How to lower elevated intraocular pressure

Abstract

The present invention relates to a method for reducing elevated intraocular pressure in a human suffering from open angle glaucoma or ocular hypertension, the method comprising administering brimonidine or a pharma- ceutically acceptable salt thereof.The present invention further relates to a pharmaceutical composition suitable for ophthalmic use comprising brimonidine or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to a method for reducing elevated intraocular pressure in a human suffering from open angle glaucoma or ocular hypertension, the method comprising administering brimonidine or a pharma- ceutically acceptable salt thereof.The present invention further relates to an aqueous suspension comprising brimonidine and pharmaceutical uses thereof. [Background technology]

[0002] Glaucoma is the leading cause of irreversible blindness worldwide. It is generally associated with elevated intraocular pressure, which damages retinal ganglion cells and, if untreated, can progress to blindness. Intraocular pressure is a measure of the dynamic balance between secretion (inflow) and drainage (outflow) of aqueous humor, a fluid secreted continuously by the ciliary epithelium of the eye. Once secreted, aqueous humor enters the eye from the anterior chamber through the pupil and exits primarily through the trabecular meshwork, or, to a lesser extent, through the uveoscleral outflow pathway. The trabecular meshwork drains the aqueous humor via Schlemm's canal into the scleral plexus and systemic blood circulation. Elevated intraocular pressure, resulting from insufficient drainage of aqueous humor from the eye, is the major risk factor for glaucoma.

[0003] There are two main types of glaucoma: open-angle and closed-angle. Open-angle glaucoma is caused by reduced drainage of aqueous humor due to blockages in the trabecular meshwork, resulting in increased intraocular pressure. Closed-angle glaucoma is characterized by contact between the iris and the trabecular meshwork, thereby preventing the outflow of aqueous humor and causing increased intraocular pressure. In approximately 50% of cases of closed-angle glaucoma, prolonged contact between the iris and the trabecular meshwork leads to the formation of adhesions that permanently block aqueous outflow.

[0004] "Ocular hypertension" refers to a condition in which intraocular pressure is elevated above normal levels, which is not associated with visual impairment but may lead to glaucoma over time. Medical treatment of ocular hypertension or glaucoma aims to reduce the elevated intraocular pressure to a non-impairing normal IOP, and also aims to maintain a normal IOP.

[0005] Ophthalmic drug delivery is one of the most challenging endeavors faced by pharmaceutical scientists. The eye is an anatomically and physiologically unique organ, containing several diverse structures with independent physiological functions. The complexity of the eye poses unique challenges to drug delivery strategies. Typically, the ocular bioavailability of drugs administered topically as eye drops is extremely low. Drug absorption in the eye is severely limited by several protective mechanisms and other concomitant factors that ensure the proper functioning of the eye (e.g., nasolacrimal drainage of eye drops; lacrimation and tear turnover; short corneal contact time; metabolism; tear evaporation; non-productive absorption / adsorption; limited corneal area and low corneal permeability; and binding by tear proteins). These factors greatly affect drug absorption and disposition by the eye, resulting in reduced ocular drug bioavailability. It is therefore a challenge to develop an ocular drug delivery system that provides optimal drug bioavailability.

[0006] Brimonidine tartrate is an alpha-2-adrenergic agonist that reduces the elevated intraocular pressure (IOP) in the eye associated with glaucoma. It is known to use topical brimonidine to reduce intraocular pressure in patients suffering from glaucoma or ocular hypertension.

[0007] Brimonidine typically produces a moderate peak IOP reduction of about 20-25% in ocular hypertensive eyes and 6-18% in normotensive eyes (<21 mmHg). The peak effect is within 2 hours after instillation, the duration of effect is usually less than 12 hours, and the moderate effect usually requires administration 2-3 times per day.

[0008] The first ophthalmic brimonidine product in the United States was approved by the FDA in 1996. Sold under the trade name "Alphagan®", it contained brimonidine in the form of brimonidine tartrate at a concentration of 0.2%. In 2001, a second ophthalmic brimonidine product was approved by the US FDA. Sold under the trade name "Alphagan® P", it contained brimonidine tartrate in two different concentrations of brimonidine (0.15% and 0.1%), each of which is lower than the 0.2% brimonidine concentration in Alphagan®. Summary of the Invention [Problem to be solved by the invention]

[0009] One object of the present invention is to provide a composition for treating ocular hypertension or glaucoma, which has excellent ocular hypotensive effect (i.e., effect of lowering intraocular pressure), is free of significant side effects, and in particular, has minimal irritating effect on the eye.

[0010] Another object of the present invention is to provide an efficient and stable ophthalmic drug delivery system that provides increased ocular bioavailability of the drug after administration to the eye, prolongs the ocular action of the drug, is more convenient to use, and minimizes irritation or other discomfort associated with administration to the eye.

[0011] The present invention meets this need and provides an ophthalmic composition in the form of a novel aqueous suspension containing brimonidine or a pharma- ceutically acceptable salt thereof that can be instilled into the eye once daily and is effective in reducing elevated intraocular pressure in humans suffering from open-angle glaucoma or ocular hypertension.

[0012] The novel compositions of the present invention provide efficacy equivalent to Alphagan P® with less frequent administration, i.e., once daily instillation, compared to the three times daily instillation prescribed for Alphagan P®. [Means for solving the problem]

[0013] A first aspect of the present invention relates to an aqueous suspension comprising (a) reversible clusters of brimonidine loaded nano-resin particles and (b) a suspending agent, wherein the brimonidine loaded nano-resin particles have a particle size distribution with a D90 value of 70-900 nm and a D50 value of 50-700 nm, and wherein the suspension is for use in the treatment of elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension.

[0014] The present invention further relates to a method of treating elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, which method comprises administering to a patient in need of such treatment the aqueous suspension described above.

[0015] In a further aspect, the present invention relates to a method of reducing elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, wherein the method comprises administering brimonidine or a pharma- ceutically acceptable salt thereof or an aqueous suspension as described above, wherein the method reduces intraocular pressure in said patient by at least 2-6 mmHg, and wherein the method is effective in reducing intraocular pressure for a period of about 7-15 weeks.

