MX2008008016A - Topical mecamylamine formulations for ocular administration and uses therof - Google Patents

Abstract

Provided are methods, pharmaceutical formulations and kits thereof for the treatment and/or prevention of conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of posterior and/or anterior tissues and fluids of the eye, including conditions associated with proliferative retinopathies, for example, diabetic retinopathy, age-related maculopathy, retinopathy of prematurity, retinopathy associated with macular edema, or retinopathy associated with sickle cell disease, using the topical administration of mecamylamine or a pharmaceutically acceptable salt thereof to the eye. Methods of preparing the pharmaceutical formulations are also provided.

Description

TOPICAL FORMULATIONS OF MECAMILAMINE FOR THE OCULAR ADMINISTRATION AND USES OF THE SAME BACKGROUND OF THE INVENTION Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss among elderly people in North America and Europe (See Arch Ophthalmol. (2004), 1122: 564-72; Olejnik; et al., (2005) Adv. Drug, Dev. Rev. 57: 1991-1993; Kulkami et al., (200S) Adv. Drug. Dev. Rev. 57: 1994-2009; Gryziewicz (2005) Adv. Drug. Dev. Rev. 57: 2092-2098). There are two forms of AMD: non-neovascular (also known as dry or non-exudative form), and neovascular (also known as wet or exudative form). Although less common, the neovascular form presents the majority of cases of blindness. In neovascular AMD, the newly created abnormal blood vessels grow under the center of the retina, to a process called choroidal neovascularization, which is then accompanied by vascular leakage and vascular permeability. This leads to scarring of the retina resulting in distorted vision or destruction of central vision. While several growth factors are associated with the angiogenic processes, the isozymes of VEGF (vascular endothelial growth factor) are central to the sequence of events, leading to the REF. : 194131 neovascularization, angiogenesis and vascular leakage (See Ferrara et al., Recent Prog Horm Res., (2000), 55: 15-35, discussion 35-6). The dry or non-neovascular form of macular degeneration often appears before diagnosis of the neovascular ("wet") form of macular degeneration and is a risk factor for the development of the neovascular form of macular degeneration. The individuals at highest risk to develop the neovascular form of macular degeneration are those with the large areas of macular degeneration caused by the neovascular form. Studies in animals have shown that VEGF expression is sufficient to induce neovascularization in the eye (see, for example, Tolentino et al., Arch Ophthalmol, 1996, 1114: 964-70), while its antagonists reduce or eliminate this effect (see for example, Adamis et.al., Arch Ophthalmol., 1996, 1114: 66-71). In addition, the presence of VEGF is temporally and spatially correlated with ocular neovascularization in the primate model (see, for example, Miller et al., Am J. Pathol, 1994, 145: 574-84). Patients with ocular neovascularization secondary to proliferative diabetic retinopathy also have high vitreous levels of VEGF (see, for example, Aiello et al., N Engl J Med., 1994, 331: 1480-7). Currently available modalities for the treatment of exudative AMD include photocoagulation by thermal laser, photodynamic therapy and administration of the VEGF receptor antagonist, pegaptanib (Macugen®; Pfizer) by infraocular injections which are invasive and can cause significant side effects, such as retinal detachment, vitreous hemorrhage, endophthalmitis, and damage to the crystalline (Peyman et al, (1995) Adv. Drug. Delivery Rev. 16: 107-123). Cigarette smoke has been shown to be the most important environmental risk factor for AMD in humans (Tomany et al., Ophthalmology, 2004, 111: 1280-1287) and passive cigarette smoke has been linked to myopia in children ( Stone et al, (2001) Investigative Ophth., Vis. Sci. 42 (3): 557-565; Stone et al., (2001) Investigative Ophth., Vis. Sci 47 (10): 4277-4287; United States No. 2003-0096831). In experimental animal models, nicotine has been shown to increase colloidal neovasculapzation, an effect mediated through the activation of nicotinic acetylcholine receptors (nAChR) on endothelial cells (Suñer et al, Invest Ophthalmol Vis Sci., 2004, 45 (1): 311-317). This pro-angiogenic effect of nicotine has been shown to be blocked by the nAChR antagonist, hexamethonium. These results indicate that the activation of nAChRs plays a significant role in the pathological angiogenesis associated with AMD, and that the inhibition of this pathway can inhibit the progression of the disease.

Nicotine stimulates endothelial nAChRs to induce endothelial cell proliferation (Villablanca et al, J. Appl. Physiol. 1988, 2089-2098), mobilization and tube formation (Cooke et al., J. Clin. Invest, 2002, 110: 527-536; U.S. Patent Nos. 6,720,340, 6,417,205) and it has been reported that the maximum effect of nicotine occurs at concentrations similar to those achieved in smokers, e.g. 10-100. nM. Nicotine also increases the migration of endothelial cells, an important event in angiogenesis (U.S. Patent Nos. 6,720,340, 6,417,205; WO 01/08684; WO 01/08683.) This effect of nicotine to increase the migration of the Endothelial cells can be blocked by mecamylamine, a known antagonist of nAChR, which has been previously approved by the administration of drugs and drugs from the United States (FDA) for use in the treatment of hypertension. Agents such as mecamylamine that antagonize endothelial nAChR could represent a novel class of drugs for use in the treatment of diseases characterized by abnormal angiogenesis, such as neovascular or oxidative AMD (WO 03/068208; No. 2003/0216314) Abnormal angiogenesis and / or neovascularization leading to proliferative retinopathies is believed to they mediate other serious conditions that affect the eye and visual acuity. For example, conditions that include diabetic retinopathy, premature retinopathy (WO 03/068208; US Patent Application No. 2003/0216314) and retinopathy associated with sickle cell disease are believed to be associated with angiogenesis. and abnormal neovascularization or combinations thereof. Mecamylamine has been marketed since the late 1950s for the treatment of hypertension. In normotensive subjects, mecamylamine can cause orthostatic hypotension with a concomitant increase in heart rate. The frequently reported adverse effects associated with the systemic administration of mecamylamine include constipation, dry mouth, blurred vision of impaired accommodation, weakness, fatigue, cycloplegia, mydriasis (dilated pupil), decreased libido, and urinary retention, as well as disturbance of the Central Nervous System such as tremor, hypersomnia, sedation, convulsion, attacks, coleiform movements, insomnia, mental aberrations, depression and altered mind. In view of these dose limiting side effects associated with mecamylamine, particularly with the systemic distribution of mecamylamine, the targeted distribution of mecamylamine to ocular tissue, for example, the Topical distribution to the surface of the eye, could be highly desirable and could decrease, if not completely eliminate, the systemic side effects of ganglonear blockade. In addition, treatment methods and formulations that avoid the use of intraocular injection to treat conditions associated with proliferative retinopathies, could likewise increase patient compliance with treatment regimens as well as reduce the costs associated with administration. of injections under local anesthesia, and reduce discomfort to the patient, caused by the injection itself and the complications associated with intraocular injection (Peyman et al, (1995) Adv. Drug. Delivery Rev. 16: 107-123; Tojo et al. (2001) Adv. Drug. Delivery Rev. 52: 17-24). Thus, methods and formulations using topical ocular administration of therapeutically effective mecamylamine (or the pharmaceutically acceptable salts thereof) have many advantages, from the standpoint of efficacy, cost, side effects, complications and comfort for the patient. Such advantages are even more important in the treatment of retinopathy of prematurity in premature infants, since the side effects of the drugs, the difficulties and complications associated with intraocular injection are increased in premature infants due to a number of premature infants. factors, including the small size of the infant's eye, the immaturity of the immune system and the trauma caused by such injections. One of the first successful topical eye formulations was a gel formulation in itself of timolol, a beta-blocker used to treat glaucoma. The gel formation has been marketed by Merck & Co. as TIMOPTIC® and is a formulation of timolol and GELRITE® gel, a gel based on gelan gum, which was originally developed as a gelling agent for use in culture media and food products (US Patent No 4,861,760). Other topical gel-based eye formulations include gels based on xanthan gum (U.S. Patent Nos. 6,174,524 and 6,264,935), which also describe the glaucoma treatment formulations. Other ocular formulations include various components such as polymers or components that are complexed with the active drug (e.g., U.S. Patent Nos. 6,159,458, U.S. Patent Applications Publications Nos. 2005/0084534, 2005/0031697 , 2005/0255144). U.S. Patent No. 6,174,524 also suggests use with timolol, anti-inflammatory agents, growth factors, immunosuppressive agents and other anti-glaucoma agents. In part, it is believed that the success of these formulations is due to the targeted region of the treatment, since glaucoma is a condition that affects the anterior region of the eye and thus, to be effective, the drug does not have to reach the posterior region of the eye, through which structures are traversed Traditional diseases within the eye are exposed for longer periods to the purification mechanisms within the eye. However, despite the success of TIMOPTIC® and intensive research in the field, the development of topical eye formulations of other drugs has proved difficult and unpredictable, particularly the development of formulations capable of delivering therapeutically effective drugs to the posterior regions of the oo, including the posterior tissues such as the choroid and the retina. For many years researchers have tried to identify the different mechanisms by which drugs are distributed to the eye in general, and the posterior region of the eye in particular (for example, the retina and / or the choroid). Research areas include the barrier functions (eg, transmembrane flow, etc.) of the various tissues and ocular fluids (eg, the retinal pigment epithelium, the cornea, the retina, the choroid, conjunctiva, the body vitreous, aqueous humor, etc.), clearing routes (for example, purification from the various tissues and / or eye fluids), the depuration due to lacrimal drainage, the precorneal tear film, the systemic absorption, the blood-ocular barrier (from the back of the eye), the lachrymal reflex, etc. (See, for example, Peyman et al, ibid; Lang et al, (1995) Adv. Drug. Delivery Rev. 16: 39-43; Dey et al (2005) Expert Opin. Drug Deliv. 2 (2): 201- 204; Jarvinen et al (1995) Adv. Drug. Delivery Rev. 16: 3-19; Pitkanen et al., (2005) Investigative Ophthalmol, Vis. Sci. 46 (2): 641-646). Whether or not a particular drug can be sufficiently absorbed through one or more of these barriers and avoid elimination through the processes that clear the exogenous materials of the eye, in order to distribute an effective amount of the drug to the later region of the eye, this depends on a plurality of factors, including the physicochemical properties of the drug itself (eg, size, structure, ionic / charge state, lipophilicity, hydrophilicity, etc.), as well as the reciprocal influence between the drug and each of the components in the formulation in which it is administered, and the characteristics of the non-pharmacological components of the formulation (for example, viscosity, pH, ionicity, etc.). (See, for example, Lang et al, (1995) ibid; Dey et al. (2005) ibid). Not surprisingly, the plurality of factors, which are difficult to model precisely in vi tro, has impeded the development of the guidelines or the prediction of which drugs or types of drugs can be successfully developed for topical administration to the posterior regions of the eye. Even in vivo model studies are difficult to perform accurately and can lead to conflicting results (Maurice (2002) Survey of Ophthalmology 47 (Supp.1): S41-S52). Thus, it is not at all unexpected that a topical method of treatment for conditions associated with proliferative retinopathy, which affects the posterior tissues of the eye, is not yet commercially available. Very unexpectedly, due to the difficulties and the predictive inability associated with the successful development of topically administered ocular formulations, it has been found and is further described herein that mecamylamine when formulated for topical administration may be distributed to the posterior region of the eye in amounts considered to be therapeutically effective for the treatment or prevention of ocular conditions mediated by angiogenesis and / or abnormal neovascularization in the posterior tissues (e.g., retina, choroid) of the eye, e.g. proliferative retinopathies, including diabetic retinopathy, retinopathy of prematurity, retinal neovascularization due to macular degeneration, etc. Even more surprisingly, the Administration of mecamylamine via the topical ocular distribution results in extremely low levels of mecamylamine in plasma (and in red blood cells), whereas it preferably distributes high levels of mecamylamine to the target or target tissue in the back of the eye (e.g. , the retina and the choroid). The formulations and methods described herein may also be used to distribute mecamylamine to other tissues of interest in the eye and eye fluids (which may also be affected by neovascularization, abnormal angiogenesis or combinations thereof) . The tissues of interest throughout the eye include the anterior tissues of the eye, when affected by angiogenic disorders such as corneal neovascularization, pterygium, neovascularization of postcorneal transplant, iridis rubeosis, neovascular glaucoma, etc .; as well as the posterior tissues of the eye when affected by angiogenic disorders that affect ocular fluids, retinal or choroidal tissues, such as age-related macular degeneration or diabetic retinopathy. In view of the numerous well-documented ocular effects associated with systemic (eg, parenteral (eg, intravenous, etc.) or oral) administration of mecamylamine, the low levels of mecamylamine in the plasma and the high levels of mecamylamine in the posterior tissues and in the anterior tissues (where the conditions described herein are manifested) observed with topical ocular administration, suggests that the side effects associated with systemic administration will be greatly reduced or they will be absent from the therapeutic doses of mecamylamine when administered topically, and these conclusions are supported by the results of the non-human animal models and the clinical tests on humans as described in more detail below and in the examples. When formulated with particular gel-forming polymers, these characteristics of mecamylamine can be further improved, preferably by increasing the relative amount of mecamylamine deposited to the tissues of interest, while minimizing the amount of mecamylamine in plasma further, although data to date suggest that the solution formulation (free of gel / polymeric forming components) is well tolerated in animals including humans, and provides levels of mecamylamine in the tissues of interest that will be effective for use in the treatment and / or prevention of the conditions described herein. The advantages of being able to increase mecamylamine, shown as effective in reducing the pathological or unwanted angiogenesis (WO 03/068208; United States Patent Application No. 2003/0216314), in a local (ocular topical), site-specific manner to the eye at therapeutically effective doses are numerous and immediately apparent on the current standard of care, which usually includes infraocular injections, and the systemic (eg, oral, intravenous, etc.) administration of mecamylamine. Not only will patients suffer less discomfort and pain than that associated with the administration of any given intraocular drug, but complications related to intraocular injections will be absent, specific side effects of mecamylamine will be minimized or eliminated, medical costs related complications and complex intraocular administration will be reduced, and in view of these advantages, it is likely that patient compliance will also increase. Thus, it is apparent that effective methods and formulations for the distribution of mecamylamine, or pharmaceutically acceptable salts thereof, to the posterior regions of the eye, for the treatment and / or prevention of the conditions described herein will be highly beneficial and are currently necessary. The formulation will probably also be effective in treating angiogenic disorders of the anterior tissues of the eye, such as corneal neovascularization, terigion neovascularization of postcorneal transplant, rubeosis iridis, neovascular glaucoma, etc.

BRIEF DESCRIPTION OF THE INVENTION Formulations of the mecamylamine formulated for topical ocular distribution, including pharmaceutical formulations, kits and methods of making and using the formulations, are provided herein. In one aspect, methods are provided for treating or preventing conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, posterior tissues, anterior tissues or eye fluids, which comprise topically applied to one or both eyes of an individual in need thereof a formulation comprising mecamylamine, or a pharmaceutically acceptable salt thereof and a carrier suitable for topical administration to the eye, wherein the mecamylamine or a pharmaceutically acceptable salt thereof is present in the formulation in an amount sufficient to distribute a therapeutically effective amount of the mecamylamine to one or more of the posterior or anterior tissues, or the fluids of the eye for the treatment or prevention of conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues, anterior tissues or fluid of the eye (step a). In some embodiments, methods are provided for treating or preventing conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability or combinations thereof, of the posterior tissues of the eye, which comprises applying topically to one or both eyes of an individual in need thereof, a formulation comprising mecamylamine, or a pharmaceutically acceptable salt thereof, and a suitable carrier for topical administration to the eye, wherein the mecamylamine or the pharmaceutically acceptable salt thereof is present in the formulation in a sufficient amount to distribute a therapeutically effective amount of the mecamylamine. to one or more of the posterior tissues of the eye for the treatment or prevention of conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability or combinations thereof, of the posterior tissues of the eye (step a). In some modalities, the condition or conditions are mediated by retinal neovascularization. In certain modalities, the condition or conditions is mediated by choroidal neovascularization. In certain modalities, the condition is a proliferative retinopathy. In certain modalities, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in choroidal and retinal tissue, measured in nanogram units, to the concentration of plasma mecamylamine measured in units of ng / ml ([ng / g of mechanolamine choroidal tissue + retinal]: [ng / ml plasma]) is at least about 40: 1. In some embodiments, the ratio is at least approximately 80: 1. In others, the ratio is at least approximately 300: 1. In particular embodiments, the ratio is from about 40: 1 to about 1000: 1. In some embodiments, the ratio is from about 40: 1 to about 1500: 1. In some embodiments, the ratio is from about 40: 1 to about 2000: 1. In certain embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in choroidal and retinal tissue, measured in nanogram units, to the concentration of mecamylamine in plasma measured in units of ng / ml ([ng / g of chloidal tissue + retinal mecamylamine]: [ng / ml of plasma]) is at least approximately 20: 1. In some embodiments, the ratio is at least approximately 25: 1. about 30: 1 or about 35: 1. In particular embodiments, the ratio is from about 20: 1 to about 1000: 1. In some embodiments, the ratio is from about 20: 1 to about 1500: 1. In some embodiments, the ratio is from about 20: 1 to about 2000: 1. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine in the choroidal and retinal tissue, measured as the area under the curve (AUC), measured in units of ng / g- hr, versus the concentration of mecamylamine in plasma, measured as the area under the curve (AUC) and measured in units of ng / ml-hr, is at least approximately 100: 1 ([choroidal tissue + mecamylamine retinal (ng / g-hr)]: [mecamylamine in plasma (ng / mL-hr) ] In some embodiments, the ratio is at least approximately 50: 1. In some embodiments, at least about 80: 1, at least about 90: 1, or at least about 100: 1. In some embodiments methods are provided for treating or preventing conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability or combinations thereof of the anterior tissues of the eye, which comprises applying topically to one or both eyes of an individual in need thereof, a formulation including mecamylamine, or a pharmaceutically acceptable salt thereof, and a carrier suitable for topical administration to the eye, wherein the mecamylamine or a pharmaceutically acceptable salt thereof is present in the formulation in an amount sufficient to distribute a therapeutically effective amount of mecamylamine to one or more of the above tissues or fluids of the eye for the treatment or prevention of conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability or combinations thereof, of the anterior tissues of the eye. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in the corneal tissue, measured in units of ng / g, to the concentration of the mecamylamine in plasma measured in units of ng / ml ([ng / g of mecamylamine in corneal tissue]: [ng / ml of plasma]) is at least approximately 100: 1. In some modalities, the ratio is at least 800: 1. In certain embodiments, the ratio is at least about 1000: 1. In some modalities, 1500: 1. In some embodiments, the ratio is from about 100: 1 to about 4000: 1. In certain embodiments, the ratio is from about 100: 1 to about 3000: 1. In certain embodiments, the ratio is from about 1000: 1 to about 4000: 1. In certain embodiments, the ratio is from about 1000: 1 to about 3000: 1.

In some modalities, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine in the cornea, measured under the area under the curve (AUC), measured in units of ng / g-hour, versus the concentration of mecamilamma in plasma, measured as the area under the curve (AUC) and measured in units of ng / m-hour, is at least approximately 100: 1 ([mecamylamine in cornea (ng / g-hr)]: [mecamylamine in plasma (ng / ml-hr)]. In some embodiments, the ratio is at least about 800: 1. In some embodiments, at least about 1000: 1 or at least about 1500: 1. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine in the aqueous humor, measured in units of ng / ml, versus the concentration of mecamylamine in plasma, measured in units of ng / ml, is at least about 50: 1 ([mecamylamine in aqueous humor (ng / ml)]: [mecamilamma in plasma (ng / ml)]). In some embodiments, the ratio is at least about 70: 1. In some embodiments, it is at least about 100: 1 or at least about 150: 1. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine in the aqueous humor, measured as the area under the curve (AUC), measured in units of ng / ml-hour, versus the concentration of mecamylamine in plasma, measured as the area under the curve (AUC) and measured in units of ng / ml-hour , is at least about 50: 1 ([mecamylamine in aqueous humor (ng / ml-hr)]: [mecamylamine in plasma (ng / ml-hr)] In some embodiments, the ratio is at least about 90: 1. In some embodiments, at least about 100: 1 or at least about 150: 1. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the average maximum concentration of mecamylamine in plasma is less than about 70 ng / In certain embodiments, the maximum mean concentration of mecamylamine in plasma is less than about 50 ng / ml In certain embodiments, the maximum average concentration of mecamylamine in plasma is less than about 25 ng / ml. the maximum average concentration of mecamilami Plasma is approximately 10 ng / ml. In certain embodiments, the maximum average concentration of mecamylamine in plasma is less than about 5 ng / ml. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the total concentration of the mecamylamine in plasma, measured as the area under the curve is less than about 100 ng / ml-hour. In some modalities, when the formulation is topically administered to the eye of a rabbit, the total concentration of the mecamylamine in plasma measured as the area under the curve is less than about 85 ng / ml-hour. In some embodiments, the carrier comprises water.

In certain embodiments, the formulation is substantially free of surfactant. In some embodiments, the formulation also includes one or more of a preservative or a surfactant. In some of these modalities, the formulation includes a conservative. In some embodiments, the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate, and phenylmercuric acetate. In particular embodiments, the preservative is benzalkonium chloride. In some embodiments, the carrier further comprises one or more tonicity agents. In particular embodiments, one or more tonicity agents is a polyol. In some embodiments, the polyol is a sugar alcohol, trihydroxy alcohol, propylene glycol or polyethylene glycol. In certain embodiments, one or more tonicity agents is mannitol, glycerin or a combination thereof. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the maximum mean concentration of mecamylamine in plasma is less than about 70 ng / ml. In particular embodiments, the maximum average concentration of the mecamylamine in plasma is less than about 50 ng / ml. In some embodiments, the maximum average concentration of mecamylamine in plasma is less than about 25 ng / ml. In particular embodiments, the maximum average concentration of the mecamylamine in plasma is less than about 10 ng / ml. In particular embodiments, the maximum average concentration of mecamylamine in plasma is less than about 5 ng / ml. In some embodiments, the formulation may also include a chelating agent. In some embodiments, the formulation also includes a chelating agent, one or more preservatives, one or more buffering agents, and one or more tonicity agents. In some embodiments, the formulation also includes a chelating agent, one or more preservatives, one or more tonicity agents, one or more buffering agents and is free of polymer. In some embodiments, the formulation also includes a chelating agent, one or more preservatives, and one or more tonicity agents. In some embodiments, the formulation also includes a chelating agent, one or more preservatives, one or more tonicity agents and is free of polymer. In certain embodiments, the carrier may include a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selects from the group consisting of water soluble cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, hyaluronic acid, and soluble starches. In certain embodiments, the viscosity enhancing agent is a water soluble cellulose derivative. In some embodiments, the viscosity enhancing agent is hypromellose. In some embodiments, the formulation is substantially free. In some embodiments, the formulation is substantially free of one or more viscosity-increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the viscosity of the formulation is about the same as the viscosity of the saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some of these modalities, the formulation is isotonic. In some embodiments, the formulation is substantially free of surfactant. In some embodiments, the formulation may further include a chelating agent, in certain embodiments, the chelating agent is disodium edeterate (dihydrate). In some modalities, the individual is a human. In some embodiments, the formulation includes mecamylamine (or a pharmaceutically acceptable salt thereof), a chelating agent, and a preservative, wherein the carrier is water. In certain modalities, the conservator is benzalkonium chloride, and the chelating agent is disodium edeteate (dihydrate). In some embodiments, the formulation includes mecamylamine (or a pharmaceutically acceptable salt thereof), a chelating agent, one or more buffering agents and a preservative, wherein the carrier is water. In some of these embodiments, the preservative is benzalkonium chloride, the buffering agents are monobasic sodium phosphate monohydrate and sodium phosphate dibasic heptahydrate, and the chelating agent is disodium edeterate (dihydrate). In some embodiments, the formulations further include salt (e.g., sodium chloride). In some embodiments, the formulation includes from about 0.01% to about 4% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some embodiments, from about 0.01% to about 3% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some embodiments, from about 0.03% to about 3% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some embodiments, about 0.01% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some embodiments, about 0.03% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some embodiments, approximately 0.3% of mecamylamine (or the salt pharmaceutically acceptable thereof) (w / v). In some embodiments, about 1% mecamylamine (or the pharmaceutically acceptable salt thereof) (w / v). In some of these embodiments, the formulation is substantially free of polymers (e.g., gel-forming polymers, viscosity-increasing agents, etc.). In some of these embodiments, the formulation includes a viscosity enhancing agent. In some embodiments, the formulation is substantially free of one or more viscosity increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is about the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, the formulation comprises from about 0.001% up to about 6% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 0.001% up to about 5% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.001% to about 3% mecamylamine (w / v) or a salt pharmaceutically acceptable thereof. In some embodiments, from about 0.03% to about 4% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 3% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 2% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.1% to about 1% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.05% to about 1% mecamylamine (w / v) or a pharmaceutically acceptable salt thereof. In some embodiments, the carrier is an aqueous isotonic solution and the formulation may further include a chelating agent and a preservative. In certain embodiments, the formulation may include one or more buffering agents. In some embodiments, the formulation is substantially free of polymers (e.g., gel-forming polymers, viscosity-increasing agents, etc.). In particular embodiments, the formulation may include a viscosity enhancing agent. In some embodiments, the formulation is substantially free of one or more viscosity-increasing agents (e.g., carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, the viscosity enhancing agent is selected from the group consisting of water soluble cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, chondroitin sulfate, hyaluronic acid and soluble starches. In certain embodiments, the viscosity enhancing agent is a water soluble cellulose derivative. In some embodiments, the viscosity enhancing agent is hypromellose. In some of those embodiments, the formulation comprises from about 0.001% up to about 6% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.001% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain modalities, from approximately 0.1% to approximately 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is substantially free of viscosity increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, the formulation may include one or more buffering agents. In certain embodiments, one or more buffers are selected from the group consisting of phosphate buffers, citrate buffers, maleate buffers, borate buffers and combinations thereof. In certain embodiments, the buffering agent (s) is a phosphate buffer. In some embodiments, it is a combination of two phosphate buffers. In particular embodiments, the carrier may additionally include a viscosity enhancing agent. In certain embodiments, the viscosity enhancing agent is hypromellose. In some of those embodiments, the formulation comprises from about 0.001% up to about 6% (w / v) mecamylamine or a pharmaceutically acceptable salt thereof. In certain modalities, from approximately 0. 001% up to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.1% to about 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the carrier comprises an aqueous saline solution. In particular embodiments, the aqueous saline solution is isotonic. In certain embodiments, the carrier comprises from about 0.03% to about 2% (w / v) of a gel-forming polymer and water, wherein the gel-forming polymer is selected such that when the formulation is topically administered to the eye of a rabbit the ratio of the concentration of mecamylamine present in choroidal and retinal tissue, measured in units of ng / g, to the concentration of mecamylamine in plasma, measured in units of ng / ml, ([ng / g of mecamylamine in choroidal tissue + retinal]: [ng / ml plasma]) is at least about 300: 1. In some embodiments, the formulation is a gel prior to ocular topical administration. In other embodiments, the formulation forms a gel in itself after ocular administration. In particular modalities, the Gel-forming polymer is a polysaccharide. In certain embodiments, the polysaccharide is gellan gum. In some embodiments, when the formulation is topically administered to the eye of a rabbit, the maximum average concentration of the mecamylamine in plasma is less than about 70 ng / ml. In some modalities, less than 50 ng / ml. In some embodiments, the maximum average concentration of mecamylamine in plasma is less than about 25 ng / ml. In particular embodiments, the maximum average concentration of the mecamylamine in plasma is less than about 10 ng / ml. In particular embodiments, the maximum average concentration of mecamylamine in plasma is less than about 5 ng / ml. In some embodiments, the carrier further comprises one or more tonicity agents. In particular embodiments, one or more tonicity agents is a polyol. In some embodiments, the polyol is a sugar alcohol, trihydroxy alcohol, propylene glycol or polyethylene glycol. In certain embodiments, one or more tonicity agents is mannitol, glycerin or a combination thereof. In some embodiments, the formulation comprises from about 0.001% up to about 6% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.001% to about 3% (w / v) of mecamylamine or a pharmaceutically salt acceptable of it. In some embodiments, from about 0.03% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.1% to about 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the carrier comprises from about 0.05% to about 2% (w / v) of gellan gum. In particular embodiments, the carrier comprises from about 0.1% to about 1% (w / v) of gellan gum. In some embodiments, the carrier comprises from about 0.1% to about 0.6% (w / v) of gellan gum. In some embodiments, the formulation is substantially free of the surfactant. In particular embodiments, the formulation further comprises one or more of a preservative or a surfactant. In certain embodiments, the formulation further comprises a preservative. In certain embodiments, the preservative is benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate, or phenylmercuric acetate. In some embodiments, the preservative is benzalkonium chloride.

