HK1174845A - Compositions and methods for lowering intraocular pressure - Google Patents

Description

Compositions and methods for lowering intraocular pressure

Cross Reference to Related Applications

Priority of united states provisional application No. 61/288,936 filed on 12/22/2009, and united states provisional application No. 61/361,749 filed on 6/7/2010, the disclosures of which are incorporated herein by reference, are claimed.

FIELD

Embodiments disclosed herein provide compositions and methods for lowering intraocular pressure. The compositions and methods disclosed herein include bimatoprost (bimatoprost), brimonidine (brimonidine), and timolol (timolol), and combinations thereof, and are particularly suitable for patients requiring extremely high doses of medical treatment to reduce intraocular pressure and treat glaucoma.

Background

Many disorders or conditions of the eye result in elevated intraocular pressure (IOP). For example, episodes of ocular hypertension and glaucoma following surgery or laser trabeculectomy can lead to elevated IOP.

Depending on the etiology of glaucoma, it has been classified as primary or secondary glaucoma. Primary glaucoma, also known as congenital glaucoma, can occur in the absence of other ocular conditions. The underlying cause of primary glaucoma is not clear. However, it is known that the elevation of IOP observed in primary glaucoma is caused by the obstruction of the aqueous outflow of the eye. In chronic open-angle primary glaucoma, the anterior chamber and its anatomy appear normal, but drainage of aqueous humor is impeded. In acute or chronic primary glaucoma of the angle closure type, the anterior chamber becomes shallow, the angle of filtration narrows, and the iris may block the trabecular meshwork at the entrance of Schlemm's canal (canal of Schlemm). Dilation of the pupil may also advance the root of the iris against the filter angle, causing a blockage of the pupil, resulting in an acute attack. In addition, eyes with narrow anterior chamber angles are prone to acute angle closure glaucoma attacks of varying severity.

Secondary glaucoma results from another pre-existing ocular disease such as, but not limited to, uveitis, intraocular tumors, enlarged cataracts (enlargedcataracts), central retinal vein occlusion, ocular trauma, surgical procedures, and intraocular hemorrhage. Thus, any disturbance in the flow of aqueous humor from the posterior chamber out to the anterior chamber and subsequently into the canal of Schlemm can lead to secondary glaucoma.

With respect to all types of glaucoma, the incidence of this ocular disorder is approximately 2% in all people over the age of 40. Unfortunately, glaucoma can be asymptomatic for many years before it progresses to rapid loss of vision.

Where surgery is not advised, local beta-adrenergic receptor (beta-adrenoceptor) antagonists have traditionally been the first choice for the treatment of glaucoma. Certain eicosanoids and their derivatives have also been reported to have ocular hypotensive activity and have been proposed for use in glaucoma management. Eicosanoids and derivatives thereof include many biologically important compounds such as prostaglandins and derivatives thereof. Although prostaglandins were earlier considered potent ocular hypotensives, accumulated evidence suggests that some prostaglandins are highly potent ocular hypotensive agents, well suited for long-term medical management of glaucoma.

Prostaglandins can be described as derivatives of prostanoic acid, which has the structural formula:

particularly useful hypotensive prostaglandins include PGF_2α、PGF_1α、PGE_2αAnd certain fat-soluble esters such as C₁To C₅Alkyl esters, for example, the 1-isopropyl ester of such compounds. Many patients in need of reduced intraocular pressure useThe fixed combination therapy of (1). However, for some patients, combination therapy is not sufficient to lower intraocular pressure, and triple combination therapy is required. In patients with chronic open angle glaucoma or ocular hypertension who use 2 IOP lowering agents but are not well controlled, it is expected that the combined effect will potentially cause additional lowering of IOP.

SUMMARY

Embodiments disclosed herein relate to intensive medical therapy with a combination of IOP lowering agents for patients with elevated intraocular pressure (IOP). In particular, embodiments disclosed herein contain a triple combination of IOP lowering agents for use in patients with elevated IOP that provides superior efficacy while maintaining safety and tolerability. In certain embodiments, the patient or subject is a human.

Bimatoprost is a potent ocular hypotensive agent (Cantor, 2001; Sherwood et al, 2001). It is a synthetic prostamide structurally related to prostaglandin F2 α (PGF2 α) that selectively mimics the action of a biosynthetic substance known as prostamide.