[0016] Another aspect of the present invention relates to a method of reducing elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, the method comprising administering brimonidine or a pharma- ceutically acceptable salt thereof or an aqueous suspension as described above, wherein following administration, the patient achieves a reduction in intraocular pressure of >20% from baseline that is sustained for at least 12 weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention relates to an aqueous suspension comprising (a) reversible clusters of brimonidine-loaded nano-resin particles and (b) a suspending agent, wherein the brimonidine-loaded nano-resin particles are D90 Value is 70-900 nm and D 50 and wherein the suspension is for use in the treatment of elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension. The aqueous suspension was surprisingly able to increase the bioavailability of brimonidine with sustained ophthalmic action.

[0018] Without wishing to be bound by any theory, it is believed that the reversible clusters of brimonidine nano-resin particles, when instilled into the eye, are declustered under the shear forces of blinking. The declustered individual drug-loaded nano-resin particles spread on the surface of the cornea and then release the drug through ion exchange phenomenon under the influence of ions present in the ocular tissue. The drug is excreted through nasolacrimal passages is reduced. The overall phenomenon causes an increase in the bioavailability of the drug along with a prolonged ophthalmic effect.

[0019] Preferably, the nano resin particles D 90 The value is in the range of 200 to 700 nm. The inventors have found that when the particles are in this range, the aqueous suspension is particularly effective.

[0020] Furthermore, the D of the nano resin particles 50 is preferably within the range of 50 to 700 nm, more preferably 100 to 500 nm, or 150 to 350 nm, or 200 to 300 nm.

[0021] Additionally, the reversible clusters of brimonidine-loaded nanoresin particles in aqueous suspension according to the present invention may also contain brimonidine as a pharma- ceutically acceptable salt or solvate, with a particularly preferred salt being brimonidine tartrate.

[0022] As used herein, the term "IOP" is an abbreviation for "intraocular pressure." Elevated IOP above 21 mmHg has traditionally been suspected of causing glaucoma (7); the higher the IOP, the greater the likelihood of optic nerve damage and visual field loss. At an IOP >30 mmHg, the potential risk of blindness is 40 times greater compared to an IOP of 15 mmHg.

[0023] The terms "reducing" and "lowering" refer to prophylactic use to reduce the likelihood of a disease, disorder or condition to which such term applies or one or more symptoms of such disease, disorder or condition.

[0024] The term "reversible clustering" of brimonidine-loaded nanoresin particles, according to the present invention, means that individual brimonidine-loaded nanoresin particles form aggregates or agglomerates (wherein these aggregates preferably have an average size of about 2 micrometers or greater) and, upon application of shear forces, deagglomerate or decluster into individual brimonidine-loaded nanoresin particles.

[0025] Qualitatively, declustering was observed by microscopy (Morphology G3S-ID TM The observations can be made by observing the sheared (by smearing) and non-sheared samples on a glass slide using a Microscope Instrument, Make: Malvern®.

[0026] As further mentioned herein, the D 50 is obtained from the particle size distribution obtained before the application of shear. The particle size distribution can be measured with a suitable particle size analyzer such as a Malvern Mastersizer 2000®. The ultrasonic treatment means of the particle size analyzer is not used and the sample is subjected to agitation only by a mechanical stirrer.

[0027] The suspension of clusters is placed in a sonication bath and subjected to shear for 5 seconds using a sonication frequency of about 33±3 kHz, and a sample is removed to measure the particle size distribution. The process is repeated 5 times, each with an interval of 1 minute (see Example 7).

[0028] Nano resin particles or drug-loaded nano resin particles according to the present invention refer to individual ion exchange resin particles and not to clusters or aggregates of individual particles, where individual particles are D 90 The nano resin particles have a particle size distribution characterized by a value in the range of about 70 nanometers to 900 nanometers, preferably 200 to 700 nanometers. The particle size distribution of the nano resin particles can be considered as the particle size distribution obtained after subjecting the suspension to 5 pulses of frequency 33±3 KHz, each with an interval of 1 minute, as described above.

[0029] The individual brimonidine-loaded nano-resin particles have a D of 70 nm to 900 nm, preferably 200 nm to 700 nm. 90 Furthermore, such drug-loaded nano-resin particles have a mean particle size (D 50 Preferably, the nano resin particles have a D 50 is 50 to 700 nm, preferably 100 to 500 nm, alternatively 150 to 350 nm or 200 to 300 nm. The particle size distribution of the nano resin is further represented by D 10 It may also be characterized in that the thickness is less than 300 nm, preferably 10 nm to 250 nm.

[0030] The reversible clusters have a particle size distribution such that the average particle size is preferably at least 2 micrometers (μm or microns). In a further preferred embodiment, the particle size distribution of the clusters is such that the D 90 The particle size distribution is further such that the D 50The reversible clusters may also be characterized as having a diameter of less than 40 micrometers, preferably less than 20 micrometers, and more preferably less than 10 micrometers. As previously mentioned, the reversible clusters deagglomerate or deaggregate upon application of shear force to form brimonidine-loaded nanoresin particles.

[0031] The present invention provides a method for reducing elevated intraocular pressure in a human, the method comprising: (a) forming reversible clusters of brimonidine-loaded nano-resin particles, the clusters having a D of at least 2 micrometers. 50 and the brimonidine-loaded nano resin particles have a D 90 The value is 70 nm to 900 nm and D 50 The method includes administering an aqueous suspension comprising: (a) a granular material having a particle size distribution characterized by a particle size distribution having a particle size distribution value of 50 nm to 700 nm; and (b) a suspending agent; and (c) a pharma- ceutically acceptable excipient.

[0032] The inventors have surprisingly found that it is important to monitor patients who have been administered the aqueous suspension for certain side effects. For example, it is important to monitor whether patients who have been administered the suspension according to the invention suffer from, for example, nervous system disorders, eye congestion, somnolence, or gastrointestinal disorders. In view of this, it is important to provide patient monitoring in addition to administering the aqueous suspension according to the invention. The patient monitoring includes an ophthalmological examination for the appearance of one or more potential side effects. It is further important that the examination is performed within a short period of time after the start of treatment with the aqueous suspension, for example within 16 weeks, and in some cases within 12 weeks, to avoid permanent damage to the eye.

