AU2012200274B2 - Liquid formulations for treatment of diseases or conditions - Google Patents

Abstract

Diseases and conditions associated with tissues of the body, including but not limited to tissues in the eye, can be effectively treated, prevented, inhibited, onset delayed, or regression caused by administering therapeutic agents to those tissues. Described herein are liquid formulations which deliver a variety of therapeutic agents, including but not limited to rapamycin, to a subject for an extended period of time; liquid formulations which form a non-dispersed mass when placed in an aqueous medium of a subject; non-dispersed mass-forming liquid formulations which form a gel or gel-like substance in an aqueous medium; liquid formulations, comprising a therapeutic agent and a plurality of polymers; and methods for delivering therapeutic agents to a subject for an extended period of time using the liquid formulations. The liquid formulation may be placed in an aqueous medium of a subject, including but not limited to via intraocular or periocular administration, or placement proximate to a site of a disease or condition to be treated in a subject. A method may be used to administer rapamycin to treat or prevent angiogenesis, choroidal neo-vascularization, or age-related macular degeneration, or wet age-related macular degeneration in a subject. The liquid formulations may comprise rapamycin or other therapeutic agents.

Description

I AUSTRALIA Patents Act 1990 SANTEN PHARMACEUTICAL CO., LTD. COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Liquid formulations for treatment of diseases or conditions The following statement is a full description of this invention including the best method of performing it known to us:- LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS Inventors: Sreenivasu MUDUMBA, Philippe JM DOR, Thierry NIVAGGIOLI, David A. WEBER, Sidiq FAROOQ FIELD 100011 Described herein are liquid formulations for treatment, prevention, inhibition, delaying onset of, or causing regression of a disease or condition by delivery of therapeutic agents to a subject, including but not limited to a human subject, including but not limited to the treatment of age-related macular degeneration ("AMD") by delivery of a liquid formulation comprising a therapeutic agent, including but not limited to rapamycin (sirolimus), to the eye of a subject, including but not limited to a human subject. Nonlimiting examples of liquid formulations include solutions, suspensions, and in situ gelling formulations. CROSS-REFERENCES TO RELATED APPLICATIONS [00021 The present application is related to and claims priority from U.S. Provisional Patent Application Serial No. 60/664,040 titled "Liquid Formulations For Treatment Of Diseases Or Conditions," filed Mar. 21, 2005, U.S. Provisional Patent Application Serial No. 60/664,306 titled "In Situ Gelling Formulations And Liquid Formulations For Treatment of Diseases Or Conditions," filed Mar. 21, 2005, U.S. Provisional Patent Application Serial No. 60/651,790, titled "Formulations For Ocular Treatment," filed Feb. 9, 2005, each of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND [00031 The retina of the eye contains the cones and rods that detect light. In the center of the retina is the macula lutea, which is about 1/3 to 1/2 cm in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to one side (rather than resting above the cones), thereby allowing light a more direct path to the cones. lA [00041 Under the retina are the choroid, comprising a collection of blood vessels embedded within a fibrous tissue, and the deeply pigmented epithelium, which overlays the choroid layer. The choroidal blood vessels provide nutrition to the retina (particularly its visual cells). [0005] There are a variety of retinal disorders for which there is currently no treatment or for which the current treatment is not optimal. Retinal disorders such as uveitis (an inflammation of the uveal tract: iris, ciliary body, and choroid), central retinal vein occlusive diseases (CRVO), branch retinal venous occlusion (BRVO), macular degeneration, macular edema, proliferative diabetic retinopathy, and retinal detachment generally are all retinal disorders that are difficult to treat with conventional therapies. [00061 Age-related macular degeneration (AMD) is the major cause of severe visual loss in the United States for individuals over the age of 60. AMD occurs in either an atrophic or less commonly an exudative form. The atrophic form of AMD is also called "dry AMD," and the exudative form of AMD is also called "wet AMD." [0007] In exudative AMD, blood vessels grow from the choriocapillaris through defects in Bruch's membrane, and in some cases the underlying retinal pigment epithelium. Organization of serous or hemorrhagic exudates escaping from these vessels results in fibrovascular scarring of the macular region with attendant degeneration of the neuroretina, detachment and tears of the retinal pigment epithelium, vitreous hemorrhage and permanent loss of central vision. This process is responsible for more than 80% of cases of significant visual loss in subjects with AMD. Current or forthcoming treatments include laser photocoagulation, photodynamic therapy, treatment with VEGF antibody fragments, treatment with pegylated aptamers, and treatment with certain small molecule agents. [00081 Several studies have recently described the use of laser photocoagulation in the treatment of initial or recurrent neovascular lesions associated with AMD (Macular Photocoagulation Study Groups (1991) in Arch. Ophthal. 109:1220; Arch. Ophthal. 109:1232; Arch. Ophthal. 109:1242). Unfortunately, AMD subjects with subfoveal lesions subjected to laser treatment experienced a rather precipitous reduction in visual acuity (mean 3 lines) at 3 months follow-up. Moreover, at two years post-treatment treated eyes had only marginally better visual acuity than their untreated counterparts (means of 20/320 and 20/400, respectively). Another drawback of the procedure is that vision after surgery is immediately worse.

100091 Photodynamic therapy (PDT) is a form of phototherapy, a term encompassing all treatments that use light to produce a beneficial reaction in a subject. Optimally, PDT destroys unwanted tissue while sparing normal tissue. Typically, a compound called a photosensitizer is administered to the subject. Usually, the photosensitizer alone has little or no effect on the subject. When light, often from a laser, is directed onto a tissue containing the photosensitizer, the photosensitizer is activated and begins destroying targeted tissue. Because the light provided to the subject is confined to a particularly targeted area, PDT can be used to selectively target abnormal tissue, thus sparing surrounding healthy tissue. PDT is currently used to treat retinal diseases such as AMD. PDT is currently the mainstay of treatment for subfoveal choroidal neovascularization in subjects with AMD (Photodynamic Therapy for Subfoveal Choroidal Neovascularization in Age Related Macular Degeneration with Verteporfin (TAP Study Group) Arch Ophthalmol. 1999 117:1329-1345. 100101 Choroidal neovascularization (CNV) has proven to be recalcitrant to treatment in most cases. Conventional laser treatment can ablate CNV and help to preserve vision in selected cases not involving the center of the retina, but this is limited to only about 10% of the cases. Unfortunately, even with successful conventional laser photocoagulation, the neovascularization recurs in about 50-70% of eyes (50% over 3 years and >60% at 5 years). (Macular Photocoagulation Study Group, Arch. Ophthalmol. 204:694-701 (1986)). In addition, many subjects who develop CNV are not good candidates for laser therapy because the CNV is too large for laser treatment, or the location cannot be determined so that the physician cannot accurately aim the laser. Photodynamic therapy, although utilized in up to 50% of new cases of subfoveal CNV has only marginal benefits over natural history, and generally delays progression of visual loss rather than improving vision which is already decreased secondary to the subfoveal lesion. PDT is neither preventive or definitive. Several PDT treatments are usually required per subject and additionally, certain subtypes of CNV fare less well than others. [00111 Thus, there remains a long-felt need for methods, compositions, and formulations that may be used to optimally prevent or significantly inhibit choroidal neovascularization and to prevent and treat wet AMD. [00121 In addition to AMD, choroidal neovascularization is associated with such retinal disorders as presumed ocular histoplasmosis syndrome, myopic degeneration, angioid streaks, idiopathic central serous chorioretinopathy, inflammatory conditions of the retina and or choroid, and ocular trauma. Angiogenic damage associated with neovascularization occurs in a wide range of disorders including diabetic retinopathy, venous occlusions, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia and trauma. 100131 Uveitis is another retinal disorder that has proven difficult to treat using existing therapies. Uveitis is a general term that indicates an inflammation of any component of the uveal tract. The uveal tract of the eye consists of the iris, ciliary body, and choroid. Inflammation of the overlying retina, called retinitis, or of the optic nerve, called optic neuritis, may occur with or without accompanying uveitis. [00141 Uveitis is most commonly classified anatomically as anterior, intermediate, posterior, or diffuse. Posterior uveitis signifies any of a number of forms of retinitis, choroiditis, or optic neuritis. Diffuse uveitis implies inflammation involving all parts of the eye, including anterior, intermediate, and posterior structures. [00151 The symptoms and signs of uveitis may be subtle, and vary considerably depending on the site and severity of the inflammation. Regarding posterior uveitis, the most common symptoms include the presence of floaters and decreased vision. Cells in the vitreous humor, white or yellow-white lesions in the retina and/or underlying choroid, exudative retinal detachments, retinal vasculitis, and optic nerve edema may also be present in a subject suffering from posterior uveitis. [00161 Ocular complications of uveitis may produce profound and irreversible loss of vision, especially when unrecognized or treated improperly. The most frequent complications of posterior uveitis include retinal detachment; neovascularization of the retina, optic nerve, or iris; and cystoid macular edema. 100171 Macular edema (ME) can occur if the swelling, leaking, and hard exudates noted in background diabetic retinopathy (BDR) occur within the macula, the central 5% of the retina most critical to vision. Background diabetic retinopathy (BDR) typically consists of retinal microaneurisms that result from changes in the retinal microcirculation. These microaneurisms are usually the earliest visible change in retinopathy seen on exam with an ophthalmoscope as scattered red spots in the retina where tiny, weakened blood vessels have ballooned out. The ocular findings in background diabetic retinopathy progress to cotton wool spots, intraretinal hemorrhages, leakage of fluid from the retinal capillaries, and retinal exudates. The increased vascular permeability is also related to elevated levels of local growth factors such as vascular endothelial growth factor. The macula is rich in dI cones, the nerve endings that detect color and upon which daytime vision depends. When increased retinal capillary permeability effects the macula, blurring occurs in the middle or just to the side of the central visual field, rather like looking through cellophane. Visual loss may progress over a period of months, and can be very annoying because of the inability to focus clearly. ME is a common cause of severe visual impairment. 100181 There have been many attempts to treat CNV and its related diseases and conditions, as well as other conditions such as macular edema and chronic inflammation, with pharmaceuticals. For example, use of rapamycin to inhibit CNV and wet AMD has been described in U.S. Application No. 10/665,203, which is incorporated herein by reference in its entirety. The use of rapamycin to treat inflammatory diseases of the eye has been described in US patent number 5,387,589, titled Method of Treating Ocular Inflammation, with inventor Prassad Kulkarni, assigned to University of Louisville Research Foundation, the contents of which is incorporated herein in its entirety. [00191 Particularly for chronic diseases, including those described herein, there is a great need for long acting methods for delivering therapeutic agents to the eye, such as to the posterior segment to treat CNV in such diseases as AMD, macular edema, proliferative retinopathies, and chronic inflammation. Formulations with extended delivery of therapeutic agent are more comfortable and convenient for a subject, due to a diminished frequency of ocular injections of the therapeutic agent. [00201 Direct delivery of therapeutic agents to the eye rather than systemic administration may be advantageous because the therapeutic agent concentration at the site of action is increased relative to the therapeutic agent concentration in a subject's circulatory system. Additionally, therapeutic agents may have undesirable side effects when delivered systemically to treat posterior segment disease. Thus, localized drug delivery may promote efficacy while decreasing side effects and systemic toxicity. [0020A] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general 5 knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application. SUMMARY [0020B] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. [0021] The methods, compositions, and liquid formulations described herein allow delivery of a therapeutic agent to a subject, including but not limited to a human subject or to the eye of a subject. Described herein are methods, compositions, and liquid formulations for delivering a variety of therapeutic agents for extended periods of time which can be used for the treatment, prevention, inhibition, delaying onset of, or causing regression of a number of conditions or diseases, including but not limited to diseases or 5A conditions of the eye. The liquid formulations include, without limitation, solutions, suspensions, and in situ gelling formulations. [00221 Described herein are methods, compositions and liquid formulations for administering to a human subject an amount of rapamycin effective to treat, prevent, inhibit, delay onset of, or cause regression of wet AMD. [00231 As described in further detail in the Detailed Description section, the methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a human subject of therapeutically effective amounts of rapamycin for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of wet AMD. In some variations, the methods, compositions, and liquid formulations are used to treat wet AMD. In some variations, the methods, compositions, and liquid formulations are used to prevent wet AMD. In some variations, the methods and formulations described herein are used to prevent the transition from dry AMD to wet AMD. The methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a subject of therapeutically effective amounts of rapamycin for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of CNV. In some variations, the methods, compositions and liquid formulations are used to treat CNV. The methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a subject of therapeutically effective amounts of rapamycin for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of angiogenesis in the eye. In some variations, the methods, compositions and liquid formulations are used to treat angiogenesis. Other diseases and conditions that may be treated, prevented, inhibited, have onset delayed, or caused to regress using rapamycin are described in the Diseases and Conditions section of the Detailed Description. [00241 As described in further detail in the Detailed Description, the methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a subject of therapeutically effective amounts of therapeutic agents other than rapamycin for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of wet AMD. In some variations, the methods, compositions and liquid formulations are used to treat wet AMD. Therapeutic agents that may be used are described in detail in the Therapeutic Agents

A

section. Such therapeutic agents include but are not limited to immunophilin binding compounds. Immunophilin binding compounds that may be used include but are not limited to the limus family of compounds described further in the Therapeutic Agents section herein, including rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CC-779, AP23841, ABT-578, derivatives, analogs, prodrugs, salts and esters thereof. The methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a subject of therapeutically effective amounts of therapeutic agents for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of CNV. In some variations, the methods, compositions and liquid formulations are used to treat CNV. The methods, compositions and liquid formulations may also be used for delivery to a subject, including but not limited to a human subject or to the eye of a subject of therapeutically effective amounts of therapeutic agents for the treatment, prevention, inhibition, delaying of the onset of, or causing the regression of angiogenesis in the eye. In some variations, the methods, compositions and liquid formulations are used to treat angiogenesis. Other diseases and conditions that may be treated, prevented, inhibited, have onset delayed, or caused to regress using therapeutic agents other than rapamycin are described in the Diseases and Conditions section of the Detailed Description. [0025] One liquid formulation described herein comprises a solution that includes a therapeutic agent dissolved in a solvent. Generally, any solvent that has the desired effect may be used in which the therapeutic agent dissolves and which can be administered to a subject, including but not limited to a human subject or an eye of a subject. Generally, any concentration of therapeutic agent that has the desired effect can be used. The formulation in some variations is a solution which is unsaturated, a saturated or a supersaturated solution. The solvent may be a pure solvent or may be a mixture of liquid solvent components. In some variations the solution formed is an in situ gelling formulation. Solvents and types of solutions that may be used are well known to those versed in such drug delivery technologies. [0026] The liquid formulations described herein may form a non-dispersed mass when placed into a rabbit eye, including but not limited to the vitreous of a rabbit eye. In some variations the non-dispersed mass comprises a gel. In some variations, the liquid formulation comprises a therapeutic agent and a plurality of polymers. In some '7 variations one of the polymers is polyacrylate or polymethacrylate. In some variations one of the polymers is polyvinylpyrrolidone. [00271 In some variations, the non-dispersed mass comprises a depot. In some variations, the non-dispersed mass consists of a depot. [00281 For liquid formulations which form a non-dispersed mass, the non-dispersed mass may generally be any geometry or shape. The non-dispersed mass-forming liquid formulations may, for instance, appear as a compact spherical mass when placed in the vitreous. In some variations the liquid formulations described herein form a milky or whitish colored semi-contiguous or semi-solid non-dispersed mass relative to the medium in which it is placed, when placed in the vitreous. [00291 The liquid formulations may generally be administered in any volume that has the desired effect. In one method a volume of a liquid formulation is administered to the vitreous and the liquid formulation is less than one half the volume of the vitreous. [0030] Routes of administration that may be used to administer a liquid formulation include but are not limited to (1) placement of the liquid formulation by placement, including by injection, into a medium, including but not limited to an aqueous medium in the body, including but not limited to intraocular or periocular injection; or (2) oral administration of the liquid formulation. The liquid formulation may be administered systemically, including but not limited to the following delivery routes: rectal, vaginal, infusion, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, intracisternal, cutaneous, subcutaneous, intradermal, transdermal, intravenous, intracervical, intraabdominal, intracranial, intrapulmonary, intrathoracic, intratracheal, nasal, buccal, sublingual, oral, parenteral, or nebulised or aerosolized using aerosol propellants. In some variations, the liquid formulation is administered subconjunctivally. In some variations, the liquid formulation is administered intravitreally. [00311 The liquid formulations described herein may be delivered to any medium of a subject, including but not limited to a human subject, including but not limited to an aqueous medium of a subject. [0032] One liquid formulation described herein comprises a liquid formulation of rapamycin or other therapeutic agent. The liquid formulations may comprise a solution, suspension, an in situ gelling formulation, or an emulsion. The droplets in the emulsion may generally be of any size, including but not limited to up to about 5,000 nm.

Q

[00331 In some formulations described herein, the liquid formulations may comprise a therapeutic agent including but not limited to rapamycin, and one or more solubilizing agents or solvents. In some variations, the solubilizing agent or solvent is glycerin, DMSO, DMA, N-methylpyrrolidone, ethanol, benzyl alcohol, isopropyl alcohol, polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, or propylene glycol or a mixture of one or more thereof. [00341 In some formulations described herein, the liquid formulation includes hyaluronic acid. [00351 The liquid formulations described herein may deliver a therapeutic agent or agents for an extended period of time. One nonlimiting example of such an extended release delivery system is a liquid formulation that delivers a therapeutic agent or agents to a subject, including but not limited to a human subject or to the eye of a subject in an amount sufficient to maintain an amount effective to treat, prevent, inhibit, delay onset of, or cause regression of a disease or condition in a subject for an extended period of time. In some variations, the liquid formulation is used to treat a disease or condition in a subject, including but not limited to a human subject. In some variations, the liquid formulation delivers the therapeutic agent for at least about one, about two, about three, about six, about nine, or about twelve months. [00361 The liquid formulations described herein may deliver rapamycin or other therapeutic agents for an extended period of time. One nonlimiting example of such an extended release delivery system is a liquid formulation that delivers rapamycin to a subject, including but not limited to a human subject or to the eye of a subject in an amount sufficient to maintain an amount effective to treat, prevent, inhibit, delay onset of, or cause regression of wet age-related macular degeneration for an extended period of time. In some variations, the liquid formulation is used to treat wet age-related macular degeneration for an extended period of time. In some variations, the liquid formulation is used to prevent wet age-related macular degeneration for an extended period of time. In some variations, the liquid formulation is used to prevent transition of dry AMD to wet AMD for an extended period of time. In one nonlimiting example, the liquid formulation delivers the rapamycin to the vitreous, sclera, retina, choroid, macula, or other tissues of a subject, including but not limited to a human subject in an amount sufficient to treat, prevent, inhibit, delay onset of, or cause regression of wet age-related macular degeneration for at least about three, about six, about nine, or about twelve months. In a some variations, the level of rapamycin is sufficient to treat AMD. In some variations, the level of rapamycin is sufficient to prevent onset of wet AMD. [00371 Other extended periods of release are described in the Detailed Description. [0037A] In a first aspect, the present invention provides a method for treating an ocular disease comprising administering to a subject by intraocular or periocular delivery a volume of a liquid formulation comprising rapamycin at a concentration of between 0.5% and 10% by weight, polyethylene glycol and ethanol, to treat an ocular disease in a subject, wherein the liquid formulation is a liquid solution that forms a non-dispersed mass when injected into the vitreous. [0037B] In another aspect, the present invention provides a method for treating an ocular disease comprising administering to a subject by intraocular or periocular delivery a volume of a liquid formulation consisting of rapamycin at a concentration of between 0.5% and 10% by weight, polyethylene glycol, and ethanol at a concentration between 0.1% and 10% by weight, to treat an ocular disease in a subject, wherein the liquid formulation is a liquid solution that forms a non-dispersed mass when injected into the vitreous, and wherein the ocular disease is selected from the group consisting of choroidal neovascularization, dry aged-related macular degeneration, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, dry eye, and uveitis. BRIEF DESCRIPTION OF THE DRAWINGS [00381 FIGURES IA-IC schematically depicts formation of a non-dispersed mass, after injection of a liquid formulation into the vitreous of an eye, as it is believed to occur in some variations. [00391 FIGURE 2 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes at 20, 40, 67, and 90 days after subconjunctival injection of a 1.256% solution of rapamycin in water, ethanol, and F127 (Lutrol). [00401 FIGURE 3 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes at 14, 35, 62, and 85 days after subconjunctival injection of a 5% solution of rapamycin in PEG 400 and ethanol. The 10 level of rapamycin present in the vitreous (ng/ml) is also shown at 2 days after injection. [00411 FIGURE 4 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes at 14, 35, 62, and 90 days after intravitreal injection of a 5% solution of rapamycin in PEG 400 and ethanol. The level of rapamycin present in the vitreous (ng/ml) is also shown at 2 days after injection. [00421 FIGURE 5 depicts images of rabbit eyes 8 days after intravitreal injection of 10 p.

1 (Fig. 4A), 20 pl (Fig. 4B), and 40 p.

1 (Fig. 4C) of a 6% rapamycin suspension in PEG400. [00431 FIGURE 6 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of rabbit eyes at 7, 32, 45, and 90 days after subconjunctival injection of a 4.2% solution of rapamycin in ethanol, PVP K90, PEG 400, and Eudragit RL 100. [00441 FIGURE 7 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of rabbit eyes at 14, 42, 63, and 91 days after subconjunctival injection of a 3% suspension of rapamycin in PEG 400. [0045] FIGURE 8 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid tissues (ng/mg) and sclera (ng/mg) of rabbit eyes at 14, 42, 63, and 91 days after intravitreal injection of a 3% suspension of rapamycin in PEG 400, and in the vitreous at 63 and 91 days after injection. 10A [00461 FIGURE 9 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of rabbit eyes at 14, 42, 63, and 91 days after subconjunctival injection of a 2% solution of rapamycin in ethanol and PEG 400. 100471 FIGURE 10 depicts the level of rapamycin in the retina choroid tissues (ng/mg) and sclera (ng/mg) of rabbit eyes at 14, 42, 63, and 91 days after intravitreal injection of a 2% solution of rapamycin in ethanol and PEG 400. 100481 FIGURE 11 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 63 and 91 days after intravitreal injection of a 2% solution of rapamycin in ethanol and PEG 400. [00491 FIGURE 12 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 5, 30, 60, 90, and 120 days after subconjunctival injection of 20 d, 40 ptl, and 60 pl doses of a 2% solution of rapamycin in ethanol and PEG 400. [00501 FIGURE 13 depicts the level of rapamycin in the retina choroid tissues (ng/mg) of rabbit eyes at 5, 30, 60, 90, and 120 days after subconjunctival injection of 20 pl, 40 p1, and 60 pl doses of a 2% solution of rapamycin in ethanol and PEG 400. [0051] FIGURE 14 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 5, 30, 60, 90, and 120 days after intravitreal injection of 20 tl and 40 pl doses of a 2% solution of rapamycin in ethanol and PEG 400 and of a 100 pl dose of a 0.4 % rapamycin solution in ethanol and PEG 400. [00521 FIGURE 15 depicts the level of rapamycin in the retina choroid tissues (ng/mg) of rabbit eyes at 5, 30, 60, 90, and 120 days after intravitreal injection of 20 pl and 40 pl doses of a 2% solution of rapamycin in ethanol and PEG 400 and of a 100 pl dose of a 0.4 % rapamycin solution in ethanol and PEG 400. [00531 FIGURE 16 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 5 and 14 days after subconjunctival injection of a single 10 pl dose, a single 60 pl dose, two 30 pl doses, and three 30 pl doses of a 2% solution of rapamycin in ethanol and PEG 400. 100541 FIGURE 17 depicts the level of rapamycin in the retina choroid tissues (ng/mg) of rabbit eyes at 5 and 14 days after subconjunctival injection of a single 10 pl dose, a single 60 pl dose, two 30 p.l doses, and three 30 p.l doses of a 2% solution of rapamycin in ethanol and PEG 400.

