalmically acceptable tonicity adjuster. In one embodiment, the tonicity adjuster is sodium chloride.

[041] In certain embodiments, a surfactant, such as a polysorbate, by Petition 870190042377, dated 06 / 05 / 2019, page 22 / 50 For example, a TWEEN® by Sigma can be added. Additionally, any other suitable surfactants can also be used.

[042] Various vehicles may also be used in the ophthalmic preparations of the present embodiments. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, physiological saline solution, water, purified water, and combinations thereof.

[043] Additionally, ophthalmically acceptable antioxidants may be included in the disclosed compositions. Suitable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene, and the like, and mixtures thereof.

[044] Another excipient component that may be included in ophthalmic preparations are chelating agents. A useful chelating agent is disodium edetate, although other chelating agents may also be added in place of or in conjunction with disodium edetate.

[045] The compositions and methods disclosed herein may also be used in combination with the following classes of drugs, pharmaceutically acceptable salts, or prodrugs thereof:

[046] β- Blockers (or β-adrenergic antagonists) including, without limitation, carteolol, levobunolol, metiparanolol, timolol hemihydrate, selective β1 antagonists such as betaxolol, and the like;

[047] Adrenergic agonists including, without limitation, non-selective adrenergic agonists, such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like; and α2-selective adrenergic agonists, such as apraclonidine and the like;

[048] Carbonic anhydrase inhibitors including, without limitation, acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and similar drugs; Petition 870190042377, dated 06 / 05 / 2019, page 23 / 50 13 / 26

[049] Cholinergic agonists including, without limitation, direct-acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine and the like;

[050] Chlorinesterase inhibitors such as demecarium, ecothiophate, physostigmine and similar;

[051] Glutamate antagonists and other neuroprotective agents such as Ca2+ channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, dextroam, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosin, 2309BT, and 840S, flunarizine, nicardipine, nifedipine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride, and the like;

[052] Additional prostamides or pharmaceutically acceptable salts or prodrugs thereof;

[053] Prostaglandins including travoprost, UFO-21, cloprostenol, fluprostenol, 13,14-dihydro-cloprostenol, isopropyl unoprostone, latanoprost and similar substances; and

[054] Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940, and similar.

[055] For the treatment of diseases affecting the eye, the disclosed compositions can be administered topically or as ocular implants.

[056] Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of bimatoprost, brimonidine, and timolol, according to the present disclosure, or pharmaceutically acceptable acid addition salts thereof, as active ingredients, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparing unit dosage forms for ocular use. The therapeutically effective amount will vary with the activity of the active ingredients; however, typically in combination it will be between 0.0001 and 20%. Petition 870190042377, dated 06 / 05 / 2019, page 24 / 50 14 / 26 (w / v), between 0.0001 and 10% (w / v), between 0.0001 and 5% (w / v), between 0.0005 and 3% (w / v), between 0.00075 and 2% (w / v), between 0.001 and 1.0% (w / v), between 0.2 and 1.0% (w / v), between 0.5 and 1.0% (w / v), 0.85% (w / v), or 0.843% (w / v) of the composition. The compositions may be prepared as follows: 1. Add the required amount of water, approximately 70% of the batch size, to a chosen stainless steel vessel. 2. Add dibasic sodium phosphate heptahydrate to step 1 under mechanical stirring and mixing until dissolved. 3. Add citric acid monohydrate to step 2 while stirring and mixing until dissolved. 4. Add sodium chloride to step 3 while stirring and mixing until dissolved. 5. Add bimatoprost to step 4 while stirring and mixing until a clear solution is obtained. 6. Add timolol maleate to step 5 while stirring and mixing until dissolved. 7. Add brimonidine tartrate to step 6 while stirring and mixing until dissolved. 8. Add benzalkonium chloride to step 7 as a stock solution while stirring. 9. Check the pH of the solution, adjust if necessary to pH 7.1. 10. Bring the volume to 100% of the batch size with water and stir for 5-10 minutes.

[057] Bimatoprost may be included in the compositions of the embodiments disclosed herein in an amount of between 0.0001 and 15% (w / v), between 0.0001 and 10% (w / v), between 0.0001 and 5% (w / v), between 0.0005 and 3% (w / v), between 0.00075 and 2% (w / v), between 0.001 and 1.0% (w / v), between 0.001 and 0.1% (w / v), between 0.005 and 0.05% (w / v), or 0.01%. Petition 870190042377, dated 06 / 05 / 2019, p. 25 / 50 15 / 26 (p / v) of the composition.