[0033] Thus, optionally, said treatment with the aqueous suspension according to the invention further comprises the following steps: (a) determining the ophthalmic history of the patient to be treated prior to initiating treatment with said aqueous suspension; (b) performing an ophthalmological examination, preferably by an ophthalmologist, at least within 16 weeks, preferably at least within 12 weeks, after beginning treatment with the aqueous suspension, where the examination includes checking and / or monitoring for the appearance of drowsiness, eye redness, nervous system disorders or dry mouth; (c) optionally conducting additional ophthalmic examinations at intervals determined by the ophthalmologist based on the patient's symptoms; Contains:

[0034] In a further embodiment of the aqueous suspension and its use according to the invention, brimonidine or a pharma- ceutically acceptable salt thereof is present in a concentration of 0.05% to 0.5% w / v. In a preferred embodiment, the pharma- ceutically acceptable salt is brimonidine tartrate. Most preferably, the suspension comprises about 0.35% w / v. brimonidine tartrate. In a further embodiment, the suspension comprises about 0.2% to about 0.5% w / v. brimonidine or a pharma- ceutically acceptable salt thereof, in particular brimonidine tartrate.

[0035] In one embodiment, brimonidine tartrate is present in the suspension at a concentration of 0.35% weight / volume.In another embodiment, the aqueous suspension of the present invention contains brimonidine tartrate at a concentration of 0.15% weight / volume.

[0036] In a further embodiment, the resin is polystyrene divinylbenzene sulfonate. In another embodiment, the suspending agent is a mixture of carbopol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In yet another embodiment, the resin is polystyrene divinylbenzene sulfonate and the suspending agent is a mixture of carbopol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. The weight ratio of the nano resin particles to brimonidine is about 1:1, and the pH is about 7-8.

[0037] In another embodiment, the resin is a cation exchange resin. The matrix of the cation exchanger carries ionic groups such as sulfonic acid groups, carboxylate groups and phosphate groups. The matrix of the anion exchanger carries primary, secondary, tertiary or quaternary ammonium groups. The resin matrix determines its physical properties, its behavior towards biological materials and, to some extent, its capacity. Brimonidine has a positive charge and can therefore bind to the cation exchange resin. Sulfonic acid exchangers are the most common cation exchange resins used in the pharmaceutical resinate aqueous suspension of the present invention. In general, they are crosslinked polystyrene with sulfonic acid groups introduced by treatment with sulfuric or chlorosulfonic acid after polymerization. Suitable cation exchange resins that can be used in the present invention include, but are not limited to, the following: sodium polystyrene divinylbenzene sulfonate, e.g., available from Rohm and Haas under the trade name Amberlite; TM those commercially available under the trade name IRP69; polacrilex resins, which are derived from porous copolymers of methacrylic acid and divinylbenzene, such as those available under the trade name Amberlite from Rohm and Haas; TM commercially available under the trade name IRP64; polacrilin potassium, which is the potassium salt of a crosslinked polymer derived from methacrylic acid and divinylbenzene, e.g. available under the trade name Amberlite from Rohm and Haas; TM Marketed under IRP88.INDION by the company Ion Exchange India Ltd. TM 234;INDION TM 264;INDION TM 204;INDION TMResins available commercially under trade names such as 214 can also be used. In one embodiment, the preferred resin for use in the present invention is Amberlite IRP69, derived from a sulfonated copolymer of styrene and divinylbenzene. Amberlite IRP69 is a pharmaceutical grade strong cation exchange resin, structurally a polystyrene sulfonic acid resin crosslinked with divinylbenzene, i.e., polystyrene divinylbenzene sulfonate. Amberlite IRP69 resin is commercially available from Rhom & Haas Company. The mobile or exchangeable cation in the resin is sodium, which can be exchanged or replaced with a cationic (basic) species. In an embodiment of the present invention, a positively charged cationic drug is bound to the negatively charged sulfonic acid group of the Amberlite resin.

[0038] The amount of cation exchange resin present in the aqueous suspension of the present invention may range from about 0.05% to 5.0% weight / volume of the suspension. The weight ratio of resin to brimonidine may range from 0.1:1 to 1:0.1, more preferably from 0.3:1 to 1:0.3. In a preferred embodiment, the weight ratio of the nanoresin particles to brimonidine is about 1:1. The nanoresin particles used in accordance with the present invention are D 90 The particle size distribution may be characterized by a value of from 70 nm to 900 nm, preferably from 200 nm to 700 nm.

[0039] The aqueous suspension according to the present invention may contain one or more suspending agents. The suspending agents are used to increase the viscosity of the suspension, to cluster the nano resin particles into micron-sized clusters, and to prevent the suspension from solidifying. Suitable suspending agents are selected from anionic polymers, nonionic polymers, or mixtures thereof. The anionic polymers may be selected from the group consisting of carboxyvinyl polymers or polymers of acrylic acid such as carbomer (also known as carbopol). Various grades of carbomers, including Carbopol 934P, 974, and 1342, may be used in the present invention. The polymers of acrylic acid may be present in the aqueous suspension according to the present invention in an amount ranging from about 0.01% to 0.5% by weight / volume of the suspension. Other anionic polymers that may be used include, but are not limited to, sodium hyaluronate, sodium carboxymethylcellulose, guar gum, chondroitin sulfate, and sodium alginate. Particularly preferred anionic polymers that may be used include Carbopol 974P. The anionic polymer is most preferably used in an amount of 0.1% w / v of the suspension. Non-ionic polymers that may be used according to the invention may be selected from the group consisting of non-ionic polymers such as polyvinylpyrrolidone, Solplus-a polyvinylcaprolactam-polyvinyl acetate-PEG graft copolymer, poloxamer, polyvinyl alcohol, polypropylene glycol, cellulose derivatives (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, etc.). The non-ionic polymer may be present in the aqueous suspension of the invention in an amount ranging from about 0.1% to about 5.0% by weight / volume of the suspension. Preferred non-ionic polymers that may be used include hydroxypropyl methyl cellulose and polyvinylpyrrolidone.Various pharma- ceutically acceptable grades of hydroxypropylmethylcellulose (also known as hypromellose or HPMC or Methocel) and polyvinylpyrrolidine (also known as povidone or PVP or Plasdone) can be used. Preferred grades of polyvinylpyrrolidine that can be used in the suspensions of the present invention include PVP K-30, PVP K-25, PVP K-50, PVP K-60 and PVP K-90. It can be present in the aqueous suspension in an amount ranging from about 0.5% to about 3.0% by weight / volume of the suspension. The most preferred grade for use in the aqueous suspensions of the present invention is PVP K-90, a 10% w / v aqueous solution of which has a kinetic viscosity in the range of about 300.0 cps to about 700.0 cps at 20° C. and an approximate molecular weight of about 1,000,000 to 1,500,000. In a preferred embodiment, polyvinylpyrrolidine PVP K-90 is used in an amount of 1.2% w / v of the suspension. Preferred grades of hydroxypropyl methylcellulose that may be selected for use in the aqueous suspension of the present invention include, but are not limited to, METHOCEL E, (USP Grade 2910 / HYPROMELLOSE 2910); METHOCEL F, (USP Grade 2906 / HYPROMELLOSE 2906); METHOCEL A15 (Premium LV); METHOCEL A4C (Premium); METHOCEL A15C (Premium); METHOCEL A4M (Premium), HPMC USP Grade 1828, and the like. These materials may be present in the aqueous suspension of the present invention in an amount ranging from about 0.5% to about 3.0% w / v of the suspension. In a most preferred embodiment, the aqueous suspension contains Hypromellose 2910 in an amount of 0.3% w / v. As an adjunct to the suspending agent, aggregation of the nano-resin particles may also be aided by an electrolyte.