100551 FIGURE 18 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 5, 14, and 30 days after subconjunctival injection of a single 10 pl dose, a single 30 p1 dose, and three 30 pl doses of a 3% suspension of rapamycin in PEG 400. 100561 FIGURE 19 depicts the level of rapamycin in the retina choroid tissues (ng/mg) of rabbit eyes at 5, 14, and 30 days after subconjunctival injection of a single 10 pl dose, a single 30 pl dose, and three 30 pl doses of a 3% suspension of rapamycin in PEG 400. [00571 FIGURE 20 depicts the level of rapamycin in the retina choroid tissues (ng/mg) of rabbit eyes at 5, 30, and 90 days after intravitreal injection of 10 pl of a 0.2% solution of rapamycin in ethanol and PEG 400, of 10 pl of a 0.6% solution of rapamycin in ethanol and PEG 400, and of 10 pl of a 2% solution of rapamycin in ethanol and PEG 400. 100581 FIGURE 21 depicts the level of rapamycin in the vitreous (ng/ml) of rabbit eyes at 5, 30, and 90 days after intravitreal injection of 10 pl of a 0.2% solution of rapamycin in ethanol and PEG 400, of 10 pl of a 0.6% solution of rapamycin in ethanol and PEG 400, and of 10 pl of a 2% solution of rapamycin in ethanol and PEG 400. [00591 FIGURE 22 depicts the level of rapamycin in the aqueous humor (ng/ml) of rabbit eyes, the cornea (ng/mg), and the retina choroid tissues (ng/mg) at 1, 4, 7, 11, 14, 21, 28, 35, 54, and 56 days after subconjunctival injection of 40 p1 of a 2% solution of rapamycin in ethanol and PEG 400. DETAILED DESCRIPTION 100601 Described herein are compositions, liquid formulations and methods relating to delivery of therapeutic agents to a subject, including but not limited to a human subject or to the eye of a subject. These compositions, liquid formulations, and methods may be used for the treatment, prevention, inhibition, delaying onset of, or causing regression of diseases and conditions of the eye including but not limited to diseases or conditions of the posterior segment, including but not limited to choroidal neovascularization; macular degeneration; age-related macular degeneration, including wet AMD and dry AMD; retinal angiogenesis; chronic uveitis; and other retinoproliferative conditions. In some variations, the compositions, liquid formulations, and methods are used for the treatment of the aforementioned diseases or conditions of the eye. [00611 Herein are described (1) the therapeutic agents that may be delivered to a subject, including but not limited to a human subject or an eye of a subject using the compositions, liquid formulations, and methods described herein, (2) the diseases and 11) conditions that may be treated, prevented, inhibited, onset delayed, or regression caused by delivery of the therapeutic agents, (3) liquid formulations that may be used to deliver the therapeutic agents, (4) routes of administration for delivery of the liquid formulations, (5) extended delivery of therapeutic agents including but not limited to rapamycin, and (6) description of the treatment of CNV and wet AMD by delivery of rapamycin to a subject, including but not limited to a human subject or to the eye of a subject for an extended period of time using the described compositions and liquid formulations. [00621 The term "about," as used herein, refers to the level of accuracy that is obtained when the methods described herein, such as the methods in the examples, are used. However, by "about" a certain amount of a component of a formulation is meant 90-110% of the amount stated. Therapeutic Agents [00631 Most generally, any compounds and compositions currently known or yet to be discovered that are useful in treating, preventing, inhibiting, delaying the onset of, or causing the regression of the diseases and conditions described herein may be therapeutic agents for use in the compositions, liquid formulations, and methods described herein. [00641 Therapeutic agents that may be used include compounds that act by binding members of the immunophilin family of cellular proteins. Such compounds are known as "immunophilin binding compounds." Immunophilin binding compounds include but are not limited to the "limus" family of compounds. Examples of limus compounds that may be used include but are not limited to cyclophilins and FK506-binding proteins (FKBPs), including sirolimus (rapamycin) and its water soluble analog SDZ-RAD (Novartis), TAFA-93 (Isotechnika), tacrolimus, everolimus, RAD-001 (Novartis), pimecrolimus, temsirolimus, CCI-779 (Wyeth), AP23841 (Ariad), AP23573 (Ariad), and ABT-578 (Abbott Laboratories). Limus compound analogs and derivatives that may be used include but are not limited to the compounds described in U.S. Patents 5,527,907; 6,376,517; and 6,329,386 and U.S. Patent Application No. 09/950,307, each of which is incorporated herein by reference in their entirety. Therapeutic agents also include analogs, prodrugs, salts and esters of limus compounds. [0065] The terms rapamycin, rapa, and sirolimus are used interchangeably herein. [00661 Other rapamycin derivatives that may be used include, without limitation, 7-epi rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi 101 thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl rapamycin, mono- and di-ester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analog of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates and sulfamates, mono-esters and di-esters at positions 31 and 42, 30-demethoxy rapamycin, and other derivatives described in Vezina et al., "Rapamycin (AY-22,989), A New Antifungal Antibiotic. I. Taxonomy Of The Producing Streptomycete And Isolation Of The Active Principle" J. Antibiot. (Tokyo) 28:721-726 (1975); Sehgal et al., "Rapamycin (AY-22,989), A New Antifungal Antibiotic. II. Fermentation, Isolation And Characterization" J. Antibiot. (Tokyo) 28:727-732 (1975); Sehgal et al., "Demethoxyrapamycin (AY-24,668), A New Antifungal Antibiotic" J. Antibiot. (Tokyo) 36:351-354 (1983); and Paiva et al., "Incorporation Of Acetate, Propionate, And Methionine Into Rapamycin By Streptomycetes hygroscopicus" J Nat Prod 54:167-177 (1991), WO 92/05179, EP 467606, Caufield et al., "Hydrogenated Rapamycin Derivatives" U.S. Pat. No. 5,023,262; Kao et al., "Bicyclic Rapamycins" U.S. Pat. No. 5,120,725; Kao et al., "Rapamycin Dimers" U.S. Pat. No. 5,120,727; Failli et al., "Silyl Ethers Of Rapamycin" U.S. Pat. No. 5,120,842; Failli et al., "Rapamycin 42 Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful As Immunosuppressive Agents" U.S. Pat. No. 5,177,203; Nicolaou et al., "Total Synthesis Of Rapamycin" J. Am. Chem. Soc. 115: 4419-4420 (1993); Romo et al, "Total Synthesis Of (-) Rapamycin Using An Evans-Tishchenko Fragment Coupling" J. Am. Chem. Soc. 115:7906-7907 (1993); and Hayward et al, "Total Synthesis Of Rapamycin Via A Novel Titanium-Mediated Aldol Macrocyclization Reaction" J. Am. Chem. Soc., 115:9345-9346 (1993) , each of which is incorporated herein by reference in its entirety. [00671 The limus family of compounds may be used in the compositions, liquid formulations and methods for the treatment, prevention, inhibition, delaying the onset of, or causing the regression of angiogenesis-mediated diseases and conditions of the eye, including choroidal neovascularization. The limus family of compounds may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD. Rapamycin and rapamycin derivatives and analogs may be used to prevent, treat, inhibit, delay the onset of, or cause regression of angiogenesis-mediated diseases and conditions of the eye, including choroidal neovascularization. Rapamycin may be used to prevent, treat, inhibit, delay the onset of, or cause regression of AMD, including wet AMD. In some variations, a member of the limus family of compounds or rapamycin is 1 A used to treat wet AMD or angiogenesis-mediated diseases and conditions of the eye including choroidal neovascularization. [00681 Other therapeutic agents that may be used include those disclosed in the following patents and publications, the contents of each of which is incorporated herein by reference in its entirety: PCT publication WO 2004/027027, published April 1, 2004, titled Method of inhibiting choroidal neovascularization, assigned to Trustees of the University of Pennsylvania; US patent number 5,387,589, issued February 7, 1995, titled Method of Treating Ocular Inflammation, with inventor Prassad Kulkarni, assigned to University of Louisville Research Foundation; US patent number 6,376,517, issued April 23, 2003, titled Pipecolic acid derivatives for vision and memory disorders, assigned to GPI NIL Holdings, Inc; PCT publication WO 2004/028477, published April 8, 2004, titled Method subretinal administration of therapeutics including steroids: method for localizing pharmadynamic action at the choroid and retina; and related methods for treatment and or prevention of retinal diseases, assigned to Innorx, Inc; US patent number 6,416,777, issued July 9, 2002, titled Ophthalmic drug delivery device, assigned to Alcon Universal Ltd; US patent number 6,713,081, issued March 30, 2004, titled Ocular therapeutic agent delivery device and methods for making and using such devices, assigned to Department of Health and Human Services; US patent number 5,100,899, issued Mar. 31, 1992, titled Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof. [00691 Other therapeutic agents that may be used include pyrrolidine, dithiocarbamate (NFKB inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-i and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitors such as VelcadeTM (bortezomib, for injection; ranibuzumab (LucentisTM) and other antibodies directed to the same target; pegaptanib (MacugenTM); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor type integrins; a-v/p-3 integrin antagonists; c-v/p-l integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including y-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; AccutaneTM (13-cis retinoic acid); ACE inhibitors, including but not limited 1 C to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG 1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)- 1 -phenylethene; t RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigal locatechin-3 -gallate; cerivastatin; analogues of suramin; VEGF trap molecules; apoptosis inhibiting agents; VisudyneTM, snET2 and other photo sensitizers, which may be used with photodynamic therapy (PDT); inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4). 100701 Other therapeutic agents that may be used include anti-inflammatory agents, including, but not limited to nonsteroidal anti-inflammatory agents and steroidal anti inflammatory agents. In some variations, active agents that may be used in the liquid formulations are ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, antibacterials, antihypertensives, pressors, antiprotozoal agents, antiviral agents, antifungal agents, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents. [0071] Steroidal therapeutic agents that may be used include but are not limited to 21 acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, 1 A prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and any of their derivatives. [00721 In some variations, cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone, or their derivatives, may be used. The liquid formulation may include a combination of two or more steroidal therapeutic agents. [00731 In one nonlimiting example, the steroidal therapeutic agents may constitute from about 0.05% to about 50% by weight of the liquid formulation. In another nonlimiting example, the steroid constitutes from about 0.05% to about 10%, between about 10% to about 20%; between about 30% to about 40%; or between about 40% to about 50% by weight of the liquid formulation. [00741 Other nonlimiting examples of therapeutic agents that may be used include but are not limited to anaesthetics, analgesics, cell transport/mobility impending agents such as colchicines, vincristine, cytochalasin B and related compounds; carbonic anhydrase inhibitors such as acetazolamide, methazolamide, dichlorphenamide, diamox and neuroprotectants such as nimodipine and related compounds; antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, aminosides, gentamycin, erythromycin and penicillin, quinolone, ceftazidime, vancomycine imipeneme; antifungals such as amphotericin B, fluconazole, ketoconazole and miconazole; antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals, such as idoxuridine, trifluorothymidine, trifluorouridine, acyclovir, ganciclovir, cidofovir, interferon, DDI, AZT, foscamet, vidarabine, irbavirin, protease inhibitors and anti-cytomegalovirus agents; antiallergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine, pyrilamine and prophenpyridamine; synthetic gluocorticoids and mineralocorticoids and more generally hormones forms derivating from the cholesterol metabolism (DHEA, progesterone, estrogens); non-steroidal anti inflammatories such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam and COX2 inhibitors; antineoplastics such as carmustine, cisplatin, fluorouracil; adriamycin, asparaginase, azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine, etoposide, etretinate, 117 filgrastin, floxuridine, fludarabine, fluorouracil, florxymesterone, flutamide, goserelin, hydroxyurea, ifosfamide, leuprolide, levamisole, limustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, plicamycin, procarbazine, sargramostin, streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard, vinblastine, vincristine and vindesine; immunological drugs such as vaccines and immune stimulants; insulin, calcitonin, parathyroid hormone and peptide and vasopressin hypothalamus releasing factor; beta adrenergic blockers such as timolol, levobunolol and betaxolol; cytokines, interleukines and growth factors epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, ciliary neurotrophic growth factor, glial derived neurotrophic factor, NGF, EPO, PLGF, brain nerve growth factor (BNGF), vascular endothelial growth factor (VEGF) and monoclonal antibodies or fragments thereof directed against such growth factors; anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and triamcinolone; decongestants such as phenylephrine, naphazoline and tetrahydrazoline; miotics and anti-cholinesterases such as pilocarpine, carbachol, di-isopropyl fluorophosphate, phospholine iodine and demecarium bromide; mydriatics such as atropine sulphate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine; sympathomimetics such as epinephrine and vasoconstrictors and vasodilators, anticlotting agents such as heparin, antifibrinogen, fibrinolysin, anticlotting activase, antidiabetic agents include acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, insulin and aldose reductase inhibitors, hormones, peptides, nucleic acids, saccharides, lipids, glycolipids, glycoproteins and other macromolecules include endocrine hormones such as pituitary, insulin, insulin-related growth factor, thyroid, growth hormones; heat shock proteins; immunological response modifiers such as muramyl dipeptide, cyclosporins, interferons (including alpha-, beta- and gamma interferons), interleukin-2, cytokines, FK506 (an epoxy-pyrido-oxaazcyclotricosine tetrone, also known as Tacrolimus), tumor necrosis factor, pentostatin, thymopentin, transforming factor beta2, erythropoetin; antineogenesis proteins (e.g. anti VEGF, interferons), antibodies (monoclonal, polyclonal, humanized, etc.) or antibodies fragments, oligoaptamers, aptamers and gene fragments (oligonucleotides, plasmids, ribozymes, small interference RNA (SiRNA), nucleic acid fragments, peptides), immunomodulators such as endoxan, thalidomide, tamoxifene; antithrombolytic and 10 vasodilator agents such as rtPA, urokinase, plasmin; nitric oxide donors, nucleic acids, dexamethasone, cyclosporin A, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, rapamycin, tacrolimus (FK-506), folic acid analogs (e.g., denopterin, edatrexate, methotrexate, piritrexim, pteropterin, Tomudex@, trimetrexate), purine analogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine, thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur) fluocinolone, triaminolone, anecortave acetate, fluorometholone, medrysone, and prednislone. In some variations the immunosuppressive agent is dexamethasone. In some variations the immunosuppressive agent is cyclosporin A. [00751 In some variations the formulation comprises a combination of one or more therapeutic agents. [00761 Other nonlimiting examples of therapeutic agents that may be used in the formulations described herein include antibacterial antibiotics, aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin), amphenicols (e.g., azidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins (e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin), P-lactams (e.g., carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem, imipenem, meropenem, panipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine, pivcefalexin), cephamycins (e.g., cefbuperazone, cefinetazole, cefminox, cefotetan, cefoxitin), monobactams (e.g., aztreonam, carumonam, tigemonam), oxacephems, flomoxef, moxalactam), penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin, 10 dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penethamate hydriodide, penicillin g benethamine, penicillin g benzathine, penicillin g benzhydrylamine, penicillin g calcium, penicillin g hydrabamine, penicillin g potassium, penicillin g procaine, penicillin n, penicillin o, penicillin v, penicillin v benzathine, penicillin v hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin), ritipenem, lincosamides (e.g., clindamycin, lincomycin), macrolides (e.g., azithromycin, carbomycin, clarithromycin, dirithromycin, erythromycin, erythromycin acistrate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, leucomycins, midecamycins, miokamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides (e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin, polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin, virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, rolitetracycline, sancycline, tetracycline), and others (e.g., cycloserine, mupirocin, tuberin); synthetic antibacterials, 2.4 Diaminopyrimidines (e.g., brodimoprim, tetroxoprim, trimethoprim), nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, chloramine-b, chloramine-t, dichloramine t, n2 formylsulfisomidine, n4-p-d-glucosylsulfanilamide, mafenide, 4' (methylsulfamoyl)sulfanilanilide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol,

I'A

sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamidosalicylic acid, n4 sulfanilylsulfanilamide, sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, p sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others (e.g., clofoctol, hexedine, methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, xibomol), antifungal antibiotics, polyenes (e.g., amphotericin b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin), azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, viridin, synthetic antifungals, allylamines (e.g., butenafine, naftifine, terbinafine), imidazoles (e.g., bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole), thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triazoles (e.g., fluconazole, itraconazole, saperconazole, terconazole), acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazole dihydrochloride, exalarnide, flucytosine, halethazole, hexetidine, loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione, salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin, ujothion, undecylenic acid, zinc propionate, antineoplastics, antibiotics and analogs (e.g., aclacinomycins, actinomycin fl, anthramycin, azaserine, bleomycins, cactinomycin, carubicin, carzinophilin, chromomycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L norleucine, doxorubicin, epirubicin, idarubicin, menogaril, mitomycins, mycophenolic acid, nogalamycin, olivomycines, peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin), antimetabolites (e.g. folic acid analogs (e.g., denopterin, edatrexate, methotrexate, piritrexim, pteropterin, Tomudex@, trimetrexate), purine analogs (e.g., cladribine, fludarabine, 6-mercaptopurine, ')1 thiamiprine, thioguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, tagafur), antiinflammatory agents, steroidal antiinflammatory agents, acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25 -diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and triamcinolone hexacetonide, non-steroidal antiinflammatory agents, aminoarylcarboxylic acid derivatives (e.g., enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid), arylacetic acid derivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acid derivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin), arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine), arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles (e.g., difenamizole, epirizole), pyrazolones (e.g., apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, I -naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine), thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam, tenoxicam), &-acetamidocaproic acid, s adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, a-bisabolol, bucolome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, superoxide dismutase, tenidap, and zileuton. 100771 The therapeutic agents may also be used in combination with other therapeutic agents and therapies, including but not limited to agents and therapies useful for the treatment, prevention, inhibition, delaying onset of, or causing regression of angiogenesis or neovascularization, particularly CNV. In some variations the additional agent or therapy is used to treat regression of angiogenesis or neovascularization, particularly CNV. Non-limiting examples of such additional agents and therapies include pyrrolidine, dithiocarbamate (NFKB inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-I and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitors such as VelcadeTM (bortezomib, for injection; ranibuzumab (LucentisTM) and other antibodies directed to the same target; pegaptanib (MacugenTM); vitronectin receptor antagonists, such as cyclic peptide antagonists of vitronectin receptor-type integrins; ax-v/p-3 integrin antagonists; a-v/-l integrin antagonists; thiazolidinediones such as rosiglitazone or troglitazone; interferon, including y-interferon or interferon targeted to CNV by use of dextran and metal coordination; pigment epithelium derived factor (PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortave acetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA interference (RNAi) of angiogenic factors, including ribozymes that target VEGF expression; AccutaneTM (13-cis retinoic acid); ACE inhibitors, including but not limited to quinopril, captopril, and perindozril; inhibitors of mTOR (mammalian target of rapamycin); 3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines; AMG 1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and (E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t RNA synthase modulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor; potassium channel blockers; endorepellin; purine analog of 6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase; epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGF trap molecules; inhibitors of hepatocyte growth factor (antibodies to the growth factor or its receptors, small molecular inhibitors of the c-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosis inhibiting agents; VisudyneTM, snET2 and other photo sensitizers with photodynamic therapy (PDT); and laser photocoagulation. Diseases and conditions that may be treated, prevented, inhibited, onset delayed, or regression caused [00781 Herein are described diseases and conditions that may be treated, prevented, inhibited, onset delayed, or regression caused using the therapeutic agents and the formulations, liquid formulations, and methods described herein. In some variations, the diseases or conditions are treated using the therapeutic agents and the formulations, liquid formulations, and methods described herein. Unless the context indicates otherwise, it is envisioned that the subjects on whom all of the methods of treatment may be performed include, but are not limited to, human subjects. [00791 Generally, any diseases or condition of the eye susceptible to treatment, prevention, inhibition, delaying the onset of, or causing the regression of using the therapeutic agents and the formulations, liquid formulations and methods described herein may be treated, prevented, inhibited, onset delayed, or regression caused treated or prevented. Examples of diseases or conditions of the eye include, but are not limited to, diseases or conditions associated with neovascularization including retinal and/or choroidal neovascularization. 100801 Diseases or conditions associated with retinal and/or choroidal neovascularization that can be treated, prevented inhibited, have onset delayed, or be caused to regress using the formulations, liquid formulations, and methods described herein include, but are not limited to, diabetic retinopathy, macular degeneration, wet and dry AMD, retinopathy of prematurity (retrolental fibroplasia), infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, myopic degeneration, angioid streaks, and ocular trauma. Other non-limiting examples of diseases and conditions of the eye that may be treated, prevented inhibited, have onset delayed, or be caused to regress using the formulations, liquid formulations, and methods described herein include, but are not limited to, pseudoxanthoma elasticum, vein occlusion, artery occlusion, carotid

')A

obstructive disease, Sickle Cell anemia, Eales disease, myopia, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma, polypoidal choroidal vasculopathy, post-laser complications, complications of idiopathic central serous chorioretinopathy, complications of choroidal inflammatory conditions, rubeosis, diseases associated with rubeosis (neovascularization of the angle), neovascular glaucoma, uveitis and chronic uveitis, macular edema, proliferative retinopathies and diseases or conditions caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of proliferative vitreoretinopathy (including post-operative proliferative vitreoretinopathy), whether or not associated with diabetes. 10081] In some variations, the formulations and pharmaceutical formulations described herein are used to prevent or delay onset of a disease or condition of the eye where the subject, including but not limited to a human subject, is at heightened risk of developing the disease or condition of the eye. A subject with a heightened risk of developing a disease or condition is a subject with one or more indications that the disease or condition is likely to develop in the particular subject. In some variations the subject with a heightened risk of developing wet AMD is a subject with dry AMD in at least one eye. In some variations the subject with a heightened risk of developing wet AMD in a fellow eye is a subject with wet AMD in the other eye. In some variations, the formulations and pharmaceutical formulations described herein are used to prevent or delay onset of CNV in a subject at heightened risk of developing CNV, including but not limited to prevention or delaying onset of CNV in the fellow eye of a subject, including but not limited to a human subject with AMD in one eye. In some variations, the formulations and pharmaceutical formulations described herein are used to prevent or delay onset of CNV in the fellow eye of a subject with wet AMD in one eye. In some variations, the formulations and pharmaceutical formulations comprise a limus compound, including but not limited to rapamycin. In some variations the formulations and pharmaceutical formulations are administered periocularly, including without limitation subconjunctivally, to a human subject with vision of 20/40 or better. In some variations, the formulations and pharmaceutical formulations are administered periocularly, including without limitation subconjunctivally, to the eye of a human subject where the eye to which the formulation is administered has vision of 20/40 or better. [0082] In some variations, the formulations and pharmaceutical formulations described herein are used to treat, prevent, or delay onset of AMD. In some variations, the formulations and pharmaceutical formulations described herein are used to treat, prevent, or delay onset of dry AMD. In some variations, subjects including but not limited to human subjects with non-central geographic atrophy are administered a formulation or pharmaceutical formulations described herein to treat, prevent, or delay onset of central geographic atrophy. In some variations, the formulations and pharmaceutical formulations comprise a limus compound, including but not limited to rapamycin. In some variations the formulations and pharmaceutical formulations are administered periocularly, including without limitation subconjunctivally, to a human subject with vision of 20/40 or better. In some variations, the formulations and pharmaceutical formulations described herein are administered and the subject, including but not limited to a human subject is also treated with a second therapy for treating the disease or disorder. In some variations, the formulations and pharmaceutical formulations described herein are used to treat, prevent, or delay onset of wet or dry AMD and the subject, including but not limited to a human subject is also treated with laser therapy such as photodynamic laser therapy, either before, during, or after treatment with the formulations or pharmaceutical formulations described herein. [0083] In some variations, the formulations and pharmaceutical formulations described herein are used to treat one or more of uveitis, allergic conjunctivitis, macular edema, glaucoma, or dry eye. [00841 In some variations, a formulations or pharmaceutical formulation comprises a limus compound such as rapamycin, and is administered to treat, prevent, or delay onset of dry eye. In some variations, a formulations or pharmaceutical formulation comprises a limus compound such as rapamycin, and is administered to treat, prevent, or delay onset of allergic conjunctivitis. [00851 In some variations, the formulations and pharmaceutical formulations described herein are used to treat glaucoma. In some variations, the formulations and pharmaceutical formulations described herein for treating glaucoma comprise a limus compound such as rapamycin, and are used as a surgical adjuvant to prevent, reduce or delay surgical complications. In some variations, the formulations and pharmaceutical formulations described herein for treating glaucoma comprise a limus compound such as rapamycin, and are used to improve or prolong surgical implant success. In some variations, the formulations and pharmaceutical formulations described herein for treating glaucoma comprise a limus compound such as rapamycin, and are used to improve or prolong success of an argon laser trabeculectomy or other glaucoma-related surgery. In some variations, the formulations and pharmaceutical formulations described herein have a neuroprotective effect and are used to treat glaucoma. 100861 In some variations, the formulations and pharmaceutical formulations described herein are used to treat retinitis pigmentosa. In some variations, the formulations and pharmaceutical formulations described herein for treating glaucoma comprise a limus compound such as rapamycin, and are used to treat, prevent, or delay onset of retinitis pigmentosa. In some variations, the formulations and pharmaceutical formulations described herein have a neuroprotective effect and are used to treat retinitis pigmentosa. [00871 In some variations, the formulations and pharmaceutical formulations described herein are used to treat one or more of central retinal vein occlusive diseases (CRVO), branch retinal venous occlusion (BRVO), retinal vascular diseases and conditions, macular edema, diabetic macular edema, iris neovascularization, diabetic retinopathy, or comeal graft rejection. In some variations, a formulations or pharmaceutical formulation comprises a limus compound such as rapamycin, and is administered to treat, prevent, or delay onset of one or more of these diseases or conditions. In some variations the formulations and pharmaceutical formulations are administered subconjunctivally to an eye with vision of 20/40 or better. 100881 When used to treat, prevent, inhibit, delay the onset of, or cause regressions of uveitis, the formulations and pharmaceutical formulations described herein may be administered by a variety of routes as is known in the art, including but not limited to by ocular or oral administration. Other routes of administration are known and are routine in the art. In some variations, the formulations described herein comprise rapamycin and are used to treat uveitis. [00891 One disease that may be treated, prevented, inhibited, have onset delayed, or be caused to regress using the formulation, liquid formulations and methods described herein is the wet form of AMD. In some variations wet AMD is treated using the formulations, liquid formulations and methods described herein. The wet form of AMD is characterized by blood vessels growing from their normal location in the choroid into an undesirable position under the retina. Leakage and bleeding from these new blood vessels results in vision loss and possibly blindness. 100901 The formulations, liquid formulations, and methods described herein may also be used to prevent or slow the transition from the dry form of AMD (wherein the retinal ') 7 pigment epithelium or RPE degenerates and leads to photoreceptor cell death and the formation of yellow deposits called drusen under the retina) to the wet form of AMD. 100911 "Macular degeneration" is characterized by the excessive buildup of fibrous deposits in the macula and retina and the atrophy of the retinal pigment epithelium. As used herein, an eye "afflicted" with macular degeneration is understood to mean that the eye exhibits at least one detectable physical characteristic associated with the disease of macular degeneration. The administration of rapamycin appears to limit and regress angiogenesis, such as choroidal neovascularization in age-related macular degeneration (AMD), which may occur without treatment. As used herein, the term "angiogenesis" means the generation of new blood vessels ("neovascularization") into a tissue or organ. An "angiogenesis-mediated disease or condition" of the eye or retina is one in which new blood vessels are generated in a pathogenic manner in the eye or retina, resulting in dimunition or loss of vision or other problem, e.g., choroidal neovascularization associated with AMD. [00921 The formulations and liquid formulations described herein, including but not limited to rapamycin-containing formulations and liquid formulations, may also be used to treat, prevent, inhibit, delay the onset of, or cause regression of various immune-related diseases and conditions, including but not limited to organ transplant rejection in a host, graft vs. host disease, autoimmune diseases, diseases of inflammation, hyperproliferative vascular disorders, solid tumors, and fungal infections. In some variations, the formulations and liquid formulations described herein, including but not limited to rapamycin-containing formulations and liquid formulations, are used to treat various immune-related diseases and conditions, including but not limited to organ transplant rejection in a host, graft vs. host disease, autoimmune diseases, diseases of inflammation, hyperproliferative vascular disorders, solid tumors, and fungal infections. The formulations and liquid formulations described herein, including but not limited to rapamycin-containing formulations and liquid formulations, may be used as immunosuppressants. The formulations and liquid formulations described herein, including but not limited to rapamycin-containing formulations and liquid formulations, may be used to treat, prevent, inhibit, or delay the onset of rejection of transplanted organs or tissues including but not limited to transplanted heart, liver, kidney, spleen, lung, small bowel, pancreas, and bone marrow. In some variations, the formulations and liquid formulations described herein are used to treat the onset of rejection of transplanted 1)O organs or tissues including but not limited to transplanted heart, liver, kidney, spleen, lung, small bowel, pancreas, and bone marrow. When used to treat, prevent, inhibit, delay the onset of, or cause regressions of immune-related diseases, including but not limited to transplant rejection, the formulations and liquid formulations described herein may be administered by a variety of routes as is known in the art, including but not limited to by oral administration. [00931 Systemic administration may be achieved by oral administration of the liquid formulation. Other systemic routes of administration are known and are routine in the art. Some examples thereof are listed in the Detailed Description section. [00941 As used herein, to "inhibit" a disease or condition by administration of a therapeutic agent means that the progress of at least one detectable physical characteristic or symptom of the disease or condition is slowed or stopped following administration of the therapeutic agent as compared to the progress of the disease or condition without administration of the therapeutic agent. 10095] As used herein, to "prevent" a disease or condition by administration of a therapeutic agent means that the detectable physical characteristics or symptom of the disease or condition do not develop following administration of the therapeutic agent. [00961 As used herein, to "delay onset of' a disease or condition by administration of a therapeutic agent means that at least one detectable physical characteristic or symptom of the disease or condition develops later in time following administration of the therapeutic agent as compared to the progress of the disease or condition without administration of the therapeutic agent. [0097] As used herein, to "treat" a disease or condition by administration of a therapeutic agent means that the progress of at least one detectable physical characteristic or symptom of the disease or condition is slowed, stopped, or reversed following administration of the therapeutic agent as compared to the progress of the disease or condition without administration of the therapeutic agent. [00981 As used herein, to "cause regression of' a disease or condition by administration of a therapeutic agent means that the progress of at least one detectable physical characteristic or symptom of the disease or condition is reversed to some extent following administration of the therapeutic agent. [00991 A subject, including but not limited to a human subject, having a predisposition for or in need of prevention may be identified by the skilled practitioner by established la methods and criteria in the field given the teachings herein. The skilled practitioner may also readily diagnose individuals as in need of inhibition or treatment based upon established criteria in the field for identifying angiogenesis and/or neovascularization given the teachings herein. 1001001 As used herein, a "subject" is generally any animal that may benefit from administration of the therapeutic agents described herein. In some variations the therapeutic agents are administered to a mammalian subject. In some variations the therapeutic agents are administered to a human subject. In some variations the therapeutic agents may be administered to a veterinary animal subject. In some variations the therapeutic agents may be administered to a model experimental animal subject. 101001 Other diseases and conditions that may be treated, prevented, inhibited, have the onset delayed, or be caused to regress using the methods described herein include those disclosed in the following patents and publications, the contents of each of which is incorporated herein in its entirety: PCT publication WO 2004/027027, published April 1, 2004, titled Method of inhibiting choroidal neovascularization, assigned to Trustees of the University of Pennsylvania; US patent number 5,387,589, issued February 7, 1995, titled Method of Treating Ocular Inflammation, with inventor Prassad Kulkarni, assigned to University of Louisville Research Foundation; US patent number 6,376,517, issued April 23, 2003, titled Pipecolic acid derivatives for vision and memory disorders, assigned to GPI NIL Holdings, Inc; PCT publication WO 2004/028477, published April 8, 2004, titled Method subretinal administration of therapeutics including steroids: method for localizing pharmadynamic action at the choroid and retina; and related methods for treatment and or prevention of retinal diseases, assigned to Innorx, Inc; US patent number 6,416,777, issued July 9, 2002, titled Ophthalmic drug delivery device, assigned to Alcon Universal Ltd; US patent number 6,713,081, issued March 30, 2004, titled Ocular therapeutic agent delivery device and methods for making and using such devices, assigned to Department of Health and Human Services; and U.S. Pat. No. 5,536,729, issued July 16, 1996, titled Rapamycin Formulations for Oral Administration, assigned to American Home Products Corp., and U.S. Pat. App. Nos. 60/503,840 and 10/945,682. Liquid formulations [01011 The liquid formulations described herein contain a therapeutic agent and may generally be any liquid formulation, including but not limited to solutions, suspensions, 12 A and emulsions. In some variations the liquid formulations form a non-dispersed mass relative to a surrounding medium when placed in the vitreous of a rabbit eye. 10102] When a certain volume of a liquid formulation is administered, it is understood that there is some imprecision in the accuracy of various devices that may be used to administer the liquid formulation. Where a certain volume is specified, it is understood that this is the target volume. However, certain devices such as insulin syringes are inaccurate to greater than 10%, and sometimes inaccurate to greater than 20% or more. Hamilton HPLC type syringes are generally considered precise to within 10%, and are recommended for volumes below 10 pl are to be injected. 10103] In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's, including but not limiting a human subject's eye that is less than about 500 gl, less than about 400 pl, less than about 300 ptl, less than about 200 1 l, less than about 100 pl, less than about 90 pl, less than about 80 l, less than about 70 pl, less than about 60 pl, less than about 50 1A, less than about 40 pA, less than about 30 l, less than about 20 ptl, less than about 10 il, less than about 5 pl, less than about 3 1I, or less than about 1 pl. In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or subject's, including but not limited to a human subject's eye that is less than about 20 p1. In some variations, a volume of a liquid formulation described herein is administered to the vitreous that is less than about 10 41. In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 0.1lp and about 200 pl, between about 50 pl and about 200 p, between about 50 pl and about 150 pl, between about 0.Ipl and about 100 pl, between about 0.1 l and about 50 Rl, between about I 1d and about 40 pl, between about I pl and about 30 p, between about 1 pl and about 20 pl, between about Ipl and about 10 p, or between about Ipl and about 5 pl. In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about I l and about 10 pA. In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about IpA and about 5 gl. In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's eye that is between about I p and about 5 1. '21 In some variations, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 0.1pgl and about 200 R1. 101041 In some variations, a total volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is less than about 1000 pl, less than about 900 pl, less than about 800 gl, less than about 700 pl, less than about 600 pl, less than about 500 pl, less than about 400 pl, less than about 300 pl, less than about 200 pl, less than about 100 pl, less than about 90 pl, less than about 80 p1, less than about 70 p1, less than about 60 p1, less than about 50 pl, less than about 40 pl, less than about 30 pl, less than about 20 g], less than about 10 pl, less than about 5 p1, less than about 3 p1, or less than about I W. In some variations, a volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is less than about 20 p1. In some variations, a volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is less than about 10 pl. In some variations, a volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 0.1 pl and about 200 pl, between about 50 p1 and about 200 p1, between about 200 p1 and about 300 pl, between about 300 pl and about 400 p1, between about 400 pl and about 500 pl, between about 600 pl and about 700 p1, between about 700 p1 and about 800 p1, between about 800 pl and about 900 p1, between about 900 pl and about 1000 p1, between about 50 pl and about 150 pl, between about 0.1pl and about 100 p1, between about 0.1 pl and about 50 pl, between about 1 pl and about 40 R1, between about 1 l and about 30 pl, between about 1l and about 20 pl, between about 1pl and about 10 g1, or between about 1 l and about 5 pl. In some variations, a volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 1 pl and about 10 pl. In some variations, a volume of a liquid formulation described herein is subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 1 and about 5 p1. In some variations, a volume of a liquid formulation described herein is administered to subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 1ptl and about 5 pl. In some variations, a volume of a liquid formulation described herein is administered to subconjunctivally administered to a rabbit eye or a subject's, including but not limited to a human subject's eye that is between about 0.1 RI and about 200 pl. 101051 In some variations the liquid formulations described herein are administered in multiple subconjunctival locations within a period of time, including without limitation within an hour of one another. Without being bound by theory, it is thought that such multiple administrations, such as multiple injections, allow for a greater total dose to be administered subconjunctivally than a single dose due to a potentially limited ability of the local ocular tissues to absorb larger volumes. [01061 One liquid formulation described herein is an in situ gelling formulation. In situ gelling formulations, as described herein, comprise a therapeutic agent and a plurality of polymers which give a formulation that forms a gel or a gel-like substance when placed in an aqueous medium, including but not limited to an aqueous medium of the eye. [01071 In some variations of the liquid formulations described herein, the therapeutic agent is a solution or suspension of rapamycin in a liquid medium. Liquid media include but are not limited to solvents, including but not limited to those in the Solubilization of Therapeutic Agents section. [0108] The liquid formulations described herein may comprise a solubilizing agent component. In some variations the solubilizing agent component is a surfactant. Note that there is some overlap between components that may be solvents and solubilizing agents, and therefore the same component may in some systems be used as either a solvent or a solubilizing agent. A liquid formulation that comprises a therapeutic agent and a component that may be considered either a solvent or a solubilizing agent or surfactant will be considered a solvent if it is playing the role of a solvent; if the component is not playing the role of the solvent, the component may be considered a solubilizing agent or surfactant. [01091 Liquid formulations may optionally further comprise stabilizers, excipients, gelling agents, adjuvants, antioxidants, and/or other components as described herein. [0110] In some variations all components in the liquid formulation, other than the therapeutic agent, are liquid at room temperature. [0111] In some variations, the liquid formulation comprises a release modifying agent. In some variations, the release modifying agent is a film-forming polymer component.