In certain embodiments, the carrier may include a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from the group consisting of water soluble cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, chondroitin sulfate, hyaluronic acid, and soluble starches. In certain embodiments, the viscosity enhancing agent is a water soluble cellulose derivative. In some embodiments, the viscosity enhancing agent is hypromellose. In some embodiments, the formulation may further include a chelating agent. In certain embodiments, the chelating agent is disodium edeteate (dihydrate). In some embodiments, the carrier further comprises one or more tonicity agents. In particular embodiments, one or more tonicity agents is a polyol. In some embodiments, the polyol is a sugar alcohol, trihydroxyalcohol, propylene glycol or polyethylene glycol. In certain embodiments, one or more tonicity agents is mannitol, glycerin or a combination thereof. In particular embodiments, the formulation comprises from about 0.001% up to about 6% (w / v) mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 0.001% up to about 5% (w / v) of mecamylamine or the pharmaceutically acceptable salt thereof. In some of these embodiments, the carrier comprises from about 0.05% to about 1% (w / v) of gellan gum and water. In some embodiments, the formulation includes a pharmaceutically acceptable salt of mecamylamine. In particular embodiments, the salt of mecamylamine is mecamylamine hydrochloride. In some embodiments, the individual has been identified as having one or more conditions mediated by retinal neovascularization, choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues of the eye (including conditions associated with the Proliferative eye retinopathy). In some modalities, the individual has been identified as having a non-neovascular form of macular degeneration. In particular embodiments, the individual has been identified as being susceptible to one or more conditions mediated by retinal neovascularization, choroidal neovascularization, neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues of the eye (including conditions associated with the proliferative retinopathy of the eye). In some modalities, the individual has been identified as susceptible to a non-neovascular form of macular degeneration. In certain modalities, the condition is diabetic retinopathy, retinopathy of prematurity, retmal neovascularization due to macular degeneration, retinopathy associated with macular edema or retinopathy associated with sickle cell disease. In particular modalities, the condition is diabetic retinopathy. In other modalities, the condition is pre-mature retinopathy. In other additional modalities, the condition is a retmal neovasculapzation due to macular degeneration. In another modality but, the condition is a maculopatía related to the age. In another modality, the condition is macular degeneration related to age. In particular embodiments, age-related macular degeneration is a neovascular (e.g., wet form) form of age-related macular degeneration. In some modalities, the condition is associated with abnormal angiogenesis that affects the anterior tissues of the eye or is a condition that involves abnormal angiogenesis that affects the anterior and posterior tissues of the eye. In some modalities, the condition is associated with abnormal angiogenesis that affects the anterior tissues of the eye. In certain modalities, the condition is corneal neovasculation, tephion, neovascularization of post-corneal transplantation, indiscriminate rubeosis, or neovascular glaucoma. In some modalities, the condition is a ocular tumor. In certain modalities, the condition involves vitreal, retinal or choroidal neovascularization. In some modalities, the condition is an ocular tumor. In some modalities, the condition is associated with abnormal angiogenesis that affects the anterior and posterior tissues of the eye. In some modalities, the condition is an ocular tumor. In some modalities, the individual is a mammal. In certain embodiments, the mammal is a primate, rabbit, canine, feline or rodent. In particular embodiments, the mammal is a primate. In certain modalities, the primate is a human. In some modalities, the individual is not experiencing ocular growth. In some modalities, the individual is an adult. In certain modalities, the condition is pre-mature retinopathy and the individual is a human. In some embodiments, the therapeutically effective amount of mecamylamine is distributed to the retina. In particular embodiments, the therapeutically effective amount of mecamylamine is distributed to the choroid. In certain embodiments, the therapeutically effective amount of mecamylamine is distributed to the retina and the choroid. In some embodiments, the therapeutically effective amount of mecamylamine is distributed to the cornea, the iris, the trabecular network, the sclera, or the lens. In certain embodiments, the therapeutically effective amount of mecamylamine is distributed to the cornea. In certain embodiments, the therapeutically effective amount of mecamylamine is distributed to the sclera. In certain embodiments, the therapeutically effective amount of mecamylamine is distributed to the lens. In some embodiments, the therapeutically effective amount of mecamylamine is distributed to the iris. In certain embodiments, the therapeutically effective amount of mecamylamine is distributed to the trabecular network. In certain modalities, the condition is associated with abnormal angiogenesis that affects the anterior tissues of the eye or is a condition that involves abnormal angiogenesis that affects the anterior and posterior tissues of the eye. In some modalities, the condition is an ocular tumor.

In some modalities, the condition is corneal neovascularization, pterygium, neovascularization of post-corneal transplant, rubeosis iridis, or neovascular glaucoma. In some modalities, the application is performed once a day, twice a day, three times a day, once every third day, once a week, or twice a week. In particular modalities, the application is performed once a day or twice a day. In some embodiments, the methods further include a step (b), wherein step (b) includes administering to the individual an effective amount of a pharmaceutical agent (other than mecamylamine), the additional treatment modality, or combinations of the foregoing. Step (b) may be performed before, concomitantly with or after step (a). And in some variations, step (b) can be performed more than once. { for example, twice, three times, etc.) (eg, before and after step (a), concomitantly with and after step (a), before and concomitantly with step (a), etc.) . For example, in certain variations, step (b) may be performed before or concomitantly with step (a). In other variations, step (b) may be performed concomitantly with or after step (a). In other additional variations, step (b) may be performed before or after step (a).

In particular variations, step (b) may be performed before step (a). In some variations, step (b) may be performed concomitantly with step (a). In certain variations, step (b) may be performed after step (a). Where step (b) includes the administration of a combination of the pharmaceutical agent and one or more additional treatment modalities, each can be independently administered before, concomitantly with or after step (a). In particular embodiments, step (b) includes a pharmaceutical agent. In certain embodiments, the pharmaceutical agent is an anti-VEGF antibody or fragment thereof. In some embodiments, the anti-VEGF antibody is bevacizumab, ranibizumab, or a combination thereof. In some embodiments, the pharmaceutical agent is the VEGF antagonist. In particular embodiments, the VEGF antagonist is an aptamer of VEGF. In some of these modalities, the VEGR aptamer is pegaptanib. In some embodiments, the pharmaceutical agent is a tyrosine kinase inhibitor. In some embodiments, the pharmaceutical agent is a VEGF scavenger (e.g., VEGF TRAP, etc.). In some embodiments, the pharmaceutical agent is a non-steroidal anti-inflammatory drug. In some embodiments, the pharmaceutical agent is a prostaglandin receptor antagonist. In some variations, the pharmaceutical agent is a VEGF scavenger, VEGF antagonist or tyrosine-cmase inhibitor. In particular embodiments, step (b) includes thermal laser photocoagulation or photodynamic therapy.

In certain embodiments, step (b) includes photodynamic therapy. In some embodiments, step (b) includes thermal laser photocoagulation. In still another aspect, pharmaceutical formulations for ocular topical distribution of mecamylamine are provided. Thus, in some embodiments, pharmaceutical formulations comprising mecamylamine, or a pharmaceutically acceptable salt thereof, water and gel-forming polymer for topical ocular administration are provided, wherein the gel-forming polymer is selected such that when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in choroidal and retinal tissue, measured in units of ng / g, to the concentration of mecamylamine in plasma measured in units of ng / ml ( [ng / g of mecamylamine in choroidal + retinal tissue]: [ng / ml of plasma]) is at least about 300: 1. In certain embodiments, the ratio is from about 300: 1 to about 1000: 1. In particular embodiments, the ratio is at least about 350: 1.

In some embodiments, when the formulation is topically administered to the eye of a rabbit, the average maximum concentration of the mecamylamine in plasma is less than about 70 ng / ml. In certain embodiments, the maximum average concentration of the mecamylamine in plasma is less than about 50 ng / ml. In some embodiments, the maximum average concentration of mecamylamine in plasma is less than about 25 ng / ml. In particular embodiments, the maximum average concentration of the mecamylamine in plasma is less than about 10 ng / ml.

In particular embodiments, the maximum average concentration of mecamylamine in plasma is less than about 5 ng / ml. In some embodiments, the formulation comprises from about 0.001% up to about 6% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 0.001% up to about 5% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.001% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 4% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 0.03% to about 2% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.1% to about 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In certain embodiments, from about 0.05% to about 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the gel-forming polymer is present in a concentration of about 0.03% to about 2% (w / v). In particular embodiments, the formulation is a gel prior to topical ocular administration. In some of these embodiments, the gel-forming polymer is a polysaccharide. In certain embodiments, the formulation forms a gel in situ after topical ocular administration. In some of these particular embodiments, the gel-forming polymer is a polysaccharide. In some embodiments, the polysaccharide is gellan gum. In certain embodiments, the gel-forming polymer is gellan gum present at a concentration of about 0.05% to about 2% (w / v). In others, gellan gum is present at a concentration of about 0.1% to about 1% (p / v). In still others, gelan gum is present at a concentration of about 0.1% to about 0.6% (w / v). In certain embodiments, the formulation is substantially free of surfactant. In some of these modalities, the formulation includes a conservative. In certain embodiments, the formulations include one or more of a preservative or a surfactant. In particular embodiments, the formulations include a preservative. In some embodiments, the carrier further comprises one or more tonicity agents. In particular embodiments, one or more tonicity agents is a polyol. In some embodiments, the polyol is a sugar alcohol, hydroxyalcohol or propylene glycol or polyethylene glycol. In certain embodiments, one or more tonicity agents is mannitol, glycerin or a combination thereof. In certain embodiments, where a preservative is present, the preservative may be one or more of benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate or phenylmercuric acetate. In certain embodiments, the preservative is benzalkonium chloride. In some embodiments, the mecamylamine or a pharmaceutically acceptable salt thereof is present at a concentration from about 0.001% to about 6% (w / vol). In particular embodiments, the mecamylamine or a pharmaceutically acceptable salt thereof is present at a concentration of about 0.001% to about 5% (w / v.). In some of these embodiments, the gel-forming polymer is gellan gum present at a concentration of about 0.05% to about 1% (w / v). In certain embodiments, the formulations contain a pharmaceutically acceptable salt of mecamylamine. In particular embodiments, the salt of mecamylamine is mecamylamine hydrochloride. In some variations, the mecamylamine, or the pharmaceutically acceptable salt thereof, is incorporated into the formulation as substantially pure S-mecamylamine. In some variations, the mecamylamine, or the pharmaceutically acceptable salt thereof, is incorporated into the formulation as substantially pure R-mecamylamine. In some embodiments, the formulations also include a pharmaceutical agent, as described herein. In still another aspect, kits are provided which include the topical mecalylamine eye formulations as described herein. It is intended that any of the formulations described herein may be included in the kits of the present invention. In certain embodiments, kits are provided that include any of the mecalylamine topical eye formulations described herein, the package and instructions for use. In certain embodiments, the formulation is provided in a multiple dose form. In particular embodiments, the formulation is provided in one or more simple unit dose forms. In some embodiments, sufficient formulation is provided (either as a unit dose or in a multiple dose form) for the treatment of a period of about 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, approximately 1 month, approximately 2 months approximately 3 months approximately 4 months approximately 6 months approximately 9 months or approximately 1 year. In particular embodiments, sufficient formulation is provided for approximately 3 months. In other embodiments, sufficient formulation is provided for approximately 1 or 2 months. In some embodiments, the kits include one or more pharmaceutical agents (pharmaceutical agents not mecamylamine). In certain modalities, kits may include one or more antagonists of the nicotinic acetylcholine receptor do not mecamylamine. In particular modalities, the pharmaceutical agent is provided in a separate container of the pharmaceutical formulation of mecamylamine, or a pharmaceutically acceptable salt thereof. In another aspect of the present invention methods are provided for preparing the topical ocular formulations of mecamylamine. These methods generally include the mixing of the mecamylamine and the carrier components (including the gel-forming polymer) in amounts sufficient to prepare a formulation with the desired concentrations of each component. In particular embodiments, methods are provided for the preparation of topical ocular formulations including a gel-forming polymer, including the steps of (a) dispersing a gel forming polymer in an aqueous solution of mecamylamine, or a pharmaceutically acceptable salt Of the same; (b) mixing the mixture formed in step (a) to form a solution or gel; and (c) equilibrating the solution or the gel formed in step (b). In some embodiments, methods are provided for the preparation of topical ocular formulations including a gel-forming polymer, including the steps of (a) dispersing a gel-forming polymer in an aqueous solution of mecamylamine, or a pharmaceutically salt acceptable thereof and (b) mixing the mixture formed in step (a) to form a solution or gel. In some embodiments, the method of preparation further comprises a step, (c) of balancing the solution or gel formed in step (b). In some embodiments, the aqueous solution of the mecamylamine, or a pharmaceutically acceptable salt thereof, further comprises a pharmaceutical agent, a preservative or a surfactant. In some embodiments, the aqueous solution also includes a preservative. In others, the aqueous solution also includes a surfactant. In certain embodiments, the solution formed in step (c) forms a gel in situ after topical ocular administration. In other embodiments, the solution formed in step (b) or step (c) is a gel prior to topical ocular administration. In some embodiments, mixing in step (b) includes ation. In particular modalities, mixing in step (b) includes heating. Unless otherwise indicated, the formulations of mecamylamine as described herein are intended for use in the methods of treatment and / or prevention as described herein, and they can be incorporated into the kits described here. The pharmaceutical formulations described herein may, unless otherwise indicated, be made by the methods of preparation as described herein. In a further aspect of the invention there is provided the use of mecamylamine formulations (for example, including polymer-free formulations, formulations incorporating the viscosity enhancing agent, formulations incorporating the gel-forming polymer, etc.) as described herein in the manufacture of a medicament. Particularly the manufacture of a medicament for use in the treatment and / or prevention of conditions as described herein. In addition, the formulations herein, variously described herein (e.g., including polymer-free formulations, formulations incorporating the viscosity enhancing agent, formulations incorporating the gel-forming polymer, etc.), are also intended for use in the manufacture of a medicament for use in the treatment and / or prevention of conditions and, in accordance with the methods described herein, unless otherwise clearly indicated for the context or specifically noted. In still another aspect of the invention, the formulations are provided as described in present for use in the treatment and / or prevention of the conditions described herein (for example, including polymer-free formulations, formulations incorporating one or more viscosity-increasing agents, formulations incorporating the gel-forming polymer, etc. ). For example, formulations for the treatment and / or prevention of the conditions described herein where the carrier includes water or saline. In some embodiments, the carrier may be water and the formulation may also include sodium chloride. In some embodiments, the formulation may be isotonic. In some modalities, the formulation may be hypotonic. In others, it can be hypertonic. In some variations, the carrier includes a gel-forming polymer. In some embodiments, the carrier can be a gel-forming polymer in situ. In some embodiments, the formulation is substantially free of the gel-forming polymer. In some embodiments, the formulation is substantially free of polymers (e.g., including gel-forming polymers, viscosity-increasing agents, etc.). In some embodiments, the formulation is substantially free of viscosity-increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some variations, the carrier includes a viscosity enhancing agent.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the concentration (ng / ml) of the mecamylamine in plasma (M) and in vitreous fluid (A) after intravenous administration after an aqueous parenteral solution of mecamylamine hydrochloride over a period of 1-hour infusion to rabbits at a total dose / rabbit of 15 mg / kg. Figure 2 shows the concentration (ng / ml) of mecamylamine in plasma (M) and in vitreous fluid (A) after intravenous administration of an aqueous parenteral solution of mecamylamine hydrochloride in a 6-hour infusion period in rabbits at a total dose / rabbit of 15 mg / kg. Figure 3 shows the concentration (ng / g) of mecamylamine in retinal / choroidal eye-rabbit tissue after 1 hour (S) or 6 hours (L) of intravenous infusion of an aqueous parenteral solution of mecamylamine hydrochloride to a total dose / rabbit of 15 mg / kg. Figures 4A-4B show the concentrations of mecamylamine in plasma (ng / ml), vitreous fluid (ng / ml) and retmal / choroidal tissue (ng / g) for rabbits administered with Fig. 4A as an intravenous infusion over a period of 6 hours in an aqueous parenteral solution of mecamylamine hydrochloride at a total / rabbit dose of 15 mg / kg and Fig. 4B via topical administration to the eye of the rabbit of a solution forming in situ gel of 2% mecamylamine hydrochloride at a dose of ~ 1 mg / kg / eye. Figures 5A-5B show the concentrations of mecamylamine in plasma (ng / ml), vitreous fluid (ng / ml) and retinal / choroidal tissue (ng / g) for rabbits administered topically with Fig. 5A an aqueous isotonic ophthalmic solution of 2% mecamylamine hydrochloride at a dose of ~1 mg / kg / eye and FIG. 5B a 2% in situ gel-forming solution of mecamylamine at a dose of ~ 1 mg / kg / eye. Figures 6A-6B show the concentration (ng / ml) of mecamylamine over time (t = 0 at = 24 hours) after topical administration to rabbits of Fig. 6A an isotonic aqueous ophthalmic solution of 2% hydrochloride mecamylamine a dose of ~1 mg / kg / eye in the vitreous fluid (A), plasma (B) and red blood cells (- * •), and Fig. 6B a in situ gel-forming solution of 2% mecamylamine at a dose of ~ 1 mg / kg / eye in the vitreous fluid ( - »-), plasma (+) and red blood cells (I).

DETAILED DESCRIPTION OF THE INVENTION Formulations of mecamylamuma, or pharmaceutically acceptable salts thereof, formulated for topical administration to the eye, as well as methods for the treatment and / or prevention of conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof , of the anterior tissues, posterior tissues and eye fluids (including proliferative retinopathies, corneal neovasculapzation, tepgion, rubeosis, neovascularization of post-corneal transplantation, vitreal neovasculapzation, neovascular glaucoma, etc.) using such formulations, the kits comprising these formulations and the methods to prepare the formulations. Similarly, mecamylamine formulations, or pharmaceutically acceptable salts thereof, formulated for topical distribution to the eye, as well as methods for the treatment and / or prevention of conditions mediated by retinal or choroidal neovasculation are also provided herein. Abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues of the eye (including proliferative retinopathies) using such formulations, kits comprising these formulations and methods for preparing the formulations. In addition, methods are also provided for the treatment and / or prevention of conditions mediated by neovasculapzation, abnormal angiogenesis, vascular permeability, or combinations thereof, of the anterior tissues of the eye using such formulations, the tissues comprising these formulations and the methods for preparing the formulations. Ocular conditions mediated by neovascularization (retinal and / or choroidal), abnormal angiogenesis, vascular permeability (or combinations of two or more of the above) of the posterior tissues of the eye, eg, proliferative retinopathies, including diabetic retinopathy, Prematurity retinopathy, retinopathy due to sickle cell disease, retinopathy associated with macular edema, and retinal neovascularization due to macular degeneration, as well as the additional conditions described herein, are serious conditions that affect millions of people in the United States and throughout the United States. the world and that usually lead to significant vision loss and even blindness. Of course, age-related macular degeneration is one of the leading causes of blindness in the elderly and retinopathy of prematurity can lead to varying degrees of long-term vision period for infants born prematurely. Vision impairment, whether the partial or total loss of vision or visual acuity, adversely affects the quality of life of the individual, often restricting mobility, productivity and independence of affected individuals. Prematurity retinopathy (ROP) is a pathological neovascularization of the retina that occurs in premature infants. The significance of this disease is that it leads to poor visual acuity or blindness in 45-65% of these children ("Cryotherapy for Retinopathy of Premature Cooperative Group: 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity "(2005) Arch Ophthalmol, 123: 311-318). For those neonates who weigh < 1250 grams, the prevalence of ROP is common. In the Early Treatment Test for Premature Retinopathy (ETROP), 68% of preterm infants of < 1250 grams developed ROP (Early Treatment for Retinopathy of Prematurity Cooperative Group: The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study, Pediatrics (2005) 116: 15-23). Unfortunately, since a study of natural history earlier conducted almost 20 years ago (Palmer et al "Incidence and early course of retinopathy of prematurity" (1991) Ophthalmology 98: 1628-1640), the incidence of ROP, the time of onset , the speed of progression and the time of onset of pre-threshold disease has changed little. Consequently, there is a pressing need to obtain new introspective and develop new therapeutic procedures for this disease. Angiogenic disorders that affect the anterior tissues of the eye include abnormal angiogenesis that involves the cornea due to pathological internal growth of the vessels from the limbal vascular plexus to the cornea. This abnormal growth of the vessels can be due to infection, wear by contact lot, trauma, chemical burns, immune diseases, degeneration or infraocular events such as uveitis, glaucoma and pthisis bulbi. The typical treatment is with topical corticosteroids that can be combined with corneal laser photocoagulation. The terigion is a wedge-shaped growth, elevated from the conjunctiva. This is more common among those who live in tropical climates or spend a lot of time in the sun. Symptoms may include irritation, redness and tearing. The terigiones are fed by the thin capillaries that supply blood to the tissue. In some cases, this abnormal fibrovascular tissue grows on the central cornea and affects vision. Typical treatment includes artificial tears, corticosteroids or surgery. Rubeosis iridis is usually a complication of diabetes, and involves abnormal growth of the vessels in the iris and in the body of the kidneys, which can lead to glaucoma. Treatment includes photocoagulation and cryocoagulation.