[0040] The aqueous suspension according to the present invention may have a viscosity in the range of about 2 cps to 4000 cps, preferably about 5 cps to 400 cps. The viscosity of the aqueous suspension may be measured by known techniques and equipment, for example, by a Brookfield viscometer under standard conditions. TM It should be noted that an aqueous suspension according to one embodiment of the present invention maintains its viscosity when instilled into the eye, i.e., the viscosity does not change substantially when in contact with ocular fluids containing a variety of ions, such as sodium, potassium, calcium, magnesium, zinc, chloride, and bicarbonate.

[0041] The aqueous suspension according to the present invention may further comprise other pharma- ceutically acceptable excipients, such as chelating agents, preservatives and adjuvants for preservatives. The aqueous suspension may further comprise one or more osmotic agents / tonicity adjusting agents, one or more pharma- ceutically acceptable buffers and / or pH adjusters. These excipients may be dissolved or dispersed in a pharma- ceutically acceptable aqueous vehicle, such as water for injection.

[0042] In order to achieve and subsequently maintain an optimal pH suitable for ophthalmic preparations, the aqueous suspension of the present invention may contain an appropriate amount of a pH adjusting agent and / or a buffering agent. The preferred range of pH of the aqueous suspension is about 5.0 to about 8.0, preferably 7.0 to 8.0. The most preferred pH is about 7.4. The aqueous suspension of the present invention contains a pharma- ceutically acceptable pH adjusting agent that may be selected from the group including tromethamine, acetic acid or its salts, boric acid or its salts, phosphoric acid or its salts, citric acid or its salts, tartaric acid or its salts, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, trometamol, and the like, and mixtures thereof. In particular, preferred pH adjusting agents that may be used in the aqueous suspension of the present invention include tromethamine, acetic acid, hydrochloric acid, sodium carbonate, and sodium hydroxide, and the like, and the most preferred is tromethamine.

[0043] The aqueous suspension of the present invention can be isotonic with respect to the ocular fluid present in the human eye and is characterized by an osmotic pressure of 250 to 375 mOsm / kg. The osmotic pressure is adjusted by adding an osmotic pressure / tonicity adjusting agent. The osmotic agents that can be used in the suspension of the present invention to make it isotonic with respect to the ocular fluid present in the human eye are selected from the group including sodium chloride, potassium chloride, calcium chloride, sodium bromide, mannitol, glycerol, sorbitol, propylene glycol, glucose, sucrose, etc. and mixtures thereof. These are used in an appropriate amount to maintain the desired osmotic pressure. In a preferred embodiment of the present invention, a non-ionic osmotic agent such as mannitol is used as the osmotic agent. Mannitol can be present in the suspension of the present invention in an amount of about 2.0 w / v% to about 6.0% w / v, preferably in an amount of about 3.0 w / v% to about 5.0% w / v, and most preferably in an amount of about 4.5% w / v.

[0044] In addition, the aqueous suspension of the present invention can contain an antibacterial effective amount of a preservative.The preservative that can be used in the aqueous suspension of the present invention can be selected from, but is not limited to, the following: quaternary ammonium compounds, such as benzalkonium chloride (BKC), benzododecinium bromide, cetrimonium chloride, polixethonium, and benzethonium chloride; organic mercury, such as phenylmercuric acetate, phenylmercuric nitrate, and thimerosal; parabens, such as methylparaben and propylparaben; ethyl paraoxybenzoate or butyl paraoxybenzoate; acids and their pharma-ceutically acceptable salts, such as sorbic acid, potassium sorbate, ascorbic acid, boric acid, borax, and salicylic acid; substituted alcohols and phenols, such as chlorobutanol, benzyl alcohol, and phenylethanol; amides, such as acetamide; Other preservatives include Polyquad®, polyhexamethylene biguanide, sodium perborate, aminomethylpropanol, chlorhexidine acetate, self-preserving systems including ionic preservatives, such as zinc and borate combinations; and combinations thereof. Preferably, the ophthalmic aqueous suspension of the present invention includes a "quaternary ammonium compound" as a preservative, particularly benzalkonium chloride. Benzalkonium chloride is characterized as a mixture of alkyl dimethyl benzyl ammonium chlorides. It can be used in the aqueous suspension of the present invention at a concentration of about 0.005% w / v to about 0.05% w / v, preferably at a concentration of 0.02% w / v. The aqueous suspension can further include an appropriate amount of an adjuvant for the preservative, such as sodium N-lauroyl sarcosine. A suitable chelating agent that can be used is disodium edetate.

[0045] The aqueous suspension of the present invention remains physically and chemically stable throughout the shelf life of the product. For example, in the case of an aqueous suspension containing the drug brimonidine, no significant changes occur in the assay of brimonidine after the suspension is stored for an extended period of time. The assay of the drug remains within the specified limits, and no degradation products or impurities were observed during storage. Furthermore, there was no significant increase in related substances.

[0046] Tissue distribution studies confirmed that the method of the present invention can deliver drugs to the posterior segment of the eye. The ability of the present invention to deliver drugs to the posterior segment of the eye makes the present invention suitable for treating difficult-to-treat diseases of the posterior segment of the eye. For example, in the case of brimonidine, delivery to the posterior segment of the eye helps prevent neuronal degeneration and provide neuroprotection. This was a surprising discovery, as the method not only provided increased bioavailability of the drug in addition to sustained ophthalmic effects when instilled into the eye, but also made it possible to achieve delivery to the posterior segment of the eye. Without wishing to be bound by any theory, it is believed that the reversible clusters of brimonidine-loaded nano-resin particles decluster when instilled into the eye under the shear forces of blinking. The declustered individual drug-loaded nano-resin particles spread on the surface of the cornea and then release the drug through ion exchange phenomenon under the influence of ions present in the ocular tissue. The drug is excreted less through nasolacrimal tears. The overall phenomenon results in increased bioavailability of the drug along with prolonged ophthalmic effects.