[058] Brimonidine may be included in the compositions of the embodiments disclosed herein in an amount of between 0.0001 and 15% (w / v), between 0.0001 and 10% (w / v), between 0.0001 and 5% (w / v), between 0.0005 and 3% (w / v), between 0.00075 and 2% (w / v), between 0.001 and 1.0% (w / v), between 0.001 and 0.2% (w / v), between 0.005 and 0.05% (w / v), or 0.15% (w / v) of the composition. In one embodiment, brimonidine is provided as brimonidine tartrate in an amount of 0.15% (w / v) of the composition.

[059] Timolol may be included in the compositions of the embodiments disclosed herein in an amount of between 0.0001 and 15% (w / v), between 0.0001 and 10% (w / v), between 0.0001 and 5% (w / v), between 0.0005 and 3% (w / v), between 0.01 and 2% (w / v), between 0.1 and 1.0% (w / v), between 0.1 and 0.9% (w / v), between 0.3 and 0.8% (w / v), 0.5%, 0.6% (w / v), 0.68% (w / v) or 0.683% (w / v) of the composition. In one embodiment, timolol is provided as timolol maleate in an amount of 0.6%, 0.68% or 0.683% (w / v) of the composition.

[060] The amount of currently useful compositions administered is dependent on the desired therapeutic effect or effects, the specific patient being treated, the severity and nature of the patient's condition, the method of administration, the potency and pharmacodynamics of the particular compound or compounds employed, and the judgment of the prescribing physician. The therapeutically effective dosage of currently useful compositions is in the range of 0.01 to 200 mg / kg / day. In certain embodiments, the therapeutically effective dosage may be 0.1, 0.5, 1, 2.5, 5, 15, 20, 25, 50, 60, 70, 75, 80, 85, 90 or 100 mg / kg / day. The dosage may be provided in a single daily dose, or in a number of doses from 2 to 24 over the course of the day. In certain applications, dosages may be administered every other day, every three days, once a week, once a month, etc.

[061] In preferred embodiments, the comfort of the formulations here reveals Petition 870190042377, dated 06 / 05 / 2019, page 26 / 50 16 / 26 of the time is maximized as much as possible, although sometimes formulation considerations (e.g., drug stability) may necessitate less than optimal comfort. In cases where comfort cannot be maximized, the compositions should be formulated such that they are tolerable to the patient for ophthalmic use.

[062] The ophthalmic formulations of the present disclosure are conveniently packaged in forms suitable for metered application, such as in containers fitted with a dropper, to facilitate application to the eye. Containers suitable for drop-by-drop application are usually made of suitable inert, non-toxic plastic material and generally contain between 0.5 and 15 ml of solution. One package may contain one or more unit doses.

[063] Preservative-free solutions (e.g., Table 7) may be formulated in non-resealable containers containing up to 1, 2, 5, 10, 50, or 100 unit doses, where a typical unit dose is 1 to 8 drops. The volume of one drop will generally be 20 to 35 pl.