As noted previously, the development of topical eye formulations is highly unpredictable (Lang et al., (1995) Adv. Drug. Delivery Rev. 16: 39-43; Dey et al. (2005) Expert Opin. DrugDeliv .2 (2) ): 201-204, Jarvinen et al (1995) Adv. Drug, Delivery Rev. 16: 3-19, Maurice (2002) Survey of Ophthamology 47 (Supp.1): S41-S52; Paulsson, M., (2001) ) "Controlled Relay Gel Formulations for Mucosal Drug Delivery" Acta Universitatis Upsaliensis, Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 259. 52 pp. Uppsala, ISBN 91-554-5173 -X.) And depends on a plurality of factors. Thus, not surprisingly, to date, non-invasive, effective pharmacological therapies, capable of stopping or ameliorating those conditions without causing significant side effects and / or complications, have not been successfully developed. Current pharmacological therapies for most proliferative retinopathies commonly use the use of intraocular infection (Peyman et al, (1995) Adv. Drug. Delivery Rev. 16: 107-123; Tojo et al. (2001) Adv. Drug. Delivery Rev. 52: 17-24), for example sub-conjunctival or intra-vitreal injections, which are directed to increase the amount of drug distributed to the posterior region of the eye. These procedures, however, have numerous disadvantages, including the requirement for repeated injections, which can each carry the risk for complications such as detachment of the retina, vitreous hemorrhage, endophthalmitis, and damage to the lens. Additionally, intravitreal injections also require specialized training to administer and require the use of local anesthesia (Peyman et al, (1995) Adv. Drug. Delivery Rev. 16: 107-123), thereby substantially increasing the cost of treatment. The development of less invasive administration routes, for example topical, has been impeded by the complexity of the eye and its numerous mechanisms to exclude exogenous substances, such as the mechanisms described above. Of course, it has been estimated that in the application of ophthalmic drops less than 5% of the applied drug penetrates the cornea and reaches the infraocular tissues (Jarvinen et al, (1995) ibid). The data reported for the distribution of drugs and their formulation for distribution to the posterior region of the eye are extremely limited, and often appear cracked (Maurice (2002) ibid) and thus, generalization regarding the probability of success and the adequacy of a particular drug for topical ocular distribution is not scientifically reasonable, while the guidelines for the development of particular formulations to enable or improve such distribution are not currently available.

However, surprisingly and despite these difficulties, the present invention relates to pharmaceutical formulations and methods for using the mecamylamine formulations (or pharmaceutically acceptable salts thereof) for topical administration to the eye, with side effects. tolerable, of course, minimal, for the treatment or conditions mediated by retinal and / or choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof (eg, combinations of two or more of the above), of the tissues eye posteriors (including proliferative retinopathies), as described in more detail herein. These formulations and methods should greatly improve the quality of life and the perspective of millions of individuals, with the additional benefits of providing treatment with fewer risks of complications and side effects, as well as reduced costs for administration, while probably also increasing patient compliance and successful completion of the course of treatment due to decreased costs, and decreased discomfort compared to currently available pharmacological therapies. As described in more detail in the examples, a given dose of mecamylamine, or a pharmaceutically acceptable salt thereof, when administered topically in a formulation suitable for use in the eye, preferably distributes a higher concentration of mecamylamine to the posterior tissues in the eye (e.g., the retina and choroid) relative to the concentration of mecamylamine that appears in the plasma, compared to a given amount of mecamylamine administered systemically (e.g., intravenously, etc.). It has also been observed that high concentrations of mecamylamine are also present in the cornea and other anterior tissues (and in the fluid (eg, aqueous humor)) after topical ocular administration of mecamylamine. This surprising result can also be transferred by comparison of the proportions for the concentration of mecamylamine in the retinal / choroidal tissue (ng / g): concentration of mecamylamine in plasma (ng / ml) for mecamylamine administered systemically and mecamylamine administered topically to through the eye. A comparison of these proportions is described in Example 6, Table 6. The underlying data in support of Table 6 are described in Examples 2, 5 and 6, with the results presented graphically in Figures 1-6B. In particular, the comparison of Figures 4A and 4B / 5A and the revision of Table 6 clearly show that mecamylamine (or a pharmaceutically acceptable salt thereof), when administered topically, is preferably directed to retinal / choroidal tissues (a ratio of at least about 80: 1 (isotonic solution) versus when mecamylamine is administered systemically (a ratio of approximately 1.4: 1 in short infusion and approximately 2.1: 1 in long infusion, respectively) Such a division of mecamylamine into the retinal / choroidal tissues is unexpected in view of field work and overcomes the difficulties known in the field with respect to the successful development of topical ocular formulations, namely, mecamylamine, when applied topically in Suitable formulations for the eye, is capable of being distributed in sufficiently high concentrations to the posterior tissues of the eye to be therapeutically effective, while not being purified from the eye or absorbed systemically in large quantities (e.g., being detectable at high plasma concentrations). In addition, when the mecamylamine is formulated with Polymers fo For example, GELRITE® (gelan gel)), the proportion of the concentration of mecamylamine in the retinal / choroid: plasma can be increased further, thus improving the preferential distribution of mecamylamine to the region. of interest (for example, the posterior region of the eye (for example, the retina and / or the choroid)), where the conditions described here are manifested, while maintaining very low levels of mecamylamine in the plasma (for example, maintaining minimization and / or elimination of side effects). This increase in the proportion is even more unexpectedly large for the gel-forming polymer carrier when compared to the isotonic solution for topical administration, as shown in Table 6. While the topically applied isotonic solution of mecamylamine hydrochloride showed a large surprising concentration of mecamylamine in woven: plasma of at least about 80: 1 to about 204: 1, the in situ gel-forming agent GELRITE® (gellan gel) in mecamylamine hydrochloride solution at the same dose, showed a ratio of at least about 497: 1. By reference, when Tan et al. (J. Glaucoma (2002) 11: 134-142) investigated the disposition of timolol in the retina and plasma of rats that were topically administered at a single dose of timolol to the eye, a proportion of the concentration of timolol in the retina was observed: approximately 3: 1 (see figure 2, time point approximately 1 hour). This ratio is at least approximately 25 times lower than that currently observed for the isotonic mecamylamine solution topically administered and at least approximately 165 times lower than the ratio observed for mecamylamine topically administered in gel-forming solution in situ. Particularly in view of the data previously available for other active agents, the data obtained for mecamylamine are very surprising and unexpected. As noted previously, data showing the relative concentrations of the drug topically applied to the retina and plasma do not appear to be often reported. With respect to the anterior tissues of the eye (e.g., the cornea), mecamylamine is also present in these tissues at high concentrations when compared to the concentration of mecamylamine in plasma, and this difference can also be expressed, for example, as a ratio for the concentration of mecamylamine in corneal tissue (ng / g): concentration of mecamylamine in plasma (ng / ml). In general, the concentration of mecamylamine in corneal tissue is at least approximately 1000 times greater than the concentration in plasma (eg, [corneal mecamylamine (ng / g)]: [plasma mecamylamine (ng / ml) is at minus 1000: 1]). Similarly, the ratio of the concentration of mecamylamine in the aqueous humor versus the concentration of the mecamylamine in the plasma is also high, at least about 50: 1 (eg, [mecamylamine in aqueous humor (ng / ml)]: [ plasma mecamylamine (ng / ml) is at least 50: 1.] The exemplary data for the 3% (w / v) mecamylamine hydrochloride solutions are given below in Tables A and B, with additional details provided in the Examples.

Table A: Distribution of Mecamylamine in Cornea compared to plasma after topical ocular instillation of mecamylamine Test item Mecca concentration in tissue / plasma at 1 hour (mean values ng / g or ng / ml) Cornea Plasma Proportion Polymer-free solution 88, 425 35 2, 526 1 with simple dose of 3% Mecca at 30 minutes Polymer-free solution 36, 000 18 2, 000 1 with simple dose of 3% Meca at 1 hour Solution polymer free with the simple dose of 3% Mecca at 1 hour after 24, 817 15 1, 654 1 dosing Polymer-free solution 56, 517 43 i, 314 1 with 3% Mecca six doses in one day 1 hour after the last dose Table B: Distribution of Mecamylamine in the aqueous humor compared to plasma after topical ocular instillation of mecamylamine Study Test article Mecha concentration in the aqueous humor 1 hour (mean values ng / ml) Humor Plasma Aqueous ratio Free solution polymer with simple dose of 3% Mecca at 8,678 35 248: 1 at 30 minutes Polymer-free solution with simple dose of 3% Mecca at 1 hour 3,045 18 169: 1 Polymer-free solution with simple dose of Meca at 3% at 1 hour 2,492 after dosing 15 166: 1 Polymer-free solution with 3% Mecca six doses in one day to 1 hour 3,423 43 79: 1 after the last dose These surprising results illustrating the preferential absorption of mecamylamine into the tissues / fluids of the eye compared to mecamylamine present in the plasma can also be transferred by simply measuring the maximum mean concentration of mecamylamine present in the plasma when a therapeutically effective amount of mecamylamine (or a pharmaceutically acceptable salt thereof) to the eye (e.g., for conditions affecting the posterior tissues of the eye (e.g., diabetic retinopathy, ROP, AMD, etc.) or for conditions affecting the anterior tissues of the eye. eye (eg, terigion, corneal neovascularization, rubeosis iridis, etc.)). For example, Figures 6A and 6B clearly show that when mecamylamine hydrochloride is administered topically either with a polymer-free aqueous solution (Figure 6A) or as a gel-forming formulation in situ (Figure 6B), the maximum average concentration of the mecamylamine detected in plasma is surprisingly low, less than 50 ng / ml in each case. The comparison of the maximum average concentration of mecamylamine for topical ocular administration with the data of mean maximum concentration of mecamylamine for short (Figure 1) and long (Figure 2) intravenous administrations of mecamylamine hydrochloride is especially surprising. For short administration (Figure 1), the concentration Maximum mean plasma mecamylamine is greater than 1500 ng / ml, while for long infusion (Figure 2), the maximum average plasma concentration of mecamylamine is greater than 500 ng / m. As noted previously, side effects of the systemic administration of mecamylamine include mydriasis (dilated pupil) and blurred vision. Since these side effects are manifested in the eye, it could be expected that ocular topical application of mecamylamine (or a pharmaceutically acceptable salt thereof) could probably lead to a manifestation of one of these particular side effects. However, topical ocular application of mecamylamine hydrochloride to rabbits did not result in significant changes in pupil diameter or pupil diameter response to light, suggesting topical ocular application of mecamylamine hydrochloride The eye of the rabbit is not inducing detectable levels of mydriasis, a very surprising result. Thus, it is likely that topical ocular administration also avoids the side effect of blurred vision. Of course, clinical trials in humans support the results of studies in animals with none of the tested subjects showing an increase in pupil diameter (no mydriasis) and none of the tested subjects reported vision blurred (for example, no change in visual acuity better corrected). In addition, the initial clinical trials in humans, the results of which are described in Examples 11 and 12, confirm that topical ocular administration of mecamylamine avoids or diminishes the side effects (toxicity) described herein, associated with systemic administration. of mecamylamine (for example, oral or transdermal administration which results in appreciable amounts of mecamylamine which are present in the circulatory system), for example, constipation, urinary retention, postural hypotension, dry mouth, changes in the pulse, changes in blood pressure, changes in ECG parameters, etc., and is also extremely well tolerated as an ocular topical formulation (eg, no change in the production of tears, absence of reports of discomfort, absence of changes in intraocular pressure , no appearance of corneal erosion, absence of ulcers, absence of abnormalities in the chamber before rior, absence of conjunctival irritation / redness, absence of abnormalities in the lens and / or retina, etc.), which many drugs do not. Thus, clinical investigations in humans and tests in non-human animals (e.g. rabbits, dogs) suggest that topical ocular mecamylamine formulations are well suited for the treatment of the conditions described in the present, while also decreasing the pain, anxiety, and cost associated with the current standard of care (and thus also increase patient compliance). In addition, in vitro studies demonstrated that mecamylamine inhibited the formation of endothelial tubes induced by VEGF.

Pharmaceutical Formulations of Mecamylamine The pharmaceutical formulations of mecamylamine, or a pharmaceutically acceptable salt thereof, are provided herein, wherein the formulations are formulated for topical distribution to the eye. As will be understood by those of ordinary experience in the ocular drug distribution technique, the terms "formulation for topical distribution to the eye", "formulated for ocular topical administration", "suitable for topical administration to the eye" and terms Related thereto, refer generally to the formulations (or components of the formulations) that can be tolerated by the individual to whom they are administered via the eye. In certain embodiments, the formulations thus formulated do not cause undue lacrimation which can reduce the amount of mecamylamine that is distributed to the posterior or anterior tissues below a therapeutically effective amount. From in vivo studies in rabbits and dogs, it appears that mecamylamine, and its hydrochloride salt, are well tolerated in the ocular environment and do not cause undue irritation. In general, the formulations must also be sterile and free of pyrogens, irritants or other combination and, where they are intended for administration to humans, meet all the requirements of good manufacturing practices (GMP) and regulatory requirements. In some cases, topical eye formulations will be isotonic, but this is not a requirement for the formulations to be well tolerated by the eye and to comply with regulatory requirements. In certain embodiments, the pharmaceutical formulations may include mecamylamine, or a pharmaceutically acceptable salt thereof, and a carrier. Mecamylamine is also known as N-2,3,3-tetramethylbicyclo (2.2.1) heptan-2-amine, and marketed as INVERSINE® (indicated for the treatment of hypertension) and has the structure shown below. The pka of mecamylamine is approximately pH 11.2. The first references disclosing U.S. Patent No. 2,831,027, Stone et al, (1962) J. Med. & Pharm. Chem. 5 (4): 665-690 and Stein et al, (1956). J. Am. Chem. Soc. 78: 1514 N-2, 3, 3-tetramet? Lb? Cycle [2.2.1] heptan-2-am? Na In certain embodiments, mecamylamuma can be incorporated into formulations such as the R- or S- isomer of mecamylamine, for example, substantially pure R-mecamylamine (eg, free or substantially free of S-mecamylamine) or S-mecamylamine. substantially pure (eg, free or substantially free of R-mecamylamine). The preparation of substantially pure S-mecamylamine and R-mecamilamma have been described in the art, and various characteristics of the individual isomers have also been studied. See for example, Papke et al., (2001) J. Pharmacol. Exp. Therapuetics 297: 646-656; Pfister et al, (1962) J. Med Pharm. Chem. 5 (4): 665-690; Patent of the United States App. Nos. 2002/0016371, 2002/0016370, 2004/004408, and U.S. Patent No. 7,101,916, which are hereby incorporated by reference in their entirety. In some embodiments, mecamylamuma is substantially pure R-mecamylamine (or a pharmaceutically acceptable salt thereof). In others embodiments, the mecamylamine is substantially pure S-mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, mecamylamine can be incorporated into the formulation as a pharmaceutically acceptable salt. The pharmaceutically acceptable salts are well known to those of ordinary skill in the art. In general, pharmaceutically acceptable salts are those which substantially retain one or more of the desired pharmacological activities of mecamylamine and which are suitable for administration to humans. The pharmaceutically acceptable salts include the acid addition salts formed with inorganic acids or organic acids. Suitable inorganic acids for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid and the like. Suitable organic acids for forming the pharmaceutically acceptable acid addition salts include, by way of example, and not limitation, acetic acid. trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (eg, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo (2.2.2) -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. In certain embodiments where mecamylamine is incorporated as a pharmaceutically acceptable salt, the salt is the hydrochloride salt of mecamylamine. For example, mecamylamine hydrochloride, which is commercially available from Poli Industria Chimica, Milan, Italy. In particular embodiments, the carrier may include water. In some embodiments, the carrier may be an aqueous solution of saline, for example, water containing physiological concentrations of sodium, potassium, calcium, magnesium and chloride at a physiological pH. In some embodiments, the carrier may be water and the formulation It may also include sodium chloride. In some embodiments, the formulation may be isotonic. In some modalities, the formulation may be hypotonic. In others, it is hypertonic. In some embodiments, the formulation is substantially free of polymers (e.g., gel-forming polymers, polymeric viscosity-increasing agents, etc.). In some embodiments, the formulation is substantially free of viscosity-increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). As will be understood by the person skilled in the art, for formulations where the carrier includes gel-forming polymer, in certain formulations the inclusion of one or more salts, in particular saline, is contraindicated since the inclusion of salt may be causing the solution to gel before topical ocular administration, such as with certain gel-forming polymers in situ (eg, gellan gel), or the inclusion of salts may inhibit the gel-forming properties of the gel-forming polymer. The expert in The material will be able to select the appropriate combinations based on the desired properties of the formulation and the characteristics of the gel-forming polymers known in the art. Aqueous salt solutions suitable for use in or will be understood by those skilled in the art and may include, for example, solutions at a pH of about pH 4.5 to about pH 8.0. In further variations of the aqueous solutions (where the water is included in the carrier), the pH of the formulation is between any of about 6 and about 8.0; between about 6 and about 7.5; between about 6 and about 7.0; between about 6.2 and about 8; between about 6.2 and about 7.5; between about 7 and about 8; between about 6.2 and about 7.2; between about 5.0 and about 8.0; between about 5 and about 7.5; between approximately 5. 5 and approximately 8.0; between approximately 6. 1 and approximately 7.7; between approximately 6. 2 and approximately 7.6; between approximately 7. 3 and approximately 7.4; approximately 6.0; approximately 7.1; approximately 6.2; approximately 7.3; approximately 6.4; approximately 6.5; approximately 6.6; approximately 6.7; approximately 6.8; approximately 6.9; approximately 7.0; approximately 7.1; approximately 7.2; approximately 7.3; approximately 7.4; approximately 7.5; approximately 7.6; or approximately 8.0. In some variations, the topical ocular mecamylamine formulation has a pH of from about 6.0 to about 7.0. In some variations, the formulation has a pH of about 7.4. In particular variations, the formulation has a pH of from about 6.2 to about 7.5. In certain modalities the concentration of salt (for example, NaCl) will be, for example, from about 0% to about 0.9% (w / v). For example, the concentration of the salt may be from about 0.01 to about 0.9%, from about 0.02% to about 0.9%, from about 0.03% to about 9%, from about 0.05% to about 0.9% from about 0.07% to about 0.9%, from about 0.09% to about 0.9%, from about 0.1% to about 0.9% from about 0.2% to about 0.9%, from about 0.3% to about 0.9%, from about 0.4% to about 0.9% from about 0.5% up to about 0.9%, from about 0.6% to about 0.9%, from about 0.7% up about 0.9%, from about 0.8% to about 0.9%, about 0.9%, about 0%, about 0.05%, about 0.01%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, approximately 0.6%, approximately 0.7%, or approximately 0.8%. In certain embodiments, the aqueous saline solution will be isotonic (eg, the NaCl concentration of about 0.9% NaCl (w / v)). In certain embodiments, the aqueous solution will contain a concentration of sodium chloride about 0.5%, about 0.7%, about 0.8%, about 0.85, or about 0.75%. As will be appreciated by the person skilled in the art, depending on the concentrations of other components, for example where the mecamylamine hydrochloride or other salts of mecamylamine, are used, the concentration of sodium chloride or other salt necessary to achieve an adequate formulation for administration to the eye, they can vary. In some embodiments wherein the carrier includes water, the ratio of the concentration of mecamylamine present in the choroidal and retinal tissue when administered topically to the eye of a rabbit, measured in units of ng / g, at the concentration of the mecamylamine in plasma, measured in units of ng / ml ([ng / g of mecamylamine in choroidal tissue + retinal]: [ng / ml plasma]) is at least about 20: 1, at least about 25: 1, at least about 30: 1, at least about 35: 1, at least about 40: 1, at least about 45: 1, at least about 50: 1, at least about 55: 1, at least about 60: 1, at least about 70: 1, at least about 80: 1, at least about 100: 1, at least about 150: 1, at least about 200: 1, at least about 250: 1, at least about 300: 1, at least about 350: 1, at least about 375: 1, at least about 400: 1, at least about 425: 1, at least about 450: 1, at least about 475: 1, at least about 500: 1, at least about 550: 1, at least about 600: 1, at least about 650: 1, at least about 700: 1, at least about 750 : 1, at least about 800: 1, at least about 850: 1, at least about 900: 1, at least about 950: 1, at least about 1000: 1, at least about 1025: 1 , at least about 1050: 1, at least about 1100: 1, at least about 1200: 1, at least about 1300: 1, at least about 1500: 1, at least about 1700: 1, less approximately of 2000: 1 or at least 2500: 1. In some embodiments, the ratio is from about 20: 1 to about 2500: 1, from about 20: 1 to about 2000: 1, from about 20: 1 to about 1,500: 1, from about 20: 1 to about 1000: 1 , from about 20: 1 to about 1500: 1, from about 20: 1 to about 2000: 1, from about 20: 1 to about 800: 1, from about 20: 1 to about 500: 1, of about 20: 1 to about 300: 1, from about 20: 1 to about 200: 1, from about 20: 1 to about 100: 1, from about 30: 1 to about 2500: 1, from about 30: 1 to about 3000: 1 , from about 30: 1 to about 1500: 1, from about 30: 1 to about 1000: 1, from about 30: 1 to about 800: 1, from about 30: 1 to about 500: 1, about 30: 1 to approximately 30 0: 1, from about 30: 1 to about 300: 1, from about 30: 1 to about 100: 1, from about 40: 1 to about 2500: 1, from about 40: 1 to about 4000: 1, at least about 40: 1 to about 2500: 1, from about 40: 1 to about 1500: 1, about 40: 1 to about 1000: 1, from about 40: 1 to about 2000: 1, from about 40: 1 to about 800: 1, from about 40: 1 to about 500: 1, about 40: 1 to about 300 : 1, from about 40: 1 to about 400: 1, from about 40: 1 to about 100: 1, from about 300: 1 to about 2500: 1, from about 300: 1 to about 2000: 1, about 300: 1 to about 1500: 1, from about 300: 1 to about 1000: 1, from about 300: 1 to about 800: 1, from about 350: 1 to about 2500: 1, from about 350: 1 to about 2000: 1, from about 350: 1 to about 1500: 1, from about 350: 1 to about 1000: 1, from about 350: 1 to about 800: 1, from about 400: 1 to about 2500: 1, approximately 400: 1 to about 2000: 1, from about 400: 1 to about 1500: 1, from about 400: 1 to about 1000: 1, from about 400: 1 to about 800: 1, from about 450: 1 to about 2500: 1 , from about 450: 1 to about 2000: 1, from about 450: 1 to about 1500: 1, about 450: 1 to about 1000: 1, from about 450: 1 to about 800: 1, from about 500: 1 to about 2500: 1, from about 500: 1 to about 2000: 1, about 500: 1 to about 1500: 1, from about 500: 1 to about 1000: 1, or from about 500: 1 to about 800: 1. In particular embodiments, the ratio is at least about 300: 1, at least about 350: 1, at least about 450: 1, at least about 500: 1, at least about 1200: 1, about 300 1 to about 1000: 1, from about 300: 1 to about 2000: 1, from about 350: 1 to about 1000: 1, from about 350: 1 to about 2000: 1, from about 450: 1 to about 1000: 1, from about 450: 1 to about 1100: 1, from about 450: 1 to about 1200: 1, from about 450 to about 2000: 1, from about 500: 1 to about 1000: 1, from about 500: 1 to about 1200: 1, or about 500: 1 to about 2000: 1. In some of these embodiments, the formulation further includes a viscosity enhancing agent (e.g., hypromellose, etc.). In some modalities, the formulation it is substantially free of polymers (e.g., gel-forming polymers, polymeric viscosity-increasing agents, etc.). In some embodiments, the formulation is substantially free of viscosity-increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments where the carrier includes water, the ratio of the concentration of mecamylamine present in the corneal tissue when administered topically to the eye of a rabbit, measured in units of ng / g, at the concentration of the mecamylamine in plasma measured in units of ng / ml ([ng / g of mecamylamine in corneal tissue]: [ng / ml of plasma]) is at least about 1000: 1. In some embodiments, the ratio of the concentrations is at least about 100: 1, at least about 200: 1, at least about 300: 1, at least about 400: 1, at least about 500: 1 at least about 600: 1 , at least about 700: 1, at least about 800: 1, at least about 850: 1, at least about 900: 1, at least about 950: 1, at least about 1000: 1, at least about 1025: 1, at least about 1050: 1, at least about 1100: 1, at least about 1200 : 1, at least about 1300: 1, at least about 1500: 1, at least about 1700: 1, at least about 2000: 1 or at least 2500: 1. In some embodiments, the ratio is from at least about 100: 1 to about 4000: 1, from at least about 100: 1 to about 3000: 1, from at least about 100: 1 to about 2500: 1, of at least about 800: 1 to about 4000: 1, from at least about 800: 1 to about 3000: 1, from at least about 800: 1 to about 2500: 1, from at least about 900: 1 to about 4000: 1, from less than about 900: 1 to about 3000: 1, from at least about 1000: 1 to about 4000: 1, from at least about 1000: 1 to about 3000: 1, from at least about 1000: 1 to about 2500: 1, from at least about 1000: 1 to about 2000: 1. In certain embodiments, the ratio is at least about 850: 1, at least about 900: 1, at least about 1000: 1, at least about 1200: 1. In some of these modalities, the formulation it also includes a viscosity-increasing agent (for example, hypromellose, etc.). In other embodiments, the formulation is substantially free of polymers (e.g., gel-forming polymers, viscosity-increasing agents, etc.). In some embodiments, the formulation is substantially free of viscosity-increasing agents (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, where the formulation is substantially free of viscosity-increasing agents, the formulation may be substantially free of viscosity-increasing agents such as, but not limited to, polyanionic polymers, water-soluble cellulose derivatives (e.g., hypromellose (also known as HPMC, hydroxypropylmethylcellulose, and hydroxypropylcellulose), hydroxyethylcellulose, carboxymethylcellulose, etc.), polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, hyaluronic acid, soluble starches, etc. In some variations, the formulation does not incorporate a hydrogel or other agent of retention (e.g., such as those described in U.S. Patent Publication No. 2005/0255144 (incorporated herein by reference in its entirety), for example, where these hydrogels may include hydrogels that incorporate homopolymers, copolymers (eg, example, tetrapolymers of hydroxymethyl methacrylate, ethylene glycol, dimethyl methacrylate, and methacrylic acid), copolymers of trimethylene carbonate and polyglycolic acid, polyglactin 910, glycolonate, poly-p-dioxanone, polyglycolic acid, polyglycolic acid felt, poly-4-hydroxybutyrate, combination of poly (L-lactide) and poly (L-lactide-co-glycolide), glycol methacrylate, poly-DL-lactide, or primacryl); the compounds of oxidized regenerated cellulose, polypropylene and polydioxanone or a polypropylene and polygelcaprona compound; etc. In some variations, the formulations do not include one or more of polyvinyl alcohol, hydroxypropylmethylcellulose, castor oil emulsion of polyethylene glycol 400, sodium carboxymethylcellulose, propylene glycol, hydroxypropylguar, sodium carboxymethylcellulose, sodium petrolatum, mineral oil, dextran 70, glycerin, hypromellose, flaxseed oils, fish oils, omega 3 and omega 6 fatty acids, lutein or spring oil. In some variations, the formulations do not include one or more of the carriers described in U.S. Patent No. 4,888,354 (incorporated by reference herein in its entirety), for example, such as one or more of oleic acid, ethanol, isopropanol, glycerol monooleate, glycerol dioleate, methyl laurate, propylene glycol, propanol or dimethyl sulfoxide. In some variations, the formulations are substantially free of glycerol dioleoleate and isopropanol. In some embodiments where the carrier includes water, the ratio of the concentration of mecamylamine present in the aqueous humor when administered topically to the eye of a rabbit, measured in units of ng / ml, at the concentration of the mecamylamine in plasma measured in units of ng / ml ([ng / ml of mecamylamine in aqueous humor]: [ng / ml of plasma]) is at least about 40: 1, at least about 45: 1, at least about 50: 1, at least about 55: 1, at least about 60: 1, at least about 70: 1, at least about 80: 1, at least about 100: 1, at least about 150: 1, at least of about 200: 1, or at least about 250: 1. In some embodiments, the ratio is from about 40: 1 to about 2500: 1, from about 40: 1 to about 4000: 1, from about 40: 1 to about 2000: 1, from about 40: 1 to about 1500: 1, from about 40: 1 to about 1000: 1, of about 40: 1 up about 800: 1, from about 40: 1 to about 500: 1, about 40: 1 to about 300: 1, from about 40: 1 to about 400: 1, or from about 40: 1 to about 100: 1. In particular embodiments, the ratio is at least about 50: 1. In some of these embodiments, the formulation further includes a viscosity enhancing agent (e.g., hypromellose, etc.). In other embodiments, the formulation is substantially free of polymers (e.g., gel-forming polymers, viscosity-increasing agents, etc.). In some embodiments, the formulation is substantially free of viscosity-increasing agents (e.g., carboxymethyl cellulose, polyanionic polymers, etc.). In some embodiments, the formulation is substantially free of gel-forming polymers. In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). As noted previously, very surprisingly, topical ocular administration of an amount of mecamylamine (or a pharmaceutically acceptable salt thereof) effective to reduce abnormal angiogenesis and / or neovascularization of eye tissues (either anterior or subsequent) results in extremely low levels of mecamylamine in plasma. For example, the maximum average concentration of the mecamylamine detected is less than about 70 ng / ml. These maximum low concentrations of mecamylamine are observed in single dose and multiple dose studies (eg, multiple doses per day or multiple doses in a number of days), for rabbits administered with mecamylamine (or a pharmaceutically acceptable salt thereof). ) in an ocular topical form. Thus, for example, the maximum average concentration of the mecamylamine detected will be less than about 65 ng / ml, less than about 60 ng / ml, less than about 55 ng / ml, less than about 50 ng / ml, less than about about 45 ng / ml, less than about 40 ng / ml, less than about 20 ng / ml, less than about 15 ng / ml, less than about 10 ng / ml, or less than about 5 ng / ml. In particular embodiments, where the mecamylamine is administered in a single dose per day, the maximum mean plasma concentration may be less than about 25 ng / ml. For example, less than about 20 ng / ml, less than about 15 ng / ml, less than about 10 ng / ml, or less than about 5 ng / ml. Alternatively, the amount of mecamylamine that appears in plasma can be measured as the concentration total of mecamylamine as measured as the area under the curve (AUC) for the concentration of mecamylamine after administration. As with other measures of mecamylamine in plasma, the total mean plasma concentration of mecamylamine in a given population of subjects is surprisingly low. For example, less than about 85 ng / ml-hour. In some embodiments, the amount of mecamylamine as measured by this method is less than about 100 ng / ml-hour, less than about 90 ng / ml-hour, less than about 80 ng / ml-hour, less than about 75 ng / mL-hr, less than about 70 ng / ml-hour, less than about 65 ng / ml-hour, less than about 60 ng / ml-hour, less than about 50 ng / ml-hour or less than about 45 ng / ml-hour. The exemplary values for the AUC concentration of mecamylamine for the 3% (w / v) concentrations of mecamylamine hydrochloride administered as a single 50 μl dose to each eye are shown below. The calculated values for the AUC for tissues and plasma can also be used to calculate the proportions between the cornea, choroid / retina and aqueous humor versus plasma, as also shown in Table C below. The data was obtained as described in Example 8.

