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Cai-based systems and methods for the localized treatment of ocular and other diseasesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.)Cai-based systems and methods for the localized treatment of ocular and other diseases description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060116404, Cai-based systems and methods for the localized treatment of ocular and other diseases. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional application No. 60/612,683, filed Sep. 24, 2004, and is herein incorporated in its entirety. BACKGROUND OF THE INVENTION [0002] 5-amino-1,2,3-triazole-4-carboxamide derivatives were originally discovered as antiparasitic agents and then subsequently demonstrated to be antiproliferative agents and potential cancer therapeutics. The specific compound, 5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxa- mide (Formula I illustrated below, shown as the free base form), has been demonstrated to have antiproliferative and antimetastatic activity that was linked to decrease of intracellular calcium by inhibition of non-voltage-gated calcium channels. Tyrosine kinase and metalloproteinase pharmacological mechanistic activities and antiangiogenesis activity relevant to antitumor efficacy have also been described for this compound. The compound of Formula I will be referred to in the following discussion using the acronym CAI (carboxy-amido-triazole) which is generally used to describe the compound. [0003] Clinical investigations have been conducted with CAI in the treatment of life-threatening diseases. For example, CAI has been used in the treatment of a variety of refractory tumors, including prostate cancer, lymphomas, glioblastoma, peritoneal cancer, fallopian tube cancer, epithelial ovarian cancer, advanced renal cell carcinoma, metastatic renal carcinoma, and non-small cell lung cancer (Bauer, K. S. et al Clin Cancer Res. 5:2324-2329, 1999; Kohn, E. C. et al Cancer Res. 52:3208-3212, 1992; Kohn, E. C. et al. J Biol Chem. 269:21505-21511,1994a; Kohn, E. C. et al. Proc Natl Acad Sci USA. 92:1307-1311, 1995; Kohn, E. C. et al. Cancer Res. 56:569-573, 1996; Kohn, E. C. et al. J Clin Oncol. 15:1985-1993, 1997; Kohn, E. C. et al. Clin Cancer Res. 7:1600-1609, 2001. [0004] While these studies using CAI indicate that CAI has intrinsic clinical efficacy for many cancer types, the systemic oral dosage regimens and formulations used in a clinical setting to date have been associated with dose limiting side effects. Moreover, toxic effects (cerebellar ataxia, peripheral neuropathy and exacerbation of depression) have been observed in clinical studies at doses of CAI required to achieve circulating levels that are within a narrow range or those projected from pharmacological studies to be required for effective inhibition of pathological neovascularization. Furthermore, a serious side effect associated with clinical use of CAI by systemic administration has been the loss of vision for which two cases have been described (Berlin, J. et al. Clin Cancer Res. 8:86-94, 2002). Therefore, use of CAI as currently applied in clinical investigations for cancer is effectively precluded for acute or chronic treatment of non-life threatening conditions, in particular for the treatment of ocular diseases described herein. [0005] To treat certain ocular diseases, such as age-related macular degeneration (or AMD), and diabetic retinopathy, or diseases with specific ocular manifestations, such as von Hippel landau syndrome, therapeutic treatments rely on occlusion of the blood vessels using either threshold laser photocoagulation, or subthreshold laser combined with a photoactivated dye. However, such treatment requires either full-thickness retinal damage by thermal destruction, or damage to medium and large choroidal vessels thereby precluding any potential visual recovery. Further, the subject is left with a scar and visual scotoma. Moreover, recurrences are common, and visual prognosis is poor. Recent research in the treatment of neovascularization has had the aim of causing more selective closure of the blood vessels, in order to preserve the overlying neurosensory retina. Such strategies have been used for the treatment of diabetic retinopathy, the leading cause of blindness among working age adults in Europe and the United States. However, extensive ocular tissue damage can occur after panretinal photocoagulation, with the visual handicap of more limited peripheral vision and poor night vision. With focal laser treatment, photocoagulation often can further compromise macular blood flow. Alternatively, a variety of molecules are in development or have been approved that target angiogenic pathways (e.g. the VEGF pathway). Thus, using antiangiogenic compounds is an alternative to lasering of patients. [0006] CAI is an antiangiogenic compound; however, the poor aqueous solubilities of CAI