Bimatoprost lowers human IOP by increasing the outflow of aqueous humor through the trabecular meshwork and enhancing the uveoscleral outflow (Brubaker et al, 2001). Brimonidine tartrate is an alpha-2 adrenergic receptor agonist and has a selectivity for the alpha-2 adrenergic receptor that is over 1000 times greater than the alpha-1 adrenergic receptor (Munk et al, 1994). Brimonidine tartrate is believed to lower IOP by enhancing uveoscleral outflow and reducing aqueous humor formation (Report BIO-94-012; Serle et al, 1991). Timolol is a non-selective adrenergic receptor blocker of beta-1 and beta-2. Timolol lowers IOP by reducing aqueous humor formation (Coakes and Brubaker,1978; Yablonski et al, 1978).

According to various exemplary embodiments, the composition contains bimatoprost, brimonidine, and timolol. In another embodiment, the brimonidine is a brimonidine salt, such as brimonidine tartrate, and the timolol is a timolol salt, such as timolol maleate. In another embodiment, the composition further comprises sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the composition further comprises benzalkonium chloride.

In another embodiment, the composition contains 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, and 0.683% w/v timolol maleate. In this combination, brimonidine tartrate and timolol maleate were used in concentrations and treatments approved for the individual components. However, the concentration of bimatoprost in this combination was 0.01%, lower than the approved concentration of 0.03%.

In yet another embodiment, the composition further comprises 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, and 0.35% w/v sodium chloride. In yet another embodiment, the composition further comprises 0.005% w/v benzalkonium chloride.

In another embodiment, the composition consists essentially of bimatoprost, brimonidine, and timolol. In another embodiment, the bimatoprost is a bimatoprost salt, such as bimatoprost tartrate, and the timolol is a timolol salt, such as timolol maleate. In yet another embodiment, the composition further consists essentially of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the composition further consists essentially of benzalkonium chloride.

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

In another embodiment, the composition consists of bimatoprost, brimonidine, timolol, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In another embodiment, the brimonidine is a brimonidine salt, i.e., brimonidine tartrate, and the timolol is a timolol salt, i.e., timolol maleate. In yet another embodiment, the composition further consists of benzalkonium chloride.

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

In certain embodiments disclosed herein, the compositions are free of components other than bimatoprost, brimonidine, timolol, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, benzalkonium chloride, and sodium hydroxide in an aqueous carrier, and do not consist of, or essentially consist of, components other than bimatoprost, brimonidine, timolol, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, benzalkonium chloride, and sodium hydroxide in an aqueous carrier.

Embodiments disclosed herein also include methods of lowering IOP by administering a composition comprising bimatoprost, brimonidine, and timolol. In another embodiment, the brimonidine is a brimonidine salt, such as brimonidine tartrate, and the timolol is a timolol salt, such as timolol maleate. In yet another embodiment, the administered composition further comprises sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the administered composition further comprises benzalkonium chloride.

In another embodiment, a method of lowering IOP comprises administering a composition comprising 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, and 0.68% w/v timolol maleate. In yet another embodiment, the administered composition further comprises 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, 0.35% w/v sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the administered composition further contains 0.005% w/v benzalkonium chloride.

Embodiments disclosed herein also include methods of lowering IOP by administering to a subject or patient a composition described herein. In certain embodiments, the compositions described herein are administered to a human subject.

Embodiments disclosed herein also include methods of lowering IOP by administering a composition consisting essentially of bimatoprost, brimonidine, and timolol. In another embodiment, the brimonidine is a brimonidine salt, such as brimonidine tartrate, and the timolol is a timolol salt, such as timolol maleate. In yet another embodiment, the administered composition further consists essentially of sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the administered composition further consists essentially of benzalkonium chloride.

In another embodiment, a method of lowering IOP comprises administering a composition 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 administered composition further consists essentially of 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, 0.35% w/v sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the administered composition further consists essentially of 0.005% w/v benzalkonium chloride.

Embodiments disclosed herein also include methods of lowering IOP by administering a composition consisting of bimatoprost, brimonidine, timolol, disodium phosphate heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier. In another embodiment, the brimonidine is a salt, brimonidine tartrate, and the timolol is a salt, timolol maleate. In yet another embodiment, the administered composition further consists of benzalkonium chloride.