When the AUC value is considered as a proportion, the ratio of the AUC of the retina / choroid: the plasma AUC is at least about 50: 1, at least about 55: 1, at least about 60: 1, at least about 70: 1, at least about 75: 1, at least about 80: 1, at least about 90: 1, at least about 100: 1, at least about 150: 1, at least about 200: 1, at least about 250: 1, at least about 300: 1, or at least about 350: 1. In some embodiments, the ratio of the AUC of the retina / choroid: plasma AUC is at least about 80: 1. When the AUC value is considered as a ratio, the ratio of the corneal AUC: plasma AUC is at least about 100: 1, at least about 500: 1, at least about 600: 1, 800: 1 , at least about 900: 1, at least about 1000: 1, at least about 1500: 1, at least about 2000: 1, or at least about 2500: 1. In certain embodiments, the ratio of the AUC of the cornea: plasma AUC is at least about 1000: 1. When the AUC value is considered as a proportion, the AUC ratio of the aqueous humor: plasma AUC is at least about 50: 1, at least about 60: 1, at least about 80: 1, at least about 90: 1, at least about 100: 1, at least about 150: 1, or at least about 200: 1. In some embodiments, the ratio of the AUC of the aqueous humor: plasma AUC is at least about 90: 1. In particular embodiments, the formulations Pharmaceuticals can include mecamylamine, or a pharmaceutically acceptable salt thereof, water and the gel-forming polymer, wherein the gel-forming polymer is characterized such that the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in the choroidal and retinal, measured in units of ng / g, at the concentration of mecamylamine in plasma measured in units of ng / ml ([ng / g of mecamylamine in choroidal tissue + retinal]: [ng / ml plasma]) is at least about 300: 1. As used herein, the term "topically administered to a rabbit eye", and related terms thereof, refers to the administration of a particular mecamylamine formulation, including pharmaceutically acceptable salt formulations of mecamylamine, by the application of 100 μl of the mecamylamine formulation to the cornea of each eye (2 drops of 50 μl each), wherein at the time of application the lower eyelid is separated from the surface of the eye to make a bag to ensure that the entire dose in contact with the eye is retained. When the concentration of mecamylamine in plasma and retinal / choroidal tissue is to be measured in connection with the calculation of the ratio of mecamylamine concentration in the retina / choroid to the concentration of mecamylamine in plasma, the concentration of each one is determined 1 hour after the application of the formulation. The amount of mecamylamine present in plasma and the retina / choroid is determined by LC / MS / MS using internal standards of dextromethorphan and diphenhydramine and a standard of known concentration of mecamylamine. An exemplary method of administration of the topical mecamylamine formulation is provided in Example 5. An exemplary LC / MS / MS method for determining the proportions described herein is given in detail in Example 6. When the maximum mean concentration of the Mecamylamine in plasma will be determined, the concentration is again determined as described above and in Example 6. The term "maximum mean concentration of mecamylamine", and its related terms, as used herein, refers to the concentration maximum mean of the mecamylamine measured in plasma when it is monitored in a period of time of 6 hours after the administration of the formulation. When the total mean concentration of the mecamylamine in plasma is to be determined, the concentration is again determined as described above and in Example 6. The term "total concentration of mecamylamine in plasma measured as the area under the curve" (AUC) and related terms thereof, refers to the sum of the areas under the plasmatic drug plot versus time using a simple trapezoidal method with the points of time of the drug in plasma taken to include 1, 3 and 6 hours after topical administration. The determination of AUC for corneal tissue, retinal / choroidal tissue and aqueous humor is determined similarly. When the concentration of mecamylamine in plasma and in corneal tissue is to be measured in connection with the calculation of the ratio of the concentration of mecamylamine in the cornea (or the aqueous humor) versus the concentration of mecamylamine in plasma, the concentration of each is determined at 1 hour after the application of 50 μl of the formulation. The amount of mecamylamine present in plasma and in the cornea (or in the aqueous humor) is determined by LC / MS / MS using external standards of dextromethorphan and diphenhydramine and a standard of known concentration of mecamylamine. An exemplary method of administering the mecamylamine topical formulation is provided in Example 5. An exemplary LC / MS / MS method for determining the proportions described herein is given in detail in Example 6. In some embodiments, the formulation is a gel before topical ocular administration. In other embodiments, the formulation forms a gel in situ after topical ocular administration. Examples of gel-forming formulations in situ are formulations that form gels in response to a change in the tonicity (for example, GELRITE® (a gellan gum), temperature, salt concentration, etc.). Examples of formulations including gel-forming polymers in situ are described, for example, in U.S. Patent Nos. 6,174,524; 4,861,760. As used herein, the terms "topical ocular administration" or "topically administered" and related terms of these terms, refer to contacting the surface of the eye with the formulation. The contacting can be accomplished by methods known to those skilled in the art, including, but not limited to, eye drops, application of gel formulations, gel applications, film application, etc. In particular embodiments, the gel-forming polymer can be, for example, a polysaccharide. In certain embodiments, the polysaccharide is gellan gum. Gelan gum refers to a heteropolysaccharide made by the bacterium Pseudomonas elodea, although the name "gelan gum" is more commonly used in the field. Gelan gum, in particular the GELRITE® formulation, is described in detail in U.S. Patent No. 4,861,760 (incorporated herein by reference in its entirety), particularly in its use in the formulation of timolol. GELRITE®, a clarified low grade in acelan of gelan gum, is commercially available available from Merck & Co (Rahway, NJ) and gelan gum can be commercially obtained from, among others, CPKelco (Atlanta, GA). The preparation of polysaccharides such as gelan gum is described in, for example, U.S. Patent Nos. 4,326,053 and 4,326,052, which are incorporated herein by reference in their entirety. In certain embodiments, the gel-forming polymer is present at a concentration of about 0.03% to about 2% (w / v). In some embodiments, the gel-forming polymer is present at a concentration of about 0.03% to about 1.75%; from about 0.03% to about 1.5%, from about 0.03% to about 1.25%, from about 0.03% to about 1%, from about 0.03% to about 0.9%, from about 0.03% to about 0.8%, from about 0.03% to about 0.7%, from about 0.03% to about 0.6%, from about 0.03% to about 0.5%, of about 0.05! up to about 2%, from about 0.05% to about 1.75%; from about 0.05% to about 1.5%, from about 0.05% to about 1.25%, from about 0.05% to about 1%, from about 0.05% to about 0.9%, of about 0.05% to about 0.8%, from about 0.05% to about 0.7%, from about 0.05% to about 0.6%, from about 0.05% to about 0.5%, from about 0.1% to about 2%, from about 0.1% to about 1.75%; from about 0.1% to about 1.5%, from about 0.1% to about 1.25%, from about 0.1% to about 1%, from about 0.1% to about 0.9%, from about 0.1% to about 0.8%, from about 0.1% up to about 0.7%, from about 0.1% to about 0.6%, from about 0.1% to about 0.5%, from about 0.2% to about 2%, from about 0.2% to about 1.75%; from about 0.2% to about 1.5%, from about 0.2% to about 1.25%, from about 0.2% to about 1%, from about 0.2% to about 0.9%, from about 0.2% to about 0.8%, from about 0.2% up about 0.7%, from about 0.2% to about 0.6%, from about 0.2% to about 0.5%, or from about 0.5% to about 1.5%. In some embodiments, the concentration of the gel forming polymer is from about 0.1%, from about 0.2%, about 0.4%, from about 0.6%, about 0.8%, of about 1%. In particular embodiments, the gel-forming polymer is gellan gum at a concentration of from about 0.05% to about 2% (w / v), from about 0.1% to about 2% (w / v), from about 0.1% to about 1 % (w / v), from about 0.05% to about 1% (w / v) or from about 0.1% to about 0.6% (w / v). In some embodiments, the concentration of gelan gum is about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%. In some embodiments where a gel-forming polymer is present in the formulation, the ratio of the concentration of mecamylamine present in the choroidal and retinal tissue when administered topically to the eye of a rabbit, measured in units of ng / g, to the concentration of mecamylamine in plasma measured in units of ng / ml ([ng / g of mecamylamine in choroidal tissue + retinal]: [ng / ml of plasma]) is at least about 350: 1, at least about 375: 1, at least about 400: 1, at least about 425: 1, at least about 450: 1, at least about 475: 1, at least about 500: 1, at least about 550: 1, at least about 600: 1, at least about 650: 1, at least about 700: 1, at least about 750: 1, at least about 800: 1, at least about 850: 1, at least about 900: 1, at least about 950: 1, at least about 1000: 1, at least about 1025: 1, at least about 1050: 1, at least about 1100: 1, at least about 1200: 1, at least about 1300: 1, at least about 1500: 1, at least of about 1700: 1, at least about 2000: 1 or at least 2500: 1. In some embodiments, the ratio is from about 300: 1 to about 2500: 1, from about 300: 1 to about 2000: 1, from about 300: 1 to about 1500: 1, from about 300: 1 to about 1000: 1, from about 300: 1 to about 800: 1, from about 350: 1 to about 2500: 1, from about 350: 1 to about 2000: 1, from about 350: 1 to about 1500: 1, of about 350: 1 to about 1000: 1, from about 350: 1 to about 800: 1, from about 400: 1 to about 2500: 1, of about 400: 1 to about 2000: 1, from about 400: 1 to about 1500: 1, from about 400: 1 to about 1000: 1, from about 400: 1 to about 800: 1, from about 450: 1 to about 2500: 1, from about 450: 1 to about 2000: 1, from about 450: 1 to about 1500: 1, from about 450: 1 to about 1000: 1, from about 450: 1 to about 800: 1, from about 500: 1 to about 2500: 1, from about 500: 1 to about 2000: 1, from about 500: 1 to about 1500: 1, from about 500: 1 to about 1000: 1, or from about 500: 1 to about 800: 1 . In particular embodiments, the ratio is at least about 300: 1, at least about 350: 1, at least about 450: 1, at least about 500: 1, at least about 1200: 1, about 300 1 to about 1000: 1, from about 300: 1 to about 2000: 1, from about 350: 1 to about 1000: 1, from about 350: 1 to about 2000: 1, from about 450: 1 to about 1000: 1, from about 450: 1 to about 1100: 1, from about 450: 1 to about 1200: 1, from about 450 to about 2000: 1, about 500: 1 to about 1000: 1, from about 500: 1 to about 1200: 1, or about 500: 1 to about 2000: 1. In some embodiments, the mecamylamine, or the pharmaceutically acceptable salt thereof, may be present at a concentration of about 0.001% to about 6% (w / v). In certain embodiments, the mecamylamine, or the pharmaceutically acceptable salt thereof, may be present at a concentration (w / v) of from about 0.001% to about 5%, from about 0.005% to about 6% from about 0.005 to about 5. % from about 0.01% to about 6% from about 0.01% to about 5% from about 0.01% to about 4% from about 0.01% to about O • 32 o. from about 0.01% to about Z or from about 0.01% to about 1% from about 0.001% to about 4% from about 0.001% to about 3% from about 0.001% to about 2% from about 0.001% to about 1% of about 0.03% to about 4% from about 0.03% to about 3% from about 0.03% to about 2% of [00 about 0.03% to about 112o-, from about 0.03% to about 0.5%, from about 0.03% to about 0.2%, from about 0.03% to about 0.1%, from about 0.1% to about 6%, from about 0.1% to about R2- from about 0.1% to about? 49o-, from about 0.1% to about "52 o-, from about 0.1% to about? 2o-, from about 0.1% to about 112o-, from about 0.3% to about 6% , from about 0.3% to about JR 2o-, from about 0.3% to about? 2- from about 0.3% to about O • 59 o-, from about 0.3% to about Z 92o-, from about 0.3% to about 119o- , from about 0.5% to about 6%, from about 0.5% up to about J R2o-, from about 0.5% to about tea ? q 2o-, from about 0.5% to about 3 T2o-, from about 0.5% to about Z09o-, from about 0.5% to about 119o-, from about 1% to about 6%, from about 1% to about • J 2o-, from approximately 1% to approximately? 9th-, of about 1% to about 3%, or from about 1% to about 2%. In some embodiments, the mecamylamine, or the pharmaceutically acceptable salt thereof, may be present at a concentration of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.8%, about 0.9% , about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about, 8%, about 1%, about 1.2%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 5%, about 6% (w / v). In particular embodiments, the mecamylamine or the pharmaceutically acceptable salt thereof is present at a concentration (w / v) of, for example, from about 0.001% to about 6%, from about 0.001% to about 5%, of about 0.02% to about 2%, from about 0.02% to about 1%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.1 to about 5%, or from about 0.1 to about 3% and the gel-forming polymer is rubber gel at a concentration of from about 0.05% to about 2% (w / v), from about 0.1% to about 2% (w / v), from about 0.1% to about 1% (w / v), of about 0.05% up to about 1% (w / v) or from about 0.1% to about 0.6% (w / v). In certain embodiments, mecamylamine is present as a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is mecamylamine hydrochloride.

Additional compounds In some embodiments of the formulations, the formulation may include additional components such as one or more preservatives, one or more surfactants, or one or more pharmaceutical agents. In particular embodiments, the formulation may include additional components such as one or more preservatives, one or more surfactants, one or more tonicity agents, one or more buffering agents, one or more chelating agents, one or more viscosity increasing agents, one or more salts, or one or more pharmaceutical agents. In some embodiments, the formulation may include (in addition to mecamylamine (or a pharmaceutically acceptable salt thereof) and the carrier): one or more preservatives, one or more buffering agents (eg, example, one, two or three, etc.) one or more chelating agents and one or more salts. In some modalities, the formulation may include (in addition to the mecamylamine (or a pharmaceutically acceptable salt thereof) and the carrier): one or more preservatives, one or more tonicity agents, one or more buffering agents, one or more chelating agents and one or more viscosity-increasing agents. As used herein, the term "pharmaceutical agent" or "additional pharmaceutical agent", and cognate terms of these terms, are intended to refer to agents other than mecamylamine or pharmaceutically acceptable salts thereof, for example, the drugs that are administered to promote a therapeutic effect. The pharmaceutical agent (s) can be directed to a therapeutic effect related to the condition that the mecamylamine formulation is intended to treat or prevent, for example, conditions mediated by neovascularization (eg, retinal neovascularization, choroidal neovascularization), abnormal angiogenesis, or combinations thereof, of the posterior tissues of the eye (e.g., proliferative retinopathies); conditions mediated by neovascularization (e.g., corneal neovascularization, neovascularization of post-corneal transplantation, etc.), abnormal angiogenesis, or combinations thereof, of the anterior tissues of the eye (e.g. pterygium, rubeosis iridis, neovascular glaucoma, etc.) or the pharmaceutical agent may be intended to treat a symptom of the underlying condition or to further reduce the occurrence or severity of side effects related to the administration of mecamylamine, although it is likely that occur in a few individuals. In some embodiments, the pharmaceutical agent (s) may be an antagonist of nAChR, an anti-inflammatory agent (eg, NSAID, etc.), VEGF antagonist, VEGF (eg, VEGF TRAP, etc.), inhibitor of the tyrosine kinase, prostaglandin receptor antagonist, agent used in the treatment of glaucoma, or an agent to decrease intra-ocular pressure. The selection of the appropriate pharmaceutical agent (s) for use in the formulations and methods described herein will depend on the condition to be treated, as will be appreciated by a person skilled in the art. Exemplary pharmaceutical agents are described in more detail below. In certain embodiments, the pharmaceutical agent can be an antagonist of the nicotinic acetylcholine receptor (nAChR). Examples of nAChR antagonists are known in the art and include, for example, hexamethonium, dihydro-beta-erythroodyodine, d-tubocurarine, pempidine, chlorisondamine, erisodin, trimetaphan camsylate, pentolinium, bungarotoxin, succinylcholine, tetraethylammonium, trimetaphan, chlorisondamine, trimetidinium, etc. See for example, Suner et al, (2004) ibid. In some embodiments, the nAChR antagonist is hexamethonium. In some embodiments, the pharmaceutical agent (s) may include one or more pharmaceutical agents that are shown to be effective in treating the conditions described herein. For example, VEGF antagonists (eg, anti-VEGF (vascular endothelial growth factor) antibodies or fragments thereof, VEGF aptamers (eg, pegaptanib sodium) In certain embodiments, anti-VEGF antibodies are monoclonal antibodies ). Exemplary anti-VEGF antibodies include, but are not limited to, bevacizumab and ranibizumab (trade names AVASTIN® and LUCENTIS®, respectively, under the development of Genentech, Inc., South San Francisco, CA). Pharmaceutical agents may also include the vascular endothelial growth factor (VEGF) receptor antagonist pegaptanib (an aptamer) (MACUGEN®; Pfizer). In some embodiments, the pharmaceutical agent (s) may be the tyrosine kinase inhibitor. In some embodiments, the pharmaceutical agent is a VEGF scavenger. In some modalities, the VEGF debugger is VEGF TRAP. In some variations, the pharmaceutical agent is a VEGF scrubber, VEGF antagonist or tyrosine kinase inhibitor. In some embodiments, the pharmaceutical agent (s) may be an agent for the treatment of glaucoma (e.g., dichlorphenamide, carbocol, demacarium bromide, etc.) or an agent for lowering intraocular pressure (e.g., steroids). In some embodiments, the pharmaceutical agent (s) may be a nonsteroidal anti-inflammatory drug (NSAID). Numerous NSAIDs are well known to the person skilled in the art and can be selected based on the condition to be treated, as well as the general health of the individual to be treated. Exemplary classes of NSAIDs include, but are not limited to, for example, salicylates (e.g., aspirin, methyl salicylate, etc.), arylalkanoic acids (e.g., diclofenac, sulindac, etc.), 2-arylpropionic acid (profens (for example, ibuprofen, ketoprofen, naproxen, etc.), N-arylanthranilic acids (phenamic acids) (eg mefenamic acid, etc.), pyrazolidine derivatives (for example, oxyphenylbutazone, phenylbutazone, etc.), oxicams (eg, piroxicam, meloxicam, etc.), selective COX-2 inhibitors (eg, coxibs (eg, celecoxib, parecoxib, etc.), sulfonanilides (eg, nimesulide, etc.), and selective inhibitors of COX-3.