[0047] A further aspect of the invention relates to the aqueous suspension itself.

[0048] Another aspect of the present invention relates to a method of treating elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, the method comprising administering to a patient in need of such treatment the aqueous suspension described above.

[0049] In a further aspect, the present invention relates to a method of reducing elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, wherein the method comprises administering brimonidine or a pharma- ceutically acceptable salt thereof or an aqueous suspension as described above, wherein the method reduces intraocular pressure in said patient by at least 2-6 mmHg, and wherein the method is effective in reducing intraocular pressure for a period of about 7-15 weeks.

[0050] In a further particularly preferred embodiment, the present invention provides a method of reducing elevated intraocular pressure in a human, the method comprising forming reversible clusters of brimonidine-loaded nanoresin particles, said clusters preferably having a D of at least 2 micrometers. 50 and the brimonidine-loaded nano resin particles have a D 90 The value is 70 nm to 900 nm, and D 50 and administering said aqueous suspension comprising brimonidine tartrate, which is present in an amount of 0.35% w / v; the resin is polystyrene divinylbenzene sulfonate; and the suspending agent is a mixture of carbopol, polyvinylpyrrolidone, and hydroxylpropylmethylcellulose. The weight ratio of the nano-resin particles to brimonidine is about 1:1; and the pH is about 7-8. Moreover, surprisingly, the aqueous suspension of the present invention provided a very safe ophthalmic suspension without side effects or toxicity, despite containing a higher concentration of drug (about 0.35% w / v).

[0051] Surprisingly, the present inventors have found that the formulations of the present invention exhibit a statistically significant IOP lowering effect.

[0052] For every 1 mmHg reduction in IOP, visual field loss can be substantially prevented. The longer duration of effect of the present invention produces substantial benefits over a 24 hour period.

[0053] In one or more embodiments, the aqueous suspensions of the present invention effectively reduce mean intraocular pressure in humans suffering from open-angle glaucoma or ocular hypertension.

[0054] The mean reduction from baseline IOP was statistically significant within each treatment group at each follow-up time point.

[0055] In a preferred embodiment, mean IOP is reduced by at least 2-6 mmHg from baseline following once daily administration of the aqueous suspension of the present invention.

[0056] In one or more embodiments, the aqueous suspensions of the present invention provide an IOP reduction of at least 20% from baseline, with the IOP reduction in treated eyes being equal to or better than that seen with the most optimized formulation of brimonidine (Alphagan® P, 0.1%).

[0057] In another embodiment, the aqueous suspensions of the present invention provide an IOP reduction of about 30% to about 50% from baseline.

[0058] It is therefore highly unexpected and surprising that the aqueous suspensions of the present invention not only provide improved efficacy, but also provide a significant reduction in IOP when administered once daily compared to Alphagan P® 0.1% administered three times daily.

[0059] The present invention has been generally disclosed above, and further aspects will be further discussed and illustrated with reference to the following examples, which, however, are provided merely to illustrate the present invention and should not be construed as limiting the present invention thereto. EXAMPLES

[0060] Working Example Example 1: Aqueous suspension of brimonidine Resin Amberlite® IRP69 was washed multiple times with absolute alcohol. The resin was further washed with Millipore water until a pH close to neutral (pH 7.0) was obtained. The particle size distribution of the resin was measured using a Malvern Mastersizer 2000® Ver. 5.60 (Malvern Instruments Ltd., Malvern, UK). The resin was D 10 is 2.341 microns, D 50 5.175 microns and D 90 The resin had a particle size distribution such that the mean diameter was 10.41 microns. This resin was used to prepare the composition in Table 1 shown below. [Table 1] A stainless steel (SS316) beaker was filled with water for injection, 15% of the total batch size, and heated to 85° C. Hydroxypropyl methylcellulose (Hypromellose 2910) was dispersed with high speed stirring to obtain a uniform dispersion. Stirring was continued until the temperature reached 25° C. A portion of the total batch size of water for injection was filled into another stainless steel (SS316) beaker and brought to 25° C. Polyvinylpyrrolidone (Povidone K-90) was dispersed in the water for injection with stirring to obtain a uniform dispersion.

[0061] Approximately 10% of the total batch size of water for injection was placed in a stainless steel (SS316) beaker and heated to 65°C. Carbopol 974P was dispersed in the heated water for injection with stirring. Stirring was continued until the temperature reached 25°C. The Carbopol 974P slurry was neutralized with tromethamine (pH 7.4). The above obtained hypromellose and povidone polymer dispersions were added sequentially to the Carbopol 974P phase. The polymer mixture was autoclaved at 121°C for 20 minutes. N-lauryl sarcosine sodium was mixed into a portion of the total batch size of water for injection, filtered through a 0.2 micron nylon filter, and then added to the polymer phase. Mannitol was dissolved in a portion of the water for injection at 50-60°C, and benzalkonium chloride and disodium edetate were added to form a clear solution. This solution was added to the above polymer phase. A container was charged with water for injection of 15% of the total batch size, and Amberlite IRP69 was dispersed with stirring. A separate container was charged with water for injection of 15% of the total batch size, and brimonidine tartrate was added and dissolved with stirring. The solution was filtered through 0.2 micron and 0.45 micron nylon filters. The filtered brimonidine tartrate solution was added to the autoclaved Amberlite IRP69 dispersion and stirred for 30 minutes. The Amberlite IRP69 and brimonidine tartrate dispersion was added to the polymer mixture obtained above with stirring, and stirring was continued for 1 hour. The pH was adjusted to about 7.4 with tromethamine solution. The volume of the suspension was finally made up to 100% of the batch size. The suspension was stirred for 60 minutes, followed by homogenization at 15000 rpm for 10 minutes.