The film-forming polymer component may comprise one or more film-forming polymers. Any film-forming polymer may be used in the excipient component. In some variations, the film-forming polymer component comprises a water insoluble film forming polymer. In some variations, the release modifying agent component comprises an acrylic polymer, including but not limited to polymethacrylate, including but not limited to Eudragit RL. [01121 Described herein are compositions and liquid formulations for delivery of the therapeutic agents described in the Therapeutic Agents section. Delivery of therapeutic agents using the compositions and liquid formulations described herein may be used to treat, prevent, inhibit, delay the onset of, or cause the regression of the diseases and conditions described in the Diseases and Conditions section. The compositions and liquid formulations described herein may comprise any of the therapeutic agents described in the Therapeutic Agents section, including but not limited to rapamycin. The compositions and liquid formulations described herein may comprise one or more than one therapeutic agent. Other compositions and liquid formulations in addition to those explicitly described herein may be used. [01131 When the therapeutic agent is rapamycin, the compositions and liquid formulations may be used to maintain an amount of rapamycin in the vitreous effective to treat wet AMD. In one nonlimiting example, it is believed that a liquid formulation delivering rapamycin to maintain a concentration of rapamycin of about 10 pg/ml to about 2 pg/ml in the vitreous over a period of time may be used for the treatment of wet AMD. When the rapamycin is in a liquid formulation that forms a non-dispersed mass, the stated concentration of rapamycin represents the amount that is effectively treating the disease or condition of the eye, and not merely present in the form of the non-dispersed mass. In another nonlimiting example, it is believed that a delivery system delivering rapamycin to maintain a concentration of rapamycin of about 0.01 pg/mg to about 10 ng/mg in the retina choroid tissues over a period of time may be used for treatment of wet AMD. Other therapeutically effective amounts of therapeutic agent are also possible, and can be readily determined by one of skill in the art given the teachings herein. [0114] When the therapeutic agent is rapamycin, the compositions and liquid formulations described herein may be used to deliver a dose of rapamycin to a subject, including but not limited to a human subject or to the eye of a subject. In one nonlimiting example, it is believed that a liquid formulation containing a dose of about 20 Ig to about 4 mg may be used for the treatment of wet AMD.

[01151 In some variations the therapeutic agent in the liquid formulation comprises between about 0.01 to about 30% of the total weight of the composition; between about 0.05 to about 15%; between about 0.1 to about 10%; between about I to about 5%; or between about 5 to about 15%; between about 8 to about 10%; between about 0.01 to about 1%; between about 0.05 to about 5%; between about 0.1 to about 0.2%; between about 0.2 to about 0.3%; between about 0.3 to about 0.4%; between about 0.4 to about 0.5%; between about 0.5 to about 0.6%; between about 0.6 to about 0.7%; between about 0.7 to about 1%; between about 1 to about 5%; between about 5 to about 10%; between about 15 to about 30%, between about 20 to about 30%; or between about 25 to about 30%. [01161 Those of skill in the art, based on the teachings herein can determine what amount or concentration of a given therapeutic agent is equivalent to an amount or concentration of rapamycin by, for example, administering the therapeutic agent at various amounts or concentrations to a disease model system, such as an in vivo or in vivo model system, and comparing the results in the model system relative to the results of various amounts or concentrations of rapamycin. Those of skill in the art, based on the teachings herein can also determine what amount or concentration of a given therapeutic agent is equivalent to an amount or concentration of rapamycin by reviewing the scientific literature for experiments performed comparing rapamycin to other therapeutic agents. It is understood that even the same therapeutic agent may have a different equivalent level of rapamycin when, for example, a different disease or disorder is being evaluated, or a different type of formulation is used. Nonlimiting examples of scientific references with comparative studies of rapamycin and other therapeutic agents on ocular disease are Ohia et al., Effects of steroids and immunosuppressive drugs on endotoxin-uveitis in rabbits, J. Ocul. Pharmacol. 8(4):295-307 (1992); Kulkarni, Steroidal and nonsteroidal drugs in endotoxin-induced uveitis, J. Ocul. Pharmacol. 10(1):329-34 (1994); Hafizi et al., Differential effects of rapamycin, cyclosporine A, and FK506 on human coronary artery smooth muscle cell proliferation and signaling, Vascul Pharmacol. 41(4-5):167-76 (2004); and US 2005/0187241. 101171 For example, in a model for wet AMD, if a therapeutic agent is found to be approximately 10-fold less potent or efficacious than rapamycin in the treatment of wet AMD, a concentration of 10 ng/ml of the therapeutic agent would be equivalent to a I ng/ml concentration of rapamycin. Or if a therapeutic agent is found to be approximately 10-fold less potent or efficacious than rapamycin in the treatment of wet AMD, a 10-fold amount of the therapeutic agent would be administered relative to the amount of rapamycin. 101181 The solvent component may comprise, for instance, between about 0.01 to about 99.9 % of the total weight of the composition; between about 0.1 to about 99%; between about 25 to about 55%; between about 30 to about 50%; or between about 35 to about 45%; between about 0.1 to about 10%; between about 10 to about 20%; between about 20 to about 30%; between about 30 to about 40%; between about 40 to about 45%; between about 40 to about 45%; between about 45 to about 50%; between about 50 to about 60%; between about 50 to about 70%; between about 70 to about 80%; between about 80 to about 90%; or between about 90 to about 100%. [0119] The solubilizing agent component may comprise, for instance, between about 0.0 1 to about 30 % of the total weight of the composition; between about 0.1 to about 20%; between about 2.5 to about 15%; between about 10 to about 15%; or between about 5 to about 10%; between about 8 to about 12%; between about 10 to about 20%; between about 20 to about 30%. [01201 In some variations, the liquid formulations described herein have a viscosity of between 40% and 120% centipoise. In some variations the liquid formulations described herein have a viscosity of between 60% and 80% centipoise. [01211 In some variations the liquid formulations described herein comprise a therapeutic agent and a solvent component. The solvent component may comprise a single solvent or a combination of solvents. The therapeutic agent component may comprise a single therapeutic agent or a combination of therapeutic agents. In some variations, the solvent is glycerin, dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA), dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, polyglycolated capryl glyceride, -y butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, or propylene glycol, or a mixture of one or more thereof. [01221 In some variations the liquid formulations described herein are solutions, and comprise a therapeutic agent and a solvent component. In some variations the solvent component comprises ethanol. In some variations the solvent component comprises ethanol and a polyethylene glycol, including but not limited to a liquid polyethylene glycol, including but not limited to one or more of PEG 300 or PEG 400. [0123] In some variations the liquid formulations described herein contain no greater than about 250 pl of polyethylene glycol. In some variations the liquid formulations described herein contain no greater than about 250 ptl, no greater than about 200 pil, no greater than about 150 [d, no greater than about 125 pl, no greater than about 100 p1, no greater than about 75 pA, no greater than about 50 pl, no greater than about 25 pl, no greater than about 20 d, no greater than about 15 pl, no greater than about 10 pl, no greater than about 7.5 1l, no greater than about 5 l, no greater than about 2.5 pl, no greater than about 1.0 pl, or no greater than about 0.5 pl of polyethylene glycol. Formulations containing polyethylene glycol may contain, for example, PEG 300 or PEG 400. [0124] In some variations, the liquid formulations described herein are suspensions, and comprise a therapeutic agent and a diluent component. In some variations, the diluent component comprises one or more components listed herein as solvents or solubilizing agents, wherein the resulting mixture is a suspension. [01251 In some variations the liquid formulation is partly a solution and partly a suspension. 101261 In some variations the liquid formulation is an in situ gelling formulation, and comprises a therapeutic agent and a polymer component, wherein the polymer component may comprise a plurality of polymers. In some variations, the liquid formulation comprises a polymethacrylate polymer. In some variations, the liquid formulation comprises a polyvinylpyrrolidone polymer. [01271 Some variations of liquid formulations include a therapeutic agent or agents such as but not limited to rapamycin between about 0.01% and about 20% by weight of the total, a solvent between about 5% and about 15% by weight of the total, a solubilizing agent including but not limited to a surfactant between about 5% and about 15% by weight of the total, with water as the primary remaining component. In some variations the formulations further comprise stabilizing agents, excipients, adjuvants, or antioxidants, between about 0 and about 40% by weight of the total. 101281 In some variations, a liquid formulation comprises up to about 5% therapeutic agent, including but not limited to rapamycin, per weight of the total; and up to about 99.9% of a solvent component, by weight of the total. In some variations the liquid 'V1 formulation comprises up to about 5% therapeutic agent, including but not limited to rapamycin, per weight of the total; and up to about 99.9% of a diluent component. [01291 In some variations, a liquid formulation may comprise up to about 5% therapeutic agent, including but not limited to rapamycin, per weight of the total; up to about 10% solvent by weight of the total; and up to about 85% of a solubilizing component, by weight of the total. In some variations the solubilizing component is an aqueous solution of a surfactant. [01301 A plurality of polymers component may comprise, for instance, between about 0.01 to about 30 % of the total weight of the composition; between about 0.1 to about 20%; between about 2.5 to about 15%; between about 10 to about 15%; between about 3 to about 5%; between about 5 to about 10%; between about 8 to about 12%; between about 10 to about 20%; or between about 20 to about 30%. 101311 Some variations of liquid formulations includes a therapeutic agent or agents such as but not limited to rapamycin between about 0.01% and about 20% by weight of the total, a solvent component between about 60% and about 98% by weight of the total, and a plurality of polymers, whose combined percentage is between about 0.1% and about 15% by weight of the total. In some variations the formulations further comprise stabilizing agents, excipients, adjuvants, or antioxidants, between about 0 and about 40% by weight of the total. 101321 In some variations, a liquid formulation may comprise about 4% therapeutic agent, including but not limited to rapamycin, per weight of the total; about 91% solvent by weight of the total; and about 5% polymeric component, per weight of the total. [01331 Some examples and variations of liquid formulations described herein were prepared and are listed in Table 1. Depending on their type, the listed formulations are denoted one or more of solutions ("S"), suspensions ("SP"), emulsions ("E") or in situ gelling ("ISG"). Median particle size is listed for some of the suspensions. As described herein, some liquid formulations form a non-dispersed mass after, for example, injection into an aqueous environment such as the vitreous of an eye. For those formulations injected into the vitreous of a rabbit eye, the right-hand column of Table I indicates whether or not a non-dispersed mass (NDM) formed after a specified volume was injected into the vitreous of the rabbit eye. [01341 The following references, each of which is incorporated herein by reference in its entirety, show one or more formulations, including but not limited to rapamycin formulations, and which describe use of rapamycin at various doses and other therapeutic agents for treating various diseases or conditions: US 60/651,790, filed 2/9/2005, titled FORMULATIONS FOR OCULAR TREATMENT, attorney docket number 57796 30002.00; US 60/664,040, filed 2/9/2005, attorney docket number 57796-30004.00, titled LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; US 60/664,119, filed 3/21/2005, attorney docket number 57796-30005.00, titled DRUG DELIVERY SYSTEMS FOR TREATMENT OF DISEASES OR CONDITIONS; US 60/664,306, filed 3/21/2005, attorney docket number 57796-30006.00 titled IN SITU GELLING FORMULATIONS AND LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; US _/_, filed 2/9/2006, titled FORMULATIONS FOR OCULAR TREATMENT, attorney docket number 57796-20002.00; __/__, filed 2/9/2006, attorney docket number 57796-20004.00, titled LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; US 2005/0187241, and US 2005/0064010. Liquid formulations which form a non-dispersed mass [01351 One class of liquid formulations described herein forms a non-dispersed mass when placed in an aqueous medium. As used herein, a "non-dispersed mass" refers to the structure formed or shape assumed when the liquid formulation is placed into an environment, relative to the environment in which it is placed. Generally, a non-dispersed mass of a liquid formulation is anything other than a homogeneous distribution of the liquid formulation in the surrounding medium. The non-dispersed mass may, for instance, be indicated by visually inspecting the administered liquid formulation and characterizing its appearance relative to the surrounding medium. [0136] In some variations, the aqueous medium is water. In some variations, the water is deionized, distilled, sterile, or tap water, including but not limited to tap water available at the place of business of MacuSight in Union City, California. 10137] In some variations, the aqueous medium is an aqueous medium of a subject. In some variations the aqueous medium is an aqueous medium of the eye of a subject, including but not limited to the vitreous of an eye of a subject. In some variations the subject is a human subject. In some variations the subject is a rabbit. [01381 In some variations the liquid formulation forms a non-dispersed mass when exposed to a certain temperature or range of temperatures, including but not limited to about room temperature, about ambient temperature, about 30'C, about 37'C, or about the temperature of the aqueous medium of the subject. 101391 In some variations the liquid formulation forms a non-dispersed mass when exposed to a certain pH or range of pH, including but not limited to a pH between about 6 and about 8. [0140] In some variations, the non-dispersed mass comprises a gel or gel-like substance. 101411 In some variations, the non-dispersed mass comprises a polymer matrix. In some variations, the non-dispersed mass comprises a polymer matrix in which a therapeutic agent is dispersed. [01421 The liquid formulations described herein may generally be of any geometry or shape after administration to a subject or the eye of a subject, including but not limited to a human subject. In some variations, the non-dispersed mass is between about 0.1 and about 5 mm. In some variations, the non-dispersed mass is between about I and about 3 mm. The non-dispersed mass-forming liquid formulations may, for instance, appear as a compact spherical mass when administered to the vitreous. In some instances, the liquid formulation may appear as a non-dispersed mass relative to the surrounding medium, wherein the non-dispersed mass is less clearly defined and the geometry is more amorphous than spherical. [01431 The non-dispersed mass-forming liquid formulations described herein may form a non-dispersed mass immediately upon placement in the medium or the non-dispersed mass may form some period of time after placement of the liquid formulation. In some variations the non-dispersed mass forms over the course of about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days. In some variations the non-dispersed mass forms over the course of about I week, about 2 weeks, or about 3 weeks. [01441 In some variations, the liquid formulations described herein that form a non dispersed mass appear as a milky or whitish colored semi-contiguous or semi-solid non dispersed mass relative to the medium in which it is placed. [01451 One liquid formulation described herein forms a non-dispersed mass which has the form of a solid depot when the formulation is injected into any or all of water, the vitreous of a rabbit eye, or between the sclera and the conjunctiva of a rabbit eye. One liquid formulation described herein forms a non-dispersed mass which has the form of a semi-solid when the formulation is injected into any or all of water, the vitreous of a An( rabbit eye, or between the sclera and the conjunctiva of a rabbit eye. One liquid formulation described herein forms a non-dispersed mass which has the form of a polymeric matrix when the formulation is injected into any or all of water, the vitreous of a rabbit eye, or between the sclera and the conjunctiva of a rabbit eye. One liquid formulation described herein forms a non-dispersed mass which has the form of a gel, a hydrogel, or a gel-like substance when the formulation is injected into any or all of water, the vitreous of a rabbit eye, or between the sclera and the conjunctiva of a rabbit eye. 101461 In some variations described herein the liquid formulation forms a non-dispersed mass relative to a surrounding medium where the surrounding medium is aqueous. An "aqueous medium" or "aqueous environment" is one that contains at least about 50% water. Examples of aqueous media include but are not limited to water, the vitreous, extracellular fluid, conjunctiva, sclera, between the sclera and the conjunctiva, aqueous humor, gastric fluid, and any tissue or body fluid comprised of at least about 50% of water. Aqueous media include but are not limited to gel structures, including but not limited to those of the conjunctiva and sclera. [01471 In some variations, the liquid formulations described herein form a non dispersed mass when a test volume of the liquid formulation is placed in the vitreous of a rabbit eye. In some variations the test volume administered to a rabbit eye, and the test volume is equal to the volume of the liquid formulation administered to a subject's, including but not limited to a human subject's eye. [01481 In some variations, the test volume administered to a rabbit eye is equal to the volume administered to the subject's eye multiplied by a scale factor, and the scale factor is equal to the average volume of a rabbit eye divided by the average volume of a subject eye. The "average volume" of an eye, as used herein, refers to the average volume of an eye of a member of similar age of the species under consideration generally, as opposed to the average volume of any particular individual's eye. 101491 In some variations, the test volume administered to the rabbit eye is between about 10 l and about 50 pl. In some variations, the test volume administered to the rabbit eye is between about I d and about 30 tl. In some variations, the test volume administered to the rabbit eye is between about 50 pl and about 100 pl. In some variations, the test volume administered to the rabbit eye is between about 25 ptl and about 75 pl. In some variations, the test volume administered to the rabbit eye is about 30 41. A 1 [01501 In some variations, the liquid formulation that forms a non-dispersed mass when placed in the medium may comprises a therapeutic agent or agents with a concentration of between about 0.01% and about 10% by weight of the total, and a solvent between about 10 % and about 99 % by weight of the total. In some variations the formulation further comprises a solubilizing agent including but not limited to a surfactant. In some variations the liquid formulation further comprises a stabilizing agent, excipient, adjuvant, or antioxidant, etc., between about 0 and about 40% by weight of the total. In some variations, the therapeutic agent is about 5% by weight of the total, and the solvent component is about 95% by weight of the total. 101511 Whether a liquid formulation exhibits a non-dispersed mass relative to a surrounding medium when present in a subject, including but not limited to a human subject or the eye of a subject may be determined by, for instance, mixing a therapeutic agent with a solvent, administering it to the vitreous of an eye of a subject, including but not limited to a human subject, and comparing the liquid formulation to the surrounding medium. [01521 One liquid formulation that may be used for treating, preventing, inhibiting, delaying the onset of, or causing the regression of the diseases and conditions of a subject, including but not limited to a human subject, is a liquid formulation that forms a non dispersed mass when placed into the vitreous of a rabbit eye. When used for treating, preventing, inhibiting, delaying the onset of, or causing the regression of the disease or condition of the subject, the liquid formulation is administered to the subject. The liquid formulation may or may not form a non-dispersed mass in the subject. One liquid formulation described herein forms a non-dispersed mass when administered to a subject and forms a non-dispersed mass when administered to a rabbit eye. [01531 Without being bound by theory, it is believed that the low solubility of rapamycin in the vitreous contributes to the formation of a non-dispersed mass by some rapamycin-containing liquid formulations described herein. The vitreous is a clear gel composed almost entirely of water (up to 99%). Without being bound by theory, it is believed that as rapamycin in an injected formulation contacts the vitreous, the rapamycin precipitates. 101541 Without being bound by theory, factors believed to affect the formation of and geometry of a non-dispersed mass include the concentration of rapamycin in the formulation, the viscosity of the formulation, ethanol content of the formulation, and the Al volume of injection. It is believed that maintaining a higher local concentration of rapamycin after injection of the formulation favors formation of a non-dispersed mass, as opposed to a lower local concentration of rapamycin after injection of the formulation. As volume is increased for a given dose, formation of a non-dispersed mass may become less favorable. Formation of a non-dispersed mass may become more favorable as rapamycin concentration is increased and/or as viscosity is increased. Ethanol content affects both the solubility of the rapamycin in the formulation and the viscosity of the formulation. [01551 In one comparison, 100 pl of a solution of 0.4 % rapamycin, 4.0% ethanol, and 95.6% PEG 400 (a 400 jpg dose) did not form a non-dispersed mass after injection into a rabbit eye. In contrast, 20 pl of a solution of 2.00 % rapamycin, 4.0% ethanol, and 94% PEG 400 (also a 400 ptg dose) formed a compact spherical non-dispersed mass after injection into a rabbit eye. 101561 Without being bound by theory, in the latter example, it is hypothesized that formation of the non-dispersed mass occurred as depicted in Figures IA-I C and described as follows. Upon injection, due to its viscosity the liquid formulation formed a spherical globule 100 within the vitreous 110. Ethanol then diffused out of this globule, resulting in localized precipitation 120 of the rapamycin within the globule. Eventually, the polyethylene glycol also diffused out of the globule to leave a solid, compact non dispersed mass of rapamycin 130. 101571 In some variations, the non-dispersed masses described herein consists of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% by volume of therapeutic agent when injected into the vitreous of a rabbit eye. [01581 In some variations, upon formation a non-dispersed mass comprising rapamycin, for example, delivers the drug continuously at approximately a constant rate for an extended period of time. Without being bound by theory, it is believed that delivery of rapamycin from a non-dispersed mass in the vitreous depends on dissolution of the rapamycin in the vitreous, which depends in turn on clearance of the drug from the vitreous to other tissues. Without being bound by theory, this release process is believed to maintain a steady-state concentration of rapamycin in the vitreous. [0159] In some variations, formation of a non-dispersed mass reduces the toxicity of the injected liquid formulation compared to an equivalent dose that did not form a nondispersed mass. In variations in which a liquid formulation injected into the vitreous does not form a non-dispersed mass, the drug (e.g., rapamycin) appears to disperse in the vitreous body. In some variations this may interfere with vision. 101601 In some variations, liquid formulations that are suspensions form a non dispersed mass upon injection into the vitreous. Formation of a non-dispersed mass from an injected suspension may become more favorable as the suspension particle size increases. [01611 In some variations, it is believed that the liquid formulations will form a visually observable non-dispersed mass when injected into the eye of a subject, including but not limited to a human subject. [01621 In some variations, liquid formulations are believed to form non-dispersed masses when injected subconjunctivally. In some variations it is believed that when subconjunctivally administered the liquid formulation forms a depot in the scleral tissue. That is, it is believed that the therapeutic agent is absorbed into the sclera proximate to the injection site and forms a local concentration of drug in the sclera. In situ Gelling Formulations [01631 Described herein are non-dispersed mass-forming liquid formulations which form a gel or gel-like substance when placed in an aqueous medium. In some variations, the non-dispersed mass comprises a gel; in some variations the gel is a hydrogel. 101641 An "in situ gelling formulation," as used herein, refers to a liquid formulation which forms a gel-like non-dispersed mass when the liquid formulation is placed in an aqueous medium, including but not limited to aqueous media that are water, the vitreous of a rabbit eye, and between the sclera and the conjunctiva of a rabbit eye. In some variations, an in situ gelling formulation forms a gel-like non-dispersed mass when placed in tap water. [01651 In some variations, the in situ gelling formulation is a suspension prior to placement in an aqueous medium, and forms a gel in situ upon placement in an aqueous medium. In some variations, the in situ gelling formulation is a solution prior to placement in an aqueous medium, and forms a gel in situ upon placement in an aqueous medium. In some variations, the in situ gelling formulation is an emulsion prior to placement in an aqueous medium, and forms a gel in situ upon placement in an aqueous medium. In some variations a gel-like non-dispersed mass forms after placement of the in

AA

situ gelling formulation into an aqueous medium, including but not limited to any or all of water, the vitreous, or between the sclera and the conjunctiva of an eye. In some variations, the in situ gel is formed of a polymer matrix. In some variations a therapeutic agent is dispersed in the polymer matrix. 101661 Described herein are in situ gelling formulations which may be used for treating, preventing, inhibiting, delaying the onset of, or causing the regression of the diseases and conditions of a subject including but not limited to a human subject. When used for treating, preventing, inhibiting, delaying the onset of, or causing the regression of the disease or condition of the subject, the in situ gelling formulation is administered to the subject. One liquid formulation described herein comprises an in situ gelling formulation which forms a non-dispersed mass when administered to a subject and forms a non dispersed mass when administered to a rabbit eye. [01671 In some variations, the in situ gelling formulation comprises one or more polymers. Described herein are various types of polymers, including polymers which are solvents, polymers which are solubilizing agents, polymers which are release modifying agents, polymers which are stabilizing agents, etc. In some variations, any combination of polymers is used wherein the polymers when combined with the therapeutic agent form any or all of a non-dispersed mass, a gel, a hydrogel, or polymeric matrix when placed in an aqueous medium, including but not limited to any or all of water, the vitreous, or between the sclera and the conjunctiva. 101681 In some variations, the in situ gelling formulation delivers extended release of therapeutic agents to a subject when administered to the subject. [01691 In some variations, the liquid formulation comprises a therapeutic agent and a plurality of polymers, wherein one of the polymers is a polymethacrylate. Polymethacrylates are known by various names and are available in various preparations, including but not limited to polymeric methacrylates, methacrylic acid-ethyl acrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 per cent, methacrylic acid-methyl methacrylate copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (1:2), acidum methacrylicum et ethylis acrylas polymerisatum 1:1, acidum methacrylicum et ethylis acrylas polymerisatum 1:1 dispersio 30 per centum, acidum methacrylicum et methylis methacrylas polymerisatum 1:1, acidum methacrylicum et methylis methacrylas polymerisatum 1:2, USPNF: ammonio

A';

methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion. [01701 In some variations, one of the polymers is polyvinylpyrrolidone. Polyvinylpyrrolidone is known by various names and is available in various preparations, including but not limited to povidone, povidonum, kollidon; plasdone; poly[1-(2-oxo-I pyrrolidinyl)ethylene]; polyvidone; PVP; I-vinyl-2- pyrrolidinone polymer, and 1 Ethenyl-2-pyrrolidinone homopolymer. [0171] One liquid formulation described herein comprises a therapeutic agent and a solvent component. The solvent component may comprise a single solvent or a combination of solvents. [0172] In some variations, the solvent is glycerin, dimethylsulfoxide, N methylpyrrolidone, ethanol, isopropyl alcohol, polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, or propylene glycol, or a mixture of one or more thereof. 10173] In some variations, the solvent is polyethylene glycol. Polyethylene glycol is known by various names and is available in various preparations, including but not limited to macrogels, macrogel 400, macrogel 1500, macrogel 4000, macrogel 6000, macrogel 20000, macrogola, breox PEG; carbowax; carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol, and a-Hydro-o-hydroxy poly(oxy- 1,2-ethanediyl). Compositions and liquid formulations for delivery of therapeutic agents [0174] The compositions and liquid formulations described herein may be used to deliver amounts of the therapeutic agents effective for treating, preventing, inhibiting, delaying on set of, or causing the regression of the diseases and conditions described in the Diseases and Conditions section. In some variations the compositions and liquid formulations described herein deliver one or more therapeutic agents over an extended period of time. 10175] An "effective amount," which is also referred to herein as a "therapeutically effective amount," of a therapeutic agent for administration as described herein is that amount of the therapeutic agent that provides the therapeutic effect sought when administered to the subject, including but not limited to a human subject. The achieving of different therapeutic effects may require different effective amounts of therapeutic agent. For example, the therapeutically effective amount of a therapeutic agent used for preventing a disease or condition may be different from the therapeutically effective amount used for treating, inhibiting, delaying the onset of, or causing the regression of the disease or condition. In addition, the therapeutically effective amount may depend on the age, weight, and other health conditions of the subject as is well know to those versed in the disease or condition being addressed. Thus, the therapeutically effective amount may not be the same in every subject to which the therapeutic agent is administered. 101761 An effective amount of a therapeutic agent for treating, preventing, inhibiting, delaying the onset of, or causing the regression of a specific disease or condition is also referred to herein as the amount of therapeutic agent effective to treat, prevent, inhibit, delay the onset of, or cause the regression of the disease or condition. [0177] To determine whether a level of therapeutic agent is a "therapeutically effective amount" to treat, prevent, inhibit, delay on set of, or cause the regression of the diseases and conditions described in the Diseases and Conditions section, liquid formulations may be administered in animal models for the diseases or conditions of interest, and the effects may be observed. In addition, dose ranging human clinical trials may be conducted to determine the therapeutically effective amount of a therapeutic agent. [01781 Generally, the therapeutic agent may be formulated in any composition or liquid formulation capable of delivery of a therapeutically effective amount of the therapeutic agent to a subject or to the eye of a subject for the required delivery period. Compositions include liquid formulations. Solubilization of therapeutic agents [01791 One composition or liquid formulation that may be used is a composition or liquid formulation in which the therapeutic agent is dissolved in a solvent component. Generally, any solvent which has the desired effect may be used in which the therapeutic agent dissolves. In some variations the solvent is aqueous. In some variations the solvent is non-aqueous. An "aqueous solvent" is a solvent that contains at least about 50% water. [01801 Generally, any concentration of solubilized therapeutic agent that has the desired effect can be used. The solvent component may be a single solvent or may be a mixture of solvents. The solvent component may be a single solvent or may be a mixture of solvents. Solvents and types of solutions are well known to those versed in such drug delivery technologies. See for example, Remington: The Science and Practice of A'7 Pharmacy, Twentieth Edition, Lippincott Williams & Wilkins; 20th edition (December 15, 2000); Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Eighth Edition, Lippincott Williams & Wilkins (August 2004); Handbook Of Pharmaceutical Excipients 2003, American Pharmaceutical Association, Washington, DC, USA and Pharmaceutical Press, London, UK; and Strickley, solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, Vol. 21, No. 2, February 2004. 101811 As noted previously, some solvents may also serve as solubilizing agents. 101821 Solvents that may be used include but are not limited to DMSO, ethanol, methanol, isopropyl alcohol; castor oil, propylene glycol, glycerin, polysorbate 80, benzyl alcohol, dimethyl acetamide (DMA), dimethyl formamide (DMF), triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, glycerol formal, ethoxy diglycol (Transcutol, Gattefosse), tryethylene glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMI), y-butyrolactone, N-Methyl-2-pyrrolidinone (NMP), polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, and polyglycolated capryl glyceride (Labrasol, Gattefosse), combinations of any one or more of the foregoing, or analogs or derivatives of any one or more of the foregoing. 101831 In some variations, the solvent is a polyethylene glycol. Polyethylene glycol is known by various names and is available in various preparations, including but not limited to macrogels, macrogel 400, macrogel 1500, macrogel 4000. macrogel 6000, macrogel 20000, macrogola, breox PEG; carbowax; carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol, and a-Hydro-O-hydroxy poly(oxy-1,2-ethanediyl). [01841 In some variations the polyethylene glycol is a liquid PEG, and is one or more of PEG 300 or PEG 400. [01851 Other solvents include an amount of a C 6