In some embodiments, the pharmaceutical agent (s) may be a prostaglandin receptor antagonist. In particular embodiments, wherein the carrier is water, the formulation can be substantially free of polymers (eg, it does not contain a polymeric viscosity-increasing agent, gel-forming polymer, etc.). In some embodiments, the formulation is substantially free of the viscosity enhancing agent (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some embodiments, the formulation is substantially free of gel-forming polymers. In certain embodiments, where the carrier is water, the formulation may additionally include one or more chelating agents (e.g., disodium edeteate (EDTA), one or more preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate, phenylmercuric acetate, or combinations of two or more of the above), salt (for example, NaCl) and one or more agents buffers (e.g., one or more phosphate buffers (e.g., sodium dibasic phosphate, sodium monobasic phosphate, combinations thereof, etc.), citrate buffers, maleate buffers, borate buffers, and combinations of two or more than the previous ones.). In particular embodiments, the chelating agent is disodium edeterate, the preservative is benzalkonium chloride, the salt is sodium chloride, and the buffering agents are sodium dibasic phosphate and monobasic sodium phosphate. In some of these embodiments, the formulation is substantially free of polymer. In some embodiments, the formulation is substantially as described in Table 16. In some embodiments, the formulation is substantially free of the viscosity increasing agent (s) substantially (eg, carboxymethylcellulose, polyanionic polymers, etc.). In some embodiments, the viscosity of the formulation is approximately the same as the viscosity of a saline solution containing the same concentration of mecamylamine (or a pharmaceutically acceptable salt thereof). In some of these embodiments, the concentration of the mecamylamine (or a pharmaceutically acceptable salt thereof) is from about 0.02% to about 3%, from about 0.02% to about 2%, of about 0.02% to about 1% (w / v). In certain embodiments, the concentration of the mecamylamine (or a pharmaceutically acceptable salt thereof) is about 0.01%, about 0.02%, about 0.03%, about 0.05%, about 0.07%, about 0.1% , about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.8% or about 1% (w / v). In certain embodiments, where the carrier includes water, a viscosity enhancing agent may also be included in the formulation. The person skilled in the art will be familiar with viscosity-increasing agents that are suitable for use in the eye (eg, water-soluble cellulose derivatives (eg, hypromellose (also known as HPMC, hydroxypropylmethylcellulose, and hydroxypropylcellulose), hydroxyethylcellulose, carboxymethylcellulose, etc.), polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, hyaluronic acid, and soluble starches.It is intended that when using viscosity-increasing agents they are not included in sufficiently high concentrations that the formulation could form a gel before or after administration (for example, where the concentration of the viscosity-increasing agent is not enough to induce gel formation). While the exact concentrations of the viscosity increasing agents will depend on the selection and concentration of these components in the formulation, as well as the particular viscosity enhancing agent (s), in general, the viscosity increasing agents may be present in a concentration such that the viscosity of the resulting solution is less than about 1000 centiopoises. In certain embodiments, the formulation viscosity is less than about 900, less than about 800, less than about 700, less than about 600, less than about 500, less than about 400, less than about 300, less than about 200, less of about 150, less than about 100, less than about 50 centiopoises. In some embodiments, the viscosity of the formulation is about 200, about 150, about 100, about 50 centiopoises. In particular embodiments, the viscosity is less than about 200 centiopoises. In others, it is less than about 120 centiopoises or less than about 100 centiopoises. In some embodiments, the viscosity is about 100 centiopoises. In others, it is approximately 50 centiopoises. In other additional modalities, the eleven viscosity is approximately 200 centiopoises. The methods for measuring the viscosity are well known to the person skilled in the art. For example, as described in the United States Pharmacopeia 29 (Chapter 911) Viscosity, page 2785 (which is incorporated by reference herein in its entirety). As is well known to those skilled in the art, formulations commonly considered "gels" will have a viscosity significantly greater than 1000 centiopoises, eg, greater than about 2000 centiopoises, greater than about 5000 centiopoises. In some embodiments, including (but not limited to) wherein the use of the salts is contraindicated as described above, the formulation may also include one or more tonicity agents. As used herein, the term "tonicity agent" and its cognates refers to agents that adjust the tonicity of the formulation, but are not salts (e.g., not NaCl), which, as will be appreciated by the The person skilled in view of the teaching provided herein is contraindicated for some formulations due to the presence of some of the gel-forming polymers or viscosity-increasing agents. These agents can be used to prepare formulations that are suitable for the eye and are isotonic or quasi-isotonic (for example, somewhat hyper- or hyper-isotonic, for example, 12 within about ± 20%, about ± 15%, about ± 10%, about ± 5% being isotonic). The tonicity agent (s) can also be used in formulations where the use of the salts is not contraindicated. Tonicity agents which can be used to adjust the tonicity of the formulation of formulations described herein, and which are suitable for administration to the eye are known to the person skilled in the art, and can be selected based on the teaching provided at the moment. For example, tonicity agents include polyols (e.g., sugar alcohols) (eg, mannitol, etc.), trihydroxyalcohols (eg, glycerin, etc.), propylene glycol or polyethylene glycol, etc.), or combinations of two or more polyols. Likewise, the concentration of the tonicity agent or agents will depend on the identity and the concentrations of the other components in the formulation, and can be easily determined by the person skilled in the art in view of the teaching provided herein. In certain embodiments, the tonicity agent is glycerin or mannitol. In some embodiments, the tonicity agent is glycerin. In others, it is mannitol. In other embodiments, a combination of mannitol and glycerin can be used.

Exemplary concentrations of the tonicity agents include, for example, from about 0.001 to about 3%. In some embodiments, the concentration of the tonicity agent (e.g., mannitol or glycerin) is, for example, from about 0.001% to about 2.7%, about 0.001% to about 2.5%, about 0.001% to about 2%, about 0.001 % up to about 1.5%, about 0.001% up to about 1%, about 0.01% up to about 3%, about 0.01% up to about 2.7%, about 0.01% up to about 2.5%, about 0.01% up to about 2%, about 0.01% up about 1.5%, about 0.01% to about 1%, about 0.1% to about 3%, about 0.1% to about 2.7%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5 %, approximately 0.1% to approximately 1%, approximately 0.01% approximately 1% up approximately 3%; about 1% up to about 2.5%; about 1% to about 2%; approximately 1% up to approximately 14 1. 8%; about 1% up to about 1.5%; or about 0.001%, about 0.01%, about 0.05%, about 0.08%, about 0.1%, about 0.2%, about 0.5%, about 0.8%, about 1%, about 1.5%, about 1.8%, about 2%, about 2.2%, approximately 2.5%, approximately 2.8%, or approximately 3% (p / v). In certain embodiments, the tonicity agent is mannitol. In some of these embodiments, the carrier includes a gel-forming agent (e.g., gelatin gum). In some embodiments, the tonicity agent is mannitol. In some of these embodiments, the carrier includes a viscosity enhancing agent (e.g., water soluble cellulose derivatives (e.g., hypromellose), polyvinyl alcohol, polyvinyl pyrrolidone, chondroitin sulfate, hyaluronic acid, or soluble starches). In some embodiments, the formulation may additionally include a preservative (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate, or phenylmercuric acetate, peroxides), or a combination of two or more of the previous conservatives. In fifteen certain modalities, the preservative is benzalkonium chloride. As will be appreciated by the person skilled in the art, preservatives can be present in concentrations from about 0.001% to about 0.7% (w / v). In particular embodiments, the preservative (s) may be present in a concentration of about 0.001% to about 0.5% (w / v); from about 0.001% to about 0.05% (w / v), from about 0.001% to about 0.02% (w / v), from about 0.001% to about 0.015% (w / v), from about 0.001% to about 0.005% (w / v), from about 0.01% to about 0.02%, from about 0.002% to about 0.01%, from about 0.015% to about 0.05%, less than about < 0.5%, from about 0.005% to about 0.01%, from about 0.001% to about 0.15%, from about 0.002% to about 0.004%, from about 0.001% to about 0.002%. In some embodiments the concentration of the preservative may be, for example, from about 0.001%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.05%, about 0.1%, about 0.2%, about 0.5%, or approximately 0.7% (p / v).

Typical concentrations (w / v) for various commonly used preservatives are listed in Table 1 below.

Table 1 In certain embodiments, the formulation may additionally include a surfactant, or combinations of two or more surfactants. In particular embodiments, the formulation is substantially free of surfactant. As used herein, the term "substantially free" is intended to refer to the levels of a particular component that are undetectable using routine detection methods and protocols known to those skilled in the art. For example, high performance liquid chromatography (HPLC) (including chiral HPLC, chiral HPLC / MS, LC / MS / MS etc.), thin layer chromatography, mass spectrometry, polarimetric measurements, chromatography gas-mass spectrometry, or others. In particular embodiments, the formulation may further include a chelating agent (e.g., disodium edeteate (EDTA) (e.g., disodium edeteate). (dihydrate), etc.) citrates, etc.). In some embodiments, a combination of chelating agents may be present. As will be appreciated by those skilled in the art, chelating agents can be used to prevent degradation of the components of the formulation and thereby increase the shelf life of the ocular formulations. As will be appreciated by the person skilled in the art, the use of EDTA in combination with the gellan gum formulation can be contraindicated since EDTA can cause gel formation before administration of the gelan gum formulation. Typical concentrations for chelating agents are from about 0.005% up to 0.1% (w / v). For example, from about 0.005% to about 0.-09%, from about 0.005% to about 0.08%, from about 0.005% to about 07%, from about 0.005%, to about 0.06%, from about 0.005% to about 0.05 %, from about 0.005 to about 0.04%, from about 0.005% to about 0.03%, from about 0.01% to about 0.1%, from about 0.01% to about 0.09%, from about 0.01% to about 0.08%, of about 0.01% to about 0.07%, from about 0.01% to about 0.06%, from about 0.01% to about 0.05%, from about 0.01% to about 0.04%, etc. In certain embodiments, the concentration of the chelating agent or agents is about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or approximately 0.1%. In particular modalities, the chelating agent is 19 disodium edeteate. In certain embodiments, the chelating agent is disodium edeteate (dihydrate). In some of these embodiments, the disodium edeteate dihydrate is present at a concentration of approximately 0.01% (w / v). In some embodiments, the formulation may additionally include one or more buffering agents (e.g., one or more phosphate buffers (e.g., sodium phosphate buffers (e.g., sodium phosphate, sodium phosphate, sodium monobasic phosphate, etc.) , citrate buffers, maleate buffers, borate buffers, etc.) As will be appreciated by the person skilled in the art, one or more buffers must be selected in combination with the other components of a given formulation to achieve an adequate pH for use in the eyes (for example, pH of about 4.5 to about 8.) In certain embodiments, the buffering agent is a phosphate buffer or a combination of two or more phosphate buffers.In certain embodiments, the buffering agents are sodium dibasic phosphate and monobasic sodium phosphate Typical concentrations for the buffering agent (s) eg The phosphate buffer (s) can be from about 0.005 molar to 0.1 molar. In some modalities, the agent (s) buffers may be at a concentration of about 0.01 to about 0.1, about 0.01 to about 0.08, about 0.01 to about 0.05, about 0.01 to about 0.04, about 0.02 to about 0.1, about 0.02 to about 0.08, about 0.02 to about 0.06, from about 0.02 to about 0.05, from about 0.02 to about 0.04 molar, etc. In particular modalities, there are two buffering agents. Exemplary buffering agents include a combination of sodium dibasic phosphate (e.g., sodium dibasic phosphate-H20) and sodium monobasic phosphate (e.g., anhydrous sodium monobasic phosphate). In some embodiments, the concentration of the buffering agent (s) is about 0.005 molar, about 0.01 molar, about 0.02 molar, about 0.03 molar, about 0.04 molar, about 0.05 molar, about 0.06 molar, about 0.07 molar, or about 0.1 molar . A further aspect of the invention includes the use of the formulations as described herein in the manufacture of a medicament. Particularly, the manufacture of a drug for use in the treatment and / or prevention of conditions as described herein. In addition, the formulations, variously described herein, are also intended for use in the manufacture of a medicament for use in the treatment and / or prevention of conditions and, in accordance with the methods described herein, not to be indicated otherwise.

Methods of Preparation The pharmaceutical formulations described herein can be produced and evaluated as described in detail in the examples, particularly Examples 1, 3, 4 and 6 and in general as described below and as known to those of experience in the matter. In addition, the person skilled in the art, based on the teachings provided herein and the particular formulation to be prepared, will also be able to modify the preparation methods described herein and known in the art, without undue experimentation. In general, formulations including mecamylamine, or a pharmaceutically acceptable salt thereof, and the aqueous salt carrier can be routinely prepared by dissolving (eg, sequentially (in any order) or simultaneously) sufficient amounts of mecamylamine (or a salt pharmaceutically acceptable thereof) and salt (eg, NaCl, where present) in a sufficient volume of deionized water (DI) to achieve the desired concentration of mecamylamine and salt. The ranges for these components have been described in detail elsewhere in the present specification. The solution can be aided by stirring, mixing, heating, etc., including combinations of two or more of the foregoing. Routine methods can be used to adjust the pH of the solution, if necessary, to be suitable for topical administration to the eye. After the mecamylamine solution is prepared, it is generally advisable to filter the solution to remove any particulates before administration. The above protocol must be undertaken in sterile conditions and in accordance with the standards of Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) and, when intended for administration. to humans, it must also conform to the regulatory guidelines, as will be appreciated by the person skilled in the art. The analysis, including the confirmation of the concentration of the mecamylamine present in the saline solution, can be carried out by known techniques and available to the expert. For example, but not limited to, LC / MS / MS (e.g., as described in detail in Example 6), mass spectrometry (e.g., as described in detail in Example 6), etc. The person skilled in the art will be able to further modify these techniques and other routine techniques based on the teaching provided herein and the information available in the field, thereby optimizing detection for the particular detection technique selected and the equipment used. Additional components as described herein may be added (sequentially (in any order) or concurrently with mecamylamine (or pharmaceutically acceptable salts thereof) and salt (where present), where the formulation includes a forming polymer As described herein, the formulation can be prepared as described in detail in Example 4, with one skilled in the art who is also capable of modifying the preparation according to methods known in the art, without experimentation. In the light of the teachings herein, formulations including the gel-forming polymer can also be analyzed as described above for aqueous mecamylamine salt solutions (or a pharmaceutically acceptable salt thereof). same), with particular reference to Example 6. In addition, as described above for aqueous salt solutions of mecamylamine or other solutions of mecamylamine (for example, the polymer-free solution formulation with water as the carrier, the solution with the viscosity-increasing agent (for example, hypromellose, etc.), etc.), the protocols for the preparation of the formulations must be undertaken under sterile conditions and in accordance with the standards of GMP and GLP and, when intended for Administration to humans must also conform to the regulatory guidelines, as will be appreciated by the expert in the art. In general, the pharmaceutical formulations of mecamylamine (or a pharmaceutically acceptable salt thereof) and a gel-forming polymer (where the final formulation is either a gel prior to topical ocular administration or form a gel in itself after topical ocular administration) can be produced as described in Example 5 and, more generally, by dissolving a particular amount of the mecamylamine (or the pharmaceutically acceptable salt thereof) in a given amount of water and then dispersing the gel-forming polymer in the solution containing mecamylamine. The amounts of water, of mecamylamine (or the pharmaceutically acceptable salt thereof) and the gel-forming polymer are dictated by the final concentration of the gel-forming polymer and mecamylamine for the particular formulation being prepared. In general, after the addition of the gel-forming polymer the solution will be mixed (for example, by filtration, whirling, stirring, heating or other routine methods, including combinations of two or more of the above) for a sufficient time to Disperse and perfectly dissolve the gel forming polymer within the solution containing the mecamylamine. For example, mixing can proceed for about 10 to about 60 minutes, about 15 to about 60 minutes, about 15 to about 45 minutes, about 15 to about 40 minutes, about 15 to about 30 minutes, about 15 to about 25 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 60 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes minutes, approximately 40 minutes, approximately 50 minutes, approximately 60 minutes. The perfect mixing of the components can be determined by visual inspection, light scattering, etc., as is known to the person skilled in the art. Additional components, as described herein, may be added to the solution containing mecamylamine prior to, concurrent with, or after the addition of the gel-forming polymer. Similarly, the additional components can be alternatively added to the water before, concurrently with or after the addition of the mecamylamine (or a pharmaceutically acceptable salt thereof). In certain embodiments, the additional components are added to the water before or concurrently with the addition of mecamylamine. After the components have been perfectly dissolved (optionally including any additional components as described herein), the resulting solution containing the mecamylamine (or a pharmaceutically acceptable salt thereof), the gel-forming polymer, water and optionally Additional components, can be balanced at room temperature. Not all mecamylamine formulations will require balance. The solution should be left to equilibrate for at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 16 hours, at least about 18 hours, at least about 24 hours, about 8 to about 24 hours, about 10 to about 24 hours, about 10 to about 18 hours, about 12 to about 18 hours, about 8 hours, about 10 hours, about 12 hours , for approximately 14 hours, for approximately 16 hours, for approximately 18 hours, for approximately 20 hours, or for approximately 24 hours. In certain modalities, the solution is balanced for approximately 16 hours. In other embodiments, the solution is allowed to equilibrate for at least about 16 hours. In other additional embodiments, the solution is to equilibrate for about 16 to about 24 hours. The solutions and mixtures obtained as described herein can also be filtered to remove the particulate materials. Filtration should be undertaken preferably under sterile conditions. Routine methods known to those skilled in the art can be used to filter the solution (for example, vacuum, gravity, etc.) and filters of appropriate size, based on the viscosity of the solution, must be chosen ( for example, but not limited to, the use of 0.2 micrometer membrane filters is typical).

Particular methods for preparing the topical ocular formulation that forms a gel in itself after administration to the eye are also described, for example in U.S. Patent Nos. 6,174,524 and 4,861,760, which are incorporated by reference herein. In its whole.

Use of the Formulations Administration As previously noted, in one aspect the methods of treatment and / or prevention of the conditions described herein are provided using the pharmaceutical formulations as described herein. Unless clearly indicated otherwise by the context, the formulations described herein may be used without limitation in the methods described herein. The methods can be practiced as a therapeutic procedure towards the treatment and / or prevention of the conditions described herein. Thus, in certain embodiments, the pharmaceutical formulations can be used to treat and / or prevent the conditions described herein in individuals in need thereof, including humans. As described herein, the methods generally comprise administering topically to one or both eyes of an individual, an amount of a formulation, as detailed herein, effective in treating and / or preventing the condition. In particular embodiments, the methods include a) applying topically to one or both eyes of an individual in need thereof, a formulation comprising mecamylamine or a pharmaceutically acceptable salt thereof, and a carrier suitable for topical administration to the eye, wherein the mecamylamine or the pharmaceutically acceptable salt thereof is present in the formulation of an amount sufficient to deliver a therapeutically effective amount of the mecamylamine to one or more of the posterior tissues of the eye for the treatment or prevention of conditions mediated by retinal neovascularization, choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues of the eye. In some modalities, the condition is a proliferative retinopathy or condition associated with it. In some embodiments, the methods include a) applying topically to one or both eyes of an individual in need thereof, a formulation comprising mecamylamine, or a pharmaceutically acceptable salt thereof, and a carrier suitable for topical administration to the eye , where the mecamylamine or the pharmaceutically salt acceptable thereof is present in the formulation in an amount sufficient to deliver a therapeutically effective amount of the mecamylamine to one or more of the above tissues or fluids of the eye for the treatment or prevention of conditions mediated by neovascularizationAbnormal angiogenesis, vascular permeability, or combinations thereof, of the anterior tissues of the eye. In some modalities, the condition involves abnormal angiogenesis, affecting the anterior tissues of the eye or the condition associated with them. In certain embodiments, when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in choroidal and retinal tissue, measured in units of ng / g, to the concentration of mecamylamine in plasma measured in units of ng / ml ([ng / g of mecamylamine in choroidal + retinal tissue]: [ng / ml of plasma]) is at least about 40: 1. In some embodiments, the ratio is at least about 20: 1, at least about 25: 1, at least about 30: 1, or at least about 35: 1. In some embodiments, the ratio of mecamylamine concentration in the retinal and choroidal tissue (ng / g): concentration of mecamylamine in plasma (ng / ml) when administered topically to the eye of a rabbit is at least about 20: 1 , at least approximately 25: 1, at less about 30: 1; at least about 35: 1 at least about 45: 1; at least about 50: 1, at least about 60: 1, at least about 70: 1, at least about 80: 1, at least about 100: 1, at least about 150: 1, at least about 200: 1, less about 300: 1, at least about 350: 1, at least about 375: 1, at least about 400: 1, at least about 425: 1, at least about 450: 1, at least about 475: 1, at least about 500: 1, at least about 550: 1, at least about 600: 1, at least about 650: 1, at least about 700: 1, at least about 750: 1, at least about 800: 1, at least about 850: 1, at least about 900: 1, at least about 950: 1, at least about 1000: 1, at least about 1025: 1, at least about 1050: 1, at least about 1100: 1, at least about 1200 : 1, at least approximately 1300: 1, at least approximately 1500: 1, at about 1700: 1, at least about 2000: 1 or at least 2500: 1. In some embodiments, the ratio is from about 300: 1 to about 2500: 1, from about 300: 1 to about 2000: 1, from about 300: 1 to about 1500: 1, of about 300: 1; about 1000: 1, from about 300: 1 to about 800: 1, from about 350: 1 to about 2500: 1, from about 350: 1 to about 2000: 1, from about 350: 1 to about 1500: 1, about 350: 1 to about 1000: 1, from about 350: 1 to about 800: 1, from about 400: 1 to about 2500: 1, from about 400: 1 to about 2000: 1, from about 400: 1 to about 1500: 1, from about 400: 1 to about 1000: 1, from about 400: 1 to about 800: 1, from about 450: 1 to about 2500: 1, from about 450: 1 to about 2000: 1, of about 450: 1 to about 1500: 1, from about 450: 1 to about 1000: 1, from about 450: 1 to about 800: 1, from about 500: 1 to about 2500: 1, from about 500: 1 to about and 2000: 1, from about 500: 1 to about 1500: 1, from about 500: 1 to about 1000: 1, or from about 500: 1 to about 800: 1. In particular modalities, the ratio of the concentration of mecamylamine in the retinal and choroidal tissue (ng / g): concentration of mecamylamine in plasma (ng / mL) when administered topically to the eye of a rabbit, it is at least about 20: 1, at least about 25: 1, at least about 30: 1, at least about 35: 1, at least about 40: 1, at least about 50 : 1, at least about 80: 1, at least about 100: 1, at least about 300: 1, at least about 40: 1 to about 1000: 1, from about 40: 1 to about 1500: 1, at least about 40: 1 to about 2000: 1, at least about 40: 1 to about 2500: 1, at least about 50: 1 to about 250: 1, at least about 80: 1 to about 1000: 1, at least about 80: 1 to about 2000, at least about 100: 1 to about 1000: 1, at least about 100: 1 to about 2000: 1, at least about 200: 1 to about 1000: 1, or at least about 200: 1 to about 2000: 1. In particular embodiments, the ratio is at least about 300: 1, at least about 350: 1, at least about 450: 1, at least about 500: 1, at least about 1200: 1, from about 300: 1 to about 1000 : 1, from about 300: 1 to about 2000: 1, from about 350: 1 to about 1000: 1, from about 350: 1 to about 2000: 1, from about 450: 1 to about 1000: 1, about 450: 1 to about 1100: 1, from about 450: 1 to about 1200: 1, from about 450 to about 2000: 1, from about 500: 1 to about 1000: 1, from about 500: 1 to about 1200: 1, or approximately 500: 1 to approximately 2000: 1. In some embodiments, the ratio of the concentration of mecamylamine present in corneal tissue when administered topically to the eye of a rabbit, measured in units of ng / g, at the plasma concentration of mechalamine measured in units of ng / mL ( [ng / g mecamylamine in corneal tissue]: [ng / ml plasma]) is at least about 1000: 1. In some embodiments, the ratio of the concentrations is at least about 100: 1, at least about 200: 1, at least about 300: 1, at least about 400: 1, at least about 500: 1 at least, at least about 600: 1, at least about 700: 1, about 800: 1, at least about 850: 1, at least about 900: 1, at least about 950: 1, at least about 1000: 1, at least about 1025: 1 , at least about 1050: 1, at least about 1100: 1, at least about 1200: 1, at least about 1300: 1, at least about 1500: 1, at least about 1700: 1, at least approximately 2000: 1 or at least 2500: 1. In some embodiments, the ratio is at least about 800: 1 to about 4000: 1, from at least about 800: 1 to about 3000: 1, from at least about 800: 1 to about 2500: 1, of at least about 900: 1 to approximately 4000: 1, from at least approximately 900: 1 to approximately 3000: 1, from at least approximately 1000: 1 to approximately 4000: 1, from at least approximately 1000: 1 to approximately 3000: 1, from less about 1000: 1 to about 2500: 1, from at least about 1000: 1 to about 2000: 1. In certain embodiments, the ratio is at least about 850: 1, at least about 900: 1, at least about 1000: 1 at least about 1200: 1. In some embodiments, the ratio of the concentration of mecamylamine present in the aqueous humor when administered topically to the eye of a rabbit, measured in units of ng / ml, at the concentration of mecamylamine in plasma measured in units of ng / ml ([ ng / ml of mecamylamine in aqueous humor]: [ng / ml in plasma]) is at least about 40: 1, at least about 45: 1, at least about 50: 1, at least about 55: 1, at least about 60: 1, at least about 70: 1, at least about 80: 1, at least about 100: 1, at less about 150: 1, at least about 200: 1, or at least about 250: 1. In some embodiments, the ratio is from about 40: 1 to about 2500: 1, from about 40: 1 to about 4000: 1, at least about 40: 1 to about 2500: 1, from about 40: 1 to about 1500: 1, from about 40: 1 to about 1000: 1, from about 40: 1 to about 800: 1, from about 40: 1 to about 500: 1, about 40: 1 to about 300: 1, of about 40: 1 to about 400: 1, or from about 40: 1 to about 100: 1. In particular embodiments, the ratio is at least about 50: 1. In some embodiments, the individual is a mammal, including but not limited to bovine, horse, feline, rabbit, canine, rodent or primate. In some particular embodiments, the mammal is a primate. In certain modalities, the primate is a human. In certain modalities, the individual is human, including adults, children and premature infants. In some modalities, the individual is not experiencing ocular growth. In some modalities, the individual is an adult. In certain modalities the individual has been identified as having one or more of the conditions described in the present. The identification of conditions as described herein by the skilled practitioner is routine in the art and may also be suspected by the individual due to loss of vision or visual acuity (e.g., reduction in the field of vision, blurred vision). , etc.). In some embodiments, the individual has been identified as susceptible to one or more of the conditions as described herein. The susceptibility of an individual may be based on one or more of a number of risk factors and / or diagnostic procedures appreciated by the person skilled in the art, including, but not limited to genetic profiling, family history, medical history (for example, the appearance of related conditions (for example, diagnosis or susceptibility to a "non-neovascular" / "dry" form of macular degeneration, etc.), lifestyle or habits (for example, as previously described, cigarette smoke is one of the main risk factors for retinal neovascularization due to macular degeneration (eg, age-related macular degeneration, etc.). Certain patients are at risk of retinopathy. Individuals who are older, particularly those who are smokers, are more likely to have macular degeneration related to age, and are at risk of associated proliferative retinopathy. Individuals with diabetes mellitus may develop proliferative retinopathy. Premature infants are also at risk and are routinely selected for the development of premature retinopathy. Individuals with neo-vascular forms of macular degeneration are particularly at risk for the development of neovascular forms of macular degeneration. Conditions that can be treated and / or prevented using the formulations and methods described herein include conditions that affect the posterior tissues of the eye, as well as conditions affecting the anterior tissues of the eye or ocular fluids. These conditions are described in more detail later. In some cases, the conditions may affect one or more anterior tissues and more posterior tissues, for example, as in the case of an ocular tumor. In general, conditions are mediated by neovascularization (also commonly referred to as angiogenesis) and, in particular, abnormal angiogenesis. Suitable conditions for treatment and / or prevention using the formulations and methods described herein include conditions mediated by retinal and / or choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations of same, from posterior tissues of the o, including, but not limited to, proliferative retinopathies. In particular, proliferative retinopathies that are mediated by abnormal or increased angiogenesis and / or neovascularization of the posterior tissues of the eye, namely, the retina and the choroid. Abnormal or increased angiogenesis and / or neovascularization are easily recognized by the skilled physician and can be identified and diagnosed using routine methods known in the art. (See for example, Ophthalmology: Clinical Signs and Differential Diagnosis, Jack J. Kanski and K.K. Nischall, Elsevier 1998, which is incorporated by reference herein in its entirety). For example, intravenous administration of fluoroscein and subsequent illumination with ultraviolet light is a means to identify the presence of angiogenesis and / or neovascularization since the blood vessels resulting from angiogenesis and / or neovasculaption are characterized by a propensity to leak blood or fluid from the vessels. This leak can be visualized using fluorescein. The new blood vessels resulting from angiogenesis and / or abnormal or increased neovascularization are also characterized by a higher degree of branching than the typical blood vessels seen in healthy individuals (eg, individuals who do not suffer from vision loss). and / or impairment of visual acuity), tend to be smaller in diameter than the blood vessels usually found in the particular tissue type and also tend to appear, or appear in greater numbers / density than expected for the type or location of particular tissue. Proliferative proliferative retinopathies mediated by angiogenesis include, but are not limited to, neovascularization due to macular degeneration (e.g., wet forms (e.g., neovascular forms), age-related maculopathy, age-related macular degeneration ("AMD") ( for example, wet forms), diabetic retinopathy, retinopathy of prematurity (also commonly referred to as retrolental fibroplasia), retinopathy due to sickle cell disease, etc. [See, for example, Ophthalmology: Clinical Signs and Differential Diagnosis, Jack J. Kanski and KK Nischall, Elsevier 1998, which is incorporated by reference in the present in its entirety). The "dry" or "non-neovascular" forms of macular degeneration are often an early indication that an individual is susceptible to, or may develop a "neovascular form" or "wet form" of macular degeneration. (See Bressler et al, (1990) Arch. Ophthalmol 108 (10): 1442-7"Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration.