[0062] The suspension was subjected to ultrasonic treatment at a frequency of 33±3KHz for 5 seconds, and a sample was taken to measure particle size distribution by Malvern Mastersizer 2000®, Ver.5.60 (Malvern Instruments Ltd., Malvern, UK). After an interval of 1 minute each time, the ultrasonic treatment process and subsequent particle size measurement were repeated for 5 minutes. For particle size distribution, please refer to Table 2 below. [Table 2] Observation: The particle size distribution of the brimonidine loaded resin particles was observed to remain in micron size and after shearing by ultrasonication at a frequency of 33±3KHz for 5 seconds, the particle size distribution was D 50 was 5 microns. 90 was not affected by shear forces and remained within the 10 micron range.

[0063] Preparation of purified nano-resins Preparation of purified nano-resin: Resin Amberlite® IRP69 was washed multiple times with a suitable alcohol, such as methanol or absolute alcohol. The resin was further washed with heated Millipore water until a pH close to neutral (pH 7.0) was achieved. The washed resin was subjected to wet milling to reduce the particle size to the nanometer range (D 90 The washed resin and stabilized zirconia beads were added to water for injection in a vessel containing Teflon coated magnetic beads. The vessel was kept on a magnetic stirrer for about 24-48 hours for wet grinding to obtain nano-sized ground resin particles. The formed slurry was passed through a 25 micron sieve to remove the beads and further through a 40 micron PP filter. The ground resin suspension obtained above was subjected to diafiltration using a 500 kD hollow fiber cartridge to reduce the water extractable impurities to less than 1.0 wt% of the resin. The ground resin suspension was further washed with water for injection. The slurry was freeze-dried to obtain the dry powder form of the ground purified resin.

[0064] The particle size distribution of the ground resin was measured using a Malvern Mastersizer 2000® Ver. 5.60 (Malvern Instruments Ltd., Malvern, UK). 10 = 0.148 microns, D 50 = 0.24 microns and D 90= 0.606 microns. This nanoresin was used to prepare the aqueous suspensions of Examples 2 to 5 described below.

[0065] Example 2(A) and Example 2(B) [Table 3] The aqueous suspensions of Examples 2(A) and (B) were prepared as follows.

[0066] In a stainless steel (SS316) beaker, about 15% of the total batch size of water for injection was heated to 85°C. Certain polymer vehicles, such as hydroxypropyl methylcellulose (hypromellose 2910), were dispersed with high speed stirring to obtain a homogeneous dispersion. Stirring was continued until the temperature reached 25°C. In another stainless steel (SS316) beaker, about 12% of the total batch size of water for injection was placed at 25°C. Polyvinylpyrrolidone (Povidone K-90) was dispersed in the water for injection with stirring to obtain a homogeneous dispersion. For Example 2, in a stainless steel (SS316) beaker, about 10% of the total batch size of water for injection was placed and heated to 65°C. Carbopol 974P was dispersed in the heated water for injection with stirring. Stirring was continued until the temperature reached 25°C. The Carbopol 974P slurry was neutralized with tromethamine (pH 7.4). The above obtained hypromellose and povidone polymer dispersions were added sequentially to the Carbopol 974P phase. The polymer mixture was autoclaved at 121°C for 20 minutes. N-lauryl sarcosine sodium was mixed with a portion of the water for injection, filtered through a 0.2 micron nylon filter, and then added to the polymer phase. Mannitol was dissolved in a portion of the water for injection at 50-60°C, and benzalkonium chloride and disodium edetate were added to form a clear solution. This solution was added to the above polymer phase. A portion of the water for injection of the total batch size was placed in a container, and Amberlite IRP69 obtained according to Example 1 was dispersed therein while stirring. This dispersion was autoclaved at 121°C for 20 minutes. In another container, a portion of the water for injection was placed, and brimonidine tartrate was added and dissolved while stirring. This solution was filtered through 0.2 micron and 0.45 micron nylon filters. The filtered brimonidine tartrate solution was added to the autoclaved Amberlite IRP69 dispersion and stirred for 30 minutes.

[0067] The dispersion of Amberlite IRP69 and Brimonidine Tartrate was added to the above obtained polymer mixture under stirring and stirring was continued for about 30 minutes to 1 hour. The volume of the suspension was finally brought to 100% batch size. The suspension was stirred for about 60 minutes and then homogenized at 15000 rpm for 10 minutes. The pH was adjusted to about 7.4 with tromethamine solution. The viscosity of the aqueous suspension of Example 2(A) was measured using a Brookfield viscometer and found to be 19.7 cps.

[0068] Example 3 to Example 5 The aqueous suspensions of Examples 3 to 5 were prepared in the same manner as above, except that the step of adding HPMC and PVP was omitted. [Table 4] The viscosities of the aqueous suspensions of Examples 3 to 5 were measured using a Brookfield viscometer and were found to be 8.2 cps, 12.0 cps, and 97.9 cps, respectively.

[0069] Example 6 The aqueous suspension of Example 2(A) was placed in 5 mL white opaque LDPE containers for chemical stability evaluation. Bottles containing the suspension of Example 2(A) were subjected to accelerated stability conditions to determine the storage stability of the product over its shelf life. The bottles were stored under a variety of conditions. The bottles were stored in an upright and "sideways" position. Brimonidine assay observations are shown below in Tables 5 and 6. [Table 5] [Table 6] The results in Tables 5-6 show that there was no significant change in the assay of brimonidine after long-term storage. The assay of the drug remained within the specified limits, and no degradation products or impurities were observed during storage. Furthermore, there was no significant increase in related substances. The suspension according to the present invention remained chemically stable throughout the shelf life of the product. The suspension is stable at room temperature.

[0070] Example 7 This example illustrates the effect of shear on the reversible clusters of brimonidine-loaded nanoresin particles suspended in Example 2(A), which upon shear (e.g., shear caused by blinking of the eye) de-cluster into individual drug-loaded nanoresin particles. This effect was measured with respect to particle size distributions initially and upon shear.

[0071] Procedure: Shear was applied to the test samples by placing the vials containing the suspensions on a bath sonicator (model type: MC-109 and SI no-1909; manufactured by Oscar Ultrasonic Pvt. Ltd.). Shear was applied for 5 seconds in the form of a sonication frequency of 33±3 kHz, after which the samples were removed and the particle size distribution was measured. This process was repeated 5 times, with an interval of 1 minute between each.