In another embodiment, a method of lowering IOP comprises administering a composition consisting of 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, 0.68% w/v timolol maleate, 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, 0.35% w/v sodium chloride, and sodium hydroxide in an aqueous carrier. In yet another embodiment, the administered composition further consists of 0.005% w/v benzalkonium chloride.

Definition of terms

For the purposes of this disclosure, "treat", "treating", or "therapy" refers to the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, amelioration, or treatment of a disease or underlying condition.

A "pharmaceutically acceptable salt" is any salt which retains the activity of the parent compound and which does not have any additional deleterious or detrimental effect on the subject to which the compound is administered and the situation in which the compound is administered, as compared to the parent compound. Pharmaceutically acceptable salts also refer to any salt that can form in vivo as a result of administration of an acid, another salt, or a prodrug that is converted to an acid or salt.

Pharmaceutically acceptable salts having acidic functional groups can be derived from organic or inorganic bases. The salt may comprise a monovalent ion or a multivalent ion. Of particular importance are the inorganic ions lithium, sodium, potassium, calcium and magnesium ions. Organic salts can be prepared with amines, such as, in particular, the ammonium salts of monoalkylamines, dialkylamines and trialkylamines or ethanolamines. Salts may also be prepared 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 pyridine ring.

A "prodrug" is a compound that is converted to a therapeutically active compound after administration, and the term should be interpreted broadly herein as it is commonly understood by one of ordinary skill in the art. While not wishing to limit the scope of the present disclosure, the conversion may occur by hydrolysis of an ester group or some other biologically labile group. Typically, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is to be converted. Ester prodrugs of the compounds disclosed herein are specifically contemplated. The ester may be derived from a carboxylic acid of Cl (i.e., the terminal carboxylic acid of the native prostaglandin), or the ester may be derived from a carboxylic acid functional group on another part of the molecule (e.g., the phenyl ring). While not wishing to be limited, the esters may be alkyl esters, aryl esters, or heteroaryl esters. The term alkyl has the meaning commonly understood by those of ordinary skill in the art and refers to a straight chain, branched, or cyclic alkyl moiety. C_1-6Alkyl esters are particularly suitable, wherein the alkyl portion of the ester has from 1 to 6 carbon atoms, and includeIncluding but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1 to 6 carbon atoms.

Description of the invention

In a series of U.S. patent applications assigned to Allergan, inc, prostaglandin esters are disclosed that reduce increased ocular activity with concomitant large reduction in side effects. U.S. patent application No. 386,835 (filed on 27.7.1989) relates to certain 11-acyl-prostaglandins useful for lowering intraocular pressure (IOP), such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF_2α. U.S. patent application No. 357,394 (filed 5/25 1989) discloses 15-acyl prostaglandins that lower intraocular pressure. Similarly, the 11,15-, 9, 15-and 9, 11-diesters of prostaglandins, for example, 11, 15-ditert-pentanoyl PGF_2αHas ocular hypotensive activity. See, U.S. patent application No. 385,645 (filed on 27.7.1990), now U.S. patent No. 4,994,274; U.S. patent application No. 584,370 (filed on 18.9.1990), now U.S. patent No. 5,028,624, which is a continuation of U.S. patent application No. 386,312 (filed on 27.7.1989), and U.S. patent application No. 585,284 (filed on 18.9.1990), now U.S. patent No. 5,034,413, which is a continuation of U.S. patent application No. 385,834 (filed on 27.07.1989). The teachings of esters having ocular hypotensive activity in each of these references are incorporated herein by reference in their entirety.

Disclosed herein are compositions and methods for lowering IOP using a combination of at least three IOP lowering agents, including bimatoprost, brimonidine, and timolol, or pharmaceutically acceptable salts or prodrugs thereof. In certain embodiments, additional ingredients are added to the triple combination of bimatoprost, brimonidine, and timolol, including, without limitation, preservatives, buffers, tonicity adjusting agents, and surfactants, thereby making the composition more ophthalmically acceptable. In addition, various vehicles can be used in the disclosed embodiments. These compositions are useful for lowering IOP in patients with elevated IOP, thereby, for example, preventing or delaying glaucoma in patients with ocular hypertension and preventing or delaying further vision loss in patients with glaucoma.

While not wishing to be bound by any particular theory, it is believed that the prostamide analog bimatoprost (tradename by Allergan, incMarketing) lowers IOP by increasing the aqueous outflow of the eye. The chemical name of bimatoprost is (Z) -7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- (1E,3S) -3-hydroxy-5-phenyl-1-pentenyl]Cyclopentyl group]-5-N-ethylheptanamide with a molecular weight of 415.58.