Photocoagulation Study Group "). Thus, treatment to prevent neovascularization can be guaranteed for these individuals (eg, preventive or prophylactic treatment) .It is possible that such early treatment, even where prior to the identification of neovascularization, may be Prevent the occurrence of detectable macular degeneration due to neovascularization Thus, it is intended that the "dry" or "non-neovascular" form of macular degeneration is also a condition intended to be treated using the methods and formulations described herein In particular modalities, the condition is diabetic retinopathy, retinopathy of prematurity, retinal neovascularization due to macular degeneration, or retinopathy due to sickle cell disease.In certain modalities, the condition is diabetic retinopathy.In other modalities, the condition is retinopathy of prematurity In other modalities, the condi This is retinal neovascularization due to macular degeneration. In certain modalities, the condition is retinopathy due to sickle cell disease. In particular modalities, where the condition is retinal neovascularization due to macular degeneration, the condition may be age-related macular degeneration (AMD). In certain modalities, AMD may be the "wet" form of AMD (eg, neovascular form). In other modalities, AMD may be the "dry" form of AMD (eg, the non-neovascular form). The characterization of the various forms of AMD is well studied and is known to the person skilled in the art. In some modalities, the condition that is to be treated and / or prevented may be associated with macular edema. Conditions associated with neovascularization, abnormal angiogenesis, vascular permeability (or combinations thereof) of the anterior tissues of the eye include corneal neovascularization, terigion, post-transplant neovascularization, rubeosis iridis, neovascular glaucoma, ocular tumors, etc. In some modalities, the condition is corneal neovascularization. In other cases, the condition is terigion. In particular modalities, the condition is rubeosis iridis. In some modalities, the anterior tissue of the eye affected by neovascularization, abnormal angiogenesis, vascular permeability, or a combination thereof, is the cornea, lens, iris, sclera, or trabecular meshwork. In some modalities, the affected tissue is the cornea. In others, the lens. In particular modalities, the lens, cornea or iris is affected. The terms "pharmaceutically acceptable amount" or "therapeutically effective amount" and terms Related, as used herein, refers to an amount of a formulation sufficient to treat a specified condition (eg, disease, disorder, etc.) or one or more of its symptoms and / or to prevent the occurrence of the condition. In reference to ocular conditions mediated by neovascularization and / or abnormal angiogenesis (eg, proliferative retinopathies, etc.), a pharmaceutically acceptable or therapeutically effective amount comprises an amount sufficient among other things, to cause a reduction in the presence of newly formed blood vessels or a decrease in the rate of angiogenesis and / or neovascularization, and / or to reduce fluid leakage and / or bleeding from these vessels. In certain embodiments, the pharmaceutically effective amount is sufficient to prevent the condition, as it is administered to an individual prophylactically. For example, administration of the formulations described herein to individuals with non-neovascular macular degeneration, could prevent the onset of the neovascular form of macular degeneration. As another example, the formulation could be administered to an individual who has developed a terigion that is not yet interfering with the vision, to prevent further growth of the terigion, as a prophylactic measure to prevent its interference with vision: With respect to the conditions affecting the posterior tissues of the eye described herein, for a treatment to be therapeutically effective, a sufficient amount of mecamylamine should be distributed to the posterior region of the eye. For example, the retina and / or the choroid, which are the tissues in the posterior region of the eye in which the conditions described herein are first manifested. Subsequently, such vessels may extend into the vitreous compartment. In certain embodiments, a therapeutically effective amount of mecamylamine is distributed to the retina and choroid. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the retina. In particular embodiments, a therapeutically effective amount of mecamylamine is distributed to the choroid. Where the sclera is affected, the effective amount of mecamylamine must be distributed to the appropriate portion of the sclera (for example, either the anterior portion, the posterior portion, or both). In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the sclera. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the posterior portion of the sclera. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the anterior portion and posterior of the sclera. With respect to the conditions affecting the anterior tissues of the eye described herein, for a treatment to be therapeutically effective, a sufficient amount of mecamylamine must be distributed to the anterior region of the eye. For example, the cornea, the lens, the trabecular network, or the iris, which are the tissues in the anterior region of the eye in which the conditions described in the present are manifested. Where the sclera is affected, the effective amount of mecamylamine must be distributed to the appropriate portion of the sclera (for example, either the anterior portion, the posterior portion, or both). In certain embodiments, a therapeutically effective amount of mecamylamine is distributed to the cornea and the lens. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the cornea. In particular embodiments, a therapeutically effective amount of mecamylamine is distributed to the lens. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the sclera. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the anterior portion of the sclera. In some embodiments, a therapeutically effective amount of mecamylamine is distributed to the anterior and posterior portions of the sclera. The formulations and methods described herein may be used alone or in conjunction with (e.g., prior to, concurrent with, or after) other modes of treatment (e.g., adjunctive therapy with additional agents used to treat or prevent the condition being treated and / or administration of an additional treatment modality, or combinations thereof). For example, in combination with one or more additional pharmaceutical agents (not mecamylamine) (also referred to as therapeutic agents) as described herein and known to those of skill in the art and / or currently available treatment modalities, including photocoagulation of laser term or photodynamic therapy. As used herein, the term "additional treatment modality" refers to the treatment of the conditions described herein without the use of a pharmaceutical agent (e.g., thermal laser photocoagulation, photodynamic therapy, etc.). . Where combinations of the pharmaceutical agent (s) and / or additional treatment modalities are used, these can be independently administered prior to, concurrent with, or after administration of the topical ocular mecamylamine formulation.

As will be appreciated by the person skilled in the art, for particular conditions, one or more different pharmaceutical agents and / or one or several additional treatment modalities may be indicated. For example, in conjunction with the treatment described herein, the treatment of rubeosis indis can also include the treatment of associated glaucoma (e.g., the use of pharmaceutical agents (e.g., dichlorphenamide, carbocol, demacarium bromide, etc.). When the condition is neovascular glaucoma (often associated with diabetic retinopathy), an additional pharmaceutical agent may be the agents to decrease infraocular pressure (eg, spheroids), additional treatment modalities may include laser photocoagulation. Where the tepgion is the condition, one or more pharmaceutical agents (for example, artificial tears, anti-inflammatory agents, etc.) can be guaranteed and, additional treatment modalities possible, such as, for example, surgical or laser ablation. In some embodiments, the pharmaceutical agent (s) may be an antagonist of nAChR, anti-inflammatory agent (e.g., NSAID, etc.), VEGF antagonist, VEGF Debugger (e.g., VEGF TRAP, etc.), inhibitor of tyrosine-cmasa, prostaglandin receptor antagonist, the agent used in the treatment of glaucoma, or an agent to decrease infraocular pressure, as previously described. Combinations of two or more of the above may also be administered, as may be determined by the skilled person in view of the teaching provided herein. In certain embodiments, the pharmaceutical agent (s) may be, for example, not limited to, one or more nAChR antagonists (eg, such as those described above with respect to the mecamylamine formulations). In some embodiments, the pharmaceutical agent (s) may be an anti-inflammatory agent (e.g., NSAID). In certain embodiments, the pharmaceutical agent (s) may be a tyrosine kinase inhibitor. In certain embodiments, the pharmaceutical agent (s) may be a prostaglandin receptor antagonist. In some embodiments, the pharmaceutical agent (s) may be an agent used in the treatment of glaucoma. In some embodiments, the pharmaceutical agent (s) may be an agent to decrease infraocular pressure. In some embodiments, the pharmaceutical agent (s) may include one or more pharmaceutical agents that are effective in treating the conditions described herein. For example, VEGF antagonists (eg, anti-VEGF (vascular endothelial growth factor) antibodies or fragments thereof, VEGF aptamers (eg, pegaptanib sodium). In certain embodiments, the anti-VEGF antibodies are monoclonal antibodies. Exemplary anti-VEGF antibodies include, but are not limited to, bevacizumab and ranibizumab (trade names AVASTIN® and LUCENTIS®, respectively, under development by Genentech, Inc., South San Francisco, CA). Pharmaceutical agents can also include the Vascular Endothelial Growth Factor (VEGF) receptor antagonist pegaptanib (an aptamer) (MACUGEN®; Pfizer). In some embodiments, the pharmaceutical agent is a VEGF scavenger (e.g., VEGF TRAP, etc.). In some variations, the pharmaceutical agent is a VEGF scavenger, VEGF antagonist, or tyrosine kinase inhibitor. The formulations described herein may be administered in conjunction with one or more of the pharmaceutical agents as described herein and as are known in the art, one or more additional agents to further reduce the occurrence and / or severity of the effects side effects (including adverse reactions) and / or the clinical manifestations thereof (eg, agents that inhibit mydriasis), or in conjunction with (eg, prior to, concurrent with, or after) laser photocoagulation thermal or photodynamic therapy. However, as noted previously, based on the data In the current clinical trials and in the testing of non-human animals, it seems that the side effects are limited in occurrence and severity and thus many individuals will not need the administration of the additional pharmaceutical reagents to reduce and / or prevent these effects. Formulations as described herein may be administered prior to, concurrent with, or following the administration of one or more pharmaceutical agents described herein. The formulations thereof described herein may be administered in conjunction with (eg, prior to, concurrent with, or after) agents to alleviate symptoms associated with either the condition or the treatment regimen. For example, in certain variations, thermal laser photocoagulation or photodynamic therapy can be administered to the individual prior to the administration of mecamylamine. In some variations, thermal laser photocoagulation or photodynamic therapy can be administered to the individual after administration of mecamylamine. In particular variations, thermal laser photocoagulation or photodynamic therapy can be administered to the individual throughout the course of mecamylamine treatment. Where the pharmaceutical agents are administered in conjunction with the mecamylamine formulations described herein, additional agents may be administered parenterally or orally. For example, intravenously, via injection, orally, topically, via biodegradable implants, etc. Given the difficulty of identifying and formulating drugs for topical ocular distribution, many, if not most, pharmaceutical agents will not be formulated for topical ocular distribution, but rather will be administered according to the protocols established for the treatment. private agent. The optimal combination of one or more of surgery and / or other additional treatment modalities and / or additional pharmaceutical agents in conjunction with the administration of the formulations described herein, can be determined by a physician attending based on the individual and taking into consideration the diverse factors that affect the particular individual, including those described herein.

Formulation and Dosage As noted previously, pharmaceutical formulations as described herein may be topically administered to one or both eyes of individuals in need thereof for the treatment or prevention of conditions as described herein as a whole. with the methods of use described in the I presented . The formulations described herein will generally be used in an effective amount to achieve the intended result, for example in an amount effective to treat or prevent the particular condition being treated. The formulations can be administered therapeutically to achieve therapeutic benefit. Therapeutic benefit means the eradication or improvement of the underlying condition that is treated, and / or the eradication or improvement of one or more of the symptoms associated with the underlying condition, such that the patient reports an improvement in well-being or condition, not However, the patient may still be affected with the underlying condition. The therapeutic benefit also includes the impediment or delay of the progression of the condition, regardless of whether the improvement is made or not. In some embodiments, where the condition being treated is a proliferative retinopathy, an effective amount is an amount sufficient to reduce the proportion of angiogenesis and / or neovascularization of the retina and / or the choroid (eg, as measured by acuity). visual (for example, as with a Snellen diagram), retinal edema (for example, as with Optical Coherence Tomography) or vascular permeability (for example, as with fluorescein angiography) before and / or after treatment) . In In certain embodiments, an effective amount is an effective amount sufficient to decrease existing neovascularization (eg, where the results of one or more of the clinical tests listed above after treatment is reduced in comparison to the same clinical test (or combination thereof). tests) before treatment). As will be appreciated by the person skilled in the art, similar, and additional diagnostic methods can be used to monitor the progress of the treatment for conditions affecting the anterior tissues of the eye. The amount of the formulations administered for the purpose of administering an effective amount of mecamylamine, or a pharmaceutically acceptable salt thereof, will depend on a variety of factors, including, for example, the particular condition being treated, the frequency of administration , the particular formulation that is administered, the severity of the condition in question and the age, weight and general health of the individual, the adverse effects experienced by the individual in question, etc. The determination of an effective dose is within the capabilities of those skilled in the art in view of the teachings provided herein. In certain embodiments, the unit dose of mecamylamine administered at a particular time will be determined by the assessment of visual acuity (by Í54 example, as measured by clinical tests (for example, as with a Snellen diagram), retinal edema (for example, as with Optical Coherence Tomography) or vascular permeability (for example, as with fluorescein angiography) ) before and / or after treatment). In certain embodiments, an effective amount is an amount sufficient to decrease existing neovascularization (e.g., where the results of one or more of the aforementioned clinical tests performed after treatment are reduced compared to the results of the same one or more clinical tests done before the treatment). In certain embodiments, the unit dose of the mecamylamine administered at a particular time will be from about 0.01 mg / eye to about 15 mg / eye. For example, from about 0.01 mg / eye to about 7.5 mg / eye. In some embodiments, the dose administered will be from about 0.01 mg / eye to about 10 mg / eye, from about 0.01 mg / eye to about 5 mg / eye, from about 0.01 mg / eye to about 3 mg / eye, of about 0.01 mg / eye to about 1 mg / eye, from about 0.01 mg / eye to about 2 mg / eye, 0.03 mg / eye to about 10 mg / eye, from about 0.05 mg / eye to about 5 mg / eye, from about 0.05 mg / eye to about 3 mg / eye, from about 0.05 mg / eye to about 1 mg / eye, from about 0.05 mg / eye to about 2 mg / eye, 0.1 mg / eye to about 10 mg / eye, from about 0.5 mg / eye to about 5 mg / eye, from about 0.5 mg / eye to about 3 mg / eye, from about 0.5 mg / eye to about 2 mg / eye, from about 0.5 mg / eye to about 1 mg / eye; from about 1 mg / eye to about 10 mg / eye, from about 1 mg / eye to about 7 mg / eye, from about 1 mg / eye to about 5 mg / eye, from about 1 mg / eye to about 3 mg / eye, or from about 1 mg / eye to about 2 mg / eye; about 0.1 mg / eye, about 0.3 mg / eye, about 0.5 mg / eye, about 0.7 mg / eye, about 0.9 mg / eye, about 1 mg / eye, about 1.2 mg / eye, about 1.5 mg / eye, about 1.7 mg / eye, approximately 2 mg / eye, approximately 2.2 mg / eye, approximately 2.5 mg / eye, approximately 2.7 mg / eye, approximately 3 mg / eye, approximately 3.2 mg / eye, approximately 3.5 mg / eye, approximately 3.7 mg / eye eye, approximately 4 mg / eye, approximately 4.5 mg / eye, approximately 5 mg / eye, approximately 5.5 mg / eye, approximately 6 mg / eye, approximately 6.5 mg / eye, approximately 7 mg / eye, about 7.5 mg / eye, about 8 mg / eye, about 8.5 mg / eye, about 9 mg / eye, about 9.5 mg / eye, about 10 mg / eye, about 10.5 mg / eye, about 11 mg / eye, about 12 mg / eye, approximately 13 mg / eye, approximately 14 mg / eye or approximately 15 mg / eye. In certain embodiments, the dose in a particular administration is 0.05 mg / eye to about 1 mg / eye. In particular embodiments, the total daily dose is from about 0.01 mg / eye to about 7.5 mg / eye per day. For example, administration twice daily of doses of about 0.005 mg / eye to about 3.75 mg / eye. In others, for example, administration twice daily of doses of approximately 0.05 mg / eye to approximately 0.5 mg / eye. In some embodiments, the total daily dose is from about 0.1 mg / eye to about 3 mg / eye per day. In other embodiments, the total daily dose is from about 0.1 mg / eye to about 0.7 mg / eye, from about 0.1 mg / eye to about 0.5 mg / eye, or from about 0.1 mg / eye to about 0.3 mg / eye. In certain embodiments, the total daily dose is from about 0.1 mg / eye to about 1 mg / eye. As will be appreciated by the person skilled in the art, the dose administered at a given time and the selection of the The concentration of the mecamylamine, or pharmaceutically acceptable salt thereof, should also take into account the volume of the formulation that can be accommodated with the eye of an individual. For example, the dosage schedule may need to be altered when mecamylamine is administered to premature infants for the treatment of premature retinopathy, such as, in addition to a lower dose that is indicated due to body weight and, probably, health In general, the infant's eye will also accommodate a smaller volume of the formulation. However, such alterations and adjustments must be well within the experience of the attending physician, without undue experimentation in the light of the teachings provided herein. In some embodiments, the volume of the formulation administered per eye may be from about 50 μl to about 1 ml. In certain embodiments, the volume of the formulation administered per eye may be from about 10 μl to about 500 μl. In certain embodiments, the volume of the formulation administered per eye may be from about 10 μl to about 1 ml. For example, from about 10 μl to about 400 μl, from about 10 μl to about 300 μl, from about 10 μl to about 200 μl, of about 10 μl up to about 100 μl, from about 10 μl to about 50 μl, from about 30 μl to about 500 μl, from about 30 μl to about 400 μl, from about 30 μl to about 300 μl, from about 30 μl to about 200 μl, about 30 μl to about 100 μl, from about 30 μl to about 50 μl, from about 50 μl to about 100 μl, from about 50 μl to about 90 μl, from about 50 μl to about 80 μl, from about 50 μl to about 70 μl, from about 50 μl to about 60 μl, from about 60 μl to about 100 μl, from about 70 μl to about 100 μl, from about 80 μl to about 100 μl, from about 90 μl to about 100 μl, about 110 μl, approximately 100 μl, approximately 90 μl, approximately 80 μl, approximately 70 μl, approximately 60 μl, approximately 50 μl, 90 μl to approximately 100 μl, from approximately 90 μl to approximately 200 μl, from -about 90 μl to approximately 300 μl, from approximately 90 μl to approximately 400 μl, from approximately 90 μl to approximately 500 μl, from approximately 90 μl to approximately 600 μl, about 90 μl to about 700 μl, from about 90 μl to about 800 μl, from about 90 μl to about 900 μl, about 1 ml, about 900 μl, about 800 μl, about 700 μl, about 600 μl, about 500 μl, about 400 μl, about 450 μl, about 350 μl, about 300 μl, about 250 μl, about 200 μl, about 100 μl, about 90 μl, about 80 μl, about 70 μl, about 60 μl, or about 50 μl. The dose administered may be higher or lower than the dose ranges described herein, depending on, among other factors, the particular formulation used, the individual's tolerance to adverse side effects, the frequency of administration, and various factors discussed above. The amount and range of doses can be adjusted individually to provide levels of retmal / choroidal mecamylamine tissue that are sufficient to maintain the therapeutic effect, according to the judgment of the prescribing physician. Those skilled in the art will be able to optimize effective local doses without undue experimentation in view of the teachings provided herein.

The dose can also be estimated using animal models in vivo. Multiple doses of the formulations as described herein may also be administered to individuals in need thereof within the course of hours, days, weeks, or months. For example, but not limited to, daily, twice a day, three times a day, four times a day, every third day, once a week, twice a week, etc. In certain embodiments, the formulations are administered daily, twice a day or three times a day. In particular modalities, the formulations are administered twice a day once a day. In some embodiments, the formulations are administered once a day. In others, twice a day.

Kits The kits for ocular topical administration of the formulations described herein are also provided. In certain embodiments the kits may include a dose amount of at least one pharmaceutical formulation as described herein. The kits may further comprise suitable packages and / or instructions for the use of the formulation. The kits may also comprise a means for the distribution of the pharmaceutical formulation of the same, such as an ophthalmic dropper for the administration of gel-forming solutions and solutions in itself as described herein, or another device as described herein and known to those of ordinary skill in the art, particularly to assist in the administration of the formulations when the formulation is in the gel form prior to administration. The kits may include other pharmaceutical agents for use in conjunction with the mecamylamine formulations described herein. In certain embodiments, the pharmaceutical agent (s) may be one or more of other nAChR antagonists. These agents may be provided in a separate form, or mixed with the compounds of the present invention, provided such mixing does not reduce the effectiveness of the pharmaceutical agent or the formulations described herein, and is compatible with topical administration to the eye. . Similarly, kits may include additional agents for adjunctive therapy. For example, agents to reduce the adverse effects of mecamylamine or other agents known to the skilled person as effective in the treatment of the conditions described herein. The kits shall include the appropriate instructions for the preparation and administration of the formulation, the Side effects of the formulation, and any other relevant information. The instructions may be in any suitable format, including, but not limited to, printed material, videotape, computer-readable disk, or optical disc. In yet another aspect of the invention, kits for treating an individual who suffers from or is susceptible to the conditions described herein, are provided comprising a first container that includes a dose amount of a formulation as described herein. , and instructions for use. The container can be any of those known in the art and suitable for the storage and distribution of intravenous formulations. In certain embodiments, the kit further comprises a second container that includes a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for the preparation of the composition to be administered to the individual. The kits may also be provided containing sufficient doses of the formulations as described herein, to provide effective treatment for an individual for a prolonged period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3 , weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.