[0072] Particle size measurements were performed using a Malvern Mastersizer 2000®, Version 5.60 (Malvern Instruments Ltd., Malvern, UK), but without the ultrasonication means of the analyzer. Samples were subjected to only gentle agitation with a mechanical stirrer. Observations are summarized in Table 7 below. [Table 7] Observations: It was observed that the clusters of brimonidine loaded nano resin particles of Example 2(A) were completely disintegrated when shear force was applied to the suspension. This was evident by the observed reduction in particle size upon shear / sonication as shown in Table 7. D of drug-resin nanoparticles 50 The initial size was approximately 19.5 microns, but after 5 minutes of constant shear, it disintegrated to a D of 0.213 microns (213 nm). 50 The resulting mixture was converted into individual drug-resin nanoparticles having the formula:

[0073] In contrast, in the case of Comparative Example 1, there was no collapse and the particle size did not change. This is evident from Table 2. As shown in Table 2, the D 50 was initially about 5.2 microns, and even after applying shear at regular intervals for 5 minutes, the size of the particles did not change and remained approximately the same (i.e., 5.176 microns).

[0074] Example 8 A Randomized, Multicenter, Investigator-Concealed, Parallel-Group, Equivalence Study of Once-Daily Brimonidine Tartrate Ophthalmic Suspension Compared with Three-Daily Alphagan® P in Humans With Open-Angle Glaucoma or Ocular Hypertension The study was designed to obtain estimates of mean IOP at each of three time points (8:00 AM, 10:00 AM, 4:00 PM) at weeks 2, 6, and 12 to compare brimonidine tartrate 0.35% ophthalmic suspension (administered QD at 8:00 AM) with brimonidine tartrate 0.1% (administered TID at approximately 8:00 AM, 2:00 PM, and 8:00 PM).

[0075] The primary objective was to evaluate the efficacy of once daily (QD) administration of brimonidine tartrate ophthalmic suspension 0.35%, prepared according to Example 2(A) above, compared to brimonidine tartrate ophthalmic solution 0.1% ("Alphagan") administered TID in human subjects (i.e., patients) suffering from open-angle glaucoma or ocular hypertension.

[0076] A secondary objective was to evaluate the safety of QD administration of a brimonidine tartrate ophthalmic suspension 0.35% of the present invention compared to a brimonidine tartrate ophthalmic solution 0.1% administered TID in subjects with open-angle glaucoma or ocular hypertension.

[0077] Subjects chronically treated with ocular hypotensive medications were required to undergo an appropriate washout period before entering the study to minimize residual effects of other active ocular hypotensive medications.

[0078] Eligible subjects with open-angle glaucoma, pseudoexfoliation, pigment dispersion, or ocular hypertension were stratified into two groups based on IOP in the study eye at Visit 2 / 8:00 AM: IOP≦25 mmHg or IOP>25 mmHg. Within each stratum and site, subjects were randomly assigned (1:1 ratio) at Visit 2. Approximately 666 subjects were enrolled.

[0079] Subjects were included who had open-angle glaucoma (with or without pseudoexfoliation, pigment-dispersing elements) or ocular hypertension in both eyes that was likely to be controlled with monotherapy.

[0080] The primary efficacy variable was time-matched mean IOP (study eye) at each of three time points (8:00 AM, 10:00 AM, 4:00 PM) at weeks 2, 6, and 12. These sample values ​​were used to calculate a point estimate of the primary estimand, defined as the between-treatment difference in IOP at each of nine time points (three times on each of three days).

[0081] Secondary efficacy variables were: time-matched change from baseline mean IOP (study eye) at each of the three time points (8:00 AM, 10:00 AM, 4:00 PM) at weeks 2, 6, and 12; Standard deviation IOP (study eye) at each of the three time points (8:00 AM, 10:00 AM, 4:00 PM) at weeks 2, 6, and 12; and Time-matched percent change from baseline in IOP (study eye) at each of three time points (8:00 AM, 10:00 AM, 4:00 PM) at Weeks 2, 6, and 12.

[0082] The primary efficacy analysis was completed by constructing two-sided 95% confidence intervals for the difference in time-matched IOP measurements between the two treatment groups at each time point (8:00 AM, 10:00 AM, and 4:00 PM) at weeks 2, 6, and 12 (total of 9 time points) using the per-protocol population. These confidence intervals were constructed using a two-sample t-distribution with pooled variance. When sample variances differed significantly, the confidence intervals used were constructed by Satterthwaite adjustment. p-values ​​for testing the equivalence of these time-matched means between treatment groups were generated using the TOST (two one-sided tests) procedure with equivalence limits of (-1.0, 1.0) and (-1.5, 1.5), respectively.

[0083] Each of the secondary efficacy endpoints was summarized using descriptive statistics by treatment group and time point using the PP population. The 95% confidence intervals at each time point within treatment groups were presented along with the 95% confidence intervals for the time-matched differences between treatment groups for each of these secondary endpoints.

[0084] The primary safety analysis summarized ocular (either eye) and nonocular TEAEs for all treated subjects using separate subject-level summaries by system organ class and preferred time period for each treatment group. TEAEs were defined as occurring after the first dose of study drug.

[0085] Slit-lamp biomicroscopy was performed at every visit during the study to observe the overall health of the eye, including the eyelids / lashes, conjunctiva, anterior corneal chamber, iris, and lens.

[0086] Visit Visit 1: (Day 1 from Day 42): Screening Visit 2: (Day 0) Baseline / Randomization Visit 3: (Week 2 ± 2 days) Efficacy / safety evaluation Visit 4: (Week 6 ± 2 days) Efficacy / safety evaluation Visit 5: (Week 12 ± 2 days) Efficacy / safety assessment and termination of study.

[0087] During these visits, patients were screened for various adverse events, including somnolence, ocular hyperemia, nervous system disorders, dry mouth (all visits) and dilated ophthalmoscopy (Visit 1, Visit 5). Observations included the retina, macula, choroid, optic nerve, and optic disc pallor measurements were summarized by visit using separate summary statistics.

[0088] Visual Acuity: Data were summarized at each visit using continuous and individual summaries, including change from baseline in lines and the proportion of subjects who worsened by ≥3 lines from baseline.

[0089] Heart Rate and Blood Pressure: Data were summarized using continuous summary statistics (mean, standard deviation, minimum, median, and maximum) by visit, including change from baseline summary.