[064] Several exemplary embodiments can be formulated as shown in the following Tables: Table 1. Ingredients Quantity (% w / v of) Active Ingredients 0.001-5 Preservative 0-0.10 Vehicle 0-40 Tonicity Adjuster 1-10 Buffer 0.01-10 pH Adjuster qs pH 4.5-7.5 Antioxidant As needed Surfactant As needed Purified Water As needed to make 100% Table 2. Petition 870190042377, dated 06 / 05 / 2019, page 27 / 50 17 / 26 Ingredient Function % w / v of Bimatoprost Active 0.003-0.03 Brimonidine Active 0.005-0.2 Timolol Active 0.2-0.5 Dibasic sodium phosphate heptahydrate Buffering agent As needed to make ophthalmically acceptable Citric acid monohydrate Buffering agent As needed to make ophthalmically acceptable Sodium chloride Tonic agent As needed to make ophthalmically acceptable Sodium hydroxide pH adjuster qs Water Vehicle qs Table 3. Ingredient Function % w / v of Bimatoprost Active 0.003-0.03 Brimonidine tartrate Active 0.005-0.3 Timolol maleate Active 0.2-0.8 Dibasic sodium phosphate heptahydrate Buffering agent 1.0-2.0 Citric acid monohydrate Buffering agent 0.01-0.05 Sodium chloride Tonicity agent 0.10-0.30 Sodium hydroxide pH adjuster -3^-------------- Water Vehicle qs Table 4. Ingredient Function % w / v of Bimatoprost Active 0.003-0.03 Brimonidine Active 0.005 - 0.2 Timolol Active 0.2-0.5 Dibasic sodium phosphate heptahydrate Buffering Agent As needed to make ophthalmically acceptable Citric acid monohydrate Buffering Agent As needed to make ophthalmically acceptable Petition 870190042377, dated 06 / 05 / 2019, page 28 / 50 18 / 26 Ingredient Function % w / v of Sodium Chloride Tonic Agent As needed to make ophthalmically acceptable Benzalkonium Chloride Preservative As needed to make ophthalmically acceptable Sodium Hydroxide pH Adjuster qs Water Vehicle gs Table 5. Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine tartrate Active 0.1 Timolol maleate Active 0.6 Dibasic sodium phosphate heptahydrate Buffering agent 1.5 Citric acid monohydrate Buffering agent 0.025 Sodium chloride Tonic agent 0.35 Sodium hydroxide pH adjuster qs Water Vehicle qs Table 6. Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine tartrate Active 0.1 Timolol maleate Active 0.6 Dibasic sodium phosphate heptahydrate Buffering agent 1.5 Citric acid monohydrate Buffering agent 0.025 Sodium chloride Tonic agent 0.35 Benzalkonium chloride Preservative 0.005 Sodium hydroxide pH adjuster ---------15,--------- Water Vehicle qs Table 7. Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active 0.68 Dibasic Sodium Phosphate Heptahydrate Buffering Agent 1.5 Petition 870190042377, dated 06 / 05 / 2019, page 29 / 50 19 / 26 Ingredient Function % w / v of Citric acid monohydrate Buffering agent 0.025% Sodium chloride Tonic agent 0.35% Sodium hydroxide pH adjuster qs Water Vehicle qs Table 8. Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine tartrate Active 0.15 Timolol maleate Active 0.68 Dibasic sodium phosphate heptahydrate Buffering agent 1.5 Citric acid monohydrate Buffering agent 0.025 Sodium chloride Tonic agent 0.35 Benzalkonium chloride Preservative 0.005 Sodium hydroxide pH adjuster ---------g / L--------- Water Vehicle qs Table 9. Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine tartrate Active 0.15 Timolol maleate Active 0.683 (equivalent to 0.5 timolol) Dibasic sodium phosphate heptahydrate Buffering agent 1.5 Citric acid monohydrate Buffering agent 0.025 Sodium chloride Tonic agent 0.35 Sodium hydroxide pH adjuster qs Water Vehicle qs Table 10. Ingredient Function % w / v of Bimatoprost Active Approximately 0.01 Brimonidine Tartrate Active Approximately 0.15 Timolol Maleate Active Approximately 0.683 Dibasic Sodium Phosphate Heptahydrate Buffering Agent Approximately 1.5 Citric Acid Monohydrate Buffering Agent Approximately 0.025 Petition 870190042377, dated 06 / 05 / 2019, page 30 / 50 20 / 26 Sodium chloride Tonic agent Approximately 0.35% Benzalkonium chloride Preservative Approximately 0.005% Sodium hydroxide pH adjuster q.s. Water Vehicle q.s. * "Approximately" refers to variations in concentrations that would be considered bioequivalent by a regulatory agency.

[065] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used in the descriptive report and claims, are to be understood as being modified in all examples by the term approximately. Consequently, unless otherwise indicated, the numerical parameters set forth in the descriptive report and appended claims are approximations that may vary depending on the desired properties to be obtained by the present invention. At least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be constructed in light of the reported number of significant digits and by applying ordinary rounding techniques. Example I - Triple Combination of Bimatoprost, Brimonidine and Timolol

[066] Thirty-six female New Zealand white rabbits, obtained from Charles River Laboratories, Wilmington, Massachusetts, aged 4 months and weighing 2.96 to 3.54 kilograms at the start of dosing, were used for the study. One drop (~30 pL / drop) of the formulation in Table 11 was administered directly to the surface of the upper cornea of ​​the left eye using a dropper container 2 or 4 times daily (at 2 or 6 hour intervals) for a month. Table 11 Ingredient Function % w / v of Bimatoprost Active 0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active 0.683* Dibasic Sodium Phosphate Heptahydrate Buffering Agent 1.5 Petition 870190042377, dated 06 / 05 / 2019, page 31 / 50 21 / 26 Citric acid monohydrate Buffering agent 0.025% Sodium chloride Tonic agent 0.35% Benzalkonium chloride Preservative 0.005% Sodium hydroxide pH adjuster q.s. Water Vehicle q.s. * Equivalent to 0.5% w / v timolol

[067] The contralateral right eye served as an untreated control. Dose administration and dosing time are manually recorded on raw data sheets, the worksheets serve as the official dosing record.

