(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 27 November 2008 (27.11.2008) PCT WO 2008/144399 Al (51) International Patent Classification: (74) Agents: POWERS, Jeffrey, B. et al; Bausch & Lomb C07D 403/12 (2006.01) A61K 31/498 (2006.01) Incorporated, One Bausch & Lomb Place, Rochester, NY C07D 498/04 (2006.01) A61P 27/06 (2006.01) 14604-2701 (US). (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2008/063719 AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (22) International Filing Date: 15 May 2008 (15.05.2008) EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (25) Filing Language: English LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, (26) Publication Language: English PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW 60/938,766 18 May 2007 (18.05.2007) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): BAUSCH kind of regional protection available): ARIPO (BW, GH, & LOMB INCORPORATED [US/US]; One Bausch & GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Lomb Place, Rochester, NY 14604-2701 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, (75) Inventors/Applicants (for US only): MCINTIRE, Gre¬ NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, gory, L. [US/US]; 6 1 Cardogan Square, Rochester, NY CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). 14625 (US). DAVIO, Stephen, R. [US/US]; 10 Birling Declaration under Rule 4.17: Gap, Fairport, NY 14450 (US). HARMS, Arthur, E. — as to the identity of the inventor (Rule 4.17(i)) [US/US]; 12000 Long Street, Apt. 1122, Overland Park, KS 66213 (US). WANG, Hongna [US/US]; 19 Rende Published: Park, Fairport, NY 14450 (US). — with international search report α (54) Title: COMPLEXES COMPRISING 2-ADRENERGIC RECEPTOR AGONISTS AND COMPOSITIONS α (57) Abstract: A complex comprises at least an 2-adrenergic receptor agonist and a compound that provides an opposite charge α to a charge on the 2-adrenergic receptor agonist, wherein the complex is charge neutral as a whole and has a solubility in a range from about 0.3 µg/ml to about 2.5 mg/ml in water at pH of about 7 and temperature of about 25°C. The complex is included in a composition, device, or implant for use in the neuroprotection of components of a, neurological tissue to prevent progressive degeneration of such components. In particular, such a composition, device, or implant can be used to provide neuroprotection to cells and components of the optic nerve system. A preferred complex is brimonidine pamoate. COMPLEXES COMPRISING (^-ADRENERGIC RECEPTOR AGONISTS AND COMPOSITIONS BACKGROUND OF THE INVENTION The present invention relates to complexes comprising (^-adrenergic receptor agonists and compositions comprising such complexes. In particular, the present invention relates to such compositions suitable for sustained release α of 2-adrenergic receptor agonists. Many pathological ocular conditions, if left untreated, often lead to vision loss and eventual blindness, which are the result of progressive death of optic nerve cells. As defined by the American Academy of Ophthalmology, glaucoma is an optic neuropathy with characteristic structural damage to the optic nerve, associated with progressive retinal ganglion cell death, loss of nerve fibers, and visual field loss. On the basis of its etiology, glaucoma has been classified as primary or secondary. Primary glaucoma is an independent syndrome in adults and may be classified as either chronic open-angle or chronic (acute) angle-closure. Primary open-angle glaucoma is the most commonly occurring form of glaucoma, which appears to have no attributable underlying cause. Angle-closure glaucoma usually afflicts those persons having "shallow" angles in the anterior chamber and results from the sides (or angles) of the chamber coming together and blocking aqueous outflow through the trabecular meshwork. Secondary glaucoma, as the name suggests, results from pre-existing ocular diseases such as uveitis, intraocular tumor, or enlarged cataract. Considering all types together, glaucoma occurs in about 2 percent of all persons over the age of 40 and may be asymptomatic for years before progressing to rapid loss of vision. The underlying causes of primary glaucoma are not yet well known. An intraocular pressure ("lOP") that is high compared to the population mean is a risk factor for the development of glaucoma. However, many individuals with high IOP do not have glaucomatous loss of vision. Conversely, there are glaucoma patients with normal IOP. Therefore, continued efforts have been devoted to elucidate the pathogenic mechanisms of glaucomatous optic nerve degeneration. It has been postulated that optic nerve fibers are compressed by high IOP, leading to an effective physiological axotomy and problems with axonal transport. High IOP also results in compression of blood vessels supplying the optic nerve heads ("ONHs"), leading to the progressive death of retinal ganglion cells (" RGCs"). See; e.g., M. Rudzinski and H .U. Saragovi, Curr. Med. Chem.