Brimonidine is an alpha 2-adrenergic agonist receptor that reduces the production of body aqueous humor and increases the waterproof outflow of the eye, thereby causing a reduction in IOP. Brimonidine is available from Allergan, Inc. under the trade name brimonidineBrimonidine tartrate is a brimonidine salt with the chemical name of 5-bromo-6- (2-imidazolidinylideneamino) quinoxaline L-tartrate. Brimonidine as the tartrate salt has a molecular weight of 442.24.

Timolol is a non-selective beta-adrenergic receptor blocker that reduces the production of body aqueous humor by blocking beta receptors on the ciliary epithelium. In one embodiment, the timolol component contains an acid salt of timolol, and in another embodiment timolol maleate. Timolol maleate has a chemical name of (-) -1- (tert-butylamino) -3- [ (4-morpholino-1, 2, 5-thiadiazol-3-yl) oxy]-2-propanol maleate (1:1) (salt). Timolol maleate has a molecular weight of 432.50. Timolol is commercially available from Merck under the trade name timolol

Preservatives that may be used in the pharmaceutical compositions of embodiments of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. In one non-limiting embodiment, preservative-free compositions are contemplated for patients who develop an allergic reaction to the preservatives listed above or other non-listed preservatives.

Various buffers and various means may be used to adjust the pH as long as the resulting formulation is ophthalmically acceptable. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations can also be adjusted with acids or bases as desired. The pH of the disclosed composition should preferably be maintained between 6.5 and 7.2 with a suitable buffering system.

Tonicity adjusting agents may be added as desired, including without limitation glycerin, sorbitol, sodium chloride, potassium chloride, and mannitol, or any other suitable ophthalmically acceptable tonicity adjusting agent. In one embodiment, the tonicity modifier is sodium chloride.

In certain embodiments, surfactants such as polysorbates, for example, of Sigma, may be addedIn addition, any other suitable surfactant may also be used.

Various vehicles may also be employed in the ophthalmic formulations of the present embodiments. Such vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers (poloxamers), carboxymethyl cellulose, hydroxyethyl cellulose, physiological saline solution, water, purified water, and combinations thereof.

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

Another excipient component that may be included in the ophthalmic formulation is a chelating agent. A suitable chelating agent is disodium edetate, but other chelating agents may be used instead of or in combination with disodium edetate.

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

beta-blockers (or beta-adrenergic antagonists) including, but not limited to, carteolol (carteolol), levobunolol (levobunolol), metipranool (metipranool), timolol hemihydrate, beta 1-selective antagonists such as betaxolol (betaxolol), and the like;

adrenergic agonists, including but not limited to non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin (dipivfrin), and the like; and alpha 2-selective adrenergic agonists such as apraclonidine (apraclonidine), and the like;

carbonic anhydrase inhibitors, including without limitation, acetazolamide (acetazolamide), dichlorfenamide (dichlorphenamide), methazolamide (methazolamide), brinzolamide (brinzolamide), dorzolamide (dorzolamide), and the like;

cholinergic agonists, including, without limitation, direct-acting cholinergic agonists such as carbachol (carbachol), pilocarpine hydrochloride (pilocarpine hydrochloride), pilocarpine nitrate (pilocarpine nitrate), pilocarpine, and the like;

cholinesterase inhibitors such as decamethylenediaminium (decacarbanium), diethylthiophholine (echothiophonate), physostigmine (physostimine), and the like;

glutamate antagonists and other neuroprotective agents, e.g. Ca²⁺Channel blockers such as memantine (memantine), amantadine (amantadine), rimantadine (rimantadine), nitroglycerinNordextromethorphan (dextromethorphan), dextromethorphan (detrometorphan), CGS-19755, dihydropyridine, verapamil (verapamil), emopamil (emopamil), benzothiazepine, bepridil (bepridil), diphenylbutylpiperidine, diphenylpiperazine, HOE 166 and related drugs, fluspirilene (fluspirilene), eliprodil (eliprodil), ifenprodil (ifenprodil), CP-101,606, tibalosin (tibalosine), 2309BT and 840S, flunarizine (flunarizine), nicardipine (nicardipine), nifedipine (nifedipine), nimodipine (modiipine), barnidipine (barnidipine), verapamil (verapamil), ridazine (liflozine), lipalazolamide (liprazine), lactonilamide (atrolopride), and the like;