-C

24 fatty acid sufficient to solubilize a therapeutic agent. 10186] Phospholipid solvents may also be used, such as lecithin, phosphatidylcholine, or a mixture of various diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid; hydrogenated soy phosphatidylcholine (HSPC), distearoylphosphatidylglycerol (DSPG), L-a-dimyristoylphosphatidylcholine (DMPC), L a-dimyristoylphosphatidyl glycerol (DMPG). 101871 Further examples of solvents include, for example, components such as alcohols, propylene glycol, polyethylene glycol of various molecular weights, propylene A O glycol esters, propylene glycol esterified with fatty acids such as oleic, stearic, palmic, capric, linoleic, etc; medium chain mono-, di-, or triglycerides, long chain fatty acids, naturally occurring oils, and a mixture thereof. The oily components for the solvent system include commercially available oils as well as naturally occurring oils. The oils may further be vegetable oils or mineral oils. The oils can be characterized as non-surface active oils, which typically have no hydrophile lipophile balance value. Commercially available substances comprising medium chain triglycerides include, but are not limited to, Captex 100, Captex 300, Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol 829, and Dynacerin 660. Propylene glycol ester compositions that are commercially available encompass Captex 200 and Miglyol 840, and the like. The commercial product, Capmul MCM, comprises one of many possible medium chain mixtures comprising monoglycerides and diglycerides. [01881 Other solvents include naturally occurring oils such as peppermint oil, and seed oils. Exemplary natural oils include oleic acid, castor oil, safflower seed oil, soybean oil, olive oil, sunflower seed oil, sesame oil, and peanut oil. Soy fatty acids may also be used. Examples of fully saturated non-aqueous solvents include, but are not limited to, esters of medium to long chain fatty acids (such as fatty acid triglycerides with a chain length of about C 6 to about C 24 ). Hydrogenated soybean oil and other vegetable oils may also be used. Mixtures of fatty acids may be split from the natural oil (for example coconut oil, palm kernel oil, babassu oil, or the like) and refined. In some embodiments, medium chain (about C 8 to about C 1 2 ) triglycerides, such as caprilyic/capric triglycerides derived from coconut oil or palm seed oil, may be used. Medium chain mono- and diglycerides may also be used. Other fully saturated non-aqueous solvents include, but are not limited to, saturated coconut oil (which typically includes a mixture of lauric, myristic, palmitic, capric and caproic acids), including those sold under the MiglyolTM trademark from Huls and bearing trade designations 810, 812, 829 and 840). Also noted are the NeoBeeTM products sold by Drew Chemicals. Non-aqueous solvents include isopropyl myristate. Examples of synthetic oils include triglycerides and propylene glycol diesters of saturated or unsaturated fatty acids having 6 to 24 carbon atoms such as, for example hexanoic acid, octanoic (caprylic), nonanoic (pelargonic), decanoic (capric), undecanoic, lauric, tridecanoic, tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic, heptadecanoic, eicosanoic, heneicosanoic, docosanoic and lignoceric acids, and the like. Examples of unsaturated dQ carboxylic acids include oleic, linoleic and linolenic acids, and the like. The non-aqueous solvent can comprise the mono-, di- and triglyceryl esters of fatty acids or mixed glycerides and/or propylene glycol mono- or diesters wherein at least one molecule of glycerol has been esterified with fatty acids of varying carbon atom length. A non-limiting example of a "non-oil" useful as a solvent is polyethylene glycol. [01891 Exemplary vegetable oils include cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower oil, almond oil, avocado oil, palm oil, palm kernel oil, babassu oil, beechnut oil, linseed oil, rape oil and the like. Mono-, di-, and triglycerides of vegetable oils, including but not limited to corn, may also be used. 101901 Polyvinyl pyrrolidone (PVP), cross-linked or not, may also be used as a solvent. Further solvents include but are not limited to C 6

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24 fatty acids, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS including but not limited to PLURONICS F108, F127, and F68, Poloxamers, Jeffamines), Tetronics, F 127; cyclodextrins such as a cyclodextrin, p-cyclodextrin, hydroxypropyl- p-cyclodextrin, sulfobutylether- p cyclodextrin (Captisol); CMC, polysorbitan 20, Cavitron, polyethylene glycol of various molecular weights including but not limited to PEG 300 and PEG 400. [01911 Beeswax and d-a-tocopherol (Vitamin E) may also be used as solvents. [01921 Solvents for use in the liquid formulations can be determined by a variety of methods known in the art, including but not limited to (1) theoretically estimating their solubility parameter values and choosing the ones that match with the therapeutic agent, using standard equations in the field; and (2) experimentally determining the saturation solubility of therapeutic agent in the solvents, and choosing the ones that exhibit the desired solubility. Solubilization of rapamycin 101931 Where the therapeutic agent is rapamycin, solvents that may be used for making solutions or suspensions of rapamycin include but are not limited to any solvent described herein, including but not limited to any one or more of DMSO, glycerin, ethanol, methanol, isopropyl alcohol; castor oil, propylene glycol, polyvinylpropylene, glycerin, polysorbate 80, benzyl alcohol, dimethyl acetamide (DMA), dimethyl formamide (DMF), glycerol formal, ethoxy diglycol (Transcutol, Gattefosse), tryethylene glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMI), y-butyrolactone, N-Methyl-2-pyrrolidinone (NMP), polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, and polyglycolated capryl glyceride (Labrasol, Gattefosse). [01941 Further solvents include but are not limited to C 6

-C

24 fatty acids, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS including but not limited to PLURONICS F108, F127, and F68, Poloxamers, Jeffamines), Tetronics, F127, beta cyclodextrin, CMC, polysorbitan 20, Cavitron, softigen 767, captisol, and sesame oil. [01951 Other methods that may be used to dissolve rapamycin are described in Solubilization of Rapamycin, P. Simamora et al. Int'lJ. Pharma 213 (2001) 25-29, the contents of which is incorporated herein in its entirety. [01961 As a nonlimiting example, rapamycin can be dissolved in 5% DMSO or methanol in a balanced salt solution. The rapamycin solution can be unsaturated, a saturated or a supersaturated solution of rapamycin. The rapamycin solution can be in contact with solid rapamycin. In one nonlimiting example, rapamycin can be dissolved in a concentration of up to about 400 mg/ml. Rapamycin can also, for example, be dissolved in propylene glycol esterified with fatty acids such as oleic, stearic, palmic, capric, linoleic, etc. [01971 Many other solvents are possible. Those of ordinary skill in the art will find it routine to identify solvents for rapamycin given the teachings herein. Solubilizing Agents [01981 Generally, any solubilizing agent or combination of solubilizing agents may be used in the liquid formulations described herein. [01991 In some variations, the solubilizing agent is a surfactant or combination of surfactants. Many surfactants are possible. Combinations of surfactants, including combinations of various types of surfactants, may also be used. For instance, surfactants which are nonionic, anionic (i.e. soaps, sulfonates), cationic (i.e. CTAB), zwitterionic, polymeric or amphoteric may be used. [0200] Surfactants that can be used may be determined by mixing a therapeutic agent of interest with a putative solvent and a putative surfactant, and observing the characteristics of the formulation after exposure to a medium. [02011 Examples of surfactants include but are not limited to fatty acid esters or amides or ether analogues, or hydrophilic derivatives thereof; monoesters or diesters, or hydrophilic derivatives thereof; or mixtures thereof; monoglycerides or diglycerides, or hydrophilic derivatives thereof; or mixtures thereof; mixtures having enriched mono or/and diglycerides, or hydrophilic derivatives thereof; surfactants with a partially derivatized with a hydrophilic moiety; monoesters or diesters or multiple-esters of other alcohols, polyols, saccharides or oligosaccharides or polysaccharides, oxyalkylene oligomers or polymers or block polymers, or hydrophilic derivatives thereof, or the amide analogues thereof; fatty acid derivatives of amines, polyamines, polyimines, aminoalcohols, aminosugars, hydroxyalkylamines, hydroxypolyimines, peptides, polypeptides, or the ether analogues thereof. 102021 Hydrophilic Lipophilic Balance ("HLB") is an expression of the relative simultaneous attraction of a surfactant for water and oil (or for the two phases of the emulsion system being considered). [02031 Surfactants are characterized according to the balance between the hydrophilic and lipophilic portions of their molecules. The hydrophilic-lipophilic balance (HLB) number indicates the polarity of the molecule in an arbitrary range of I - 40, with the most commonly used emulsifiers having a value between I - 20. The HLB increases with increasing hydrophilicity. [02041 Surfactants that may be used include but are not limited to those with an HLB greater than 10, 11, 12, 13 or 14. Examples of surfactants include polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oils or polyethoxylated hydrogenated castor oil, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene castor oil derivatives and the like, for example, Nikkol HCO-50, Nikkol HCO-35, Nikkol HCO-40, Nikkol HCO-60 (from Nikko Chemicals Co. Ltd.); Cremophor (from BASF) such as Cremophor RH40, Cremophor RH60, Cremophor EL, TWEENs (from ICI Chemicals) e.g., TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, Cremophor RH 410, Cremophor RH 455 and the like. [02051 The surfactant component may be selected from compounds having at least one ether formed from at least about I to 100 ethylene oxide units and at least one fatty alcohol chain having from at least about 12 to 22 carbon atoms; compounds having at least one ester formed from at least about I to 100 ethylene oxide units and at least one fatty acid chain having from at least about 12 to 22 carbon atoms; compounds having at least one ether, ester or amide formed from at least about 1 to 100 ethylene oxide units and at least one vitamin or vitamin derivative; and combinations thereof consisting of no more than two surfactants.

[0206] Other examples of surfactants include Lumulse GRH-40, TGPS, Polysorbate-80 (TWEEN-80), Polysorbate-20 (TWEEN-20), polyoxyethylene (20) sorbitan mono-oleate), glyceryl glycol esters, polyethylene glycol esters, polyglycolyzed glycerides, and the like, or mixtures thereof; polyethylene sorbitan fatty acid esters, polyoxyethylene glycerol esters, such as Tagat TO, Tagat L, Tagat I, tagat 12 and Tagat 0 (commercially available from Goldschmidt Chemical Co., Essen, Germany); ethylene glycol esters, such as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostearates; sorbitan esters, such as spans and TWEENs; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as PEG 300 linoleic glycerides or Labrafil 2125 CS, PEG 300 oleic glycerides or Labrafil M 1944 CS, PEG 400 caprylic/capric glycerides or Labrasol, and PEG 300 caprylic/capric glycerides or Softigen 767; cremophors, such as Cremophor E, polyoxyl 35 castor oil or Cremophor EL, Cremophor EL-P, Cremophor RH 40P, polyoxyl 40 hydrogenated castor oil, Cremophor RH40; polyoxyl 60 hydrogenated castor oil or Cremophor RH 60, glycerol monocaprylate/caprate, such as Campmul CM 10; polyoxyethylated fatty acids (PEG stearates, PED-laurates, Brij@), polyoxylated glycerides of fatty acid, polyoxylated glycerol fatty acid esters i.e. Solutol HS-15; PEG-ethers (Mirj@), sorbitan derivatives (TWEENs), sorbitan monooleate or Span 20, aromatic compounds (Tritons@), PEG glycerides (PECEOL

TM

), PEG-PPG (polypropylene glycol) copolymers (PLURONICS including but not limited to PLURONICS F 108, F127, and F68, Poloxamers, Jeffamines), Tetronics, Polyglycerines, PEG-tocopherols, PEG-LICOL 6-oleate; propylene glycol derivatives, sugar and polysaccharide alkyl and acyl derivatives (octylsucrose, sucrose stearate, laurolydextran etc.) and/or a mixture thereof; surfactants based on an oleate or laureate ester of a polyalcohol copolymerized with ethylene oxide; Labrasol Gelucire 44/14; polyoxytheylene stearates; saturated polyglycolyzed glycerides; or poloxamers; all of which are commercially available. Polyoxyethylene sorbitan fatty acid esters can include polysorbates, for example, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Polyoxyethylene stearates can include polyoxyl 6 stearate, polyoxyl 8 stearate, polyoxyl 12 stearate and polyoxyl 20 stearate. Saturated polyglycolyzed glycerides are, for example, GELUCIRE 44/14 or GELUCIRE T M 50/13 (Gattefosse, Westwood, N.J., U.S.A.). Poloxamers used herein include poloxamer 124 and poloxamer 188. [02071 Surfactants include d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate) and peppermint oil. [0208] In some variations, surfactants having an HLB lower than 10 are used. Such surfactants may optionally be used in combination with other surfactants as co-surfactants. Examples of some surfactants, mixtures, and other equivalent compositions having an HLB less than or equal to 10 are propylene glycols, glyceryl fatty acids, glyceryl fatty acid esters, polyethylene glycol esters, glyceryl glycol esters, polyglycolyzed glycerides and polyoxyethyl steryl ethers. Propylene glycol esters or partial esters form the composition of commercial products, such as Lauroglycol FCC, which contains propylene glycol laureate. The commercially available excipient Maisine 35-1 comprises long chain fatty acids, for example glyceryl linoleate. Products, such as Acconon E, which comprise polyoxyethylene stearyl ethers, may also be used. Labrafil M 1944 CS is one example of a surfactant wherein the composition contains a mixture of glyceryl glycol esters and polyethylene glycol esters. Solubilizing agents for rapamycin [0209] Many solubilizing agents may be used for rapamycin, including but not limited to those in the solubilizing agents section above. [0210] In some variations the solubilizing agent is a surfactant. Nonlimiting examples of surfactants that may be used for rapamycin include but are not limited to surfactants with an HLB greater than 10, 11, 12, 13 or 14. One nonlimiting example is Cremophor EL. In some variations, the surfactant may be a polymeric surfactant including but not limited to PLURONICS F108, F127, and F68, and Tetronics. As noted herein, some solvents may also serve as surfactants. Those of ordinary skill in the art will find it routine to identify which solubilizing agents and surfactants may be used for rapamycin given the teachings herein. Viscosity Modifying Agents [0211] The liquid formulations described herein may be administered with or further comprise a viscosity modifying agent.

[02121 One exemplary viscosity modifying agent that may be used is hyaluronic acid. Hyaluronic acid is a glycosaminoglycan. It is made of a repetitive sequence of glucuronic acid and glucosamine. Hyaluronic acid is present in many tissues and organs of the body, and contributes to the viscosity and consistency of such tissues and organs. Hyaluronic acid is present in the eye, including the vitreous of the eye, and along with collagen contributes to the viscosity thereof. The liquid formulations described herein may further comprise or be administered with hyaluronic acid. [02131 Other nonlimiting examples of viscosity modifying agents include polyalkylene oxides, glycerol, carboxymethyl cellulose, sodium alginate, chitosan, dextran, dextran sulfate and collagen. These viscosity modifying agents can be chemically modified. [02141 Other viscosity modifying agents that may be used include but are not limited to carrageenan, cellulose gel, colloidal silicon dioxide, gelatin, propylene carbonate, carbonic acid, alginic acid, agar, carboxyvinyl polymers or carbomers and polyacrylamides, acacia, ester gum, guar gum, gum arabic, ghatti, gum karaya, tragacanth, terra, pectin, tamarind seed, larch arabinogalactan, alginates, locust bean, xanthan gum, starch, veegum, tragacanth, polyvinyl alcohol, gellan gum, hydrocolloid blends, and povidone. Other viscosity modifying agents known in the art can also be used, including but not limited to sodium carboxymethyl cellulose, algin, carageenans, galactomannans, hydropropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum, and zein. Other components of liquid formulations [0215] The formulations described herein may further comprise various other components such as stabilizers, for example. Stabilizers that may be used in the formulations described herein include but are not limited to agents that will (1) improve the compatibility of excipients with the encapsulating materials such as gelatin, (2) improve the stability (e.g. prevent crystal growth of a therapeutic agent such as rapamycin) of a therapeutic agent such as rapamycin and/or rapamycin derivatives, and/or (3) improve formulation stability. Note that there is overlap between components that are stabilizers and those that are solvents, solubilizing agents or surfactants, and the same component can carry out more than one role.

102161 Stabilizers may be selected from fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinylethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and combinations thereof. Amide analogues of the above stabilizers can also be used. The chosen stabilizer may change the hydrophobicity of the formulation (e.g. oleic acid, waxes), or improve the mixing of various components in the formulation (e.g. ethanol), control the moisture level in the formula (e.g. PVP), control the mobility of the phase (substances with melting points higher than room temperature such as long chain fatty acids, alcohols, esters, ethers, amides etc. or mixtures thereof; waxes), and/or improve the compatibility of the formula with encapsulating materials (e.g. oleic acid or wax). Some of these stabilizers may be used as solvents/co-solvents (e.g. ethanol). Stabilizers may be present in sufficient amount to inhibit the therapeutic agent's (such as rapamycin's) crystallization. 102171 Examples of stabilizers include, but are not limited to, saturated, monoenoic, polyenoic, branched, ring-containing, acetylenic, dicarboxylic and functional-group containing fatty acids such as oleic acid, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), DHA; fatty alcohols such as stearyl alcohol, cetyl alcohol, ceteryl alcohol; other alcohols such as ethanol, isopropyl alcohol, butanol; long chain fatty acid esters, ethers or aides such as glyceryl stearate, cetyl stearate, oleyl ethers, stearyl ethers, cetyl ethers, oleyl amides, stearyl amides; hydrophilic derivatives of fatty acids such as polyglyceryl fatty acids, polyethylene glycol fatty acid esters; polyvinylpyrrolidones, polyvinylalcohols (PVAs), waxes, docosahexaenoic acid and de hydroabietic acid etc. [0218] The formulations described may further contain a gelling agent that alters the texture of the final formulation through formation of a gel. [02191 The therapeutic agents for use as described herein, such as rapamycin, may be subjected to conventional pharmaceutical operations, such as sterilization and compositions containing the therapeutic agent may also contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. The therapeutic agents may also be formulated with pharmaceutically acceptable excipients for clinical use to produce a pharmaceutical composition. Formulations for ocular administration may be presented as a solution, suspension, particles of solid material, a discrete mass of solid material, incorporated within a polymer matrix, liquid formulations or in any other form for ocular administration. The therapeutic agents may be used to prepare a medicament to treat, prevent, inhibit, delay onset, or cause regression of any of the conditions described herein. In some variations, the therapeutic agents may be used to prepare a medicament to treat any of the conditions described herein. 102201 A composition containing a therapeutic agent such as rapamycin may contain one or more adjuvants appropriate for the indicated route of administration. Adjuvants with which the therapeutic agent may be admixed with include but are not limited to lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol. When a solubilized formulation is required the therapeutic agent may be in a solvent including but not limited to polyethylene glycol of various molecular weights, propylene glycol, carboxymethyl cellulose colloidal solutions, methanol, ethanol, DMSO, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art and may be used in the practice of the methods, compositions and liquid formulations described herein. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. The formulations for use as described herein may also include gel formulations, erodible and non-erodible polymers, microspheres, and liposomes. [0221] Other adjuvants and excipients that may be used include but are not limited to

C

8

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10 fatty acid esters such as softigen 767, polysorbate 80, PLURONICS, Tetronics, Miglyol, and Transcutol. [02221 Additives and diluents normally utilized in the pharmaceutical arts can optionally be added to the pharmaceutical composition and the liquid formulation. These include thickening, granulating, dispersing, flavoring, sweetening, coloring, and stabilizing agents, including pH stabilizers, other excipients, anti-oxidants (e.g., tocopherol, BHA, BHT, TBHQ, tocopherol acetate, ascorbyl palmitate, ascorbic acid propyl gallate, and the like), preservatives (e.g., parabens), and the like. Exemplary preservatives include, but are not limited to, benzylalcohol, ethylalcohol, benzalkonium chloride, phenol, chlorobutanol, and the like. Some useful antioxidants provide oxygen or peroxide inhibiting agents for the formulation and include, but are not limited to, butylated hydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid palmitate, a tocopherol, and the like. Thickening agents, such as lecithin, hydroxypropylcellulose, aluminum stearate, and the like, may improve the texture of the formulation. 102231 In some variations, the therapeutic agent is rapamycin, and the rapamycin is formulated as rapamune in solid or liquid form. In some variations, the rapamune is formulated as an oral dosage. [02241 In addition, a viscous polymer may be added to the suspension, assisting the localization and ease of placement and handling. In some uses of the liquid formulation, a pocket in the sclera may be surgically formed to receive an injection of the liquid formulations. The hydrogel structure of the sclera can act as a rate-controlling membrane. Particles of therapeutic agent substance for forming a suspension can be produced by known methods including but not limited to via ball milling, for example by using ceramic beads. For example, a Cole Parmer ball mill such as Labmill 8000 may be used with 0.8 mm YTZ ceramic beads available from Tosoh or Norstone Inc. [0225] The formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the therapeutic agent and the pharmaceutical carrier(s) or excipient(s). The formulations may be prepared by uniformly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [02261 In some variations, the formulations described herein are provided in one or more unit dose forms, wherein the unit dose form contains an amount of a liquid formulation described herein that is effective to treat or prevent the disease or condition for which it is being administered. In some variations, the formulations described herein are provided in one or more unit dose forms, wherein the unit dose form contains an amount of a liquid rapamycin formulation described herein that is effective to treat or prevent the disease or condition for which it is being administered. [02271 In some embodiments, the unit dose form is prepared in the concentration at which it will be administered. In some variations, the unit dose form is diluted prior to administration to a subject. In some variations, a liquid formulation described herein is diluted in an aqueous medium prior to administration to a subject. In some variations the aqueous medium is an isotonic medium. In some variations, a liquid formulation described herein is diluted in an non-aqueous medium prior to administration to a subject.

[02281 In a further aspect, provided herein are kits comprising one or more unit dose forms as described herein. In some embodiments, the kit comprises one or more of packaging and instructions for use to treat one or more diseases or conditions. In some embodiments, the kit comprises a diluent which is not in physical contact with the formulation or pharmaceutical formulation. In some embodiments, the kit comprises any of one or more unit dose forms described herein in one or more sealed vessels. In some embodiments, the kit comprises any of one or more sterile unit dose forms. [02291 In some variations, the unit dose form is in a container, including but not limited to a sterile sealed container. In some variations the container is a vial, ampule, or low volume applicator, including but not limited to a syringe. In some variations, a low volume applicator is pre-filled with rapamycin for treatment of an ophthalmic disease or condition, including but not limited to a limus compound for treatment of age-related macular degeneration. Described herein is a pre-filled low-volume applicator pre-filled with a formulation comprising a therapeutic agent, including but not limited to rapamycin. In some variations a low-volume applicator is pre-filled with a solution comprising a therapeutic agent, including but not limited to rapamycin and a polyethylene glycol, and optionally further comprises one or more additional components including but not limited to ethanol. In some variations a pre-filled low-volume applicator is pre-filled with a solution comprising about 2% rapamycin, about 94% PEG-400, about 4% ethanol. [02301 Described herein are kits comprising one or more containers. In some variations a kit comprises one or more low-volume applicators is pre-filled with a formulation described herein comprising a therapeutic agent, including but not limited to formulations comprising rapamycin, formulations comprising rapamycin and a polyethylene glycol, and optionally further comprises one or more additional components including but not limited to ethanol, and formulations in liquid form comprising about 2% rapamycin, about 94% PEG-400, about 4% ethanol. In some variations the kit comprises one or more containers, including but not limited to pre-filled low-volume applicators, with instructions for its use. In a further variation a kit comprises one or more low-volume applicators pre-filled with rapamycin, with instructions for its use in treating a disease or condition of the eye. In some variations, the containers described herein are in a secondary packaging. Routes ofAdministration [02311 The compositions, methods, and liquid formulations described herein deliver one or more therapeutic agents to a subject, including but not limited to a human subject. 102321 In some variations, the compositions, methods, and liquid formulations described herein deliver one or more therapeutic agents to an aqueous medium of a human subject. [0233] In some variations, the compositions, methods, and liquid formulations described herein deliver one or more therapeutic agents to an aqueous medium in or proximal to an area where a disease or condition is to be treated, prevented, inhibited, onset delayed, or regression caused. [02341 In some variations, the compositions, methods, and liquid formulations described herein deliver one or more therapeutic agents to an eye of a subject, including the macula and the retina choroid tissues, in an amount and for a duration effective to treat, prevent, inhibit, delay the onset of, or cause the regression of the diseases and conditions described in the Diseases and Conditions section. 102351 "Retina choroid" and "retina choroid tissues," as used herein, are synonymous and refer to the combined retina and choroid tissues of the eye. [02361 As a non-limiting example, the compositions, liquid formulations, and methods described in herein may be administered to the vitreous, aqueous humor, sclera, conjunctiva, between the sclera and conjunctiva, the retina choroid tissues, macula, or other area in or proximate to the eye of a subject, either by direct administration to these tissues or by periocular routes, in amounts and for a duration effective to treat, prevent, inhibit, delay the onset of, or cause the regression of CNV and wet AMD. The effective amounts and durations may be different for each of treating, preventing, inhibiting, delaying the onset of, or causing the regression of CNV and wet AMD, and for each of the different sites of delivery. [0237] Intravitreal administration is more invasive than some other types of ocular procedures. Because of the potential risks of adverse effects, intravitreal administration may not be optimal for treatment of relatively healthy eyes. By contrast, periocular administration, such as subconjunctival administration, is much less invasive than intravitreal administration. When a therapeutic agent is delivered by a periocular route, it may be possible to treat patients with healthier eyes than could be treated using intravitreal administration. In some variations, subconjunctival injection is used to prevent or delay onset of a disease or condition of the eye, where the eye of the subject has visual acuity of 20/40 or better. [02381 "Subconjunctival" placement or injection, as used herein, refers to placement or injection between the sclera and conjunctiva. Subconjunctival is sometimes referred to herein as "sub-conj" administration. [0239] Routes of administration that may be used to administer a liquid formulation include but are not limited to placement of the liquid formulation, for example by injection, into an aqueous medium in the subject, including but not limited to placement, including but not limited to by injection, into the eye of a subject, including but not limited to a human subject. The liquid formulation may be administered systemically, including but not limited to the following delivery routes: rectal, vaginal, infusion, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, intracisternal, cutaneous, subcutaneous, intradermal, transdermal, intravenous, intracervical, intraabdominal, intracranial, intraocular, intrapulmonary, intrathoracic, intratracheal, nasal, buccal, sublingual, oral, parenteral, or nebulised or aerosolized using aerosol propellants. [02401 Compositions and liquid formulations comprising therapeutic agent can be administered directly to the eye using a variety of procedures, including but not limited to procedures in which (1) the therapeutic agent is administered by injection using a syringe and hypodermic needle, (2) a specially designed device is used to inject the therapeutic agent, (3) prior to injection of the therapeutic agent, a pocket is surgically formed within the sclera to serve as a receptacle for the therapeutic agent or therapeutic agent composition. For example, in one administration procedure a surgeon forms a pocket within the sclera of the eye followed by injection of a solution or liquid formulation comprising the therapeutic agent into the pocket. 102411 Other administration procedures include, but are not limited to procedures in which (1) a formulation of the therapeutic agent is injected through a specially designed curved cannula to place the therapeutic agent directly against a portion of the eye, (2) a compressed form of the therapeutic agent is placed directly against a portion of the eye, (3) the therapeutic agent is inserted into the sclera by a specially designed injector or inserter, (4) the liquid formulation comprising the therapeutic agent is incorporated within a polymer, (5) a surgeon makes a small conjunctival incision through which to pass a suture and any therapeutic agent delivery structure so as to secure the structure adjacent K1 to the sclera, (6) a needle is used for injection directly into the vitreous of an eye, or into any other site described. 102421 The liquid formulations described herein may be used directly, for example, by injection, as an elixir, for topical administration including but not limited to via eye drops, or in hard or soft gelatin or starch capsules. The capsules may be banded to prevent leakage. Delivery by injection [02431 One method that may be used to deliver the compositions and liquid formulations described herein is delivery by injection. In this method compositions and liquid formulations may be injected into a subject, including but not limited to a human subject, or into a position in or proximate to an eye of the subject for delivery to a subject or to the eye of a subject. Injection includes but is not limited to intraocular and periocular injection. Nonlimiting examples of positions that are in or proximate to an eye of a subject are as follows. [02441 Injection of therapeutic agent into the vitreous may provide a high local concentration of therapeutic agent in the vitreous and retina. Further, it has been found that in the vitreous the clearance half-lives of drugs increases with molecular weight. [0245] Intracameral injection, or injection into the anterior chamber of they eye, may also be used. In one example, up to about 100 il may be injected intracamerally. [02461 Periocular routes of delivery may deliver therapeutic agent to the retina without some of the risks of intravitreal delivery. Periocular routes include but are not limited to subconjunctival, subtenon, retrobulbar, peribulbar and posterior juxtascleral delivery. A "periocular" route of administration means placement near or around the eye. For a description of exemplary periocular routes for retinal drug delivery, see Periocular routes for retinal drug delivery, Raghava et al. (2004), Expert Opin. Drug Deliv. 1(l):99-114, which is incorporated herein by reference in its entirety. [02471 In some variations the liquid formulations described herein are administered intraocularly. Intraocular administration includes placement or injection within the eye, including in the vitreous. [02481 Subconjunctival injection may be by injection of therapeutic agent underneath the conjunctiva, or between the sclera and conjunctiva. In one example, up to about 500 pl may be injected subconjunctivally. As one nonlimiting example, a needle of up to about 25 to about 30 gauge and about 30 mm long may be used. Local pressure to the subconjunctival site of therapeutic agent administration may elevate delivery of the therapeutic agent to the posterior segment by reducing local choroidal blood flow. [02491 Subtenon injection may be by injection of therapeutic agent into the tenon's capsule around the upper portion of the eye and into the "belly" of the superior rectus muscle. In one example, up to about 4 ml may be injected subtenon. As one nonlimiting example, a blunt-tipped cannula about 2.5 cm long may be used. [02501 Retrobulbar injection refers to injection into the conical compartment of the four rectus muscles and their intermuscular septa, behind the globe of the eye. In one example, up to about 5 ml may be injected retrobulbarly. As one nonlimiting example, a blunt needle of about 25 - or about 27-gauge may be used. [02511 Peribulbar injection may be at a location external to the confines of the four rectus muscles and their intramuscular septa, i.e., outside of the muscle cone. A volume of, for example, up to about 10 ml may be injected peribulbarly. As one nonlimiting example, a blunt-tipped cannula about 1.25 inches long and about 25-gauge may be used. (02521 Posterior juxtascleral delivery refers to placement of a therapeutic agent near and above the macula, in direct contact with the outer surface of the sclera, and without puncturing the eyeball. In one example, up to about 500 ml may be injected posterior juxtasclerally. As one nonlimiting example, a blunt-tipped curved cannula, specially designed at 560, is used to place the therapeutic agent in an incision in the sclera. 102531 In some variations the liquid formulations described herein are injected intraocularly. Intraocular injection includes injection within the eye. 102541 Sites to which the compositions and liquid formulations may be administered include but are not limited to the vitreous, aqueous humor, sclera, conjunctiva, between the sclera and conjunctiva, the retina choroid tissues, macula, or other area in or proximate to the eye of a subject. Methods that may be used for placement of the compositions and liquid formulations include but are not limited to injection. [02551 In one method that may be used, the therapeutic agent is dissolved in an solvent or solvent mixture and then injected into or proximate to the vitreous, aqueous humor, sclera, conjunctiva, between the sclera and conjunctiva, the retina choroid tissues, macula, other area in or proximate to the eye of a subject, or other medium of a subject, according to any of the procedures mentioned above. In one such method that may be used, the therapeutic agent is rapamycin in a liquid formulation.