[068] Intraocular pressure (IOP) in both eyes of all rabbits was measured before the start of dosing and at the end of the 1-month period. Further examinations will occur at the end of the 3-month treatment period and following the 1-month recovery period. IOP measurements are taken at approximately the same time each day of examination. A topical ophthalmic anesthetic (e.g., proparacaine HCl) is administered to the eye before measurements. If deemed necessary, the eye is rinsed with sterile saline upon completion of the measurement. IOP measurements are manually recorded on raw data sheets.

[069] In conclusion, female NZW rabbits (12 / group) were administered a topical eye drop (~30 pL / drop) of Triple Combination or Triple Combination Placebo two or four times daily in the left eye for 1 month. No drug-related effects were observed in ophthalmology, overall eye observations, body weight, clinical observations, or food consumption. Expected acceptable drug-related decreases in intraocular pressure were observed in rabbits given the Triple Combination Ophthalmic Solution. The Triple Combination Ophthalmic Solution was well tolerated. OS - Triple Combination Ophthalmic Solution, 50ppm BAK, (1 drop ~30μI, 4X / day) OD - Untreated | Animal Number in | OS | OD Petition 870190042377, dated 06 / 05 / 2019, p. 32 / 50 22 / 26 Study Baseline Day 27 Baseline Day 27 350 9 9 9 9 351 13 8 12 8 352 11 8 11 9 353 9 8 9 10 354 10 8 11 9 355 12 9 11 9 356 11 9 13 9 357 10 7 11 8 358 12 9 11 9 359 11 9 10 10 360 10 9 11 10 361 12 9 12 10 Average (n = 12) 10.8 8.5 10.9 9.2 SD 1.3 0.7 1.2 0.7 % Change from Baseline - -21.5 - -16.0 % of Change in OD -0.8 -7.3 - - % Change from Placebo 0.8 -19.0 -5.8 -19.1 OS = Left eye; OD = Right eye; Baseline = Day -6;= Not applicable % Change from Baseline = [(average - Baseline Average) + Average Baseline] x 100 % change in OD =[(average OS - average OD) + average OD] x 100. Example II - Lowering effect of the IOP of the triple combination product from Table 11.

[070] A 71-year-old Caucasian male is suffering from open-angle glaucoma and elevated intraocular pressure that is threatening to worsen his left vision if left untreated. After three months on combination therapy, the patient's IOP has not been lowered to his doctor's satisfaction. The 71-year-old Caucasian male began daily dosing in both eyes of the triple combination from Table 11 and the patient experienced IOP lowering that was not achievable. Petition 870190042377, dated 06 / 05 / 2019, page 33 / 50 23 / 26 Example III - Lowering of the IOP of the triple combination product from Table 11 in a 64-year-old African American woman.

[071] A 64-year-old African American woman suffering from glaucoma is having difficulty lowering her IOP adequately with brimonidine and timolol combination therapy. After four months of brimonidine and timolol combination therapy, her doctor switched to the triple combination therapy product in Table 11. After three weeks on the triple combination therapy product, the patient's IOP in both eyes is expected to be at acceptable levels. Example III - Glaucoma treatment in a 57-year-old Caucasian woman

[072] A 57-year-old Caucasian woman suffering from open-angle glaucoma was largely unresponsive to first monotherapy and then combination therapy to lower an IOP. She changed to twice-daily dosing of the composition in Table 11 and her IOP is expected to return to normal levels. After 30 days of dosing in both eyes with the formulation in Table 11, the 57-year-old Caucasian woman's IOP returns to normal levels assuming she continues dosing with the formulation in Table 11. Example IV - Treatment of elevated intraocular pressure in a 61-year-old Asian man

[073] A 61-year-old Asian man's IOP was measured with a tonometer as being between 21.3 mmHg and 23.7 mmHg. Both monotherapy and combination therapy with several known therapeutic agents to lower IOP failed to bring the patient's IOP to acceptable levels. The patient began taking twice-daily administration of the formulation in Table 11, with a single drop per eye in the morning and a single drop in the eye 12 hours later at night. After 31 days, the patient's IOP is expected to decrease to between 16.1-18.2 mmHg, which is Petition 870190042377, dated 06 / 05 / 2019, page 34 / 50 24 / 26 is considered acceptable. After 90 days, the patient's IOP is expected to decrease to between 15.5-16.8 mmHg.