an additional prostamide or a pharmaceutically acceptable salt or prodrug thereof;

prostaglandins including travoprost (travoprost), UFO-21, chloroprostenol (chloroprostenol), fluprostenol (fluprostenol), 13, 14-dihydro-chloroprostenol, isopropyl unoprostone (isoprostone), latanoprost (latanoprost), and the like; and

cannabinoids (cannabinoids) include CB1 agonists such as WIN-55212-2 and CP-55940.

For the treatment of diseases that are harmful to the eye, the disclosed compositions may be administered topically or as ocular implants.

Pharmaceutical compositions may be prepared by combining as the active ingredient a therapeutically effective amount of bimatoprost, brimonidine and timolol according to the present disclosure, or a pharmaceutically acceptable acid addition salt thereof, with conventional ophthalmically acceptable pharmaceutical excipients, and in unit dosage forms suitable for ocular use. The therapeutically effective amount will vary with the activity of the active ingredient; however, typically in combination, the composition is from 0.0001% (w/v) to 20% (w/v), from 0.0001% (w/v) to 10% (w/v), from 0.0001% (w/v) to 5% (w/v), from 0.0005% (w/v) to 3% (w/v), from 0.00075% (w/v) to 2% (w/v), from 0.001% (w/v) to 1.0% (w/v), from 0.2% (w/v) to 1.0% (w/v), from 0.5% (w/v) to 1.0% (w/v), from 0.85% (w/v) or from 0.843% (w/v). The composition may be prepared as follows:

1. a quantity of water, i.e., about 70% of the batch size, is added to the selected stainless steel container.

2. Disodium phosphate heptahydrate was added to step 1 with mechanical stirring and mixed until dissolved.

3. Citric acid monohydrate was added to step 2 with stirring and mixed until dissolved.

4. Add sodium chloride to step 3 with stirring and mix until dissolved.

5. Bimatoprost is added to step 4 with stirring and mixed until a clear solution is obtained.

6. Timolol maleate was added to step 5 with stirring and mixed until dissolved.

7. Brimonidine tartrate was added to step 6 with stirring and mixed until dissolved.

8. Benzalkonium chloride was added to step 7 as a stock solution under stirring.

9. The pH of the solution was checked and adjusted to 7.1 if necessary.

10. The volume was made up to 100% batch size with water and stirred for 5 to 10 minutes.

Bimatoprost may be included in the compositions of the embodiments disclosed herein in an amount of 0.0001% (w/v) to 15% (w/v), 0.0001% (w/v) to 10% (w/v), 0.0001% (w/v) to 5% (w/v), 0.0005% (w/v) to 3% (w/v), 0.00075% (w/v) to 2% (w/v), 0.001% (w/v) to 1.0% (w/v), 0.001% (w/v) to 0.1(w/v), 0.005% (w/v) to 0.05% (w/v), or 0.01% (w/v) of the composition.

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

The amount of timolol included in a composition of embodiments disclosed herein can be 0.0001% (w/v) to 15% (w/v), 0.0001% (w/v) to 10% (w/v), 0.0001% (w/v) to 5% (w/v), 0.0005% (w/v) to 3% (w/v), 0.01% (w/v) to 2% (w/v), 0.1% (w/v) to 1.0% (w/v), 0.1(w/v) to 0.9(w/v), 0.3% (w/v) to 0.8% (w/v), 0.5% (w/v), 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% (w/v), 0.68% (w/v), or 0.683% (w/v) of the composition.

The amount of a composition suitable for use in the present invention to be administered depends on the desired therapeutic effect or effects, the particular patient being treated, the severity and nature of the patient's condition, the mode of administration, the potency and pharmacodynamics of the particular compound or compounds employed, and the judgment of the prescribing physician. A therapeutically effective dose of a composition suitable for use in the present invention may range from 0.01 mg/kg/day to 200 mg/kg/day. In certain embodiments, the therapeutically effective dose can be 0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 50 mg/kg/day, 60 mg/kg/day, 70 mg/kg/day, 75 mg/kg/day, 80 mg/kg/day, 85 mg/kg/day, 90 mg/kg/day, or 100 mg/kg/day. The dose may be provided as a single daily dose, or may be provided as multiple doses from 2 to 24 times a day. In certain embodiments, a dose may be administered once every other day, once every three days, once a week, once a month, and the like.