- Central Nervous System Agents, Vol. 5, 43 (2005). In addition, there is growing evidence that other molecular mechanisms also cause direct damage to RGCs: existence of high levels of neurotoxic substances such as glutamate and nitric oxide and pro-inflammatory processes. Id. At low concentrations, NO plays a beneficial role in neurotransmission and vasodilation, while at higher concentrations, it is implicated in having a role in the pathogenesis of stroke, demyelination, and other neurodegenerative diseases. R.N. Saha and K. Pahan, Antioxidants & Redox Signaling, Vol. 8 , No. 5 & 6, 929 (2006). NO has been recognized as a mediator and regulator of inflammatory responses. It possesses cytotoxic properties and is produced by immune cells, including macrophages, with the aim of assisting in the destruction of pathogenic microorganisms, but it can also have damaging effects on host tissues. NO can also react with molecular oxygen and superoxide anion to produce reactive nitrogen species that can modify various cellular functions. R. Korhonen et al., Curr. Drug Target - 1nflam. & Allergy, Vol. 4 , 471 (2005). Furthermore, oxidative stress, occurring not only in the trabecular meshwork ("TM") but also in retinal cells, appears to be involved in the neuronal cell death affecting the optic nerve in primary open-angle glaucoma ("POAG"). A. Izzotti et al., Mutat. Res., Vol. 612, No. 2, 105 (2006). In addition, tumor necrosis factor-α ("TNF-α"), a proinflammatory cytokine, has recently been identified to be a mediator of RGC death. TNF-α and TNF-α receptor-1 are up-regulated in experimental rat models of glaucoma. In vitro studies have further identified that TNF-α-mediated RGC death involves the activation of both receptor-mediated caspase cascade and mitochondria- mediated caspase-dependent and caspase-independent components of cell death cascade. G . Tezel and X. Yang, Expt'l Eye Res., Vol. 81, 207 (2005). Moreover, TNF-α and its receptor were found in greater amounts in retina sections of glaucomatous eyes than in control eyes of age-matched normal donors. G. Tezel et al., Invest. Ophthalmol. & Vis. ScI., Vol. 42, No. 8, 1787 (2001). Regardless of the theory, glaucomatous visual field loss is a clinically recognized condition. There has been growing evidence that such vision loss results from damage to optic nerve cells. Retinitis pigmentosa, another back-of-the-eye disease, is the term for a group of inherited diseases that affect the retina, the delicate nerve tissue composed of several cell layers that line the inside of the back of the eye and contain photoreceptor cells. These diseases are characterized by a gradual breakdown and degeneration of the photoreceptor cells, the so-called rods and cones, which result in a progressive loss of vision. It is estimated that retinitis pigmentosa affects thousands of individuals in the United States. Together, rods and cones are the cells responsible for converting light into electrical impulses that transfer messages to the retinal ganglion cells which in turn transmit the impulses through the lateral geniculate nucleus into that area of the brain where sight is perceived. Retinitis pigmentosa, therefore, affects a different retinal cell type than those affected by glaucoma. Depending on which type of photoreceptor cell is predominantly affected, the symptoms vary, and include night blindness, lost peripheral vision (also referred to as tunnel vision), and loss of the ability to discriminate color before peripheral vision is diminished. Symptoms of retinitis pigmentosa are most often recognized in adolescents and young adults, with progression of the disease usually continuing throughout the patient's life. The rate of progression and degree of visual loss are variable. As yet, there is no known cure for retinitis pigmentosa. Age-related macular degeneration ("AMD"), another back-of-the eye disease, is a degenerative condition of the macula or central retina. It is the most common cause of vision loss in the over-50 age group. It is estimated that 50 million people worldwide suffer from AMD. Its prevalence increases with age and affects 15 percent of the population by age 55 and over 30 percent are affected by age 75.