The kits may also include multiple doses of formulations and instructions for use and packaging in sufficient quantities for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies. The kits may include the formulations as described herein in either a unit dose form or a multiple dose form. The kits may also include multiple units of the unit dose form. In certain embodiments, the formulations described herein are provided in a unit dosage form. In other embodiments, the formulations may be provided in a multiple dose form (eg, a solution container for dispensing drops of the solution, etc.). All patents, patent applications and publications referred to herein are incorporated herein by reference in their entirety.

EXAMPLES The present invention is further described with reference to the following Examples; however, these Examples are not limiting of the scope of the present invention.

Materials Unless stated otherwise, the chemicals and other reagents used throughout the Examples were obtained from commercial suppliers as a reactive grade and used without further purification. Mecamylamine hydrochloride USP (Poli Industria Chimica, Milan, Italy), ketamine, xylazine, GELRITE®, NaCl, NaOH, HCl, DMSO (dimethylsulfoxide), sodium EDTA (ethylenediaminetetraacetate), acetonitrile, formic acid, dextromethorphan, diphenhydramine, methanol. The water used was deionized water (DI).

Example 1: Parenteral Formulation of Mecamylamine Parenteral formulations of mecamylamine hydrochloride were prepared by dissolving 1 g of mecamylamine hydrochloride USP (white powder) and 33.33 ml of sterile 0.9% sodium chloride in a volumetric flask. The mixture was manually stirred at room temperature until the mecamylamine powder was completely dissolved, resulting in a clear solution. The pH of the solution was adjusted to 7.4 using sodium hydroxide and HCl.

Example 2: Ocular Bioavailability After Intravenous Administration This study was designed to model the ocular bioavailability of mecamylamine when administered systemically. The eyes of rabbits are the preferred model for the in vivo modeling of ocular drugs, however, the rabbit is not the subject of choice to model oral bioavailability. However, systemic administration does not emulate mecamylamine orally administered to a reasonable approximation, since mecamylamine has rapid absorption and high oral bioavailability. Therefore, intravenous injection was used to model the ocular bioavailability of systemically administered mecamylamine, in order to determine the deposition of mecamylamine to the plasma, vitreous and posterior tissues (retina / choroid) of the eye from the blood. The study comprised 2 groups (each N = 6, 12 rabbits in total) of male NZW rabbits (New Zealand White) weighing approximately 2.5-3 kg and obtained from Kralek Farms (Turlock, CA). The mecamylamine solution, prepared as described in Example 1, at a dose of 15 mg / kg was distributed via intravenous infusion either as a short infusion (1 hour) or slow infusion (6 hours) in rabbits sedated by ketamine / xylazine, with the slow infusion aimed at modeling the controlled systemic release of mecamylamine. For both groups, samples of vitreous humor (= O.l ml) and plasma were removed at 6 time points: pre-dose, 30 minutes, 1, 2, 4, and 6 hours. At 6 hours, all the animals were sacrificed and the vitreous and retinal tissues were collected. The total amount of mecamylamine administered during each infusion was the same, based on the weight of the individual rabbit. The concentrations of mecamylamine present in the various samples were analyzed as described in Example 6, below. The concentration of mecamylamine in plasma (ng / ml) and the vitreous humor (ng / ml) for the short infusion are shown in Figure 1. The concentration of mecamylamine in plasma (ng / ml) and the vitreous humor (ng / ml). ml) for prolonged infusion are shown in Figure 2. The amount of mecamylamine concentration in the retinal / choroidal tissues after the long infusion is shown in Figure 3, while FIG. 4 A shows a comparison of plasma, vitreal, and retinal / choroidal levels of mecamylamine for prolonged infusion. As is apparent from Figures 1 and 2, the Systemic administration of the same amount of mecamylamine over any period leads to a higher Cmax for mecamylamine in the plasma compared to vitreous tissue although for the prolonged infusion the last point of time shows an increased concentration in the vitreous humor in relation to the concentration plasma Figure 3 shows that mecamylamine, administered systemically, is preferably deposited in the retina / choroid when administered over a prolonged infusion, with the amount of mecamylamine reaching the retina / choroid that is more than 2 times higher for the prolonged infusion than for the short infusion.

Example 3: Preparation of the Topical Ophthalmic Solution Formulation Mecamylamine hydrochloride USP was dissolved in 100 ml of DI water. A weight of 0.9 g of sodium chloride was then added with stirring to make it isotonic to the solution (sodium chloride 0.9% w / v). The solution was then filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Example 4: Preparation of Ophthalmic Formulation for In Situ Topical Gel The mecamylamine hydrochloride USP (2.0 g) was dissolved with stirring in 100 ml of DI water. 0.6 g of GELRITE® powder was then dispersed by stirring in the aqueous solution of mecamylamine. The dispersion was then stirred for 20 minutes using a mechanical stirrer (Vortex). After 20 minutes of stirring the GELRITE® solution was dissolved, and a solution formed. The solution then equilibrated at room temperature for approximately 16 hours. The solution was then packaged under sterile conditions. Unless indicated otherwise, the content of the gel-forming polymer (GELRITE®) was 0.6% (w / v).

Example 5: Ocular Bioavailability After Topical Ocular Administration The objective of this study was to determine the pharmacokinetics of mecamylamine, administered either as an isotonic solution (prepared as in Example 3) or the gel-forming solution in itself (as prepared in Example 4), in the plasma, the vitreous humor and the retina of the eyes when applied topically to the surface of the eye. The study comprised 2 groups (N = 4 / group, 8 rabbits in total) of male NZW rabbits each weighing approximately 2 to 3 kg and obtained from Kralek Farms (Turlock, CA). Mecamylamine hydrochloride was formulated as described in Examples 3 and 4 and 100 μl was administered to each eye either as a gelation solution in itself (group 1) or isotonic solution (group 2) to the cornea of each eye and the lower eyelid is separated from the surface of the eye to make a bag, to ensure that the full dose was retained in the eye (see Table 5 for the design of the Study). For both groups, samples of the vitreous humerus (= Ol ml) were removed at 6 time points (one withdrawal per eye): pre-dose, 30 minutes, 1 (sacrifice), 3, 6, 12, and 24 hours ( sacrifice) . At all points of time, only samples of vitreous fluid in duplicate (each coming from different eyes of different animals) were collected in order to minimize pain and damage to the eyes of rabbits. Blood for plasma (> 0.5 ml) and intra-vitreal fluid (approximately 0.1 ml) were collected at 0, 30, 60 minutes from each animal with sacrifice for the 2 animals / group at 60 minutes. At 3, 6, and 12 hours, the blood was collected for the plasma, (approximately 2 ml) of each remaining animal, and the intravitreal fluid, (approximately 100 μl) (sample duplicated only at each time point) from of 2 additional animals. All the remaining animals were sacrificed at 24 hours with the collected blood and vitreous fluid. Blood was collected inside microcontainers (microtainer) using sodium EDTA as the anti-coagulant. At 60 minutes or at 24 hours, the animals were sacrificed and the vitreous fluid and the retina (including the choroid) were collected. The blood was also collected and centrifuged to separate the plasma. The plasma is separated from the red blood cell button and frozen at -80 ° C individually for each time point. The plasma, the button of red cells, the vitreous fluid (complete vitreous fluid collected after the sacrifice of the rabbits, but divided into two aliquots) and the retina, including the choroid, the samples were frozen in liquid nitrogen. The plasma and the retina .71 (including choroids) were stored at -80 ° C and, when they were shipped for analysis, they were packed with dry ice to prevent the decomposition of the samples. During the collection periods of the vitreous fluid and the collection of the blood, the rabbits were lightly sedated with a mixture of ketamine / xylazine to minimize discomfort and to facilitate the procedures. Plasma and fluid were immediately placed into the labeled Eppendorf® tube and frozen at -80 ° C. The samples were kept at -80 ° C until they were packed with dry ice and shipped for analysis. Table 5: Study Design Example 6: Preparation of the Sample Preparation of the Plasma Sample and Viral Humor A stock of 0.5 mg / ml mecamylamine hydrochloride USP in DMSO was prepared and used as the working standard to produce the calibration standards for quantification of the mecamylamine content in various samples collected as .72 described above. Calibration standards were prepared by diluting 0.5 mg / ml of the standard 1 in 100 in plasma to 5 μg / ml (5 μl + 495 μl), then further diluting with plasma in a 3-fold series to obtain a concentration of mecamylamine of 2.29 ng / ml. Calibration standards, quality control (QC) samples, and plasma, erythrocytes and vitreous humor study samples were prepared for HPLC injection by precipitation of 50 μl of plasma with 3x volumes (150 μl) of ice-cold acetonitrile containing 100 ng / ml dextromethorphan and 50 ng / ml diphenhydramine as internal standards. After centrifugation at 6000 g for 30 minutes, 40 μl of each supernatant was diluted with 200 μl of 0.2% formic acid in water.

Preparation of the Retina / Coroidal Sample Each sample of tissue collected was weighed. After weighing, 1 μl of water was added per mg of tissue per 3x volumes (relative to water) of the internal standard solution cooled with ice (acetonitrile containing 100 ng / ml dextromethorphan and 50 ng / ml diphenhydramine). The samples were homogenized using an electric rotor / stator type homogenizer (Tissue Tearor). After homogenization, an aliquot of 200 μl of each homogenate was then centrifuged and diluted as described above. The samples were analyzed using LC / MS / MS and quantified using the calibration standards prepared in plasma as described above.

Conditions of LC / MS / MS: HPLC: Shimadzu VP system Mobile phase: 0.2% formic acid in water (A) and 0.18% formic acid in methanol (B) Column: C18 Higgins Phalanx protection cartridges 2 x 10 mm Injection Volume: 100 μl Gradient: 5-95% B in 2 minutes after a 0.5 minute wash Flow rate: 400 μl / min Mass Spectrometer: Applied Biosystems / MDS SCIEX API 3000 (Applied Biosystems Inc., Fremont, CA) Interface: TurboIonSpray (ESI) at 400 ° C Polarity: positive ion Ions Q1 / Q3: 168.2 / 137.2 for mecamylamine 256.2 / 167.2 for diphenhydramine (Internal standard) 272.1 / 215.2 for dextromethorphan (Internal standard) ; 74 Analysis of the Dosing Solution: The mecamylamine dosing solutions (labeled "A" and "B") and the working standard at 0.5 mg / ml (described above) were diluted 1 in 100 in DMSO by volume. These solutions were analyzed by LC / MS / MS using the conditions listed above and the concentration of mecamylamine in the dose solutions was calculated in relation to the reference standard of mecamylamine in DMSO.

RESULTS: Calibration standards, QC samples, and plasma, erythrocytes and vitreous humor study samples were prepared for injection and HPLC injection and analyzed on day 1. Retinal study samples were prepared by HPLC injection and analyzed, together with calibration standards and QC samples, on day 5. Dosing solutions were analyzed concurrently with the retinal samples. Diphenhydramine was used as the internal standard and each calibration curve was adjusted using power regression. Samples with a concentration value above 5000 ng / ml were again analyzed by injection of 1/10 of the original injection volume to obtain the peak of the analyte on the scale. The data from the topical administration studies presented in Example 5 and analyzed as described in Example 6, are presented in Figures 4A, 5A-5B, and 6A-6B. From a comparison of Figures 4A, 4B and 5A it is apparent that the administration of mecamylamine hydrochloride via systemic administration results in higher relative amounts of mecamylamine appearing in the plasma compared to the amount that appears in the retina. / choroids, when compared to the relative amounts that appear when mecamylamine is administered topically (either as a solution or as a gel-forming solution m if your). Very unexpectedly, the ratio of mecamylamine (ng / g) present in the retinal / choroidal tissue to the concentration of mecamylamine in the plasma (ng / ml) is at least about 40 times higher for topical administration compared to the systemic administration. Thus, for a given dose of mecamylamma administered topically, much less mecamylamine will appear in the plasma compared to the retina / choroid and thus a therapeutic dose can be achieved without the side effects often experienced during the administration of mecamylamine. The data also show that the levels of mecamylamine present in erythrocytes (red blood cells) and plasma are comparable, indicating that mecamylamine in the systemic circulation has not been sequestered in red blood cells. Thus, the concentration of systemic levels of mecamylamine (as measured by plasma or red blood cells) relative to ocular tissue levels is surprisingly low and indicates that the adverse effects associated with systemic administration of the Mecamylamine (for example, effects on the central nervous system, etc.) should not be experienced by individuals when topical mecamylamine eye formulations are administered locally via the eye. In addition, the formulation of mecamylamine as a topical gel-forming solution has an even greater effect on the favorable division of mecamylamine in the retinal / choroidal tissue, with a concentration ratio of mecamylamine in the retinal / choroidal tissue (ng / g) to the concentration of plasma mecamylamine (ng / ml) which is at least about 450: 1 for the gel-forming solution in itself. The relative amounts for the various formulations and routes of administration are tabulated below in Table 6. , 77 Table 6 Example 7: Ocular Pharmacokinetics in Rabbit at Single Dose and at Multiple Dose Male Dutch-belted rabbits (Covance, Denver, PA) of ages from 2.5 to 4.5 months and with weights of 1.5 to 2.5 kg were administered with a 3% solution of mecamylamine hydrochloride (polymer free solution) by ocular instillation either as a single dose or 6 doses (50 microliters per dose), with approximately 1.5 hours of separation. Serial blood samples (approximately 0.5 ml each) were collected by direct venipuncture of a marginal vein from the ear into a blood collection tube containing EDTA as anticoagulant from various groups of animals at 0.5 hours after the dose, 2 hours after the dose. A sample of terminal blood was obtained from all the animals just before euthanasia. The animals were sacrificed 1, 3 or 6 hours after the administration of the pharmacological solution. The ocular tissues (listed in Table 7) were obtained after euthanasia. The concentration of the mecamylamine in plasma and ocular tissues was measured using an LC MS / MS method as described in Example 6. The results are presented in Table 7.

Table 7: Concentration of Mecamylamine in Rabbit Tissues After Eye Instillation of a 3% Mecamylamine Chloride Solution Time single dose Multiple dose (6X / day) Fabric (hour) N Media STD N Media STD Water humor 1 6 2492 568 6 3423 1080 3 8 820 437 ND ND ND 6 8 311 200 ND ND ND Conjunctiva 1 6 7052 4799 6 10005 5299 3 8 5420 3035 ND ND ND 6 8 4164 2632 ND ND ND Cornea 1 6 24817 8213 6 56517 38054 3 8 14569 6336 ND ND ND 6 8 25655 22541 ND ND ND Time single dose Multiple dose (6X / day) Fabric (hour) N Media STD N Media STD Extraocular muscle 1 6 8260 6340 6 798 535 3 8 1780 3040 ND ND ND 6 8 400 706 ND ND ND Iris / Ciliary Body 1 6 9952 6179 6 84383 22634 3 8 13338 7523 ND ND ND 6 8 18011 8918 ND ND ND Crystalline 1 6 111 88 6 227 136 3 8 28 28 ND ND ND 6 8 31 32 ND ND ND Optical Nerve 1 6 706 703 6 504 519 3 8 441 360 ND ND ND 6 8 178 129 ND ND ND Retina / Choroid 1 6 510 280 6 2572 1933 3 8 171 101 ND ND ND 6 8 420 279 ND ND ND Sclera / Previous 1 6 4738 2009 6 13372 2782 3 8 5303 2529 ND ND ND 6 8 3230 1219 ND ND ND Sclera / Posterior 1 6 4457 2626 6 3378 2019 3 8 2853 3075 ND, ND ND 6 8 949 1019 ND ND ND Time single dose Multiple dose (6X / day) Fabric (hour) N Media STD N Media STD Humor Vitreous 1 6 251 300 6 202 163 3 8 60 66 ND ND ND 6 8 27 20 ND ND ND Plasma 1 3 15 6 3 43 16 3 4 11 15 ND ND ND 6 4 5 8 ND ND ND The multiple dosage was 6 times per day at intervals per hour. ND = Not done Mecamylamine was found in high concentrations from the front to the back of the eyes of rabbits. The maximum average levels in the aqueous humor were approximately 310 to 920 ng / ml, and in the retina / choroids were 171 to 510 ng / g in the tissue 1 hour to 6 hours after dosing. The concentrations remained high throughout the six hours of sampling. Relatively little mecamylamine was observed in the vitreous humor. Plasma levels were low, of the order of 50 ng / ml or less. When examined 1 hour after the 6 doses every hour, a concentration of mecamylamine in the retina / choroid was five times that of the single dose. There was some accumulation observed in the aqueous humor and in the blood, but none in the vitreous humor. The ratio of the concentration of mecamylamine in the retina / choroid to plasma was high (37-147X). Topical ocular administration of the mecamylamine formulation was well tolerated in rabbits and no adverse clinical signs were observed after administration.

Example 8: Distribution of Single Eye Dose Drug in Rabbits A single dose of a polymer free solution, gellan gum formulation and hypromellose formulation containing 3% mecamylamine hydrochloride, was instilled into the eyes of rabbits (male rabbits Dutch-belted (Covance, Denver, PA) with a minimum age of 2 months and weighing 1.6 to 1.8 kg). Two animals were sacrificed at 30 minutes, 1 hour or 3 hours after dosing. The blood and ocular tissue samples (obtained as described in the previous examples) were analyzed for the concentration of mecamylamine using an LC MS / MS method up to 3 hours after the dosage The results are summarized in the Table Table 8: Concentration of mecamylamine (ng / ml or ng / g) in tissues / fluids of rabbits after a single ocular dose of 3% mecamylamine hydrochloride in polymer-free solution [83 [84 The mecamylamine administered as the polymer free solution was found in high concentrations moving anteriorly into the eye later. The maximum average levels in the aqueous humor were approximately 7700 to 9100 ng / ml, and in the retina / choroids were from 5000 to 11300 ng / ml measured between 30 minutes to 3 hours after dosing. The concentrations remained high throughout the three hours of sampling. Relatively little mecamylamine was observed in the lens and vitreous humor. Plasma levels were low - of the order of 50 ng / ml or less. The area under the curve (AUC) was calculated using a trapezoidal rule on a population pharmacokinetic basis (see Table 9). The bioavailability of mecamylamma in the retina / choroid was -7500 ng / g-hour when it was administered as the polymer free solution. Thus, it appears that mecamylamine distributed as a topical ocular formulation penetrated the eye, and reached the posterior pole of the eye - perhaps through a scleral route. The systemic bioavailability from the ocular route was low, and the proportion of the infraocular to systemic levels was high. No safety problems arose during the course of the study.

Table 9: AUC of Mecamylamine in Rabbit Tissues after Single Eye Instillation of 3% solutions (polymer-free, gellan and hypromellose gum) of mecamylamine hydrochloride (ng / ml-hour or ng / g -hr) Calculated using the trapezoidal rule on population values Example 9: Distribution of Mecamylamine in Eye Tissue of Rabbits After Intravenous Administration Mecamylamine was administered intravenously to New Zealand male white rabbits (approximately 2.5-3 kg (Kralek Frams, Turlock, CA)) at a dose of 15 mg / kg (dissolved in 0.9% sterile sodium chloride for injection) in 60 minutes or in 6 hours. The concentrations of the drug were measured as previously described at different time points in the plasma, the vitreous humor and at 6 hours in the retinal-choroidal tissue. For both groups, vitreous humor (> 0.1 ml) was withdrawn at 8 time points, with each animal being sampled no more than twice in total: pre-dose, 5 minutes, 15 minutes, 30 minutes, 1, 2, 4, and 6 hours. At all time points, only two samples of vitreous humor were collected in order to minimize pain and damage to the eyes of rabbits, in compliance with IACUC guidelines. Plasma samples were also collected at the same 8 time points: pre-dose, 5 minutes, 15 minutes, 30 minutes, 1, 2, 4, and 6 hours, with duplicate samples collected at each time point. At 6 hours, the animals were sacrificed and the vitreous and Retina-choroids were collected from all animals. Clinical observations were recorded periodically throughout the study. The biological samples for this study were analyzed using a LC / MS / MS method (see Example 6) with a lower limit of quantification of 0.5 ng / ml. The results of the analysis of the concentration of the drug in the plasma are shown immediately in Table 10.

Table 10: Concentration of mecamylamine in rabbit plasma after intravenous infusion of mecamylamine (ng / ml) Time Group MECÍ 5 mg / kg i. v. 1 hour MECÍ 5 mg / kg i. v. 6 hours N Medium Std N Medium Std 0 6 48.7 45 6 0.0 0 0. 5 6 5330.7 8816 6 350.5 77 1 6 1818.3 603 6 470.0 63 2 6 454.7 148 6 571.5 103 4 6 227.3 101 6 717.0 91 6 6 102.5 54 6 313.0 115 As expected, the plasma levels showed a higher maximum mean concentration with the infusion of the drug in a shorter period compared to the later period. prolonged (5.331 ng / ml vs 717 ng / ml). Peak or maximum levels were observed within 0.5 hours with the shortest period, while these were relatively constant over the longer infusion period. The results of the analysis of the concentration of the drug in the vitreous humerus are shown immediately in Table 11.

Table 11: Concentration of mecamylamine in the vitreous humor of rabbits after the intravenous infusion of mecamylamine (ng / ml) Time Group MECÍ 5 mg / kg i. v. 1 hour MECÍ5 mg / kg i. v. 6 hours N Average Std N Average Std 0 2 43.0 11.7 2 5.6 5.8 0. 5 2 716.6 881.7 2 59.9 14.8 1 2 1109.5 212.8 2 138.1 66.4 2 2 899.5 33.2 2 223.0 84.9 4 2 429.5 7.8 2 408.0 145.7 6 12 173.8 48.9 12 457.5 115.7 Note: The differential sample size per group reflects the tissue sampling.

The levels of mecamilamma in the vitreous humor were parallel to the time course observed in the plasma with vitreous humor levels, ranging up to an average of 1110 ng / ml with the shortest infusion period (observed at 1 hour) and an average of 458 ng / ml with the longest infusion period (observed at 6 hours). The results of the analysis of the drug concentration in the retina / choroid are shown in Table 12 below.

Table 12: Concentration of mecamylamine in retinal / choroidal rabbits after intravenous mecamylamine infusion (ng / ml) Source: Report: CB05-5160-O-PK (2006) In the retina / choroids, sampled only at slaughter at 6 hours, mean levels were 261 ng / ml for the shortest period, and 1.534 ng / ml for the longest period. [90 Example 10: 6-Hour Evaluation of Ocular Pharmacokinetics of a 2% Mecamylamine GELRITE Solution After Topical Instillation The objective of this study was to evaluate the ocular pharmacokinetics of a 2% mecamylamine in a GELRITE solution up to 6 hours after topical instillation into the eyes of White New Zealand rabbits. Nine White New Zealand female rabbits of minimum size of 9 weeks and weight of 2 to 3 kg were obtained from The Rabbit Source (Ramona, CA) and were used in the study. The dosage regimen is shown in Table 13.

Table 13: 6-Hour Evaluation of the Ocular Pharmacokinetics of a 2% Mecamylamine Solution After Topical Instillation in Eyes of White Rabbits New Zealand: Dosing Regimen Group No Treatment Treatment Volume Diameter of the pupil and Ocular Necropsy (Eye Ocular) (Eye of dose observations of the (post-left time, right, pupillary response (time dose) Topical instillation) Topical instillation) post-dose) To 3 2% Control vehicle 2X50 μl -15, 15, 30 and 45 minutes, 1 hour mecamylamine 1 hour B 2 2% 2% 2X50 μl -15, 15, 30 and 45 minutes, 1 hour mecamylamine mecamilamma 1 hour C 2 2% 2% 2X50 μl -15, 15, 30 and 45 minutes , 3 hours mecamylamine mecamylamine 1, 1 5, 2, 2 5 and 3 hours Group No Treatment Treatment Volume Diameter of the pupil and Ocular Necropsy (Eye Eye (Eye of dose observations of the (post-left time, right, pupillary response (time dose) Topical instillation) Topical instillation) post-dose) D 2 2% 2% of 2X50 μl -15, 15, 30 and 45 minutes, 6 hours mecamylamine mecamylamine 1, 1, 5, 1, 2, 5, 3 and 6 hours On day 1, 2 drops of 50 μl of mecamylamine or vehicle were administered topically into the appropriate eye or eyes of each animal as described in Table 13. The time of each dose administration was recorded. There was no mortality in the treatment group. Pupil size: No apparent differences in pupil diameter (horizontal or vertical) were observed in eyes treated with 2% mecamylamine in the course of the study. An average decrease in pupil diameter was observed at the 15 minute time point when compared to the 15 minute time point (pre-dosing) in eyes treated with 2% mecamylamine, but this decrease was not substantial or consistent. Pupillary response was normal for all eyes at all observation time points. With respect to the ocular distribution of mecamylamine, the average values for ocular tissues are shown in Table 14. In the choroid, the concentration of mecamylamine one hour after the Dosage was unilaterally approximately 2800 ng / g. The untreated companion eye in this group of animals had an average concentration of mecamylamine of approximately 700 ng / g (suggesting that there is drug distribution to the companion eye). One hour after bilateral dosing, the concentration of mecamylamine was about 14,000 ng / g, decreasing three hours later to about 500 ng / g, and six hours later at about 260 ng / g. The levels of mecamylamine in the retina were similar to that observed in the choroid. Mecamylamine was also observed in relatively high concentrations in the cornea, in the aqueous humor, but not in the vitreous humor. The mean levels in the plasma and the packed cells were approximately 5 to 38 ng / ml, higher one hour after dosing with the bilateral dose. The levels of mecamylamine in the plasma and the packed cells were similar, thus there was no evidence of sequestration in the red blood cells (Table 15).