102561 When the therapeutic agent is rapamycin, the compositions and liquid formulations may be used to deliver or maintain an amount of rapamycin in tissues of the eye, including without limitation retina, choroid, or the vitreous, which amount is effective to treat AMD. In one nonlimiting example, it is believed that a liquid formulation delivering rapamycin in an amount capable of providing a concentration of rapamycin of about 0.1 pg/ml to about 2 pig/ml in the vitreous may be used for treatment of wet AMD. In some nonlimiting examples, it is believed that a liquid formulation delivering a concentration of rapamycin of about 0.1 pg/mg to about I pig/mg in the retina choroid tissues may be used for treatment of wet AMD. Other effective concentrations are readily ascertainable by those of skill in the art based on the teachings described herein. Method of preparing liquid formulations [02571 One nonlimiting method that may be used for preparing the liquid formulations described herein, including but not limited to liquid formulations comprising rapamycin, is by mixing a solvent and a therapeutic agent together at room temperature or at slightly elevated temperature until a solution or suspension is obtained, with optional use of a sonicator, and then cooling the formulation. Other components including but not limited to those described above may then be mixed with the formulation. Other preparation methods that may be used are described herein including in the examples, and those of skill in the art will be able to select other preparation methods based on the teachings herein. Extended delivery of therapeutic agents [02581 Described herein are compositions and liquid formulations showing in vivo delivery or clearance profiles with one or more of the following characteristics. The delivery or clearance profiles are for clearance of the therapeutic agent in vivo after injection of the composition or liquid formulations subconjunctivally or into the vitreous of a rabbit eye. In some variations, the delivery or clearance profiles are for clearance of rapamycin in vivo after injection of the composition or liquid formulations subconjunctivally or into the vitreous of a rabbit eye. The volume of the rabbit vitreous is approximately 30-40% of the volume of the human vitreous. The amount of therapeutic agent is measured using techniques as described in Example 2, but without limitation to the formulation and therapeutic agent described in Example 2. [02591 In some variations, the therapeutic agents with the in vivo delivery or clearance profiles described herein include but are not limited to those described in the Therapeutic Agents section. In some variations the therapeutic agent is rapamycin. In some variations, the liquid formulations described herein are used to deliver therapeutic agents in a concentration equivalent to rapamycin. The liquid formulations described herein may comprise any therapeutic agent including but not limited to those in the Therapeutic Agents section, in a concentration equivalent to rapamycin including but not limited to those concentrations described herein including in the examples. [02601 "Average percentage in vivo" level means that an average concentration of therapeutic agent is obtained across multiple rabbit eyes for a given timepoint, and the average concentration of therapeutic agent at one timepoint is divided by the average concentration of therapeutic agent at another timepoint. In some variations of the average percentage in vivo levels, the therapeutic agent is rapamycin. [02611 The average concentration of a therapeutic agent in the tissue of a rabbit eye at a given time after administration of a formulation containing the therapeutic agent may be measured according to the following method. Where volumes below 10 pl are to be injected, a Hamilton syringe is used. [02621 The liquid formulations are stored at a temperature of 2-8*C prior to use. [02631 The experimental animals are specific pathogen free (SPF) New Zealand White rabbits. A mixed population of about 50% male, about 50% female is used. The rabbits are at least 12 weeks of age, usually at least 14 weeks of age, at the time of dosing. The rabbits each weigh at least 2.2 kg, usually at least 2.5 kg, at the time of dosing. Prior to the study, the animals are quarantined for at least one week and examined for general health parameters. Any unhealthy animals are not used in the study. At least 6 eyes are measured and averaged for a given timepoint. [02641 Housing and sanitation are performed according to standard procedures used in the industry. The animals are provided approximately 150 grams of Teklad Certified Hi Fiber Rabbit Diet daily, and are provided tap water ad libitum. No contaminants are known to exist in the water and no additional analysis outside that provided by the local water district is performed. Environmental Conditions are monitored. IfC 10265] Each animal undergoes a pre-treatment ophthalmic examination (slit lamp and ophthalmoscopy), performed by a board certified veterinary ophthalmologist. Ocular findings are scored according to the McDonald and Shadduck scoring system as described in Dermatoxicology, F. N. Marzulli and H.I. Maibach, 1977 "Eye Irritation," T.O. McDonald and J.A. Shadduck (pages 579-582). Observations are recorded using a standardized data collection sheet. Acceptance criteria for placement on study are as follows: scores of < 1 for conjunctival congestion and swelling; scores of 0 for all other observation variables. [0266] Gentamicin ophthalmic drops are placed into both eyes of each animal twice daily on the day prior to dosing, on the day of dosing (Day 1), and on the day after dosing (Day 2). Dosing is performed in two phases, the first including one set of animals and the second including the other animals. Animals are randomized separately into masked treatment groups prior to each phase of dosing according to modified Latin squares. Animals are fasted at least 8 hours prior to injection. The start time of the fast and time of injection are recorded. [0267] Animals are weighed and anesthetized with an intravenous injection of a ketamine/xylazine cocktail (87 mg/mL ketamine, 13 mg/mL xylazine) at a volume of 0.1 0.2 mL/kg. Both eyes of each animal are prepared for injection as follows: approximately five minutes prior to injection, eyes are moistened with an ophthalmic Betadine solution. After five minutes, the Betadine is washed out of the eyes with sterile saline. Proparacaine hydrochloride 0.5% (1-2 drops) is delivered to each eye. For eyes to be intravitreally injected, 1% Tropicamide (1 drop) is delivered to each eye. 102681 On Day 1, both eyes of each animal receive an injection of test or control article. Animals in selected groups are dosed a second time on Day 90 + 1. Dosing is subconjunctival or intravitreal. Actual treatments, injection locations, and dose volumes are masked and revealed at the end of the study. [02691 Subconjunctival injections are given using an insulin syringe and 30 gauge x 1/2-inch needle. The bulbar conjunctiva in the dorsotemporal quadrant is elevated using forceps. Test article is injected into the subconjunctival space. [02701 Intravitreal injections are given using an Insulin syringe and 30 gauge x 1/2-inch needle. For each injection, the needle is introduced through the ventral-nasal quadrant of the eye, approximately 2-3 mm posterior to the limbus, with the bevel of the needle directed downward and posteriorly to avoid the lens. Test article is injected in a single bolus in the vitreous near the retina. [02711 Animals are observed for mortality/morbidity twice daily. An animal determined to be moribund is euthanized with an intravenous injection of commercial euthanasia solution. Both eyes are removed and stored frozen at -70*C for possible future evaluation. If an animal is found dead prior to onset of rigor mortis, both eyes are removed and stored frozen at -70 0 C for possible future evaluation. Animals found after the onset of rigor mortis are not necropsied. 102721 Animals are weighed at randomization, on Day 1 prior to dosing, and prior to euthanasia. 10273] Ophthalmic observations (slit lamp and indirect ophthalmoscopy) are performed on all animals on Days 5 ± 1, 30 ± 1, 60 ± 1, 90 ± 1, and at later dates in some variations. Observations are performed by a board certified veterinary ophthalmologist. For animals to be dosed on Day 90 ± 1, ophthalmic observations are performed prior to dosing. Ocular findings are scored according to the McDonald and Shadduck scoring system as described in Dermatoxicology, F.N. Marzulli and H.I. Maibach, 1977 "Eye Irritation", T.O. McDonald and J.A. Shadduck (pages 579-582), and observations are recorded using a standardized data collection sheet. [02741 Whole blood samples (1-3 mL per sample) are collected from each animal prior to necropsy in vacutainer tubes containing EDTA. Each tube is filled at least 2/3 full and thoroughly mixed for at least 30 seconds. Tubes are stored frozen until shipped on dry ice. [02751 Animals are euthanized with an intravenous injection of commercial euthanasia solution. Euthanasia is performed according to standard procedures used in the industry. 10276] For treatment groups dosed intravitreally or subconjunctivally with placebo, all eyes from each of these groups are placed into Davidsons solution for approximately 24 hours. Following the 24-hour period, the eyes are transferred to 70% ethanol; these globes are submitted for masked histopathological evaluation by a board certified veterinary pathologist. The time that eyes are placed into Davidsons and the time of removal are recorded. 102771 For treatment groups dosed intravitreally or subconjunctivally with test article, some eyes from each of these groups are frozen at -70*C and submitted for pharmacokinetic analysis. The remaining eyes from each of these groups are placed into Davidsons solution for approximately 24 hours. Following the 24-hour period, the eyes are transferred to 70% ethanol; these globes are submitted for masked histopathological evaluation by a board certified veterinary pathologist. The time that eyes are placed into Davidsons and the time of removal are recorded. [0278] Frozen samples submitted for pharmacokinetic analysis are dissected with disposable instruments. One set of instruments is used per eye, and then discarded. The samples are thawed at room temperature for I to 2 minutes to ensure that the frost around the tissue has been removed. The sclera is dissected into 4 quadrants, and the vitreous is removed. If a non-dispersed mass (NDM) is clearly visible within the vitreous, the vitreous is separated into two sections. The section with the NDM is approximately two thirds of the vitreous. The section without the NDM is the portion of the vitreous that is the most distant from the NDM. The aqueous humor, lens, iris, and cornea are separated. The retina choroid tissue is removed using a forceps and collected for analysis. The conjunctiva is separated from the sclera. 102791 The various tissue types are collected into separate individual pre-weighed vials which are then capped and weighed. The vials of tissue are stored at -80'C until analyzed. [02801 The sirolimus content of the retina choroid, sclera, vitreous humor, and whole anti-coagulated blood is determined by high-pressure liquid chromatography/tandem mass spectroscopy (HPLC/MS/MS) using 32-0-desmethoxyrapamycin as an internal standard. Where an NDM was observed in the vitreous, the section of the vitreous containing the NDM and the section of the vitreous not containing the NDM are analyzed separately. 102811 The average concentration of a therapeutic agent over a period of time means for representative timepoints over the period of time the average concentration at each time point. For example, if the time period is 30 days, the average concentration may be measured at 5 day intervals: for the average concentration at day 5, the average of a number of measurements of concentration at day 5 would be calculated; for the average concentration at day 10, the average of a number of measurements of the concentration at day 10 would be calculated, etc. [02821 In some variations, the liquid formulations described herein may have in vivo delivery to the vitreous profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid

CO

formulation between the sclera and the conjunctiva of a rabbit eye. One nonlimiting variation of in vivo delivery to the vitreous profiles is shown in Fig. 2. [02831 At day 40 after injection, the average percentage in vivo vitreal level may be between about 70% and about 100%, and more usually between about 80% and about 90%, relative to the level present at day 20 after injection. At day 40 after injection, the average percentage in vivo vitreal level may be greater than about 70%, and more usually greater than about 80%, relative to the level present at day 20 after injection. 102841 At day 67 after injection, the average percentage in vivo vitreal level may be between about 75% and about 115%, and more usually between about 85% and about 105%, relative to the level present at day 20 after injection. At day 67 after injection, the average percentage in vivo vitreal level may be greater than about 75%, and more usually greater than about 85%, relative to the level present at day 20 after injection. 102851 At day 90 after injection, the average percentage in vivo vitreal level may be between about 20% and about 50%, and more usually between about 30% and about 40%, relative to the level present at day 20 after injection. At day 90 after injection, the average percentage in vivo vitreal level may be greater than about 20%, and more usually greater than about 30%, relative to the level present at day 20 after injection. [02861 In some variations, the average percentage in vivo vitreal level has the following characteristics relative to the level present at day 20 after injection: at 40 days after injection it is less than about 100%; at 67 days after injection it is less than about 115%; and 90 days after injection it is less than about 50%. 102871 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.01 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.1 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about I ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. 102881 In some variations, the liquid formulations described herein may have in vivo delivery to the retina choroid profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. 102891 At day 40 after injection, the average percentage in vivo retina choroid level may be between about 350% and about 410%, and more usually between about 360% and about 400%, relative to the level present at day 20 after injection. At day 40 after injection, the average percentage in vivo retina choroid level may be greater than about 350%, and more usually greater than about 360%, relative to the level present at day 20 after injection. 102901 At day 67 after injection, the average percentage in vivo retina choroid level may be between about 125% and about 165%, and more usually between about 135% and about 155%, relative to the level present at day 20 after injection. At day 67 after injection, the average percentage in vivo retina choroid level may be greater than about 125%, and more usually greater than about 135%, relative to the level present at day 20 after injection. [02911 At day 90 after injection, the average percentage in vivo retina choroid level may be between about 10% and about 50%, and more usually between about 20% and about 40%, relative to the level present at day 20 after injection. At day 90 after injection, the average percentage in vivo retina choroid level may be greater than about 10%, and more usually greater than about 20%, relative to the level present at day 20 after injection. [02921 In some variations, the average percentage in vivo retina choroid level has the following characteristics relative to the level present at day 20 after injection: at 40 days after injection it is less than about 410%; at 67 days after injection it is less than about 165%; and 90 days after injection it is less than about 50%. [02931 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least about 0.001 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic '7A agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least about 0.01 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. [02941 In some variations, the level of therapeutic agent present in the retina choroid first increases, then peaks and decreases. The peak may, for instance, occur at about day 40 after injection. 102951 In some variations, the liquid formulations described herein may have in vivo clearance from the sclera profiles with the following described characteristics, where the clearance profiles are for clearance of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. Where injection is between the sclera and the conjunctiva, the scleral level is thought to include the injected liquid formulation. 102961 At day 40 after injection, the average percentage in vivo scleral level may be between about 150% and about 230%, and more usually between about 170% and about 210%, relative to the level present at day 20 after injection. At day 40 after injection, the average percentage in vivo scleral level may be greater than about 150%, and more usually greater than about 170%, relative to the level present at day 20 after injection. [02971 At day 67 after injection, the average percentage in vivo scleral level may be between about 30% and about 70%, and more usually between about 40% and about 60%, relative to the level present at day 20 after injection. At day 67 after injection, the average percentage in vivo scleral level may be greater than about 30%, and more usually greater than about 40%, relative to the level present at day 20 after injection. [02981 At day 90 after injection, the average percentage in vivo scleral level may be between about 110% and about 160%, and more usually between about 125% and about 145%, relative to the level present at day 20 after injection. At day 90 after injection, the average percentage in vivo scleral level may be greater than about 110%, and more usually greater than about 125%, relative to the level present at day 20 after injection. 102991 In some variations, the average percentage in vivo scleral level has the following characteristics relative to the level present at day 20 after injection: at 40 days after injection it is less than about 230%; at 67 days after injection it is less than about 70%; and 90 days after injection it is less than about 160%.

10300] In some variations, the level of therapeutic agent present in the sclera first increases, then peaks and decreases. The peak may, for instance, occur at about day 40 after injection. 103011 In some variations, the liquid formulations described herein may have in vivo delivery to the vitreous profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. 103021 At day 14 after injection, the average percentage in vivo vitreal level may be between about 1350% and about 1650%, and more usually between about 1450% and about 1550%, relative to the level present at day 2 after injection. At day 14 after injection, the average percentage in vivo vitreal level may be greater than about 1350%, and more usually greater than about 1450%, relative to the level present at day 2 after injection. [0303] At day 35 after injection, the average percentage in vivo vitreal level may be between about 200% and about 300%, and more usually between about 225% and about 275%, relative to the level present at day 2 after injection. At day 35 after injection, the average percentage in vivo vitreal level may be greater than about 200%, and more usually greater than about 225%, relative to the level present at day 2 after injection. [03041 At day 62 after injection, the average percentage in vivo vitreal level may be between about 100% and about 160%, and more usually between about 115% and about 145%, relative to the level present at day 2 after injection. At day 62 after injection, the average percentage in vivo vitreal level may be greater than about 100%, and more usually greater than about 115%, relative to the level present at day 2 after injection. 10305] At day 85 after injection, the average percentage in vivo vitreal level may be between about 5% and about 30%, and more usually between about 10% and about 25%, relative to the level present at day 2 after injection. At day 85 after injection, the average percentage in vivo vitreal level may be greater than about 5%, and more usually greater than about 10%, relative to the level present at day 2 after injection. 10306] In some variations, the average percentage in vivo vitreal level has the following characteristics relative to the level present at day 2 after injection: at 14 days after injection it is less than about 1600%; at 35 days after injection it is less than about 300%; at 62 days after injection it is less than about 160% and 85 days after injection it is less than about 30%.

[0307] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.01 ng/mL for at least about 30, at least about 60, or at least about 85 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.1 ng/mL for at least about 30, at least about 60, or at least about 85 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 1 ng/mL for at least about 30, or at least about 60 days after administration of the liquid formulation to the rabbit eyes. [03081 In some variations, the level of therapeutic agent present in the vitreous first increases, then peaks and decreases. The peak may, for instance, occur at about day 14 after injection. 103091 In some variations, the liquid formulations described herein may have in vivo delivery to the retina choroid profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. [0310] At day 35 after injection, the average percentage in vivo retina choroid level may be between about 320% and about 400%, and more usually between about 340% and about 380%, relative to the level present at day 14 after injection. At day 35 after injection, the average percentage in vivo retina choroid level may be greater than about 320%, and more usually greater than about 340%, relative to the level present at day 14 after injection. [03111 At day 62 after injection, the average percentage in vivo retina choroid level may be between about 3% and about 25%, and more usually between about 6% and about 20%, relative to the level present at day 14 after injection. At day 62 after injection, the average percentage in vivo retina choroid level may be greater than about 3%, and more usually greater than about 6%, relative to the level present at day 14 after injection. [03121 At day 85 after injection, the average percentage in vivo retina choroid level may be between about 0.1% and about 6%, and more usually between about 0.5% and about 4%, relative to the level present at day 14 after injection. At day 85 after injection, the average percentage in vivo retina choroid level may be greater than about 0.1%, and more usually greater than about 0.5%, relative to the level present at day 14 after injection. 103131 In some variations, the average percentage in vivo retina choroid level has the following characteristics relative to the level present at day 14 after injection: at 35 days after injection it is less than about 400%; at 62 days after injection it is less than about 25%; and 85 days after injection it is less than about 6%. 103141 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least about 0.001 ng/mg for at least about 30, at least about 60, or at least about 85 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least about 0.01 ng/mg for at least about 30, at least about 60, or at least about 85 days after administration of the liquid formulation to the rabbit eyes. 10315] In some variations, the liquid formulations described herein may have in vivo clearance from the sclera profiles with the following described characteristics, where the clearance profiles are for clearance of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. For injection between the sclera and conjunctiva, the scleral level is thought to include the injected liquid formulation. [03161 At day 35 after injection, the average percentage in vivo scleral level may be between about 0.1% and about 0.7%, and more usually between about 0.2% and about 0.6%, relative to the level present at day 14 after injection. At day 35 after injection, the average percentage in vivo scleral level may be greater than about 0.1%, and more usually greater than about 0.2%, relative to the level present at day 14 after injection. [03171 At day 62 after injection, the average percentage in vivo scleral level may be between about 0.05% and about 0.35%, and more usually between about 0.07% and about 0.3%, relative to the level present at day 14 after injection. At day 62 after injection, the average percentage in vivo scleral level may be greater than about 0.05%, and more usually greater than about 0.07%, relative to the level present at day 14 after injection. '7 A [03181 At day 85 after injection, the average percentage in vivo scleral level may be between about 0.1% and about 0.9%, and more usually between about 0.3% and about 0.7%, relative to the level present at day 14 after injection. At day 85 after injection, the average percentage in vivo scleral level may be greater than about 0.1%, and more usually greater than about 0.3%, relative to the level present at day 14 after injection. 103191 In some variations, the average percentage in vivo scleral level has the following characteristics relative to the level present at day 14 after injection: at 35 days after injection it is less than about 0.7%; at 62 days after injection it is less than about 0.35%; and 85 days after injection it is less than about 0.9%. 103201 In some variations, the liquid formulations described herein may have in vivo clearance from the vitreous profiles with the following described characteristics, where the clearance profiles are for clearance of therapeutic agent in vivo after injection of the liquid formulation into the vitreous of a rabbit eye. Where injection is into the vitreous, the measured vitreous level is thought to include the injected formulation. [03211 At day 35 after injection, the average percentage in vivo vitreal level may be between about 1% and about 40%, and more usually between about 1% and about 10%, relative to the level present at day 14 after injection. At day 35 after injection, the average percentage in vivo vitreal level may be greater than about 1% relative to the level present at day 14 after injection. [03221 At day 62 after injection, the average percentage in vivo vitreal level may be between about 1% and about 40%, and more usually between about 5% and about 25%, relative to the level present at day 14 after injection. At day 62 after injection, the average percentage in vivo vitreal level may be greater than about 1% relative to the level present at day 14 after injection, and more usually greater than about 5% relative to the level present at day 14 after injection. 103231 At day 90 after injection, the average percentage in vivo vitreal level may be between about 1% and about 40%, and more usually between about 10% and about 30%, relative to the level present at day 14 after injection. At day 90 after injection, the average percentage in vivo vitreal level may be greater than about 1% relative to the level present at day 14 after injection, and more usually greater than about 10% relative to the level present at day 14 after injection.

[03241 In some variations, the level of therapeutic agent present in the vitreous first increases, then peaks and decreases. The peak may, for instance, occur at about day 14 after injection. 10325] In some variations, the liquid formulations described herein may have in vivo delivery to the retina choroid profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation into the vitreous of a rabbit eye. [03261 At day 35 after injection, the average percentage in vivo retina choroid level may be between about 3400% and about 5100%, and more usually between about 3750% and about 4750%, relative to the level present at day 14 after injection. At day 35 after injection, the average percentage in vivo retina choroid level may be greater than about 3400%, and more usually greater than about 3750%, relative to the level present at day 14 after injection. [0327] At day 62 after injection, the average percentage in vivo retina choroid level may be between about 0.1% and about 5%, and more usually between about 1% and about 3%, relative to the level present at day 14 after injection. At day 62 after injection, the average percentage in vivo retina choroid level may be greater than about 0.1%, and more usually greater than about 1%, relative to the level present at day 14 after injection. [0328] At day 90 after injection, the average percentage in vivo retina choroid level may be between about 10% and about 50%, and more usually between about 20% and about 40%, relative to the level present at day 14 after injection. At day 90 after injection, the average percentage in vivo retina choroid level may be greater than about 10%, and more usually greater than about 20%, relative to the level present at day 14 after injection. [03291 In some variations, the average percentage in vivo retina choroid level has the following characteristics relative to the level present at day 14 after injection: at 35 days after injection it is less than about 5100%; at 62 days after injection it is less than about 5%; and 90 days after injection it is less than about 50%. [03301 In some variations, the liquid formulations described herein may have in vivo delivery to the sclera profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation into the vitreous of a rabbit eye. [03311 At day 35 after injection, the average percentage in vivo scleral level may be between about 1700% and about 2600%, and more usually between about 1900% and

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about 2400%, relative to the level present at day 14 after injection. At day 35 after injection, the average percentage in vivo scleral level may be greater than about 1700%, and more usually greater than about 1900%, relative to the level present at day 14 after injection. [03321 At day 62 after injection, the average percentage in vivo scleral level may be between about 120% and about 180%, and more usually between about 140% and about 160%, relative to the level present at day 14 after injection. At day 62 after injection, the average percentage in vivo scleral level may be greater than about 120%, and more usually greater than about 140%, relative to the level present at day 14 after injection. [0333] At day 90 after injection, the average percentage in vivo scleral level may be between about 95% and about 155%, and more usually between about 115% and about 135%, relative to the level present at day 14 after injection. At day 90 after injection, the average percentage in vivo scleral level may be greater than about 95%, and more usually greater than about 115%, relative to the level present at day 14 after injection. 103341 In some variations, the average percentage in vivo scleral level has the following characteristics relative to the level present at day 14 after injection: at 35 days after injection it is less than about 2600%; at 62 days after injection it is less than about 180%; and 90 days after injection it is less than about 155%. 103351 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the sclera of the rabbit eye of at least about 0.001 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the sclera of the rabbit eye of at least about 0.01 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the sclera of the rabbit eye of at least about 0.1 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eyes. 1 77 10336] In some variations, the level of therapeutic agent present in the vitreous first increases, then peaks and decreases. The peak may, for instance, occur at about day 35 after injection. [0337] In some variations, in situ gelling liquid formulations described herein may have in vivo delivery to the vitreous profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. [0338] At day 32 after injection, the average percentage in vivo vitreal level may be between about 25% and about 85%, and more usually between about 45% and about 65%, relative to the level present at day 7 after injection. At day 40 after injection, the average percentage in vivo vitreal level may be greater than about 25%, and more usually greater than about 45%, relative to the level present at day 7 after injection. [0339] At day 45 after injection, the average percentage in vivo vitreal level may be between about 2% and about 50%, and more usually between about 8% and about 20%, relative to the level present at day 7 after injection. At day 67 after injection, the average percentage in vivo vitreal level may be greater than about 2%, and more usually greater than about 5%, relative to the level present at day 7 after injection. [0340] At day 90 after injection, the average percentage in vivo vitreal level may be between about 40% and about 100%, and more usually between about 60% and about 80%, relative to the level present at day 7 after injection. At day 90 after injection, the average percentage in vivo vitreal level may be greater than about 40%, and more usually greater than about 60%, relative to the level present at day 7 after injection. [0341] In some variations, the average percentage in vivo vitreal level has the following characteristics relative to the level present at day 7 after injection: at 32 days after injection it is less than about 80%; at 45 days after injection it is less than about 30%; and 90 days after injection it is less than about 100%. [0342] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.1 pg/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least "70 about 0.01 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.1 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about I ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 10 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. 103431 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 0.001 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 0.01 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 0.1 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 0.5 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. 10 10344] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of between 0.001 ng/mL and 10.0 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of between 0.01 ng/mL and 10 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of between 0.1 ng/mL and 10 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0345] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of between 0.5 ng/mL and 10.0 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03461 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of a rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of a rabbit eye less than 100 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of a rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of a rabbit eye less than 50 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of a rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of a rabbit eye less than 10 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of a rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of a rabbit eye less than 5 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03471 "Approximately constant," as used herein, means that the average level does not vary by more than one order of magnitude over the extended period of time, i.e., the difference between the maximum and minimum is less than a 10-fold difference for measurements of the average concentration at times in the relevant period of time. [03481 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of a rabbit eye that is approximately constant at a value greater than 0.001 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the solution to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of a rabbit eye that is approximately constant at a value greater than 0.01 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of a rabbit eye that is approximately constant at a value greater than 0.1 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of a rabbit eye that is approximately constant at a value of 1.0 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0349] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.001 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.005 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.01 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. 103501 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.001 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.001 ng/mg and 0.50 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.001 ng/mg and 0.15 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.001 ng/mg and 0.1 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0351] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.005 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid 0) formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.005 ng/mg and 0.50 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.005 ng/mg and 0.15 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.005 ng/mg and 0.1 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. 103521 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.01 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.01 ng/mg and 0.50 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.01 ng/mg and 0.15 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of between 0.01 ng/mg and 0.1 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. 0.1 [0353] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye less than 100 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye less than 50 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye less than 10 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye less than 5 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0354] In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye that is approximately constant at a value greater than 0.001 ng/mg for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye that is approximately constant at a value greater than 0.005 ng/mg for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid

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formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of a rabbit eye that is approximately constant at a value greater than 0.01 ng/mg for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0355] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 100 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 1000 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least 10,000 ng/mL for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03561 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye between 100 ng/mL and 100,000 ng/mL for day 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye between 100 ng/mL and 50,000 ng/mL for day 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03571 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye between 1000 ng/mL and 100,000 ng/mL for day 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye between 1000 ng/mL and 50,000 ng/mL for day 30 0OC to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03581 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of the rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of the rabbit eye less than 100 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of the rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of the rabbit eye less than 50 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the vitreous of the rabbit eye to a minimum average concentration of therapeutic agent in the vitreous of the rabbit eye less than 10 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03591 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye that is approximately constant at a value greater than 100 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye that is approximately constant at a value greater than 1000 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye that is approximately constant at a value greater than 10,000 ng/mL for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes.