In preferred embodiments, the comfort of the formulations disclosed herein is maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may not result in optimal comfort. In the event that comfort is not maximized, the composition should be formulated so that the composition is tolerable to the patient for ophthalmic use.

Ophthalmic formulations of the present disclosure are suitably packaged in a form suitable for metered administration to facilitate administration to the eye, such as in a dropper-equipped container. Containers suitable for drop-wise administration are typically made of suitable inert, non-toxic plastic materials and typically contain from 0.5ml to 15ml of solution. A package may contain one or more unit doses.

Preservative-free solutions (e.g., table 7) can be formulated in non-resealable containers containing as many as 1,2,5, 10, 50, or 100 unit doses, with typical unit doses being 1 to 8 drops. The volume of 1 drop is generally 20 to 35. mu.l.

Various exemplary embodiments may be formulated as shown in the following table:

TABLE 1

Composition (I)	Amount (% w/v)
		Active ingredient	0.001-5
Preservative	0-0.10
		Media	0-40
Tension regulator	1-10
		Buffer solution	0.01-10
pH regulator	Proper amount, pH 4.5-7.5
		Antioxidant agent	According to the need
Surface active agent	According to the need
		Purified water	Is supplemented to 100% according to the requirement

TABLE 2

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.003-0.03

Brimonidine	Active agent	0.005-0.2
			Timolol	Active agent	0.2-0.5
Disodium hydrogen phosphate heptahydrate	Buffering agent	Made as required to be accepted by ophthalmology
			Citric acid monohydrate	Buffering agent	Made as required to be accepted by ophthalmology
Sodium chloride	Tension agent	Made as required to be accepted by ophthalmology
			Sodium hydroxide	pH regulator	Proper amount of
Water (W)	Media	Proper amount of

TABLE 3

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.003-0.03
Brimonidine tartrate	Active agent	0.005-0.3
			Timolol maleate	Active agent	0.2-0.8
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.0-2.0
			Citric acid monohydrate	Buffering agent	0.01-0.05
Sodium chloride	Tension agent	0.10-0.30
			Sodium hydroxide	pH regulator	Proper amount.
Water (W)	Media	Proper amount.

TABLE 4

TABLE 5

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.1
			Timolol maleate	Active agent	0.6
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
			Citric acid monohydrate	Buffering agent	0.025
Sodium chloride	Tension agent	0.35
			Sodium hydroxide	pH regulator	Proper amount of
Water (W)	Media	Proper amount of

TABLE 6

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.1
			Timolol maleate	Active agent	0.6
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
			Citric acid monohydrate	Buffering agent	0.025
Sodium chloride	Tension agent	0.35
			Benzalkonium chloride	Preservative	0.005
Sodium hydroxide	pH regulator	Proper amount of
			Water (W)	Media	Proper amount of

TABLE 7

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.15
			Timolol maleate	Active agent	0.68
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
			Citric acid monohydrate	Buffering agent	0.025
Sodium chloride	Tension agent	0.35
			Sodium hydroxide	pH regulator	Proper amount of
Water (W)	Media	Proper amount of

TABLE 8

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.15
			Timolol maleate	Active agent	0.68
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
			Citric acid monohydrate	Buffering agent	0.025
Sodium chloride	Tension agent	0.35
			Benzalkonium chloride	Preservative	0.005
Sodium hydroxide	pH regulator	Proper amount of
			Water (W)	Media	Proper amount of

TABLE 9

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.15
			Timolol maleate	Active agent	0.683 (equivalent to 0.5 timolol)

		Er)
			Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
Citric acid monohydrate	Buffering agent	0.025
			Sodium chloride	Tension agent	0.35
Sodium hydroxide	pH regulator	Proper amount of
			Water (W)	Media	Proper amount of

Watch 10

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	About 0.01
Brimonidine tartrate	Active agent	About 0.15
			Timolol maleate	Active agent	About 0.683
Disodium hydrogen phosphate heptahydrate	Buffering agent	About 1.5
			Citric acid monohydrate	Buffering agent	About 0.025
Sodium chloride	Tension agent	About 0.35
			Benzalkonium chloride	Preservative	About 0.005
Sodium hydroxide	pH regulator	Proper amount of
			Water (W)	Media	Proper amount of

"about" refers to the range of concentration variations deemed biologically equivalent by a regulatory agency.