[074] Although the numerical ranges and parameters placed in the broad scope of the invention are approximations, the numerical values ​​placed in the specific examples are reported as accurately as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in its respective test measurements.

[075] The terms a, an, and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be constructed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. *About refers to variations in the concentrations of excipients and active agents that would be considered bioequivalent by a regulatory agency.

[076] The recitation of value ranges herein is merely intended to serve as a method of individually referring to each separate value that falls within the range. Unless otherwise indicated herein, each individual value is incorporated into the descriptive report as if it were individually recited herein. All methods disclosed herein may be carried out in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., such as) provided herein is intended merely to better illuminate the invention and not to impose a limitation on the scope of the invention otherwise claimed. No language in the descriptive report shall be constructed as indicating any unclaimed element essential to the practice of the invention.

[077] Alternative groupings of elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each member Petition 870190042377, dated 06 / 05 / 2019, page 35 / 50 25 / 26 of group may be referred to, and claimed individually, or in any combination with other members of the group, or other elements found herein. It is anticipated that one or more members of a group may be included in, or omitted from, a group for reasons of convenience and / or patentability. When any such inclusion or omission occurs, the descriptive report is deemed to contain the group as modified, thereby fulfilling the written description of all Markush groups used in the appended claims.

[078] Certain embodiments of this invention are disclosed herein, including the best known method to the inventors for carrying out the invention. Naturally, variations in these described embodiments will become apparent to those skilled in the art after reading the preceding description. The inventor expects that a person skilled in the art will employ such variations as appropriate, and the inventors intend that the invention be carried out in a manner other than specifically disclosed herein. Consequently, this invention includes all modifications and equivalents of the subject matter set forth in the appended claims, as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is involved in the invention, unless otherwise indicated herein or otherwise clearly contradicted by the context.

[079] Specific embodiments disclosed herein may be further limited in the claims using the terms consisting of, or, and consisting essentially of language. When used in the claims, whether as filed or added by amendment, the transitional term consisting of excludes any element, step, or ingredient not specified in the claims. The transitional term consisting essentially of limits the scope of a claim to the materials or steps specified, and those that do not materially affect the basic and novel feature(s). The embodiments of the invention thus claimed are inherently or expressly described and enabled herein. Petition 870190042377, dated 06 / 05 / 2019, page 36 / 50 26 / 26

[080] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not limitation, alternative configurations of the present invention may be used in accordance with the teachings herein. Consequently, the present invention is not limited to that precisely as shown and described.

Claims

1. Pharmaceutical composition to lower intraocular pressure in a patient suffering from elevated intraocular pressure, CHARACTERIZED by the fact that it consists essentially of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate and 0.68% w / v timolol maleate, dibasic sodium phosphate heptahydrate, citric acid monohydrate, sodium chloride and sodium hydroxide in an aqueous vehicle.

2. Pharmaceutical composition, according to claim 1, CHARACTERIZED in that it consists essentially of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate and 0.35% w / v sodium chloride, and 0.005% w / v benzalkonium chloride.

3. Pharmaceutical composition, according to claim 1, CHARACTERIZED in that said composition consists of 0.01% w / v bimatoprost, 0.15% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 1.5% w / v dibasic sodium phosphate heptahydrate, 0.025% w / v citric acid monohydrate, 0.35% w / v sodium chloride, 0.005% w / v benzalkonium chloride, and sodium hydroxide in an aqueous vehicle.

4. Use of a pharmaceutical composition, as defined in any one of claims 1 to 3, CHARACTERIZED by the fact that it is for the preparation of a medicament to reduce intraocular pressure (IOP) in a patient suffering from elevated intraocular pressure.

5. Use according to claim 4, CHARACTERIZED in that the medication is applied to the eye at least once a day.

6. Use according to claim 5, CHARACTERIZED in that the medication is applied twice a day.