[0360] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.001 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.01 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.05 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least 0.10 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0361] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.001 ng/mg and 10.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.00 1 ng/mg and 5.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.001 ng/mg and 1.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0362] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.01 ng/mg and 10.00 ng/mg for at o'7 least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.01 ng/mg and 5.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.01 ng/mg and 1.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0363] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.05 ng/mg and 10.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.05 ng/mg and 5.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.05 ng/mg and 1.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [0364] In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.10 ng/mg and 10.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.10 ng/mg and 5.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving an average on concentration of therapeutic agent in the retina choroid tissues of the rabbit eye between 0.10 ng/mg and 1.00 ng/mg for at least 30, at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. [03651 In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye less than 100 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. In some variations, the liquid formulation when injected into the vitreous of a rabbit eye delivers therapeutic agent giving a ratio of a maximum average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye to a minimum average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye less than 50 for days 30 to at least 60, at least 90, or at least 120 days after administration of the liquid formulation to the rabbit eyes. 10366] In some variations, in situ gelling liquid formulations described herein may have in vivo delivery to the retina choroid tissue profiles with the following described characteristics, where the delivery profiles are for delivery of therapeutic agent in vivo after injection of the liquid formulation between the sclera and the conjunctiva of a rabbit eye. [03671 At day 32 after injection, the percentage in vivo vitreal level may be between about 20% and about 80%, and more usually between about 40% and about 60%, relative to the level present at day 7 after injection. At day 40 after injection, the percentage in vivo vitreal level may be greater than about 20%, and more usually greater than about 40%, relative to the level present at day 7 after injection. 103681 At day 45 after injection, the percentage in vivo vitreal level may be between about 15% and about 55%, and more usually between about 25% and about 45%, relative to the level present at day 7 after injection. At day 67 after injection, the percentage in vivo vitreal level may be greater than about 15%, and more usually greater than about 25%, relative to the level present at day 7 after injection. [03691 At day 90 after injection, the percentage in vivo vitreal level may be between about 60% and about 100%, and more usually between about 70% and about 90%, relative to the level present at day 7 after injection. At day 90 after injection, the

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percentage in vivo vitreal level may be greater than about 60%, and more usually greater than about 70%, relative to the level present at day 7 after injection. [03701 In some variations, the percentage in vivo vitreal level has the following characteristics relative to the level present at day 7 after injection: at 32 days after injection it is less than about 80%; at 45 days after injection it is less than about 60%; and 90 days after injection it is less than about 100%. [03711 In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye of at least about 0.1 pg/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.01 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 0.1 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving an average concentration of therapeutic agent in the vitreous of the rabbit eye of at least about 1 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. 103721 In some variations, the ratio of the base ten logarithms of the average levels of a therapeutic agent in two or more of the retina choroid tissues, the sclera, and the vitreous is approximately constant over an extended period of time after placement of the in situ gelling formulation in or proximate to the eye. In some variations, the ratio of the base ten logarithms of the average levels of a therapeutic agent in two or more of the retina choroid tissues, the sclera, and the vitreous is approximately constant over an extended period of time after placement of the in situ gelling formulation between the sclera and the conjunctiva of an eye. In some variations, the ratio of the base ten logarithms of the average levels of a therapeutic agent in the vitreous and the sclera is approximately constant over an extended period of time after placement of the in situ gelling formulation between the sclera and the conjunctiva of an eye. [0373] In some variations, the ratio of the base ten logarithms of the average levels of a therapeutic agent in the vitreous and the retina choroid tissues is approximately constant over an extended period of time. Put another way, as the level of therapeutic agent in the vitreous rises, the level of therapeutic agent in the retina choroid tissues rises to a similar degree when considered on the logarithmic scale, and vice versa. [0374] In some variations, the ratio of the base ten logarithms of the average levels of a therapeutic agent in the vitreous versus the retina choroid tissues is approximately constant over an extended period of time of about 7, about 30, about 60, or about 90 days. In some variations, the ratio of the average level of therapeutic agent in the vitreous relative to the level of therapeutic agent in the retina choroid tissues after placement of the in situ gelling formulation between the sclera and the conjunctiva of an eye is constant at about 37:1 at day 7, about 40:1 at day 32, about 10:1 at day 45, and about 34:1 at day 90. [0375] In some variations, the ratio of the average level of therapeutic agent in the vitreous relative to the level of therapeutic agent in the retina choroid tissues is constant at about 40:1 over a period of about 7, about 32, about 45, or about 90 days. [03761 In some variations, the average level of the therapeutic agent in any or all of the retina choroid tissues, the sclera, and the vitreous is approximately constant over an extended period of time after placement of the in situ gelling formulation in or proximate to the eye. 103771 In some variations, after placement of an in situ gelling formulation between the sclera and the conjunctiva, the average level of therapeutic agent in the vitreous is approximately constant at about 8.1 ng/ml. In some variations, after placement of an in situ gelling formulation between the sclera and the conjunctiva, the average level of therapeutic agent in the retina choroid tissues is approximately constant at about 0.25 ng/mg. In some variations, after placement of an in situ gelling formulation between the sclera and the conjunctiva, the average level of therapeutic agent in the sclera is approximately constant at about 1930 ng/mg. [03781 In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 0.1 pg/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to 01 the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 0.001 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 0.01 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 0.1 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about I ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 10 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the vitreous that is approximately constant at about 100 ng/mL for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. [03791 In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about 0.1 pg/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about 0.001 ng/mg for at least about 30, at least about 60, or at least about 90 days after 0-, administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about 0.0 1 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about 0.1 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about I ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the retina choroid tissues that is approximately constant at about 10 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. 103801 In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 0.1 pg/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 0.001 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 0.01 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 0.1 ng/mg for at least about 30, at n I least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 1 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 10 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 100 ng/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 1 pg/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. In some variations, the in situ gelling formulation when injected between the sclera and conjunctiva of a rabbit eye maintains an average level of therapeutic agent in the sclera that is approximately constant at about 10 pig/mg for at least about 30, at least about 60, or at least about 90 days after administration of the liquid formulation to the rabbit eye. [03811 For treatment, prevention, inhibition, delaying the onset of, or causing the regression of certain diseases or conditions, it may be desirable to maintain delivery of a therapeutically effective amount of the therapeutic agent for an extended period of time. Depending on the disease or condition being treated, prevented, inhibited, having onset delayed, or being caused to regress this extended period of time may be at least about I week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, or at least about 1 year. Generally, however, any extended period of delivery may be possible. A therapeutically effective amount of agent may be delivered for an extended period by a liquid formulation or composition that maintains for the extended period a concentration of agent in a subject n A or an eye of a subject sufficient to deliver a therapeutically effective amount of agent for the extended time. [0382] Delivery of a therapeutically effective amount of the therapeutic agent for an extended period may be achieved via placement of one composition or liquid formulation or may be achieved by application of two or more doses of composition or liquid formulations. As a non-limiting example of such multiple applications, maintenance of the therapeutic amount of rapamycin for 3 months for treatment, prevention, inhibition, delay of onset, or cause of regression of wet AMD may be achieved by application of one liquid formulation or composition delivering a therapeutic amount for 3 months or by sequential application of a plurality of liquid formulations or compositions. The optimal dosage regime will depend on the therapeutic amount of the therapeutic agent needing to be delivered, and the period over which it need be delivered. Those versed in such extended therapeutic agent delivery dosing will understand how to identify dosing regimes that may be used based on the teachings provided herein. [03831 When using certain therapeutic agents or for the treatment, prevention, inhibition, delaying the onset of, or causing the regression of certain diseases, it may be desirable for delivery of the therapeutic agent not to commence immediately upon placement of the liquid formulation or composition into the eye region, but for delivery to commence after some delay. For example, but in no way limiting, such delayed release may be useful where the therapeutic agent inhibits or delays wound healing and delayed release is desirable to allow healing of any wounds occurring upon placement of the liquid formulation or composition. Depending on the therapeutic agent being delivered and/or the diseases and conditions being treated, prevented, inhibited, onset delayed, and regression caused this period of delay before delivery of the therapeutic agent commences may be about 1 hour, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, or about 42 days. Other delay periods may be possible. Delayed release formulations that may be used are known to people versed in the technology. Intravitreal and subconjunctival delivery of rapamycin for treatment, prevention, inhibition, delay of onset, or cause of regression of AMD 103841 In one method described herein, a liquid formulation comprising rapamycin is delivered subconjunctivally or to the vitreous of an eye to prevent, treat, inhibit, delay onset of, or cause regression of angiogenesis in the eye, including but not limited to treating CNV as observed, for example, in AMD. In some variations, the liquid formulation is used to treat angiogenesis in the eye, including but not limited to treating CNV as observed, for example, in AMD. Rapamycin has been shown to inhibit CNV in rat and mice models, as described in U.S. Application No. 10/665,203, which is incorporated herein by reference in its entirety. Rapamycin has been observed to inhibit MatrigelTm and laser-induced CNV when administered systemically and subretinally. Also, periocular injection of rapamycin inhibits laser-induced CNV. [03851 Other therapeutic agents that may be delivered to the eye, particularly the vitreous of an eye, for treatment, prevention, inhibition, delaying onset, or causing regression of angiogenesis in the eye (such as CNV) are members of the limus family of compounds other than rapamycin including but not limited to everolimus and tacrolimus (FK-506). 103861 As described herein, the dosage of the therapeutic agent will depend on the condition being addressed, whether the condition is to be treated, prevented, inhibited, have onset delayed, or be caused to regress, the particular therapeutic agent, and other clinical factors such as weight and condition of the subject and the route of administration of the therapeutic agent. It is to be understood that the methods, liquid formulations, and compositions described herein have application for both human and veterinary use, as well as uses in other possible animals. As described herein, tissue concentrations of therapeutic agents expressed in units of mass per volume generally refer to tissues that are primarily aqueous such as the vitreous, for example. Tissue concentrations of therapeutic agents expressed in unit of mass per mass generally refer to other tissues such as the sclera or retina choroid tissues, for example. [03871 One concentration of rapamycin that may be used in the methods described herein is one that provides about 0.0 1 pg/ml or pg/mg or more of rapamycin at the tissue level. Another concentration that may be used is one that provides about 0.1 pg/ml or ng/mg or more at the tissue level. Another concentration that may be used is one that provides about 1 pg/ml or ng/mg or more at the tissue level. Another concentration that may be used is one that provides about 0.01 ng/ml or ng/mg or more at the tissue level. Another concentration that may be used is one that provides about 0.1 ng/ml or ng/mg or more at the tissue level. Another concentration that may be used is one that provides about 0.5 ng/ml or ng/mg or more at the tissue level. Another concentration that may be used is one that provides about I ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 2 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 3 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 5 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 10 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 15 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 20 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 30 ng/ml or more at the tissue level. Another concentration that may be used is one that provides about 50 ng/ml or more at the tissue level. One of ordinary skill in the art would know how to arrive at an appropriate concentration depending on the route and duration of administration utilized, given the teachings herein. [03881 Generally, the amount of rapamycin administered in a liquid formulation is an amount sufficient to treat, prevent, inhibit, delay the onset, or cause regression of the disease or condition of the eye for the required amount of time. In some variations the amount of rapamycin administered in the liquid formulation is an amount sufficient to treat the disease or condition of the eye for the required amount of time. [03891 In some variations, a total amount of rapamycin less than about 5 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 5.0 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 4.5 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 4.0 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 3.5 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 3.0 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 2.5 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 2 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 1.2 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 1.0 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 0.8 mg Q7 is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 0.6 mg is administered subconjunctivally. In some variations, a total amount of rapamycin less than about 0.4 mg is administered subconjunctivally. In some variations, a volume of a formulation is administered that contains an amount of rapamycin described herein. [03901 In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 0.5% and about 6% is subconjunctivally administered to a human subject by administering between about 0.1 jl and about 200 ld of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 0.5% and about 4% is subconjunctivally administered to a human subject by administering between about I d and about 50 pl of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 1.5% and about 3.5% is subconjunctivally administered to a human subject by administering between about 1 VI and about 15 pl of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of about 2% is subconjunctivally administered to a human subject by administering between about I ptl and about 15 pl of a liquid formulation described herein. 103911 In some variations, a liquid formulation containing an amount of rapamycin of between about 0.2 pg and about 4 mg is subconjunctivally administered to a human subject by administering between about 0.1 W and about 200 p1 of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 ptg and about 2 mg is subconjunctivally administered to a human subject by administering between about 1 Rl and about 100 pl of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 ptg and about I mg is subconjunctivally administered to a human subject by administering between about I pl and about 50 1 of a liquid formulation described herein.In some variations, a liquid formulation containing an amount of rapamycin of between about 20 jig and about 500 pg is subconjunctivally administered to a human subject by administering between about I p1 and about 25 [L of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 pg and about 300 pg is subconjunctivally no administered to a human subject by administering between about I Pl and about 15 pl of a liquid formulation described herein. [03921 In some variations, a total amount of rapamycin less than about 200 Ig is administered intravitreally. In some variations, a total amount of rapamycin less than about 200 ig is administered intravitreally. In some variations, a total amount of rapamycin less than about 300 pg is administered intravitreally. In some variations, a total amount of rapamycin less than about 400 ptg is administered intravitreally. In some variations, a total amount of rapamycin less than about 500 pg is administered intravitreally. In some variations, a total amount of rapamycin less than about 600 pg is administered intravitreally. In some variations, a total amount of rapamycin less than about 800 pg is administered intravitreally. In some variations, a total amount of rapamycin less than about I mg is administered intravitreally. In some variations, a total amount of rapamycin less than about 2 mg is administered intravitreally. In some variations, a total amount of rapamycin less than about 2.5 mg is administered intravitreally. In some variations, a total amount of rapamycin less than about 3 mg is administered intravitreally. In some variations, a total amount of rapamycin less than about 3.5 mg is administered intravitreally. In some variations, a total amount of rapamycin less than about 4 mg is administered intravitreally. In some variations, a volume of a formulation is administered that contains an amount of rapamycin described herein. 103931 In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 0.5% and about 6% is intravitreally administered to a human subject by administering between about 0.1 pil and about 200 pl of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 0.5% and about 4% is intravitreally administered to a human subject by administering between about I jil and about 50 pil of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of between about 1.5% and about 3.5% is intravitreally administered to a human subject by administering between about 1 pl and about 15 pl of a liquid formulation described herein. In some variations, a liquid formulation containing a concentration of rapamycin by weight of the total of about 2% is intravitreally administered to a human subject by n administering between about I pl and about 15 ptl of a liquid formulation described herein. [03941 In some variations, a liquid formulation containing an amount of rapamycin of between about 0.2 jg and about 4 mg is intravitreally administered to a human subject by administering between about 0.1 pl and about 200 lI of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 pg and about 2 mg is intravitreally administered to a human subject by administering between about 1 pA and about 100 pl of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 pg and about I mg is intravitreally administered to a human subject by administering between about I pl and about 50 pl of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 jig and about 500 jig is intravitreally administered to a human subject by administering between about I R1 and about 25 pl of a liquid formulation described herein. In some variations, a liquid formulation containing an amount of rapamycin of between about 20 jig and about 300 pg is intravitreally administered to a human subject by administering between about 1 jI and about 15 pl of a liquid formulation described herein. [03951 In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 1 pg and about 5 mg is administered to a human subject for treatment of wet AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 pg and about 4 mg is administered to a human subject for treatment of wet AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 pg and about 1.2 mg is administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about 10 pg and about 0.5 mg is administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about 10 pg and 90 pg is administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about 60 pg and about 120 pg is administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about 100 pg and about 400 jig is administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about 400 jg and about I mg is 1 nn administered to a human subject for treatment of wet AMD. In some variations an amount of rapamycin of between about I mg and about 5 mg is administered to a human subject for treatment of wet AMD. In some variations, an amount of rapamycin of between about 3 mg and about 7 mg is administered to a human subject for treatment of wet AMD. In some variations, an amount of rapamycin of between about 5 mg and about 10 mg is administered to a human subject for treatment of wet AMD. [03961 In some variations a liquid formulation as described herein containing an amount of rapamycin of between about I pg and about 5 mg is administered to a human subject for prevention of wet AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 Vg and about 4 mg is administered to a human subject for prevention of wet AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 kg and about 1.2 mg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about 10 pg and about 0.5 mg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about 10 kg and 90 pg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about 60 pg and about 120 kg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about 100 pg and about 400 pg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about 400 kg and about 1 mg is administered to a human subject for prevention of wet AMD. In some variations an amount of rapamycin of between about I mg and about 5 mg is administered to a human subject for prevention of wet AMD. In some variations, an amount of rapamycin of between about 3 mg and about 7 mg is administered to a human subject for prevention of wet AMD. In some variations, an amount of rapamycin of between about 5 mg and about 10 mg is administered to a human subject for prevention of wet AMD. [03971 In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 1 kg and about 5 mg is administered to a human subject for treatment of dry AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 pg and about 4 mg is administered to a human subject for treatment of dry AMD. In some variations a liquid formulation as described herein containing an amount of rapamycin of between about 20 1A1 pg and about 1.2 mg is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 10 pig and about 0.5 mg is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 10 pig and 90 ptg is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 60 pg and about 120 ig is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 100 pg and about 400 pg is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 400 ptg and about I mg is administered to a human subject for treatment of dry AMD. In some variations an amount of rapamycin of between about 1 mg and about 5 mg is administered to a human subject for treatment of dry AMD. In some variations, an amount of rapamycin of between about 3 mg and about 7 mg is administered to a human subject for treatment of dry AMD. In some variations, an amount of rapamycin of between about 5 mg and about 10 mg is administered to a human subject for treatment of dry AMD. [03981 In some variations, a liquid formulation as described herein containing an amount of rapamycin of between about I pg and about 5 mg is administered to a human subject for treatment of angiogenesis, including but not limited to choroidal neovascularization. In some variations, an amount of rapamycin of between about 20 pg and about 4 mg is administered to the human subject; between about 20 pg and about 1.2 mg; between about 10 ig and about 0.5 mg is administered to a human subject for treatment of wet AMD, between about 10 pg and 90 pg, between about 60 jig and 120 pg is administered to the human subject; between about 100 jig and 400 pg, between about 400 jg and 1 mg is administered to the human subject; in some variations, an amount of rapamycin of between about I mg and 5 mg is administered to the human subject ; in some variations, an amount of rapamycin of between about 3 mg and 7 mg is administered to the human subject; in some variations, an amount of rapamycin of between about 5 mg and 10 mg is administered to the human subject for treatment of angiogenesis, including but not limited to choroidal neovascularization. [03991 In one method, a liquid formulation as described herein contains an amount of a therapeutic agent equivalent to an amount of rapamycin. [04001 In one method, a liquid formulation as described herein containing an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 1 jig and 1 Al) about 5 mg is administered to a human subject for treatment of wet AMD. In some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 1 jig and about 5 mg is administered to the human subject; between about 20 pg and about 1.2 mg; between about 10 jig and about 0.5 mg is administered to a human subject for treatment of wet AMD, between about 10 ig and 90 pig, between about 60 pig and 120 pg is administered to the human subject; between about 100 pg and 400 pg, between about 400 pg and 1 mg is administered to the human subject is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about I mg and 5 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 3 mg and 7 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 5 mg and 10 mg is administered to the human subject. 104011 In some variations, a liquid formulation as described herein containing an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 1 jig and about 5 mg is administered to a human subject for treatment of dry AMD. In some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 20 pg and about 4 mg is administered to the human subject; between about 20 pg and about 1.2 mg; between about 10 pg and about 0.5 mg is administered to a human subject for treatment of wet AMD, between about 10 jig and 90 pg, between about 60 pg and 120 pg is administered to the human subject; between about 100 jig and 400 pg, between about 400 jig and 1 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 400 pg and 1 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 1 mg and 5 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 3 mg and 7 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 5 mg and 10 mg is administered to the human subject to treat dry AMD. 104021 In some variations, a liquid formulation as described herein containing an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 1 jig and about 5 mg is administered to a human subject for prevention of wet AMD. In I fill some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 20 pg and about 4 mg is administered to the human subject; between about 20 tg and about 1.2 mg; between about 10 pg and about 0.5 mg is administered to a human subject for prevention of wet AMD, between about 10 pg and 90 ptg, between about 60 pg and 120 pg is administered to the human subject; between about 100 pg and 400 pg, between about 400 pg and 1 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 400 ptg and I mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about I mg and 5 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 3 mg and 7 mg is administered to the human subject; in some variations, an amount of a therapeutic agent equivalent to an amount of rapamycin of between about 5 mg and 10 mg is administered to the human subject to prevent wet AMD. 104031 In some variations, any one or more of the formulations described herein are administered intravitreally every 3 or more months, every 6 or more months, every 9 or more months, or every 12 or more months, or longer, to treat one or more of choroidal neovascularization, wet AMD, dry AMD, to prevent wet AMD, or to prevent progression of dry AMD to wet AMD. In some variations, any one or more of the formulations described herein are administered subconjunctivally every 3 or more months, every 6 or more months, every 9 or more months, or every 12 or more months, or longer, to treat one or more of choroidal neovascularization, wet AMD, dry AMD, or to prevent wet AMD. [0404] In some variations, any one or more of the rapamycin formulations described herein are administered intravitreally every 3 or more months, every 6 or more months, every 9 or more months, or every 12 or more months, or longer, to treat one or more of choroidal neovascularization, wet AMD, dry AMD, to prevent wet AMD, or to prevent progression of dry AMD to wet AMD. In some variations, any one or more of the rapamycin formulations described herein are administered subconjunctivally every 3 or more months, every 6 or more months, every 9 or more months, or every 12 or more months, or longer, to treat one or more of choroidal neovascularization, wet AMD, dry AMD, or to prevent wet AMD. In some variations, the effect of the rapamycin persists beyond the period during which it is present in the ocular tissues. 1 AA [04051 Delivery of the therapeutic agents described herein may, for example, be delivered at a dosage range between about 1 ng/day and about 100 tg/day, or at dosages higher or lower than this range, depending on the route and duration of administration. In some variations of liquid formulation or composition used in the methods described herein, the therapeutic agents are delivered at a dosage range of between about 0.1 pg/day and about 10 pg/day. In some variations of liquid formulation or composition used in the methods described herein, the therapeutic agents are delivered at a dosage range of between about I pg/day and about 5 ptg/day. Dosages of various therapeutic agents for treatment, prevention, inhibition, delay of onset, or cause of regression of various diseases and conditions described herein can be refined by the use of clinical trials. [04061 The liquid formulations, including but not limited to solutions, suspensions, emulsions and situ gelling formulations, and compositions described herein may be used for delivery to the eye, as one nonlimiting example by ocular or periocular administration, of therapeutically effective amounts of rapamycin for extended periods of time to treat, prevent, inhibit, delay the onset of, or cause regression of CNV, and thus may be used to treat, prevent, inhibit, delay the onset of, or cause regression of wet AMD, or transition of dry AMD to wet AMD. It is believed that by changing certain characteristics of the liquid formulations described herein, including but not limited to the components of the liquid formulations, the location in the eye to which the liquid formulation is delivered, including without limitation subconjunctival or intravitreal placement, the liquid formulations may be used to deliver therapeutically effective amounts of rapamycin to the eye for a variety of extended time periods including delivery of therapeutic amounts for greater than about 1 week, for greater than about 2 weeks, for greater than about 3 weeks, for greater than about 1 month, for greater than about 3 months, for greater than about 6 months, for greater than about 9 months, for greater than about 1 year. 104071 When a therapeutically effective amount of rapamycin is administered to a subject suffering from wet AMD, the rapamycin may treat, inhibit, or cause regression of the wet AMD. Different therapeutically effective amounts may be required for treatment, inhibition or causing regression. A subject suffering from wet AMD may have CNV lesions, and it is believed that administration of a therapeutically effective amount of rapamycin may have a variety of effects, including but not limited to causing regression of the CNV lesions, stabilizing the CNV lesion, and preventing progression of an active CNV lesion. in<~ [04081 When a therapeutically effective amount of rapamycin is administered to a subject suffering from dry AMD, it is believed that the rapamycin may prevent or slow the progression of dry AMD to wet AMD. EXAMPLES [04091 Unless the context indicates otherwise, the error bars in the charts show one standard deviation. Where ethanol is used, it is 200 proof ethanol from Gold Shield Distributors, Hayward, CA. Where rapamycin is used, it is from LC laboratories, Woburn, MA, or Chunghwa Chemical Synthesis & Biotech Co., LTD (CCSB), Taipei Hsien, Taiwan, ROC. Where PEG 400 is used, it is from The Dow Chemical Company, New Milford, CT. Some of the graphs use the expression "uL" or "ug" to refer to [LL or ptg, respectively. Where a volume of 10 pL or less is administered, Hamilton HPLC syringes were used. Example I - Preparation and Characterization of a Rapamycin-Containing Solution [04101 1.256% rapamycin (percentage of the total weight) was dissolved in 9.676% ethanol (percentage of the total weight). An aqueous solution of 15% F127 (Lutrol) in sterile water was slowly added under continuous agitation. The final concentration was approximately 78.57% sterile water (percentage of the total weight) and approximately 10.50% F127 (Lutrol) (percentage of the total weight). This solution is listed as formulation #32 in Table 1. The solution was placed at 2 0 C until use. Example 2 - Subconjunctival Injection of a Rapamycin-Containing Solution 104111 50 pl of the solution described in Example I was injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. [0412] Fig. 2 depicts the average concentration of rapamycin present in the vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) on a logarithmic scale at 20, 40, 67, and 90 days after injection. [04131 The analysis was by liquid chromatography mass spectroscopy (LCMS) using an internal standard. [04141 At each timepoint, the average concentration of rapamycin was calculated by adding the concentrations of rapamycin obtained for each eye from each rabbit, and dividing the total by the number of eyes analyzed. In this experiment, each timepoint I Ak; represents the average of either two eyes of each of two rabbits (four eyes at that timepoint) or the average of two eyes of one rabbits (two eyes at that timepoint). [04151 The full vitreous was homogenized and analyzed. The average concentration of the vitreous was calculated by dividing the mass of rapamycin measured by the volume of vitreous analyzed. The sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the vitreous via the solution. [04161 The average level of rapamycin in the vitreous at 20, 40, 67, and 90 days after subconjunctival injection was about 4.425, 3.800, 4.100, and 1.500 ng/ml, respectively. [04171 The full retina choroid was homogenized and analyzed. The average concentration of the retina choroid was calculated by dividing the mass of rapamycin measured by the mass of retina choroid analyzed. The sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the retina choroid via the solution. 104181 The average level of rapamycin in the retina choroid at 20, 40, 67, and 90 days after subconjunctival injection was about 0.055, 0.209, 0.080, and 0.0 17 ng/mg, respectively. [04191 The sclera was analyzed in the same way as the retina choroid. The scleral sample included the site of injection; thus, this measurement indicated clearance of rapamycin from the sclera. [04201 The average level of rapamycin in the sclera at 20, 40, 67, and 90 days after subconjunctival injection was about 0.141, 0.271, 0.067, and 0.192 ng/mg, respectively. Example 3 - Preparation and Characterization of a Rapamycin-Containing Solution [04211 5.233% rapamycin (per weight of the total of the formulation after all components were added) was dissolved in 0.4177 g of EtOH; the quantity of EtOH was reduced by forced evaporation (heat) to 0.1 296g (6.344%, w/w). PEG 400 was added under continuous agitation. Final concentrations as a percentage of the total weight were approximately: rapamycin 5.233%, ethanol 6.344%, and PEG 400 88.424%. When contacted with the vitreous, the formulation formed a non-dispersed mass relative to the surrounding medium. This solution is listed as formulation #34 in Table 1. Example 4 - Subconjunctival Injection of a Rapamycin-Containing Solution 1 Y7 104221 25ptl of the solution described in Example 3 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. [04231 Fig. 3 depicts the level of rapamycin present in the vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) on a logarithmic scale at 14, 35, 62, and 85 days after injection. The level of rapamycin present in the vitreous (ng/ml) is also shown at 2 days after injection. [04241 The vitreous was homogenized and analyzed as described in Example 2, except on day 2 a single eye of each of three rabbits was analyzed; at day 14 two eyes from each of two rabbits were analyzed; at day 35 two eyes from a single rabbit were analyzed; at day 62 two eyes from a single rabbit were analyzed; and at day 85 one eye from a single rabbit plus two eyes from a second rabbit were analyzed. [04251 The vitreous sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the vitreous via the solution. The average level of rapamycin in the vitreous at 2, 14, 35, 62, and 85 days after subconjunctival injection was about 3.57, 53.65, 9.00, 4.700, and 0.600 ng/ml, respectively. 104261 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken on the days as described for the vitreous above. No day 2 analysis was done. The retina choroid sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the retina choroid via the solution. The average level of rapamycin in the retina choroid at 14, 35, 62, and 85 days after subconjunctival injection was about 0.4815, 1.725, 0.057, and 0.009 ng/mg, respectively. [04271 The scleral sample was analyzed as described in Example 2, and the samples were taken on the days as described for the retina choroid as above. The scleral sample included the site of injection; thus, this measurement indicated clearance of rapamycin from the sclera. The average level of rapamycin in the sclera at 14, 35, 62, and 85 days after subconjunctival injection was about 34.5815, 0.135, 0.042, and 0.163666667 ng/mg, respectively. Example 5 - Intravitreal Injection of a Rapamycin-Containing Solution [04281 25 pl of the solution described in Example 3 was injected into the vitreous of the eye of New Zealand white rabbits. Fig. 4 depicts the level of rapamycin present in the 1MR vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) on a logarithmic scale at 14, 35, 62, and 90 days after injection. The level of rapamycin present in the vitreous (ng/ml) is also shown at 2 days after injection. (04291 The vitreous was homogenized and analyzed as described in Example 2, except on day 2 approximately I ptl of a single eye of each of three rabbits was analyzed; at day 14 two eyes from each of two rabbits were analyzed; at day 35 two eyes from a single rabbit were analyzed; at day 62 two eyes from a single rabbit were analyzed; and at day 90 two eyes from each of two rabbits were analyzed. 104301 Excepting the day 2 sample, the vitreous samples included the site of administration. An effort was made to avoid the administered solution where possible. However, the accuracy of the measured levels of rapamycin was potentially affected by sampling errors due to inadvertent inclusion of the administered solution. 104311 The average level of rapamycin in the vitreous at 2, 14, 35, 62, and 90 days after intravitreal injection was about 11.4, 136538, 2850.3, 21820.35, and 27142.75 ng/ml, respectively. 104321 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken on the days described for the vitreous above. No day 2 analysis was done. The retina choroid sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the retina choroid via the solution. The average level of rapamycin in the retina choroid at 14, 35, 62, and 90 days after intravitreal injection was about 5.78975, 244.485, 0.105, and 1.782 ng/mg, respectively. [04331 The scleral sample was analyzed as described in Example 2, and the samples were taken on the days as described for the retina choroid above. The scleral sample did not include the site of injection; thus, this measurement indicated level of rapamycin delivered to the sclera. The average level of rapamycin in the sclera at 14, 35, 62, and 90 days after intravitreal injection was about 0.5695, 12.34, 0.8505, and 0.71175 ng/mg, respectively. Example 6 - Preparation and Characterization of a Rapamycin-Containing Suspension 104341 6% rapamycin (percentage of the total weight) was dispersed in 94% PEG400 (percentage of the total weight). This suspension is listed as formulation #55 in Table 1. 1 o Example 7 - Intravitreal Injection of a Rapamycin-Containing Suspension [0435] The solution prepared in Example 6 was injected intravitreally into the eyes of New Zealand white rabbits. Fig. 5 depicts images of rabbit eyes after intravitreal injection of 10 pl (Fig. 5A), 20 pl (Fig. 5B), and 40 pl (Fig. 5C) of a 6% rapamycin suspension in PEG400. This resulted in an injected dose of about 0.6, about 1.2, and about 2.4 mg. The images were focused on the administered suspension. These images show that the suspension forms a non-dispersed mass relative to the surrounding vitreal medium. Example 8 - Preparation and Characterization of a Rapamycin-Containing In Situ Gelling Formulation [04361 A liquid formulation of 4.2% rapamycin (obtained from LC laboratories in Woburn, MA, and Chunghwa Chemical Synthesis & BioTech. Co, Ltd in Taiwan), 4.3% ethanol (obtained from Gold Shield Chemical in Hayward, CA), 2.2% PVP K90 (obtained from BASF), 87.1% PEG 400 (obtained from DOW Chemical), and 2.2% Eudragit RL 100 (obtained from Rohm Pharma Polymers), where all percentages are by weight of the total. [0437] Eudragit RL 100 was dissolved in ethanol. Sonication and heat may be required at this step. Ethanol - Eudragit was added to PEG 400. PVP was slowly added to the Eudragit-Ethanol-PEG solution, and a uniformly mixed solution was obtained. Vigorous mixing may be required for this step. [04381 Rapamycin was added to and dissolved in the Eudragit-ethanol-PEG-PVP mix. Heat and sonication may be used. The formulation was mixed thoroughly (using a vortex or mixer) to achieve uniformity. This formulation is listed as #37 in Table 1. [04391 When placed in deionized water or tap water, the liquid formulation formed a non-dispersed mass. The non-dispersed mass appeared as a gel-like substance. Example 9 -Subconjunctival Injection of a Rapamycin-Containing Non-Dispersed Mass Forming Formulation [0440] 50 pl of the solution described in Example 8 was injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. [04411 Fig. 6 depicts the average concentration of rapamycin present in the vitreous (ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) on a logarithmic scale at 7, 32, 45, and 90 days after injection of the in situ gelling formulation. 1 1fn [04421 The analysis was by LCMS (liquid chromatography - mass spectroscopy). [04431 Where more than a single eye was analyzed, the average concentration of rapamycin was calculated by adding the concentrations of rapamycin obtained for each eye from each rabbit, and dividing the total by the number of eyes analyzed. In this experiment, the vitreous day 7 and the sclera day 7, 32, and 45 timepoints represent a single eye, as opposed to an average level. The remaining day 7, 32, and 45 timepoints represent the average of two eyes of one rabbit, and the day 90 timepoint represents the average of two eyes of each of two rabbits (four eyes total). 104441 The full vitreous was homogenized and analyzed. The average concentration of the vitreous was calculated by dividing the mass of rapamycin measured by the volume of vitreous analyzed. The sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the vitreous via the in situ gelling formulation. [0445] The average level of rapamycin in the vitreous at 7, 32, 45, and 90 days after subconjunctival injection was about 13.9, about 7.4, about 1.35, and about 9.9 ng/ml, respectively. (04461 The full retina choroid tissues were homogenized and analyzed. The average concentration of the retina choroid tissues was calculated by dividing the mass of rapamycin measured by the mass of retina choroid tissues analyzed. The sample did not include the site of administration; thus, this measurement indicated the level of rapamycin delivered to the retina choroid tissues via the in situ gelling formulation. 104471 The average level of rapamycin in the retina choroid tissues at 7, 32, 45, and 90 days after subconjunctival injection was about 0.376, about 0.1875, about 0.136, and about 0.29 ng/mg, respectively. [04481 The sclera was analyzed in the same way as the retina choroid tissues. The scleral sample may have included the injected liquid formulation; thus, this measurement was indicative of clearance of rapamycin from the sclera. [04491 The average level of rapamycin in the sclera at 7, 32, 45, and 90 days after subconjunctival injection was about 2033, about 1653, about 3626, and about 420.5 ng/mg, respectively. Example 10 - Preparation and characterization of a Rapamycin-Containing suspension. 111 [04501 A rapamycin containing suspension was formed by dispersing 150.5 mg of rapamycin (3.004 % by weight) in 4860.3 mg of PEG 400 (96.996% by weight). This formulation is listed as #49 in Table 1. 150.5 mg rapamycin (3.004 % by weight) and 4860.3 mg of PEG 400 (96.996% by weight) were placed in an amber vial. High Wear Resistant Zirconia Grinding Media (beads) of 3 mm diameter were added, up to three quarters of the total volume. The vial was sealed and placed in a Cole-Parmer milling apparatus for 48 hrs. The particle size median for rapamycin was 2.8386 mm and the mean was 3.1275 mm. The formulation was kept at 4C until use. Volumes of 20 p1 and 40 pl each formed a non-dispersed mass when placed in the vitreous of a rabbit eye. Example II - Subconjunctival Injection of a Rapamycin-Containing Suspension. [04511 40 pd of the suspension described in Example 10 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 7 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid (ng/mg), and the sclera (ng/mg) on a logarithmic scale at 14, 42, 63, and 91 days after injection. [04521 The vitreous was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point except for day 91, on which two eyes from one rabbit were analyzed. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 14, 42, 63, and 91 days after subconjunctival injection was about 4.031, 23.11, 53.27, and 13.94 ng/ml, respectively. [04531 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 14, 42, 63, and 91 days after subconjunctival injection was about 0.1577, 4.965, 0.385, and 0.05 ng/mg, respectively. [04541 The scleral sample was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The scleral sample included the site of injection. The average level of rapamycin in the sclera at 14, 42, 63, and 91 days after subconjunctival injection was about 1283, 476.3, 854.2, and 168.5 ng/mg, respectively. 1 12 Example 12 - Intravitreal Injection of a Rapamycin-Containing Suspension [04551 20 tl of the suspension described in Example 10 were injected into the vitreous of the eye of New Zealand white rabbits. The injected suspension formed a non-dispersed mass relative to the surrounding medium. Fig. 8 depicts the level of rapamycin in the retina choroid (ng/mg) and the sclera (ng/mg) on a logarithmic scale at 14, 42, 63, and 91 days after injection and in the vitreous (ng/ml) at 63 and 91 days after injection. [04561 The vitreous was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 63 and 91 days after intravitreal injection was about 381,600 and 150,400 ng/ml, respectively. [0457] The retina choroid was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 14, 42, 63, and 91 days after intravitreal injection was about 2.588, 4.249, 21.42, and 0.922 ng/mg, respectively. 104581 The scleral sample was homogenized and analyzed as described in Example 2, with the samples taken as described for the retina choroid above. The scleral sample did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the sclera. The average level of rapamycin in the sclera at 14, 42, 63, and 91 days after intravitreal injection was about 0.7327, 6.053, 1.373, and 17.49 ng/mg, respectively. Example 13 - Preparation and Characterization of a Rapamycin-Containing Solution. [04591 A rapamycin containing solution was formed by placing 116.6 mg of rapamycin in ethanol and storing the mixture at 4'C for 6 hours. This solution was then mixed with 4647.5 mg of PEG 400 to give a solution having final concentrations by weight of 2.29% rapamycin, 6.05% ethanol, and 91.66% PEG 400. This solution is listed as formulation #51 in Table 1. A volume of 30 pl formed a non-dispersed mass when placed in the vitreous of rabbit eyes.