Unless otherwise indicated, all numbers expressing quantities of ingredients, such as molecular weights, properties of reaction conditions, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very 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 construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Example I triple combination of Bimamprost, brimonidine and timolol

36 female New Zealand white rabbits were used in this study, obtained from Charles river laboratories (Wilmington, Mass.), 4 months old and weighed 2.96 to 3.54 kg at the start of dosing. 1 drop (~ 30. mu.L/drop) of the formulation of Table 11 was applied directly to the upper corneal surface of the left eye using a dropper bottle, 2 or 4 times daily (2 or 6 hour intervals) for 1 month.

TABLE 11

Composition (I)	Function of	%w/v
			Bimatoprost	Active agent	0.01
Brimonidine tartrate	Active agent	0.15
			Timolol maleate	Active agent	0.683*
Disodium hydrogen phosphate heptahydrate	Buffering agent	1.5
			Citric acid monohydrate	Buffering agent	0.025
Sodium chloride	Tension agent	0.35
			Benzalkonium chloride	Preservative	0.005
Sodium hydroxide	pH regulator	Proper amount of
			Water (W)	Media	Proper amount of

Timolol equivalent to 0.5% w/v

The contralateral right eye was used as an untreated control. Dose administration (Dose administration) and time of administration were manually recorded on the raw data sheet, which was used as a formal record of administration.

Intraocular pressure (IOP) was measured in both eyes of all rabbits before the start of dosing and at the end of the 1-month rest period. Later examinations will be performed at the end of the 3 month treatment period and after the 1 month recovery period. IOP measurements were taken at approximately the same time on each examination day. An ocular local anesthetic (e.g., proparacaine hydrochloride) is administered to the eye prior to the measurement. The eye is rinsed with sterile saline at the completion of the measurement if deemed necessary. IOP measurements were manually recorded on the raw data sheet.

Finally, a triple combination topical eye drop (about 30 μ L/drop) or triple combination placebo was administered to the left eye of female NZW rabbits (12/group) 2 or 4 times daily for 1 month. No drug-related effects were observed in ophthalmology, gross visual observation, body weight, clinical observation or food consumption. The expected acceptable drug-related reduction in intraocular pressure was observed in rabbits given the triple combination ophthalmic solution. Triple combination ophthalmic solutions are well tolerated.

OS-triple combination ophthalmic solution, 50ppm BAK, (1 drop of 30. mu.L, 4X/day)

OD-untreated

OS = left eye; OD = right eye; baseline = days-6; "- -" = not applicable

Change from baseline (%) = [ (mean-baseline mean) ÷ baseline mean ] × 100

Change from OD (%) = [ (average OS-average OD) ÷ average OD ] x 100.

Example II IOP lowering of the triple combination of Table 11

A white male 71 years old suffers from open angle glaucoma and high intraocular pressure, which if left untreated, may deteriorate his vision. After 3 months of treatment with the combination, the patient's IOP was not reduced to his physician's satisfaction. This 71 year old white began daily administration of the triple combination of table 11 in both eyes and the patient's IOP was expected to undergo a sufficient reduction that was previously unattainable.

Example III-triple combination of Table 11 for IOP lowering in 64 year old African American women

A 64 year old african american female suffering from glaucoma has difficulty adequately lowering her IOP with a combination therapy of brimonidine and timolol. After 4 months of brimonidine and timolol product combination therapy, her physician transferred her to the triple combination therapy product of table 11. The IOP of both eyes of the patient is expected to drop to acceptable levels after 3 weeks of administration of the triple combination therapy product.

Example III treatment of glaucoma in a 57 year old white female

A 57 year old white female suffering from open angle glaucoma is essentially non-responsive to monotherapy for lowering IOP first, and then to combination therapy for lowering IOP. She was expected to return her IOP to normal levels with 2 administrations per day using the compositions of Table 11. After 30 days of binocular administration with the formulation of Table 11, the IOP of the 57 year old white female was restored to a normal level as long as the administration of the formulation of Table 11 was continued.