compounds, as well as reported neurotoxicity for CAI, means that novel methods of administration and targeted administration of CAI compounds are required for providing safe and effective doses to treat disease and non-life threatening diseases in particular. [0007] High local concentrations of CAI may be required to treat acute disease symptoms while lower concentrations can be effective as continuation therapy or prophylactic therapy. Additionally the frequency of administration of a formulation of a CAI compound can also be used to ensure safe and effective local concentrations to slow vascular outgrowth. Treatment may be necessary from every week, to every month to few months, to yearly dosing with appropriate molecules in sustained delivery systems. [0008] Posterior segment neovascularization (NV) is the vision-threatening pathology responsible for the two most common causes of acquired blindness in developed countries: exudative AMD and proliferative diabetic retinopathy (PDR). Currently the only approved treatments for posterior segment NV that occurs during exudative AMD are laser photocoagulation, photodynamic therapy with VISUDYNE.RTM., and the VEGF binding oligonucleotide aptamer Macugen.RTM.. Laser and photodynamic therapies involve occlusion of affected vasculature which results in localized laser-induced damage to the macula. For patients with PDR, surgical interventions with panretinal laser, or vitrectomy and removal of preretinal membranes, or treatment with Macugen.RTM. are the only treatment options currently available. However, in addition to the recently approved anti-VEGF aptamer oligonucleotide Macugen.RTM.; several different compounds are being evaluated clinically, including, for example, anecortave acetate (Alcon Research, Ltd.), and Lucentis (ranibizumab, Genentech), Squalamine lactate (Genaera Corporation), LY333531 (Lilly), Cand5 (Acuity Pharmaceuticals), Talaporfin sodium (Light Sciences Corp.), and Fluocinolone (Bausch & Lomb). [0009] Treatments using dosage regimens, routes of administration and formulations of CAI described to date do not have adequate safety for treating severe proliferative diseases that are non-life threatening. There exists an unfulfilled need for new dosage regimens, routes of administration and formulations of CAI that can provide therapeutic effects on non-life threatening proliferative diseases, as exemplified by ocular diseases that are characterized by neovascularization and pathological cellular proliferation and invasion. BRIEF SUMMARY OF THE INVENTION [0010] The subject invention provides novel sterile aqueous formulations of CAI compounds, their use in the localized treatment of ocular diseases, as well as methods for their manufacture. In some embodiments of the invention, novel and advantageous CAI compounds, their respective formulations, and methods for their use are provided. The novel CAI compounds and aqueous, sterile formulations of the invention are particularly useful in the localized treatment of non-life threatening diseases such as proliferative diseases, ocular diseases or conditions, inflammatory conditions, edematous diseases, signal transduction-mediated diseases, and matrix metalloproteinase-mediated diseases, and neovascular diseases. [0011] In certain embodiments, CAI compounds of the present invention are crystalline and small particulate pure free base forms of CAI, CAI prodrugs, and CAI acid addition salt forms. Further embodiments of the invention provide novel, therapeutically effective formulations of crystalline and small particulate pure free base forms of CAI compounds of the invention. [0012] Specific diseases that can be treated with the CAI compounds of the invention include, but are not limited to, ocular disease including neovascular ocular disease, edematous ocular disease, ocular tumors, and intraocular inflammation; dermatological disease including psoriasis, eczema, actinic keratosis, and rosacea; inflammatory disease including arthritis and arthrosis; neurological diseases including neurodegenerative disease, pain, and epilepsy; cancers including cancers of the bladder, brain, breast, colon, endometria, kidney, lungs, pancreas, and thyroid; and proliferative vascular disorders including restenosis or proliferation associated with angioplasty. [0013] Aqueous, sterile formulations as described herein provide for the localized administration of high concentrations of CAI compounds (which are normaly poorly soluble) for the treatment of such acute therapeutic indications as exemplified by severe neovascular ocular disease stages of "wet" ARMD or diabetic retinopathy. Similarly, for chronic use, the subject invention provides sterile, aqueous formulations for the controlled release of CAI compounds via oral, systemic or local routes of administration, where such formulations ensure the maintenance of therapeutic CAI compound drug levels with low variability