Table 14: Concentration of mecamylamine in ocular tissues (ng / g) Matrix Group / hour MEC OS 1 hour MEC OU 1 hour MEC OU 3 hours MEC OU 6 hours MEC companion N Media Std N Media SW N Media Std N Media Std N Media SW Aqueous humor 1 3 25133 705 7 4 39075 2855 1 ND ND ND ND ND ND 3 97 2 1 2 NA NA NA NA NA NA 4 499 5 94 4 NA NA NA NA NA NA 3 ND ND ND ND ND ND ND ND ND 4 48 9 26 8 ND ND ND Choroid 1 3 2806 7 176 2 4 14170 0 12230 1 ND ND ND ND ND ND 3 705 7 248 2 3 ND ND ND ND ND ND 4 1086 0 513 0 ND ND ND ND ND ND 6 ND ND ND ND ND ND ND ND 4 264 5 156 0 ND ND ND Cornea 1 3 9600 0 2656 1 4 17892 5 10586 9 ND ND ND ND ND ND 3 652 3 335 0 3 NA NA NA NA NA NA 4 3825 0 454 6 NA NA NA NA NA NA 6 ND ND ND ND ND ND ND ND ND 4 1232 5 672 8 ND ND ND Retina 1 3 41600 1103 2 4 14710 0 12889 4 ND ND ND ND ND ND 3 781 3 373 1 3 NA NA NA NA NA NA 4 563 0 272 8 NA NA NA NA NA NA 6 ND ND ND ND ND ND ND ND ND 4 3098 1585 ND ND ND Vitreous humor 1 3 378 64 4 130 6 809 ND ND ND ND ND ND 3 104 1 0 3 ND ND ND ND ND ND 4 177 11 6 ND ND ND ND ND ND 6 ND ND ND ND ND ND ND ND ND 4 59 1 5 ND ND ND Table 15: Concentration of mecamylamine in blood (ng / ml) Example 11: Safety of Topical Eye Instillation of a Saline Solution Containing Mecamylamine Hydrochloride A phase 1 study entitled: "A Phase 1, Double Mask, Randomized, 1 day and Scale Dose Study to 14 days to Evaluate The Ocular and Systemic Safety of the Ophthalmic Solution of Mecamylamine "was initiated in the United States in healthy adults. The safety objectives of this study were to evaluate the ocular and systemic safety of 4 concentrations of the ophthalmic solution of mecamylamine after 1 day (administered twice) and administration of 14 days (BID). The dose levels of the ophthalmic solution of mecamylamine evaluated were 0.03%, 0.1%, 0.3%, and 1%. A summary of the composition of the mecamylamine ophthalmic solution and the placebo formulation is shown below in Table 7.

In the portion of day 1 of the study, 10 subjects in each group were dosed in a single eye twice with 6 hours between dosing. Within each group, 8 subjects received the ophthalmic solution of mecamylamine and 2 subjects received vehicle (placebo) only. In the portion of day 14, 10 subjects were dosed twice a day at 12-hour intervals in both eyes for 14 consecutive days. The subjects were evaluated for local (ocular) safety and tolerance based on the evaluation of ocular symptoms, ocular comfort, better corrected visual acuity, biomicroscopy with fluorescein stain, and intraocular pressure (IOP) measurement. Flattening phonometry of Goldman, ophthalmoscopy, pupil size, and Schirmer's test. These were also evaluated for systemic safety based on the evaluation of the physical examination, ECG of 12 guides, vital signs, adverse events, hematology, clinical chemistry, and, urinalysis. On October 26, 2006, 70 of the total of 80 planned subjects were treated. The dosage is currently continuing for the final dosing group of 10 subjects (ATG003 1% BID x 14 days). The results to date have not shown indications related to ocular or systemic toxicity treatment. Specifically: • All subjects in all dosage groups rated the comfort or comfort level as either "Very Comfortable" or "Comfortable" after study drug administration. No subject in any of the dosing groups experienced "Uncomfortable" or "Intolerable" symptoms at any time. There have not been significant changes in the best corrected visual acuity in any subject. • No emergent effects were seen on clinically relevant treatment in any subject, based on biomicroscopic examination (divided lamp) with dilation and fluorescein staining. In particular, there have been no observations of corneal erosions or ulcers, abnormalities in the anterior chamber, irritation in the conjunctiva or redness, or any abnormalities in the lens or retina noted in any subject. There are no abnormal or clinically relevant increases in intraocular pressure that have been noticed in a subject. No change in pupil size is noticed in any subject. • There are no emergent changes to the treatment in the production of tears noticed in some subject.

• No clinically relevant changes in pulse or blood pressure (including postural changes) have been noted in any subject. There have been no serious or severe adverse events reported in any subject. All the adverse events reported to date have been of average severity, and of a transitory nature. No subject has discontinued the study medication as a result of an adverse event. Significantly, there has been no evidence of a drug-related increase in the adverse effects resulting from systemic glanglionar blockage (such as constipation, urinary retention, postural hypotension, or dry mouth). No clinically relevant changes in the parameters of the electrocardiogram (ECG) have been noted in any subject. • No clinically relevant changes in any laboratory value (hematology, clinical chemistry, and urinalysis) have been noted: Table 16: Composition of the Ophthalmic Solution of Mecamylamine and Placebo: Example 12: Determination of Mecamylamine Levels in Plasma of Human Subjects After Eye Administration of the Ophthalmic Solution of Mecamylamine Hydrochloride In a randomized, placebo-controlled, double-blind, phase 1 design, healthy volunteers received a solution ophthalmic mecamylamine hydrochloride at concentrations of 0.03%, 0.1%, 0.3%, and 1%. In the first part of this study, subjects received two doses of ophthalmic solution of mecamylamine in one eye and placebo in the other eye. Doses were administered as a topical ophthalmic drop in a single day with a 6-hour dose interval. In the second part of the study, subjects received two doses per day of assigned treatment in both eyes for 14 consecutive days. Blood samples were not taken for the analysis of the drug in the first dose of a single day, part of the study. In the second, the 14-day dosage, part of the study, blood samples were taken in the subjects on days 1, 7 and 14 of the dosage (pre-dose, 1.5 and 3 hours after the first dose). A final sample was taken 72 hours after the final dose. Blood samples were analyzed using a LC-MS / MS method to determine the concentration of mecamylamine.

Example 13: Toxicology Study in Dogs of 14 Days for the Ocular Administration of Mecamylamine An ophthalmic saline formulation containing 3% mecamylamine hydrochloride was evaluated for the toxicological effects and the pharmacokinetics of the drug in healthy beagle dogs. The drug solution or a comparable vehicle control was administered 2, 4 and 8 times daily for 14 or 15 consecutive days to both eyes of the Beagle dogs. Thirty-two experimentally intact Beagle dogs (16 males and 16 females), from 5 to 7 months of age and weighing 6.0-8.5 kg were assigned to the treatment groups as shown in Table 17 below.

Table 17: Ocular Toxicity in Dogs of 14 days with LPG: Treatment Groups The dosage was as follows: 2 / day = q. approximately 4 hours, 4 / day = q, approximately 2 hours, and 6 / day = q. approximately 1.5 hours for a minimum of 14 days (males) / 15 days (females) Animals were dosed 2, 4 or 6 times a day for 14 consecutive days for males or 15 consecutive days for females. The dose (50 microliters) was administered to the eyeball on each occasion of the dosage. Mortality and clinical observations were evaluated twice a day. The ocular observations were evaluated according to the Draize rating system twice a day (Draize et al, (1944) J. Pharm, Exp. Ther. 82: 377-390, incorporated by reference herein). All eyes from all animals had ophthalmic examinations using an indirect ophthalmoscope and split lamp and were evaluated according to McDonald and Shadduck (McDonald & amp; amp; amp;; Shadduck (1977) Advances in Modern Toxicology 4: 162 (New York, Wiley), incorporated by reference herein) before the start of treatment and 1 to 2 hours after the final dosing of Groups 1 and '4 in Days 7 and 14. The approximate size of the pupil was determined for each animal before the start of the study, at least 30 minutes after the final daily dose on Days 1 and 8 and before terminal slaughter on Days 15/16. The Electrorethograms (ERG) were obtained from all animals before the start of treatment on day 14. Blood samples for evaluation of hematology, coagulation and clinical chemistry parameters were collected before the start of treatment and before sacrifice terminal on Days 15/16. The selected tissues were harvested at necropsy, the selected organs were weighed, and the selected tissues from all the animals were evaluated microscopically. There were no deaths scheduled during the study. In addition, there were no effects related to the test article on body weights, food consumption, hematology parameters, coagulation parameters, organ weights, infraocular pressures, or pupil sizes during the study. There were no adverse effects related to the test article on clinical chemistry parameters. On most days of dosing, except for days 2 and 11, there was at least one animal from Group 4 was noted with strabismus of the left eye and / or right approximately 30 minutes after the dose 6. Since it was not noticed similar observations on none of the days in Group 1 animals, who received the same number of vehicle doses to the right eye, the findings they were considered related to the dosage six times a day of mecamylamine hydrochloride with a 3% ophthalmic solution. The most common ocular observation by the Draize evaluation was a redness rating of 1 (rating 3), a definitive injection of the conjunctival vessels. The finding was more common in the post-dosing observation of 1-2 hours of the animals of Group 3 and / or 4, less frequently the animals of Group 2 and rarely observed in the animals of Group 1. The sign was generally observed in fewer eyes in the Draize evaluation of the daily pre-dose, indicating the resolution of the findings from the previous day. There were no effects related to the apparent test article observed on days 7 by McDonald and Shadduck in the rating and indirect ophthalmology and split lamp biomicroscopy. On day 14, the results of the eye examinations were complicated by, or possibly the direct result of, the manipulations of the eyes by the ERG procedure. The results showed no conjunctival congestion, observed in at least one eye of a male of Group 1, three animals of Group 2, two animals of Group 3, and five of the eight animals of Group 4 had bilateral conjunctival congestion. Corneal erosions, however, were confined to the animals of the Group 4 and suggesting an effect of the test article. Examination of all electroretinographic, qualitative and quantitative data did not provide evidence to support retinal degeneration or other physiological abnormality attributable to the test compound or vehicle. There were no gross necropsy findings related to the test article, and the lesions related to the test article were not apparent from the histopathological evaluation of the balloons (sections that include the retina, choroid, sclera, lens, cornea , the iris / ciliary body, and the optic nerve), the eyelid (when present), the conjunctiva, the extraocular muscle and the lacrimal glands (when present) for all animals of the sacrifices on the 15th and 16th The sectioning of the eyes included a central section of approximately 5 mm, which after evaluation did not reveal detectable corneal erosions for Group 4 animals that were positive for fluorescein tension on day 14, indicating a plausible resolution of those injuries The maximum concentrations observed (Cmax) were highly variable, most notably for the first dosage of Group 2. Cmax was generally linearly proportional to the dose for Groups 3 and 4 (means of 44 and 64 ng / ml) but Group 2 was well above the linearly proportional dose (mean of 49 ng / ml) and had the highest total value (185 ng / ml) despite being dosed with the lowest dose. For Group 2, the values of day 1 were more variable (relatively) than on day 13; for Groups 3 and 4, the values of day 1 were less relatively variable than the values of day 13. The high-dose group (Group 4) had small but measurable mecamylamine values before dosing on day 13. Except as is scored for Group 2, no significant differences were found in the toxicokinetics between day 1 and day 13. The accumulation ratios were a maximum of 1.14, indicating no significant accumulation for any group after 13 days of ophthalmologic dosing. There was also no indication of significant induction or inhibition of drug metabolism. In conclusion, an 3% ophthalmic solution of 3% mecamylamine hydrochloride was not associated with definitive adverse effects after dosing twice a day (approximately 4 hours between doses, totaling 3 mg / eye / day) or dosing four times a day (approximately 2 hours between doses, totaling 6 mg / eye / day) for fourteen (males) or fifteen (females) on consecutive days to Beagle dogs. Beagle dogs administered at doses six times a day (approximately 1. 5 hours between doses, totalized 9 mg / eye / day) of mecamylamine hydrochloride, 3% ophthalmic solution, had clinical signs of strabismus (not present in the controls) in several days, more consistent, although slight, Draize scores. and the appearance of corneal erosions on day 14 in two of the eight dogs may have been suggestive of an effect of the test article. Therefore, the level of unobservable adverse effects (NOAEL) of the topical hydrochloride, as a 3% ophthalmic solution, is considered to be four times the daily dosage (approximately 2 hours between doses) totaling 6 mg / eye / day for fifteen consecutive days.

Example 14: A 39-Week Ocular Toxicity Study of Mecamylamine Hydrochloride Ophthalmic Solution in Dogs with a Recovery of 4 Weeks The purpose of this study is to characterize the general and ocular toxicity and toxic toxicity of the test article when administered to dogs Healthy beagle, twice a day by topical ocular application for thirty-nine weeks, followed by a four-week recovery period including an interim sacrifice of 13 weeks. Conducting a chronic toxicity study in a non-rodent species is required before use in humans long term. The Beagle dog is a standard non-rodent species used in toxicology studies based on substantial amounts of published historical data. The number of animals used in this study is required to define the toxicity, and the reversibility of the same, and the toxicocinetica of the test article with repeated dosage in the longer term. Three treatment groups were included in this study as described in the following table.

Table 18. Group Assignments and Dosage Levels The study drug is being administered by ocular instillation twice a day (approximately 6 hours between doses). The ocular route was chosen since this is the preferred route of administration in humans. After 13 weeks of dosing, 3 animals / sex in Groups 1, 2 and 3 will be sacrificed by overdose or barbiturate and subjected to necropsy. After 39 weeks of dosing, 4 animals / sex / group they will be sacrificed by overdose with barbiturate and subjected to necropsy. After the treatment phase, 3 animals / sex in Groups 1 and 3 will remain in the study, not treated, and will be sacrificed by overdose with barbiturate and subjected to necropsy after of a four-week recovery period. During the study the animals are being observed for mortality and clinical observations at least once a day. The eye observations according to Draize are being recorded twice a week with the first recorded observations occurring on day 1. The observations are being recorded before the first dose on a particular day and approximately 1 to 2 hours after the first dose. second dose on the same day. The ocular rating is being recorded once before the scheduled sacrifices after 13 weeks and 39 weeks of dosing and after the recovery period of four weeks. After about 1 month of drug administration there have been no clinically significant observations related to the possible toxicology of the test article. It is noted that in relation to this date the best me known to the applicant to carry out said invention, is that which is clear from the present description of the invention.

Claims (67)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. The method for treating or preventing conditions mediated by neovascularization, abnormal angiogenesis, vascular permeability, or combinations thereof, of the posterior tissues of the eye. , characterized in that it comprises the step of: a) applying topically by eye drops to one or both eyes of an individual in need thereof, a formulation comprising mecamylamine, or a pharmaceutically acceptable salt thereof, and a suitable carrier for topical administration to the eye, wherein the mecamylamine or a pharmaceutically acceptable salt thereof is present in the formulation in an amount sufficient to deliver a therapeutically effective amount of mecamylamine to one or more of the posterior tissues of the eye for treatment or prevention of conditions mediated by neovascularization, abnormal angiogenesis mal, vascular permeability, or combinations thereof, of the posterior tissues of the eye and wherein the formulation is substantially free of agents that increase viscosity.
2. 2. The method in accordance with the claim

   1, characterized in that when the formulation is topically administered to the eye of a rabbit, the ratio of the concentration of mecamylamine present in the choroidal and retinal tissue, measured in units of ng / g, to the concentration of mecamylamine in the plasma measured in units of ng / ml ([ng / g of mecamylamine in choroidal tissue + retinal]: [ng / ml of plasma]) is at least about 20: 1.
3. 3. The method according to claim 2, characterized in that the ratio is at least about 300: 1.
4. 4. The method of compliance with the claim

   2, characterized in that the ratio is from about 40: 1 to about 1000: 1.
5. 5. The method of compliance with the claim
6. 2, characterized in that the ratio is from about 20: 1 to about 1000: 1. The method according to any of claims 1, 2, 3-4 or 5, characterized in that when the formulation is topically administered to the eye of a rabbit, the maximum mean concentration of mecamylamine in the plasma is less than about 70 ng / ml. The method according to claim 6, characterized in that the maximum mean concentration of mecamylamine in the plasma is less than about 50
7. ng / ml.
8. 8. The method according to any of claims 1-7, characterized in that when the formulation is topically administered to the eye of a rabbit, the total concentration of mecamylamine in plasma measured as the area under the curve is less than about 100 ng / ml-hour The method according to any of claims 1-8, characterized in that the carrier comprises an aqueous saline solution.
9. The method according to claim 9, characterized in that the aqueous saline solution is isotonic.
10. The method according to any of claims 1-8, characterized in that the carrier consists of an aqueous saline solution, one or more preservatives, one or more chelating agents and one or more buffering agents.
11. The method according to any of claims 1-11, characterized in that the mecamylamine is incorporated into the formulation as substantially pure S-mecamylamine.
12. The method according to any of claims 1-11, characterized in that the mecamylamine is incorporated into the formulation as R-mecamylamine
13. substantially pure.
14. The method according to any of claims 1-13, characterized in that the formulation comprises from about 0.001% to about 6% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof.
15. 15. The method of compliance with the claim

    14, characterized in that the formulation comprises from about 0.03% to about 3% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof.
16. 16. The method of compliance with the claim

    15, characterized in that the formulation comprises from about 0.03% to about 2% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof.
17. 17. The method according to claim '

    16, characterized in that the formulation comprises from about 0.1% to about 1% (w / v) of mecamylamine or a pharmaceutically acceptable salt thereof.
18. 18. The method according to any of claims 1-17, characterized in that the formulation is substantially free of surfactant.
19. 19. The method of compliance with any of the

    claims 1-18, characterized in that the formulation comprises a preservative.
20. 20. The method of compliance with the claim

    19, characterized in that the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate and phenylmercuric acetate.
21. 21. The method according to the claim

    20, characterized in that the preservative is benzalkonium chloride.
22. 22. The method according to any of claims 1-21, characterized in that the formulation further comprises a chelating agent.
23. 23. The method according to claim 22, characterized in that the chelating agent is disodium edeteate (dihydrate).
24. 24. The method according to any of claims 1-22, characterized in that the carrier comprises an aqueous isotonic solution and wherein the formulation further comprises a chelating agent and a preservative.
25. 25. The method according to any of claims 1-24, characterized in that the formulation

    further comprises one or more damping agents.
26. 26. The method according to claim 25, characterized in that one or more buffers are selected from the group consisting of phosphate buffers, citrate buffers, maleate buffers, borate buffers and combinations thereof.
27. 27. The method according to any of claims 1-5 or 6-26, characterized in that the individual has been identified as having one or more conditions mediated by retinal neovascularization, choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations of the same, of the posterior tissues of the eye.
28. The method according to any of claims 1-5 or 6-26, characterized in that the individual has been identified as susceptible to one or more conditions mediated by retinal neovascularization, choroidal neovascularization, abnormal angiogenesis, vascular permeability, or combinations of the same, of the posterior tissues of the eye.
29. 29. The method according to any of claims 1-5 or 6-26, characterized in that the individual has been identified as possessor or because he is susceptible to proliferative retinopathy.
30. 30. The method according to claim 29, characterized in that the individual has been identified as possessor or because he is susceptible to a non-neovascular form of macular degeneration.
31. 31. The method according to any of claims 1-5 or 6-26, characterized in that the condition is diabetic retinopathy, rematurity retinopathy, retinal neovascularization associated with macular degeneration, choroidal neovascularization associated with macular degeneration, retinopathy associated with macular edema , or retinopathy associated with sickle cell disease.
32. 32. The method according to any of claims 1-5 or 6-26, characterized in that the condition is diabetic retinopathy.
33. 33. The method according to any of claims 1-5 or 6-26, characterized in that the condition is retinopathy of prematurity.
34. 34. The method according to any of claims 1-5 or 6-26, characterized in that the condition is retinal neovascularization or choroidal neovascularization associated with macular degeneration.
35. 35. The method according to any of claims 1-5 or 6-26, characterized in that the condition is an age-related maculopathy.
36. 36. The method of compliance with any of the

    claims 1-5 or 6-26, characterized in that the condition is macular degeneration related to age.
37. 37. The method according to claim 36, characterized in that age-related macular degeneration is a neovascular form of macular degeneration related to age.
38. 38. The method according to any of claims 1-27, characterized in that the condition is an ocular tumor.
39. 39. The method according to any of claims 1-38, characterized in that the individual is a mammal.
40. 40. The method of compliance with the claim

    39, characterized in that the mammal is a primate, rabbit, canine, feline or rodent.
41. 41. The method according to the claim

    40, characterized in that the mammal is a primate.
42. 42. The method of compliance with the claim

    41, characterized in that the primate is a human.
43. 43. The method according to any of claims 1-5, 6-37, or 38-42, characterized in that the therapeutically effective amount of mecamylamine is distributed to the choroid.
44. 44. The method according to any of claims 1-5, 6-37, or 38-42, characterized in that the

    Therapeutically effective amount of mecamylamine is distributed to the retina and the choroid.
45. 45. The method according to any of claims 1-44, characterized in that step (a) is performed once a day, twice a day, three times a day, four times a day, once every third day, once a week, or twice a week.
46. 46. The method according to any of claims 1-45, characterized in that it further comprises a step (b), wherein step (b) comprises: administering to the individual a pharmaceutical agent, the additional treatment modality or combination thereof .
47. 47. The method according to claim 46, characterized in that step (b) is performed before or concomitantly with step (a).
48. 48. The method according to claim 46 or 47, characterized in that the pharmaceutical agent is a VEGF antagonist, VEGF scrubber or tyrosine kinase inhibitor.
49. 49. The method according to claim 46 or 47, characterized in that the pharmaceutical agent is an anti-VEGF antibody or fragment thereof.
50. 50. The method according to claim 49, characterized in that the anti-VEGF antibody is

    bevacizumab, ranibizumab, or a combination thereof.
51. 51. The method according to any of claims 46-50, characterized in that, the additional treatment modality is photocoagulation by thermal laser or photodynamic therapy.
52. 52. A kit characterized in that it is for ocular topical administration of mecamylamine comprising an eye dropper; and a formulation consisting of a therapeutically effective amount of mecamylamine, an aqueous saline solution, one or more preservatives, one or more chelating agents and one or more buffering agents.
53. 53. The kit according to claim 52, characterized in that it also comprises a package and instructions for use.
54. 54. The kit according to any of claims 52-53, characterized in that the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, thimerosal, phenylmercuric nitrate, phenylmercuric borate and phenylmercuric acetate.
55. 55. The kit according to claim 54, characterized in that the preservative is benzethonium chloride.
56. 56. The kit in accordance with any of the

    claims 52-55, characterized in that the chelating agent is disodium edeteate (dihydrate).
57. 57. The kit according to any of claims 52-56, characterized in that the damping agent is selected from the group consisting of phosphate buffers, citrate buffers, maleate buffers, borate buffers and combinations thereof.
58. 58. The kit according to claim 57, characterized in that the buffering agent is a phosphate buffer.
59. 59. The kit according to any of claims 52-58, characterized in that the formulation is isotonic.
60. 60. The kit according to any of claims 52-59, characterized in that the formulation is provided in a multiple dose form.
61. 61. The kit according to any of claims 52-59, characterized in that the formulation is provided in one or more simple unit dosage forms.
62. 62. The kit according to any of claims 52-61, characterized in that sufficient formulation is provided for the treatment in a period of about 1 day, about 1 week,

    about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months or about 1 year.
63. 63. The kit according to any of claims 52-62, characterized in that it further comprises one or more nicotinic acetylcholine receptor antagonists not mecamylamine.
64. 64. The kit according to any of claims 52-63, characterized in that it also comprises one or more pharmaceutical agents.
65. 65. The kit according to claim 64, characterized in that the pharmaceutical agent is provided in a separate container of the pharmaceutical formulation of mecamylamine, or a pharmaceutically acceptable salt thereof.
66. 66. The kit according to any of claims 52-65, characterized in that the mecamylamine is incorporated into the formulation as substantially pure S-mecamylamine.
67. 67. The kit according to any of claims 52-65, characterized in that the mecamylamine is incorporated in the substantially pure R-mecamylamine formulation.