Example IV-treatment of elevated intraocular pressure in 61 year old Asian males

IOP measured by tonometer for a 61 year old Asian male was between 21.3mmHg and 23.7 mmHg. Both monotherapy and combination therapy using various therapeutic agents known to lower IOP have failed to achieve acceptable levels of IOP in patients. The patient began taking the formulation of table 11 twice a day, 1 drop for each eye in the morning and 1 drop for each eye in the evening after 12 hours. After 31 days, the IOP of the patient is expected to drop to 16.1mmHg to 18.2mmHg, which is considered acceptable. After 90 days, the IOP of the patient is expected to decrease to 15.5mmHg to 16.8 mmHg.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. By "about" is meant the range of concentration of excipients and active agents that are considered biologically equivalent by regulatory agencies.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if each separate value was individually recited herein. All methods disclosed herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by 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 does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that one or more members of the group may be included in the group or deleted from the group for reasons of brevity and/or patentability. When any such inclusion or deletion occurs, the specification should be considered to encompass the modified group so as to satisfy the written description of all Markush (Markush) groups used in the appended claims.

Certain embodiments of this invention are disclosed herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of those embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in the claims by the language consisting of, or consisting essentially of. The consistent term "consisting of", when used in a claim, does not include any elements, steps or components not specified in the claim, whether initially filed or each amended later. The coherent term "consisting essentially of" limits the scope of the claims to the specified substances or steps, as well as those substances or steps that do not materially affect the basic and novel characteristics. The embodiments of the invention so claimed are described or enabled inherently or explicitly herein.

It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be used are also within the scope of the invention. Thus, for example, but not limiting of, alternative configurations of the present invention may be used in accordance with the teachings herein. Accordingly, the invention is not limited to the arrangements specifically shown and described.

Claims (20)

1. A pharmaceutical composition for reducing intraocular pressure in a patient suffering from elevated intraocular pressure comprising bimatoprost (bimatoprost), brimonidine (brimonidine), and timolol (timolol).

2. The pharmaceutical composition according to claim 1, wherein the brimonidine is brimonidine tartrate and the timolol is timolol maleate.

3. The pharmaceutical composition of claim 2, further comprising sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier.

4. The pharmaceutical composition of claim 3, further comprising benzalkonium chloride.

5. The pharmaceutical composition of claim 2, comprising about 0.01% w/v bimatoprost, about 0.15% w/v brimonidine tartrate, and about 0.68% w/v timolol maleate.

6. The pharmaceutical composition of claim 5, further comprising about 1.5% w/v sodium phosphate dibasic heptahydrate, about 0.025% w/v citric acid monohydrate, and about 0.35% w/v sodium chloride.

7. The pharmaceutical composition of claim 6, further comprising about 0.005% w/v benzalkonium chloride.

8. A pharmaceutical composition consisting essentially of bimatoprost, brimonidine tartrate, timolol maleate, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier.

9. The pharmaceutical composition of claim 8, further consisting essentially of benzalkonium chloride.

10. The pharmaceutical composition of claim 8, consisting essentially of 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, 0.68% w/v timolol maleate, 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, and 0.35% w/v sodium chloride.

11. The pharmaceutical composition of claim 10, consisting essentially of 0.005% w/v benzalkonium chloride.

12. The pharmaceutical composition of claim 8, wherein the composition consists of bimatoprost, brimonidine tartrate, timolol maleate, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier.

13. The pharmaceutical composition of claim 12, further consisting of benzalkonium chloride.

14. A method of reducing intraocular pressure (IOP) in a patient suffering from elevated IOP comprising:

administering a pharmaceutical composition comprising bimatoprost, brimonidine, and timolol to an eye of a subject in need thereof.

15. The method of claim 14, wherein the pharmaceutical composition further comprises sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier.

16. The method of claim 15, wherein the pharmaceutical composition further comprises benzalkonium chloride and is administered to the eye at least once per day.

17. The method of claim 15, wherein the composition consists essentially of bimatoprost, brimonidine tartrate, timolol maleate, sodium phosphate dibasic heptahydrate, citric acid monohydrate, sodium chloride, and sodium hydroxide in an aqueous carrier.

18. The method of claim 17, wherein the composition further consists essentially of benzalkonium chloride.

19. The method of claim 17, wherein the composition consists essentially of 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, 0.68% w/v timolol maleate, 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate, and 0.35% w/v sodium chloride.

20. The method of claim 18, wherein the composition consists essentially of 0.005% w/v benzalkonium chloride.