and reliability for chronic application. [0014] Treating localized proliferative diseases, including those characterized by neovascular pathology, by the local administration of CAI compounds of the invention as described herein, provides significant advantages to the systemic administration of CAI with such systemic administration having been practiced in cancer to date. [0015] Local administration of CAI compounds as provided herein allows for the maintenance of efficacious, non-toxic levels of active CAI free drug at the local tissue disease site, thus providing a high margin of safety and enables therapeutically effective treatment of diseases, particularly non-life threatening diseases. The localized treatment of non-life threatening diseases using CAI compounds as described herein provides significant advantages relative to systemic treatment with forms and formulations of CAI described to date which have unacceptable low safety thresholds. [0016] Similarly, according to the subject invention, the local administration of CAI compounds, and formulations thereof, by means of a drug delivery device or implant placed in proximity to the local tissue site provides for the maintenance of efficacious, safe levels of active CAI drug ingredient at the local tissue disease site. Thus, the subject invention provides a high margin of safety and enables use in treating non-life threatening diseases for which CAI dosed systemically, in forms described to date, is practically precluded. [0017] In one embodiment, local administration of CAI compounds as described herein is suitable for acute disease therapy and induction of remission of disease signs and symptoms. In another embodiment local administration of CAI compounds as described herein is suitable for chronic disease therapy and maintenance of remission of disease signs and symptoms. [0018] According to the subject invention, the local ocular administration of CAI compounds of the invention, and/or formulations thereof, attenuate ocular pathological disease processes without unduly compromising normal healthy ocular function. Thus, local ocular administration of a CAI compound of the invention, and/or formulations thereof, provides for an efficacious but safe controlled concentration range of CAI directly in the eye. [0019] Ocular CAI-based therapies, as describe herein, provide significant advantages for treating neovascular ocular disease relative to current laser surgery treatment modalities including panretinal photocoagulation, which can be accompanied by extensive ocular tissue damage. In the examples of posterior neovascular ocular diseases, such as Age Related Macular Degeneration and Diabetic Retinopathy, target ocular pathologies and tissues for treatment are especially localized to the retinal, choroidal and corneal ocular compartments. [0020] It is contemplated herein that CAI compounds of the invention can readily penetrate the human scleral tissue after periocular administration in patients with ocular disease. This particular property of CAI compounds and CAI-based formulations of the invention enable effective minimally invasive delivery of the parent CAI therapeutic entity (or also referred to herein as CAI free base) to the patient's diseased ocular tissue compartment(s) in therapeutic concentration without causing ocular toxicity that has been previously observed with the systemic administration of the biologically active CAI parent drug to cancer patients. [0021] According to the subject invention, tissue targets for localized treatment using the CAI compounds include, but are not limited to, dermal, ocular, pulmonary, vascular, joint, nasal, ictic, bone, gastrointestinal, and localized neural tissues e.g. brain and spinal column of the central nervous system. Accordingly, administrations of CAI compounds of the invention as described herein can be used to treat ocular, dermatological, pulmonary, vascular, joint, bone, nasal, ictic, gastrointestinal and neurological diseases. In a preferred embodiment, CAI compounds of the invention, and/or formulations thereof, are useful for treating local disease pathologies that are targeted by the established pharmacological mechanism(s) of action of CAI to inhibit the pathological increase in intracellular calcium concentration that blocks hyperproliferative, inflammatory, neurodegenerative, edematous, macroscopic pathologies associated with localized target diseases described herein. Continue reading about Cai-based systems and methods for the localized treatment of ocular and other diseases... Full patent description for Cai-based systems and methods for the localized treatment of ocular and other diseases Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Cai-based systems and methods for the localized treatment of ocular and other diseases patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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