[0090] The results are shown in Tables 8 and 9 below. [Table 8] Per-protocol population: The PP population included all randomized subjects who met all inclusion / exclusion criteria, did not miss scheduled applications for more than 3 consecutive days, and completed evaluations at weeks 2, 6, and 12 without any protocol violations that would affect treatment evaluations, and whose compliance was ≥75% to ≤125%. [Table 9] In a test for equivalence of brimonidine (i.e., the aqueous suspension of the present invention) with Alphagan for the difference in time-concordant IOP measurements between the two treatment groups at each time point (8:00 a.m., 10:00 a.m., and 4:00 p.m.) at weeks 2, 6, and 12, the results were significant. Thus, the primary objective of the study was achieved, i.e., the brimonidine formulation of the present invention is equivalent to Alphagan.

[0091] Regarding adverse events, it has already been observed in a study of 70 patients who received the aqueous suspension of the present invention that, among others, eye redness, somnolence and nervous system disorders occurred. The incidence of side effects in the study was as follows: [Table 10]

Claims

1. An aqueous suspension comprising (a) reversible clusters of brimonidine loaded nano-resin particles and (b) a suspending agent, wherein the brimonidine loaded nano-resin particles are ９０ Values ​​between 70 and 900 nm (inclusive) and D ５０ 1. The aqueous suspension of claim 1, wherein the aqueous suspension has a particle size distribution having a particle size distribution having a value between 50 and 700 nm, inclusive, and the suspension is for use in the treatment of elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension.

2. The above D ９０ 2. The aqueous suspension of claim 1, wherein the value is between 200 nm and 700 nm.

3. D of the nano resin particles ５０ 2. The aqueous suspension of claim 1, wherein the value is between 100 and 500 nm.

4. D of the nano resin particles ５０ 2. The aqueous suspension according to claim 1, wherein the value is between 150 and 350 nm.

5. D of the nano resin particles ５０ 2. The aqueous suspension according to claim 1, wherein the value is between 200 and 300 nm.

6. 6. The aqueous suspension of any one of claims 1 to 5, wherein the reversible clusters comprise brimonidine as a pharma- ceutically acceptable salt or solvate.

7. 7. The aqueous suspension of claim 6, wherein the brimonidine is brimonidine tartrate.

8. 8. The aqueous suspension of any one of claims 1 to 7, wherein the suspension is administered to the patient's eye once daily.

9. 9. The method of claim 1, wherein the mean intraocular pressure is reduced by at least 2-6 mmHg.

10. 10. An aqueous suspension according to any one of claims 1 to 9, wherein the suspension comprises from about 0.05% w / v to about 0.5% w / v of brimonidine or a pharma- ceutically acceptable salt thereof.

11. 11. An aqueous suspension according to any one of claims 1 to 10, wherein the suspension comprises from about 0.2% w / v to about 0.5% w / v brimonidine or a pharma- ceutically acceptable salt thereof.

12. 12. An aqueous suspension according to any one of claims 1 to 11, wherein the suspension comprises about 0.35% weight / volume of brimonidine tartrate.

13. 13. A pharmaceutical composition comprising an aqueous suspension for use in a method of treating elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, said method comprising administering to a patient in need of such treatment an aqueous suspension according to any one of claims 1 to 12.

14. The method further comprises the steps of: (a) determining the ophthalmic history of the patient to be treated prior to initiating treatment with said aqueous suspension; and (b) performing an ophthalmologic examination at least 16 weeks, preferably at least 12 weeks, after beginning treatment with the aqueous suspension, which examination includes checking and / or monitoring for the appearance of drowsiness, eye redness, nervous system disorders, or dry mouth; Including, (c) conducting additional ophthalmic examinations at intervals determined by an ophthalmologist based on the patient's symptoms; 14. The pharmaceutical composition for use according to claim 13, which may comprise:

15. 15. The pharmaceutical composition for use according to any of claims 13 or 14, wherein the method reduces intraocular pressure in the patient by at least 2-6 mmHg, and wherein the method is effective in reducing intraocular pressure for a period of about 7 to 15 weeks.

16. The pharmaceutical composition for use according to any one of claims 13 to 15, wherein the patient achieves a reduction in intraocular pressure of >20% from baseline that is sustained for at least 12 weeks.

17. The pharmaceutical composition for use according to any one of claims 13 to 16, wherein the patient achieves a reduction in intraocular pressure of >40% from baseline that is sustained for at least 12 weeks.

18. 18. The pharmaceutical composition for use according to any one of claims 13 to 17, wherein brimonidine or a pharma- ceutically acceptable salt thereof is present in a concentration of about 0.05% to 0.5% weight / volume.

19. 19. A pharmaceutical composition for use according to any one of claims 13 to 18, wherein the brimonidine or pharma- ceutically acceptable salt thereof is brimonidine tartrate and is present in a concentration of about 0.35% weight / volume.

20. The pharmaceutical composition for use according to any one of claims 13 to 19, wherein the method is effective in reducing intraocular pressure for at least 12 weeks.

21. The pharmaceutical composition for use according to any one of claims 13 to 20, wherein brimonidine is administered to the patient's eye once daily.

22. 1. A pharmaceutical composition comprising brimonidine or a pharma- ceutical acceptable salt thereof for use in a method of reducing elevated intraocular pressure in a human patient suffering from open angle glaucoma or ocular hypertension, the method comprising administering brimonidine or a pharma- ceutical acceptable salt thereof, wherein the method reduces intraocular pressure in the patient by at least 2-6 mmHg, and wherein the method is effective in reducing intraocular pressure for a period of about 7 to 15 weeks.

23. A pharmaceutical composition comprising brimonidine or a pharma- ceutical acceptable salt thereof for use in a method for reducing elevated intraocular pressure in a human patient suffering from open-angle glaucoma or ocular hypertension, the method comprising administering brimonidine or a pharma- ceutical acceptable salt thereof, wherein following administration, the patient achieves a reduction in intraocular pressure of >20% from baseline that is sustained for at least 12 weeks.

24. 24. The pharmaceutical composition for use according to claim 22 or 23, wherein brimonidine or a pharma- ceutically acceptable salt thereof is present in a concentration of about 0.05% to 0.5% weight / volume.

25. 25. A pharmaceutical composition for use according to any one of claims 22 to 24, wherein the brimonidine or pharma- ceutically acceptable salt thereof is brimonidine tartrate and is present in a concentration of about 0.35% weight / volume.

26. A pharmaceutical composition for use according to any one of claims 22 to 25, wherein brimonidine is administered to the patient's eye once daily.