Example 14 - Subconjunctival Injection of a Rapamycin-Containing Solution 10460] 40 l of the solution described in Example 13 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 9 depicts the level of rapamycin in the vitreous (ng/ml), retina choroid (ng/mg), and the sclera (ng/mg) on a linear scale at 14, 42, 63, and 91 days after injection. 104611 The vitreous was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point except for day 91, on which two eyes from one rabbit were analyzed. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 14, 42, 63, and 91 days after subconjunctival injection was about 1.804, 1.854, 1.785, and 1.255 ng/ml, respectively. [0462] The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 14, 42, 63, and 91 days after subconjunctival injection was about 1.221, 4.697, 0.1075, and 0.02 ng/mg, respectively. 104631 The scleral sample was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The scleral sample included the site of injection. The average level of rapamycin in the sclera at 14, 42, 63, and 91 days after subconjunctival injection was about 1.987, 1.884, 0.56, and 10.84 ng/mg, respectively. Example 15 - Intravitreal Injection of a Rapamycin-Containing Solution [04641 30 pl of the solution described in Example 13 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Fig. 10 depicts the level of rapamycin in the retina choroid (ng/mg) and the sclera (ng/mg) on a linear scale at 14, 42, 63, and 91 days after injection. [04651 The retina choroid was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point. The retina choroid did not include the site of administration, so this measurement indicated the level of 1 1 A rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 14, 42, 63, and 91 days after intravitreal injection was about 5.515, 5.388, 0.3833, and 11.52 ng/mg, respectively. [04661 The scleral sample was homogenized and analyzed as described in Example 2, with the samples taken as described for the retina choroid above. The scleral sample did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the sclera. The average level of rapamycin in the sclera at 14, 42, 63, and 91 days after intravitreal injection was about 1.077, 0.9239, 0.0975, and 2.0825 ng/mg, respectively. 104671 Fig. 11 depicts the level of rapamycin in the vitreous (ng/ml) on a linear scale at 63 and 91 days after injection. The vitreous was homogenized and analyzed as described in Example 2. Two eyes from each of two rabbits were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 63 and 91 days after intravitreal injection was about 299,900 and 196,600 ng/ml, respectively. Example 16 - Preparation and Characterization of a Rapamycin-Containing Solution. [04681 About 320 g of ethanol was sparged with N 2 for about 10 minutes, and then about 40 g of sirolimus was added to the ethanol. The mixture was sonicated for about 20 minutes, by the end of which all of the sirolimus had gone into solution to form a sirolimus stock solution. A diluent solvent was prepared by sonicating about 1880 g of PEG 400 for about 60 minutes, and then sparging the solvent with Nitrogen for about 10 minutes. [04691 The sirolimus stock solution and the PEG 400 were then rotated at about room temperature in a rotary evaporator for about 10 minutes to mix the stock solution with the diluent solvent. After mixing, the solution was sparged with nitrogen for about 10 minutes and blanketed with nitrogen for about 5 minutes. After the solution was sparged and filled with nitrogen, about 240 g of excess ethanol was evaporated from the solution by increasing the solution temperature, maintaining a temperature that did not exceed 40'C for an extended period of time and continuing to rotate the solution for about 2.5 hours. [04701 The resulting solution comprised about 40 g of sirolimus (about 2% by weight), about 80 g of ethanol (about 4% by weight), and about 1880 g of PEG 400 (about 94% by 1 1 C weight). This solution was sparged with nitrogen for about 10 minutes and blanketed with nitrogen for about 5 minutes. The solution was then filtered through a 0.2 micron filter. HPLC vials were filled with 2 ml each of the filtered solution to leave a head space in each container of about 400 d. This head space was filled with nitrogen gas and capped. Example 17 - Preparation and Characterization of a Rapamycin-Containing Solution. [04711 Rapamycin, ethanol and PEG 400 were placed in a container to give final concentrations by weight of about 2.00% rapamycin, about 4.00% ethanol, and about 94.00% PEG 400. The mixture was capped and sonicated for 1-2 hours. The sonication generated heat, with temperatures of up to about 40 or 50*C. This solution is listed as formulation #100 in Table 1. Volumes of I pl, 3 d, 20 pl, and 40 pl formed a non dispersed mass in the vitreous of rabbit eyes. Example 18 - Subconjunctival Injection of a Rapamycin-Containing Solution [04721 20 d of the solution described in Example 17 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 12 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days after injection. Fig. 13 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. For comparison, Fig. 12 and Fig. 13 also depict results of similar studies, performed with 40 d and 60 pl injections, described below in Example 19 and Example 20. [04731 In Figs. 12-15, discussed in this and following examples, some outlier points have been omitted. Individual data points from the same study at the same time point were compared to each other. When the arithmetic mean of the data points was lower than their standard deviation, the data points that were higher or lower by an order of magnitude were considered as outliers. [0474] The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 1 1 c 30, 60, 90, and 120 days after subconjunctival injection was about 1.81, 0.45, 0.39, 1.85, and 1.49 ng/ml, respectively. [04751 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days after subconjunctival injection was about 0.14, 0.03, 0.02, 0.02, and 0.01 ng/mg, respectively. Example 19 - Subconjunctival Injection of a Rapamycin-Containing Solution [04761 40 pl of the solution described in Example 17 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 12 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days after injection. Fig. 13 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [0477] The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 30, 60, 90, and 120 days after subconjunctival injection was about 2.39, 0.65, 0.54, 2.07, and 1.92 ng/ml, respectively. [04781 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days after subconjunctival injection was about 0.47, 0.04, 0.01, 0.05, and 0.0 ng/mg, respectively. Example 20 - Subconjunctival Injection of a Rapamycin-Containing Solution [04791 60 tl of the solution described in Example 17 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 12 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days after 1 1 '7 injection. Fig. 13 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. (04801 The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 30, 60, 90, and 120 days after subconjunctival injection was about 8.65, 0.29, 0.18, 2.00, 1.41 ng/ml, respectively. 104811 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days after subconjunctival injection was about 0.63, 0.02, 0.02, 0.06, and 0.01 ng/mg, respectively. Example 21 - Intravitreal Injection of a Rapamycin-Containing Solution [04821 20 pl of the solution described in Example 17 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Fig. 14 depicts the level of rapamycin in the vitreous on a logarithmic scale 5, 30, 60, 90, and 120 days after injection. Fig. 15 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. For comparison, Fig. 14 and Fig. 15 also depict results of other studies described below in Example 22 and Example 24. [04831 The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5, 30, 60, 90, and 120 days after intravitreal injection was about 162,100; 18,780; 57,830; 94,040; and 13,150 ng/ml, respectively. [04841 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 11Q 30, 60, 90, and 120 days after intravitreal injection was about 2.84, 2.26, 0.17, 0.22, and 0.05 ng/mg, respectively. Example 22 - Intravitreal Injection of a Rapamycin-Containing Solution 10485] 40 1 .l of the solution described in Example 17 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Fig. 14 depicts the level of rapamycin in the vitreous on a logarithmic scale 5, 30, 60, 90, and 120 days after injection. Fig. 15 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. 104861 The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5, 30, 60, 90, and 120 days after intravitreal injection was about 415,600; 4,830; 74,510; 301,300; and 7,854 ng/ml respectively. 104871 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days after intravitreal injection was about 5.36, 0.23, 1.27, 1.08, and 0.08 ng/mg, respectively. Example 23 - Preparation and Characterization of a Rapamycin-Containing Solution. 104881 Rapamycin, ethanol and PEG 400 were added to a container to give final concentrations by weight of about 0.4% rapamycin, 4.0% ethanol, and 95.6% PEG 400. The mixture was sonicated for 1-2 hours. Sonication resulted in elevated temperatures of up to about 40 to 50'C. This solution is listed as formulation #99 in Table 1. Example 24 - Intravitreal Injection of a Rapamycin-Containing Solution [0489] 100 ptl of the solution described in Example 23 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution did not form a non-dispersed mass relative to the surrounding medium. Fig. 14 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days after injection. Fig. 15 1 10 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. 10490] The vitreous was homogenized and analyzed as described in Example 2. Between two and five rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5, 30, 60, 90, and 120 days after intravitreal injection was about 151,000; 14,890; 4,743; and 1620 ng/ml respectively. [04911 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days after intravitreal injection was about 1.21, 1.84, 0.04, 0.71, and 0.0 ng/mg, respectively. Example 25 - Preparation and Characterization of a Rapamycin-Containing Solution. [04921 A rapamycin containing solution was formed by placing 102.4 mg of rapamycin in ethanol, adding 4719.3 mg of PEG 400, and vortexing. The resulting solution had final concentrations by weight of 2.036% rapamycin, 4.154%% ethanol, and 93.81% PEG 400. This solution is listed as formulation #139 in Table 1. Example 26 - Subconjunctival Injection of a Rapamycin-Containing Solution 104931 10 pl of the solution described in Example 25 were injected as a single dose between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 16 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5 and 14 days after injection. Fig. 17 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. For comparison, Fig. 16 and Fig. 17 also depict results of other studies described below in Examples 27-29. 104941 The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5 and 14 days after subconjunctival injection was about 2.45 and 20.13 ng/ml, respectively. I in [04951 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 14 days after subconjunctival injection was about 0.13 and 0.19 ng/mg, respectively. Example 27 - Subconjunctival Injection of a Rapamycin-Containing Solution 104961 60 ptl of the solution described in Example 25 were injected as a single dose between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 16 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5 and 14 days after injection. Fig. 17 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [0497] The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5 and 14 days after subconjunctival injection was about 17.98 and 87.03 ng/ml, respectively. 104981 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 14 days after subconjunctival injection was about 0.27 and 0.21 ng/mg, respectively. Example 28 - Subconjunctival Injection of a Rapamycin-Containing Solution [0499] 60 pl of the solution described in Example 25 were injected as two 30 pl doses at two sites between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 16 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5 and 14 days after injection. Fig. 17 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [0500] The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the 111 vitreous. The average level of rapamycin in the vitreous at 5 and 14 days after subconjunctival injection was about 502.2 and 31.80 ng/ml, respectively. [05011 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 14 days after subconjunctival injection was about 0.80 and 0.15 ng/mg, respectively. Example 29 - Subconjunctival Injection of a Rapamycin-Containing Solution [05021 90 tl of the solution described in Example 25 were injected as three 30 pl doses at three sites between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 16 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5 and 14 days after injection. Fig. 17 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [0503] The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5 and 14 days after subconjunctival injection was about 39.05 and 13.63 ng/ml, respectively. [05041 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 14 days after subconjunctival injection was about 0.83 and 0.10 ng/mg, respectively. Example 30 - Preparation and characterization of a Rapamycin-Containing suspension. [05051 A rapamycin containing suspension was formed by placing 201.6 mg of rapamycin (3.000 % by weight) in 6518.8 mg of PEG 400 (97.000% by weight) and vortexing. The resulting particle size was not quantified but it was large, estimated at about 10 pm. This suspension is listed as formulation #147 in Table 1. Example 31 - Subconjunctival Injection of a Rapamycin-Containing Suspension 1,Y) [05061 10 pl of the suspension described in Example 30 were injected as a single dose between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 18 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 14, and 30 days after injection. Fig. 19 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. For comparison, Fig. 18 and Fig. 19 also depict results of other studies described below in Example 32 and Example 33. [05071 The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 14, and 30 days after subconjunctival injection was about 2.68, 0.90, and 5.43 ng/ml, respectively. 105081 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 14, and 30 days after subconjunctival injection was about 0.20, 0.06, and 1.23 ng/mg, respectively. Example 32 - Subconjunctival Injection of a Rapamycin-Containing Suspension [05091 30 pl of the solution described in Example 30 were injected as a single dose between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 18 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 14, and 30 days after injection. Fig. 19 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [0510] The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 14, and 30 days after subconjunctival injection was about 84.55, 11.23, and 66.35 ng/ml, respectively. [05111 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin 11%, delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 14, and 30 days after subconjunctival injection was about 1.09, 0.19, and 1.02 ng/mg, respectively. Example 33 - Subconjunctival Injection of a Rapamycin-Containing Suspension [05121 90 ptl of the solution described in Example 30 were injected as three 30 pl doses at three sites between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 18 depicts the level of rapamycin in the vitreous on a logarithmic scale at 5, 14, and 30 days after injection. Fig. 19 depicts the level of rapamycin in the retina choroid on a logarithmic scale at the same time points. [05131 The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the vitreous. The average level of rapamycin in the vitreous at 5, 14, and 30 days after subconjunctival injection was about 29.95, 15.30, and 49.20 ng/ml, respectively. 105141 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 14, and 30 days after subconjunctival injection was about 0.55, 1.31, and 5.74 ng/mg, respectively. Example 34 - Preparation and Characterization of a Rapamycin-Containing Solution. 105151 10.3 mg of rapamycin was placed in ethanol, 4995.8 mg of PEG 400 was added, and the mixture was vortexed to give a solution having final concentrations by weight of 0.205% rapamycin, 0.544% ethanol, and 99.251% PEG 400. This solution is listed as formulation #140 in Table 1. A volume of 10 pl of this solution formed a non-dispersed mass when placed in the vitreous of a rabbit eye. Example 35 - Intravitreal Injection of a Rapamycin-Containing Solution 105161 10 pd of the solution described in Example 34 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass 1 'A relative to the surrounding medium. Fig. 20 depicts the level of rapamycin in the retina choroid on a logarithmic scale at 5 and 30 days after injection. Fig. 21 depicts the level of rapamycin in the vitreous on a logarithmic scale at the same timepoints. For comparison, Fig. 20 and Fig. 21 also depict results of other studies described below in Example 37 and Example 39. [05171 The vitreous was homogenized and analyzed as described in Example 2. Five rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5 and 30 days after intravitreal injection was about 12.02 and 0.92 ng/ml, respectively. 105181 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 30 days after intravitreal injection was about 0.08 and 0.02 ng/mg, respectively. Example 36 - Preparation and Characterization of a Rapamycin-Containing Solution. 10519] 31.5 mg of rapamycin was placed in ethanol, 4918.9 mg of PEG 400 was added, and the solution was vortexed. Final concentrations by weight were 0.6238% rapamycin, 1.337% ethanol, and 98.035% PEG 400. This solution is listed as formulation #142 in Table 1. The formulation was stored at 4'C until use. A volume of 10 Pl of this solution formed a non-dispersed mass when placed in the vitreous of a rabbit eye. Example 37 - Intravitreal Injection of a Rapamycin-Containing Solution 105201 10 pl of the solution described in Example 36 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Fig. 20 depicts the level of rapamycin in the retina choroid on a logarithmic scale at 5 and 30 days after injection. Fig. 21 depicts the level of rapamycin in the vitreous on a logarithmic scale at the same timepoints. [05211 The vitreous was homogenized and analyzed as described in Example 2. Five rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5 and 30 days after intravitreal injection was about 87.46 and 44.34 ng/ml, respectively. 1 105221 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5 and 30 days after intravitreal injection was about 1.40 and 0.01 ng/mg, respectively. Example 38 - Preparation and Characterization of a Rapamycin-Containing Solution. [05231 103.5 mg of rapamycin was placed in ethanol, 4720.8 mg of PEG 400 was added, and the mixture was vortexed to give a solution having final concentrations by weight of 2.057% rapamycin, 4.116% ethanol, and 93.827% PEG 400. This solution is listed as formulation #144 in Table 1. A volume of 10 pl of this solution formed a non dispersed mass in the vitreous of a rabbit eye. Example 39 - Intravitreal Injection of a Rapamycin-Containing Solution [05241 10 p1 of the solution described in Example 38 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Fig. 20 depicts the level of rapamycin in the retina choroid on a logarithmic scale at 5, 30, and 90 days after injection. Fig. 21 depicts the level of rapamycin in the vitreous on a logarithmic scale at the same timepoints. 105251 The vitreous was homogenized and analyzed as described in Example 2. Four rabbit eyes were analyzed at each time point. The vitreous sample may have included the site of administration. The average level of rapamycin in the vitreous at 5, 30, and 90 days after intravitreal injection was about 120,500; 55,160; and 0.55 ng/ml, respectively. 105261 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above except that five rabbit eyes were analyzed at the 5 and 30 day time points. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 5, 30, and 90 days after intravitreal injection was about 4.75, 0.17, and 0.01 ng/mg, respectively. Example 40 - Subconjunctival Injection of a Rapamycin-Containing Solution 105271 40 pl of the solution described in Example 17 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. Fig. 22 depicts on a logarithmic scale the level of rapamycin in the aqueous humor (ng/ml) at 1, 4, 7, 11, 14, 21, 28, 35, 54, and 56 days after injection, and the levels of rapamycin in the cornea (ng/mg) and the retina choroid (ng/mg) at 4, 14, 21, and 35 days after injection. The retina choroid level is labeled as "R/Choroid" in figure 22. [05281 The aqueous humor was homogenized and then analyzed by liquid chromatography and mass spectroscopy. Four rabbit eyes were analyzed for each time point. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. The average level of rapamycin in the aqueous humor at 1, 4, 7, 11, 14, 21, 28, 35, 54, and 56 days after injection was about 0.875, 1.0, 7.0, 0.725, 0.5, 0.525, 0.0, 0.125, 0.014, and 0.0485 ng/ml, respectively. [05291 The cornea was homogenized and then analyzed by liquid chromatography and mass spectroscopy. The cornea did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the cornea. Four rabbit eyes were analyzed for each time point. The average level of rapamycin in the cornea at 4, 14, 21, and 35 days after injection was about 0.3225, 0.1, 0.0275, and 0.0125 ng/mg, respectively. [05301 The retina choroid was homogenized and analyzed as described in Example 2, with the samples taken as described for the vitreous above. The retina choroid did not include the site of administration, so this measurement indicated the level of rapamycin delivered to the retina choroid. The average level of rapamycin in the retina choroid at 4, 14, 21, and 35 days after injection was about 11.61, 0.2, 0.0275, and 2.655 ng/mg, respectively. Example 41 - Intravitreal Injection of a Rapamycin-Containing Solution [05311 1.0 pl of the solution described in Example 17 was injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Table 2 reports the average level of rapamycin in the aqueous humor one day after injection. For comparison, Table 2 also reports results of studies described in Examples 42-45 below. 10532] The aqueous humor was homogenized and analyzed as described in Example 40. Two rabbit eyes were analyzed. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. I1 ~7 The average level of rapamycin in the aqueous humor at I day after injection was about 0.438 ng/ml with a standard deviation of about 0.141 ng/ml. Example 42 - Intravitreal Injection of a Rapamycin-Containing Solution [0533] 3.0 ptl of the solution described in Example 17 were injected into the vitreous of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Table 2 reports the average level of rapamycin in the aqueous humor one day after injection. 105341 The aqueous humor was homogenized and analyzed as described in Example 40. Two rabbit eyes were analyzed. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. The average level of rapamycin in the aqueous humor at I day after injection was about 0.355 ng/ml with a standard deviation of about 0.234 mg/ml. Example 43 - Subconjunctival Injection of a Rapamycin-Containing Solution [05351 3.0 pl of the solution described in Example 17 were injected between the sclera and the conjunctiva of the eye of New Zealand white rabbits. The injected solution formed a non-dispersed mass relative to the surrounding medium. Table 2 reports the average level of rapamycin in the aqueous humor one day after injection. [05361 The aqueous humor was homogenized and analyzed as described in Example 40. Two rabbit eyes were analyzed. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. The average level of rapamycin in the aqueous humor at 1 day after injection was about 0.338 ng/ml with a standard deviation of about 0.122 ng/ml. Example 44 - Anterior Chamber administration of a Rapamycin-Containing Solution [05371 5.0 pl of the solution described in Example 17 were injected into the anterior chamber of the eye of New Zealand white rabbits by injection into the front-end of the eye. The aqueous humor was withdrawn using a syringe. Table 2 reports the average level of rapamycin in the aqueous humor 14 days after injection. [05381 The aqueous humor was homogenized and analyzed as described in Example 40. Two rabbit eyes were analyzed. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. 1 0 The average level of rapamycin in the aqueous humor at 14 days after injection was about 0.166 ng/ml with a standard deviation of about 0.183 ng/ml. Example 45 - Anterior Chamber Administration of a Rapamycin-Containing Solution [05391 10 pl of the solution described in Example 17 were injected into the anterior chamber of the eye of New Zealand white rabbits. Table 2 reports the average level of rapamycin in the aqueous humor 14 days after injection. [05401 The aqueous humor was homogenized and analyzed as described in Example 40. Two rabbit eyes were analyzed. The aqueous humor did not include the site of injection, so this measurement indicated the level of rapamycin delivered to the aqueous humor. The average level of rapamycin in the aqueous humor at 14 days after injection was about 0.004 ng/ml with a standard deviation of about 0.006 ng/ml. 10541] All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entireties, whether previously specifically incorporated or not. Table 1 Liquid Formulations Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 1 DMSO = 2000mg (20%) S Water = 8000mg (80%) 2 F68 = 1000mg (10%) S Water = 9000mg (90%) 3 F68 = 3000mg (30%) S Water = 7000mg (70%) 4 F127 = 1000mg (10%) S Water = 9000mg (90%) 5 F127 = 1500mg (15%) S Water = 8500mg (85%) 6 Beta-cyclodextrin = 250mg (2.5%) S Water = 9750mg (97.5%) 7 Rapa = 10.2mg (0.101%) S No, 50 pL Pluronic, F68 = 1010mg (9.99%) Water = 9090mg (89.909%) 8 Rapa = 10.2mg (0.102%) S No, 50 pL Pluronic, F68 = 3000mg (29.969%) Water = 7000mg (69.929%) 9 Rapa = 10.5mg (0.104%) S No, 50 pL Pluronic, F127 = 1010mg (9.99%) Water = 9090mg (89.907%) 10 Rapa = 10.5mg (0.105%) S No, 50 pL Pluronic, F127 = 1500mg (14.984%) Water = 8925mg (84.9%) 124 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 11 Rapa = 10.7mg (0.105%) S No, 50 pL Beta-cyclodextrin = 255mg (2.497%) Water = 9945mg (97.398%) 12 Rapa = 6.4mg (0.0999%) SP CMC = 48mg (0.7493%) Polysorbitan 20 = 2.56mg (0.04%) Water = 6349.44mg (99.111%) 13 Rapa = 6.5mg (0.0999%) S DMSO = 325mg (4.995%) Water 6175mg (94.905%) 14 Rapa = 13.5mg (0.0999%) SP CMC = 101.25mg (0.7493%) Polysorbitan 20 = 5.4mg (0.04%) Water= 13393.35mg (99.112%) 15 Rapa = 11.0mg (0.2%) S EtOH = 5500mg (99.8%) 16 Rapa = 6.6mg (0.1%) S EtOH = 1054.6mg (15.933%) F127 = 833.64mg (12.595%) Water = 4723.96mg (71.372%) 17 Rapa = 5 mg (0.1%) S Cavitron = 0.25 g (5%) Ethanol, 95% = 57 mg (1.1%) Sterile water = 4.753 g (93.8%) 18 Rapa = 5 mg (0.1%) S Ethanol, 95% =150 mg (2.9%) PEG400 = 1.0 g (19.4%) Sterile water = 4.01 g (77.6%) 19 Rapa = 5 mg (0.1%) S Yes, 50 pL Ethanol, 95% =152 mg (3.2%) PEG400 = 1.5227 g (30.2%) Sterile water = 3.3592 g (66.67%) 20 Rapa = 6.6mg (0.1%) S EtOH = 505.1mg (7.618%) F127 917.8mg (13.843%) Water = 5200.6mg (78.44%) 21 Rapa = 6.6mg (0.1%) S No, 50 pL EtOH = 536mg (7.5%) Pluronic, F127 = 983.75mg (14.0%) Water = 5574.56mg (78.4%) 22 Rapa = 5.2mg (0.1023%) S EtOH = 56.6mg (1.127%) Captisol = 2008.9mg (39.5%) Water = 3013.3mg (59.3%) 23 Rapa = 6.9mg (0.201%) S EtOH = 3418.0mg (99.799%) 24 Rapa = 9.1mg (0.491%) S EtOH = 90.9mg (4.908%) F127 = 262.8mg (14.191%) Water = 1489.1mg (80.409%) 25 Rapa = 0mg (0%) S EtOH = 310.2mg (5.144%) F127 = 858.1mg (14.228%) Water = 4862.6mg (80.628%) 26 Rapa = 0mg (0%) S EtOH = 613.1mg (10.19%) F127 = 810.6mg (13.471%) 1 Water = 4593.6mg (76.339%) 1 2 A Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 27 Rapa = 53.5mg (1.095%) S Yes, 50 pL EtOH = 414.8mg (8.488%) F127 = 662.8mg (13.563%) Water = 3755.7mg (76.854%) 28 Rapa = 0.3 g (10%) ISG, SP PVP K90 = 0.35 g (12%) Eudragit RS30D = 2.35 g (78%) 29 Rapa = 0.2154 g (7.31%) ISG, SP PVP K90 = 0.25 g (8.5%) Eudragit RS30D = 2.48 g (84.19%) 30 Rapa = 53.9mg (1.103%) S No, 50 pL EtOH = 413.6mg (8.463%) Sterile water = 3843.5mg (78.647%) F127 (Lutrol) = 576.0mg (11.786%) 31 Rapa = Omg (0%) S EtOH = 411.9mg (8.513%) Sterile Water = 3849.3mg (79.554%) F127(Lutrol) = 577.4mg (11.933%) 32 Rapa = 54.1mg (1.256%) S EtOH = 416.8mg (9.676%) Sterile Water = 3836.3mg (78.569%) F127(Lutrol) = 577.5mg (10.499%) 33 Rapa = 80.7g (1.964%) S EtOH = 65.0mg (0.158%) PEG400 = 4021.8mg (97.878%) 34 Rapa = 106.9g (5.233%) S Yes, 25 pL EtOH = 129.6mg (6.344%) PEG400 = 1806.5mg (88.424%) 35 Rapa = 0 mg (0%) ISG, SP PVP K90 = 0.204 g (2.3%) Ethanol, 100% = 0.4 g (4.5%) Eudragit RL100 =0.201g (2.3%) PEG 400 = 8.00 g (90.9%) 36 Rapa = 0 mg (0%) ISG, SP PVP K90 = 0.2 g (2.2%) Ethanol, 100% = 0.4 g (4.4%) PVAP = 0.4 g (4.4%) PEG 400 = 8.00 g (88.9%) 37 Rapa = 106.1 mg (4.2%) ISG, SP PVP K90 = 55.2 mg (2.2%) Ethanol, 100% = 108 mg (4.3%) Eudragit RL100 = 55 mg (2.2%) PEG 400 = 2.2 g (87.1%) 38 Rapa = 399.6mg (9.965%) S Yes, 20 pL F68(Lutrol) = 40.6mg (1.012%) Sterile Water = 3569.7mg (89.022%) 39 Rapa = 53.8mg (1.1%) S EtOH = 415.2mg (8.489%) Sterile Water = 3844.2mg (78.594%) F127 = 578.0mg (11.817%) 40 Rapa = 208.1mg (3.148%) S Yes, 20 pL PEG400 = 6403.4mg (96.852%) 41 Rapa = 200.4mg (5.148%) SP F68(Lutrol) = 20.8mg (0.534%) PEG400 = 3569.3mg (91.697%) EtOH (95%) = 102mg (2.62%) 1 21 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 42 Rapa = 200.4g (5.259%) SP PEG400 = 3561.4mg (93.46%) Tween 80 = 48.8mg(l.281%) 43 Rapa = 30.9 mg (1.03%) S No, 50 pL PEG 400 = 2.9624 g (98.97%) 44 Rapa = 61 mg (1.96%) S Yes, 50 pL Ethanol, 100% = 0.1860 g (6%) PEG 400 = 2.8588 g (92.04%) 45 Rapa = 90.7 mg (3.02%) S Yes, 50 pL Ethanol, 100% = 0.2722 g (9.06%) PEG 400 = 2.6423 g (87.94%) 46 Rapa = 101.6mg (4.997%) S EtOH = 331.6mg (16.308%) PEG400 = 1600.1mg (78.695%) 47 Rapa = 120.99 (3.189%) SP F68(Lutrol) = 42.4mg (1.118%) Sterile Water = 3627.7mg (95.692%) 48 Rapa = 100.1g (1.999%) S EtOH = 305.1mg (6.092%) PEG400 = 4602.9mg (91.909%) 49 Rapa = 150.5mg (3.004%) SP Yes, 20 pL, 40 pL PEG400 = 4860.3mg (96.996%) 50 Rapa = 153.4mg (3.055%) SP No, 20 pL F68(Pluronic)= 50.6mg (1.008%) Sterile Water = 4816.6mg (95.937%) 51 Rapa = 116.6mg (2.29%) S Yes, 30 pL EtOH = 306.6mg (6.05%) PEG400 = 4647.5mg (91.66%) 52 Rapa = 150.4 mg (2.994%) SP F68 Lutrol = 15.4 mg (0.306%) Sterile water = 4859.1 mg (96.7%) 53 Rapa = 306.5 mg (6.088%) SP PEG 400 = 4727.7 mg (93.912%) 54 Rapa = 309.3 mg (6.146%) SP PEG 400 = 4723.3 mg (93.854%) 55 Rapa = 303.3 mg (6.061%) SP PEG 400 = 4700.6 mg (93.939%) 56 Rapa = 305.4 mg (6.088%) SP PEG 400 = 4711.0 mg (93.912%) 57 Rapa = 306.9 mg (6.098%) SP PEG 400 = 4725.5 mg (93.902%) 58 Rapa = 302.5 mg (6.021%) SP PEG 400 = 4721.6 mg (93.979%) 59 Rapa = 304.5 mg (6.053%) SP PEG 400 = 4726.4 mg (93.947%) 60 Dexamethasone = 251.4 mg SP (5.011%) PEG 400 = 4765.2 mg (94.989%) 61 Dexamethasone = 252.4 mg (5%) SP PEG 400 = 4600 mg (92%) EtOH = 150 mg (3%) 62 Rapa = 32.2 mg (0.641%) S PEG 400 = 4677.9 mg (93.096%) EtOH = 314.7 mg (6.263%) 63 Rapa = 32.3 mg (0.6%) S PEG 400 = 5516.3 mg (93.1%) EtOH = 314.7 mg (6.263%) Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 64 Rapa = 54.4 mg (1.007%) S PEG 400 = 4638.9 mg (92.702%) EtOH = 314.8 mg (6.291%) 65 Rapa = 50.8 mg (1.013%) S PEG 400 = 4963.2 mg (98.987%) 66 Rapa = 52.1 mg (1.035%) S PEG 400 = 4868.6 mg (96.718%) EtOH = 113.1 mg (2.247%) 67 Rapa = 50.5 mg (1.009%) S Yes, 20 pL PEG 400 = 4752.8 mg (94.953%) No, 40 pL, 100 pL EtOH = 202.1 mg (4.038%) 68 Rapa = 101.8 mg (2.030%) S PEG 400 = 4712.4 mg (93.970%) EtOH = 200.6 mg (4.000%) 69 Rapa = 102.1 mg (2.036%) S PEG 400 = 4605.5mg (91.847%) EtOH = 306.7 mg (6.117%) 70 Rapa = 101.6 mg (2.025%) S PEG 400 = 4510.6 mg (89.892%) EtOH = 405.6 mg (8.083%) 71 Rapa 75.9 mg (3.019%) SP PEG 400 = 2438.4 mg (96.981%) 72 Rapa = 50.9 mg (2.034%) S PEG 400 = 2350.1 mg (93.914%) EtOH = 101.4mg (4.052%) 73 Rapa = 12.5 mg (0.620%) SP PEG 400 = 2004.8 mg (99.380%) 74 Rapa = 1.20949 g (2.0152%) S EtOH = 2.401 g (4.000%) PEG 400 = 56.407 g (93.9848%) 75 Rapa = 16.0 mg g (0.795%) S No, 50 pL EtOH = 80.0 mg (3.976%) PEG 400 = 1916.0 mg (95.2298%) 76 Rapa = 8.1 mg (0.400%) SP PEG 400 = 2014.5 mg (99.600%) 77 Rapa = 8.6 mg (0.428%) S PEG 400 = 2002.5 mg (99.572%) 78 Rapa = 8.2 mg (0.410%) S PEG 400 = 1992.0 mg (99.590%) 79 Rapa = 8.7 mg (0.433%) S I PEG 400 = 1998.8 mg (99.567%) 80 Rapa = 8.6 mg (0.427%) S PEG 400 = 2003.2 mg (99.573%) 81 Rapa = 8.6 mg (0.428%) S PEG 400 = 1999.3 mg (99.572%) 82 Rapa = 9.0 mg (0.448%) S PEG 400 = 2000.8 mg (99.552%) 83 Rapa = 8.0 mg (0.397%) S PEG 400 = 2008.8 mg (99.603%) 84 Rapa = 8.5 mg (0.422%) S PEG 400 = 2006.8 mg (99.578%) 85 Rapa = 8.0 mg (0.399%) S PEG 400 = 1998.2 mg (99.601%) 86 Rapa = 8.5 mg (0.422%) S PEG 400 = 2004.3 mg (99.578%) 87 Rapa = 8.6 mg (0.428%) S PEG 400 = 2002.5 mg (99.572%) 111 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 88 Rapa = 0.7 g (1.983%) S EtOH = 1.4 g (3.966%) PEG 400 = 33.2 g (94.051%) 89 Rapa = 0 g (0%) S EtOH = 0.574 g (1.995%) PEG 400 = 28.2 g (98.005%) 90 Rapa = 1.95 g (1.950%) S EtOH = 4.05 g (4.050%) PEG 400 = 94.00 g (94000.%) 91 Rapa = 0.0107 g (0.534%) S No, 80 pL EtOH = 0.0805 g (4.019%) PEG 400 = 1.912 g (95.447%) 92 Rapa = 0.0081 g (0.403%) S No, 100 pL EtOH = 0.0804 g (4.003%) PEG 400 = 1.920 g (95.594%) 93 Rapa = 1.992 g (2%) S EtOH = 3.9419 (4%) PEG 400 = 93.95 g (94%) 94 Rapa = 0.405 g (0.4%) S EtOH = 4.24 g (4%) PEG 400 = 95.6 (95.6%) 95 PEG 400 = 96 g (96%) S EtOH = 3.9027 (4%) 96 Rapa = 0.4020 g (0.402%) S EtOH = 3.970 g (3.971%) PEG 400 = 95.600 g (95.627%) 97 Rapa = 2.000 g (1.990%) S EtOH = 4.000 g (3.980%) PEG 400 = 94.500 g (94.030%) 98 PEG 400 = 96 g (96%) S EtOH = 3.92 g (4%) 99 Rapa = 0.4036 g (0.4%) S No, 100 pL EtOH = 3.9054 g (4%) PEG 400 = 95.6 (95.6%) 100 Rapa = 2.0025 g (2%) S Yes, 1 pL, 3 pL, 20 EtOH = 3.98 g (4%) pL, 40 pL PEG 400 = 94.00 g (94%) 101 Rapa = 9.5 mg (0.472%) S EtOH = 90.3 mg (4.485%) PEG 600 = 1913.5 mg (95.043%) 102 Rapa = 44.6 mg (2.21%) S EtOH = 86.1.0 mg (4.26%) PEG 600 = 1891.1 mg (93.53%) 103 Rapa = 1.97 g (2%) S EtOH = 4.10 g (4%) PEG 400 = 94.15 g (94%) 104 Rapa = 1.95 g (2%) S EtOH = 4.00 g (4%) PEG 400 = 94.0 g (94%) 105 Rapa = 8.00 g (2%) S PEG 400 = 376.0 g EtOH = 16.0 g (4%) 106 Rapa = 6.00 g (2%) S PEG 400 = 282.0 g (94%) EtOH = 12.0 g (4%) 107 Rapa = 8.9 mg (0.4434%) S EtOH = 80.3 mg (4.0006%) PEG 300 = 1918.0 mg (95.556%) I I A Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 108 Rapa = 40.8 mg (2.00886%) S EtOH = 110.0mg (5.41605%) PEG 300 = 1880.2 mg (92.57509%) 109 Rapa = 9.9 mg (0.488%) S EtOH = 86.7mg (4.277%) PEG 400/300(50/50) = 1930.3 mg (95.235%) 110 Dexamethasone = 142.5 mg SP 0.3305 pm Yes, 30 pL (4.994%) PEG 400 = 2710.7 mg (95.006%) 111 Dexamethasone = 134.3 mg SP >10 pm (4.891%) PEG 400 = 2611.4 mg (95.109%) 112 Triamcinolone = 139.2 mg (5.087%) SP 3.98 pm Yes, 30 pL PEG 400 = 2597.4 mg (94.913%) 113 Triamcinolone = 135.3 mg (5.089%) SP >10 pm PEG 400 = 2523.5 mg (94.911%) 114 EtOH = 206.4 mg (4.121%) S No, 30 pL PEG 400 = 4801.6 mg (95.879%) 115 Rapa = 43.0 mg (2.144%) SP 61.4390 pm PEG 400 = 1962.3mg (97.8567%) 116 Rapa = 40.0 mg (2.001%) SP 3.7128 pm PEG 400 = 1959.1mg (97.999%) 117 Rapa = 42.9 mg (2.142%) SP 2.7313 pm PEG 400 = 1959.7mg (97.858%) 118 Rapa = 100.8 mg (2.013%) SP 4.1063 pm PEG 400 = 4906.0 mg (97.987%) 119 Rapa = 20.9 mg (0.42%) S EtOH = 209.1mg (4.17%) PEG 400 = 4784.9 mg (95.41%) 120 Rapa = 20.6 mg (0.41%) S EtOH = 211.5mg (4.22%) Benz. Chl = 19.1 mg (0.38%) PEG 400 = 4762.0 mg (94.99%) 121 Rapa = 20.1 mg (0.40%) S EtOH = 211.5mg (4.22%) Benz. Chl = 2.3 mg (0.05%) PEG 400 = 4782.3 mg (95.34%) 122 Rapa = 8.0 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376.0 g (94%) 123 Rapa = 351.3 mg (2.006%) S EtOH = 2353.1mg (4.093%) PEG 400 = 16448.2 mg (93.901%) 124 Rapa = 2.2035 g (2%) S EtOH = 4.45 g (4%) PEG 400 = 103.7 g (94%( 125 Rapa = 515.5 mg (2.021%) SP 18.1453 pm PEG 400 = 24,993.8 mg (97.979%) 126 Rapa = 0.3 g (2%) S EtOH = 0.6 g (4%) PEG 400 = 14.1 g (94%) BHT = 0.0002 (0.002%) 127 Rapa = 0.3 g (2%) S EtOH = 0.6 g (4%) PEG 400 = 14.1 g (94%) BHT = 0.00037 (0.004%) 135 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 128 Rapa = 0.3 g (2%) S EtOH = 0.6 g (4%) PEG 400 = 14.1 g (94%) BHT = 0.0081 (0.05%) 129 Rapa = 243.2 mg (1.869%) S EtOH = 4.88.4 mg (3.753%) PEG 400 = 12283.3 mg (94.378%) 130 Rapa = 0.404 g (2%) S EtOH = 0.8 g (4%) PEG 400 = 18.8 g (94%) BHT = 0.00051 (0.002%) 131 Rapa = 0.6024 g (2%) S EtOH = 1.2 g (4%) PEG 400 = 28.25 g (94%) 132 Rapa = 2.001 g (2%) S EtOH = 4.05 g (4%) PEG 400 = 94.45 g (94%) 133 Rapa = 0.5155 g (2.057%) S EtOH = 1.0198 g (4.070%) PEG 400 = 23.5225 g (93.873%) 134 PEG 400 = 9.6 g (96%) S EtOH = 0.4 g (4%) 135 Rapa = 0.610 g (2%) S EtOH = 1.2 g (4%) PEG 400 = 28.2 g (94%) 136 Rapa = 24.6 mg (1.193%) S EtOH = 91.1mg (4.418%) Tyloxapol = 219.6 mg (10.649%) BSS = 1726.8 mg (83.740%) 137 Rapa = 100.0 mg (1.993%) SP PEG 400 = 4916.9 mg (98.007%) 138 Rapa = 201.6 mg (4.005%) SP PEG 400 = 4831.5 mg (95.995%) 139 Rapa = 102.4 mg (2.036%) S EtOH = 209.0 mg (4.154%) PEG 400 = 4719.3 mg (93.810%) 140 Rapa = 10.3 mg (0.205%) S Yes, 10 pL EtOH = 27.4 mg (0.544%) PEG 400 = 4995.8 mg (99.251%) 141 Rapa = 10.6 mg (0.211%) S No, 10 pL EtOH = 208.4 mg (4.150%) PEG 400 = 4802.3 mg (95.639%) 142 Rapa = 31.5 mg (0.628%) S Yes, 10 pL EtOH = 67.1 mg (1.337%) PEG 400 = 4918.9mg (98.035%) 143 Rapa = 30.8 mg (0.613%) S No, 10 pL, 100 pL EtOH = 204.5 mg (4.073%) PEG 400 = 4786.1 mg (95.314%) 144 Rapa = 103.5 mg (2.057%) S Yes, 10 pL EtOH = 207.1 mg (4.116%) PEG 400 = 4720.8 mg (93.827%) 145 Rapa = 283.0 mg (2.020%) S EtOH = 566.1 mg (4.041%) PEG 400 = 13,160.8 mg (93.939%) 146 Rapa = 280.1 mg (1.998%) S EtOH = 565.2 mg (4.033%) PEG 400 = 13,171.7 mg (93.969%)-r Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 147 Rapa = 201.6 mg (3.000%) SP PEG 400 = 6518.8 mg (97.000%) 148 Rapa = 31.9 mg (1.019%) S Benzyl Alcohol = 1021.9 mg (20.070%) Sesame Oil = 4017.9 mg (78.911%) 149 Rapa = 51.5 mg (1.03%) S Benzyl Alcohol = 259.9 mg (5.19%) Sesame Oil = 4694.3 mg (93.78%) 150 Rapa = 5.96 g (2%) S EtOH = 12.0 g (4%) PEG 400 = 282.0 g (94%) 151 Rapa = 54.5 mg (1.07%) S Benzyl Alcohol = 1014.3 mg (19.95%) Olive Oil = 4014.8 mg (78.98%) 152 Rapa =0 mg (0.00%) S Benzyl Alcohol = 269.4 mg (5.421%) Tyloxapol = 608.2 mg (12.238%) Sesame Oil = 4092.2 mg (82.341%) 153 Rapa = 76.3 mg (1.75%) S Benzyl Alcohol = 307.0 mg (7.06%) Tyloxapol = 607.8 mg (13.97%) Sesame Oil = 3000.5 mg (68.97%) Span 80 = 63.1 mg (1.45%) EtOH = 295.5 mg (6.79%) 154 Form. # 150 = 200 g (99.998) S BHT = 0.004 g (0.002%) 155 Rapa = 51.0 mg (0.87%) S EtOH = 642.3 mg (10.93%) Benzyl Alcohol = 431.8 mg (7.34%) Sesame Oil = 4753.7 mg (80.86%) 156 Rapa = 51.4 mg (1.03%) S Benzyl Alcohol = 518.4 mg (10.34%) , Olive Oil = 4444.7 mg (88.64%) 157 Rapa = 8.1 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376.0 g (94%) 158 Form. # 157 = 225.00 g (99.998%) S BHT = 0.0045 g (0.002%) 159 Rapa = 8.1 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376 g (94%) 160 Form. # 159 = 112.0 g (99.998%) S BHT = 0.00224 g (0.002%) 161 Form. # 159 = 112.0 g (99.998%) S BHT = 0.0019 g (0.002%) 162 Rapa = 55.4 mg (1.10%) S EtOH = 112.7 mg (2.25%) Benzyl Alcohol = 157.8 mg (3.15%) Cotton Seed Oil = 4688.0 mg (93.50%) 163 Rapa = 5.005 g (1%) S EtOH = 10.0 g (2%) PEG 400 = 485.5 g (97%) 164 PEG 400 = 9.82 g (98%) S EtOH = 0.235 g (2%) 165 Form. # 163 = 100.25 g (99.998%) S BHT = 0.0026g (0.002%) Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 166 Rapa = 203.1 mg (2.025%) SP 2.8651 pm F68 = 30.3 mg (0.303%) Sterile Water = 9792.6 mg (97.672%) 167 Rapa = 201.4 mg (2.0005%) SP 1.0984 pm Tween 20 = 43.9 mg (0.436%) Sterile Water = 9822.8 mg (97.564%) 168 EtOH = 0.8301 g (4.144%) S PEG 400 = 19.2014 g (95.856%) 169 Form. # 168 = 300I S 170 Form. # 168 = 250 i S Form. # 154 = 50 pI 171 Form. # 168 = 200 | S Form. # 154 = 100 l 172 Form. # 168 = 150 pl S Form. # 154 = 150 V1 173 Form. # 154 = 300 pl S 174 Rapa = 102.2 mg (2.041%) SP 0.4165 pm F68 = 16.0 mg (0.32%) Sterile Water = 4889.0 mg (97.639%) 175 Rapa = 101.1 mg (2.010%) SP 0.5294 pm Tween 20 = 27.7 mg (0.551%) Sterile Water = 4901.0 mg (97.439%) 176 BSS+ = 0 PI S Sterile Water = 0 pl Form. # 154 = 1000 p1 177 BSS+ = 200 pl SP Sterile Water = 0 p1 Form. # 154 = 800 pl 178 BSS+ = 400 PI SP Form. # 154 = 600 p1 179 BSS+ = 500 pl SP Form. # 154 = 500 1_ 180 BSS+ = 600 Pl SP Form. # 154 = 400 p 181 BSS+ =800 pI SP Form. # 154 = 200 p| 182 Sterile Water = 200 pl SP Form. # 154 = 800 pl 183 Sterile Water = 400 pl SP Form. # 154 = 600 p1 184 Sterile Water = 500 pl SP Form. # 154 = 500 1l 185 Sterile Water = 600 pl SP Form. # 154 = 400 1_ _ 186 Sterile Water = 800 pl SP Form. # 154 = 200 p 187 BSS+ = 2536.9 mg (49.98%) SP 60.2075 pm Form. # 154 = 2538.7 mg (50.02%) 188 Sterile Water = 2515.6 mg (49.84%) SP 617.5157 pm Form. # 154 = 2532.2 mg (50.16%) . 189 F68 = 12.6 mg (0.25%) SP 70.6089 pm Sterile Water = 2524.7 mg (49.79%) Form. # 154 = 2533.1 mg (49.96%) 110 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 190 Rapa = 2.0225 g (2%) S EtOH = 3.65 g (4%) PEG 400 = 94.0 g (94%) BHT = 0.002 g (0.002%) 191 F68 =12.1 mg SP Sterile Water = 2558.9 mg Form. # 154 = 2556.4 mg 192 F68 = 19.8 mg SP Sterile Water = 2564.1 mg Form. # 154 = 25557.5 mg 193 F68 = 25.3 mg SP Sterile Water = 2575.1 mg Form. # 154 = 2572.9 mg 194 F68 = 32.4 mg SP Sterile Water = 2572.1 mg Form. # 154 = 2562.1 mg 195 F68= 38.3mg SP Sterile Water = 2563.2 mg Form. # 154 = 2573.5 mg 196 F68 = 43.6 mg SP Sterile Water = 2541.1 mg Form. # 154 = 2556.0 mg 197 F68 = 51.2 mg SP Sterile Water = 2594.5 mg Form. # 154 = 2594.1 mg 198 PEG 400 = 1920 g (96%) S EtOH = 80 g (4%) 199 Form. #168 = 1000 pl S 200 Form. # 168 =20 0 pl S Form. # 154 = 800 pl 201 Form. # 168 = 400 pl S Form. # 154 = 600 pl 202 Form. # 168 = 500 pl S Form. # 154 = 500 pl 203 Form. # 168 = 600 pl S Form. # 154 = 400 p1 204 Form. # 168 = 800 pl S Form. # 154 = 200 1_ 205 PEG 400 = 200 pl S Form. # 154 = 800 pl 206 PEG 400 = 400 p S Form. # 154 = 600 1l 207 PEG400=500 pl S Form. # 154 = 500 V1 208 PEG400=600 I S Form. # 154 = 400 1l 209 PEG 400 = 800 pl S Form. # 154 = 200 1 210 Phosal 50PG = 6735.0 mg (99.002%) S Tween 80 = 67.9 mg (0.998%) 211 Rapa = 2.0047 g (2%) S EtOH = 4.00 g (4%) PEG 400 = 94.05 g (94%) 212 Phosal 50PG = 20.0662 g (98.999%) S Tween 80 = 0.2029 g (1.001%) I 1'0 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 213 Form. # 154 = 100 pI S Form. # 168 = 900 pI 214 Form. # 154 = 100 pl S Form. # 168 = 900 pil 215 Form. # 154 = 100 p S Form. # 168 = 900 p1 216 Form. # 154 = 100 pI S PEG 400 = 900 V1 217 Form. # 154 = 100 p S PEG 400 = 900 p1 218 Form. # 154 = 100 p S PEG 400 = 900 pi 219 Form. # 154 = 100 pI SP BSS+ = 900 PI 220 Form. # 154 = 100 pI SP BSS+ = 900 P_ 221 Form. # 154 = 100 pI SP BSS+ = 900 pI 222 Form. # 154 = 1000 p| S 223 Form. # 154 = 1000 |_ s 224 Form. # 154 = 100 pI S Form. # 168 = 900 p 1 225 Form. # 154 = 100 pl S Form. # 168 = 900 pI 226 Form. # 154 = 100 p S Form. # 168 = 900 pl 227 Form. # 154 = 100 pl S PEG 400 = 900 p 228 Form. # 154 = 100 pl S PEG 400 = 900 pI 229 Form. # 154 = 100 I s PEG 400 = 900 p1 230 Form. # 154 = 100 pI SP BSS+ = 900 P1 231 Form. # 154 = 100 pI SP BSS+ = 900 pI 232 Form. # 154 = 100 pI SP BSS+ = 900 pI 233 Form. # 154 = 200 pl S Form. # 168 = 800 p1 234 Form. # 154 = 200 pl S Form. # 168 = 800 p1 235 Form. # 154 = 200 pl S Form. # 168 = 800 p1 236 Form. # 154 = 200 pl S Form. # 168 = 800 pl 237 Form. # 154 = 200 pl S PEG 400 = 800 p1 238 Form. # 154 = 200 pl S PEG 400 = 800 p1 239 Form. # 154 = 200 pl SP BSS+ = 800 P1 240 Form. # 154 = 200 pi SP BSS+ = 800 p1l 1 AA Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 241 Form. # 154 =200 pl SP BSS+ = 800 1 242 Form. #154= 100 pl S No, 10 pL Form. # 168 = 900 I 243 Form. # 154 =100 1 S Yes, 10 pL PEG 400 = 900 pl 244 Form. # 154 = 100 pl SP Yes, 10 pL BSS+ = 900 11 245 Form. # 154 = 100 pi SP BSS+/CMC(0.5%)= 900 I 246 Form. # 154 = 400 pl S No, 10 pL Form. # 168 = 900 1_ 247 Form. # 154 = 400 pl S Yes, 10 pL PEG 400 = 900 1I 248 Form. # 154 = 400 pI SP Yes, 10 pL BSS+ = 900 Pl 249 Form. # 154 = 400 pl SP BSS+/CMC(0.5%)= 900 Al 250 Form. # 154 = 100 pl SP BSS+/CMC(0.5%)= 900 pl 251 Form. # 154 = 100 pI SP BSS+/CMC(0.5%)= 900 1_ _ 252 Form. # 154 = 100 pl SP BSS+/CMC(0.5%)= 900 p_ 253 Form. # 154 = 200 pIl SP BSS+/CMC(0.5%)= 800 I 254 Form. # 154 = 200 I SP BSS+/CMC(0.5%)= 800 1_ 255 Form. # 154 = 200 pi SP BSS+/CMC(0.5%)= 800 [L 256 Form. # 154 = 400 pI SP BSS+/CMC(0.5%)= 900 1_ 257 Form. # 154 = 400 pl SP BSS+/CMC(0.5%)= 900 1_ 258 Form. # 154 = 400 pl SP BSS+/CMC(0.5%)= 900 1_ 259 EtOH = 17.1 mg (0.57%) S PEG 400 = 2997.3 mg (99.43%) 260 EtOH = 40.8 mg (1.35%) S PEG 400 = 2980.2 mg (98.65%) 261 EtOH = 47.1 mg (1.57%) S PEG 400 = 2950.1 mg (98.43%) 262 Rapa = 2.0032 g (2%) S EtOH = 3.92 g (4%) PEG 400 = 94.00 g (94%) 263 Triamcinolone acetomide = 80.8 mg SP (4.04%) PEG 400 = 1920.8 mg (95.96%) 264 NFF-0007 filled in glove box S 265 PEG 400 = 9.598 g (96%) S EtOH = 0.4052 (4%) 266 Triamcinolone acetomide = 42.2 mg SP (4.123%) PEG 400 = 981.3 mg (95.877%) 1 A 1 Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 267 Phosal 50PG = 20.0783 g S (99.00835%) Tween 80 = 0.2011 g (0.99165%) 268 PEG 400 = 96.1 g (96%) S EtOH = 4.00 g (4%) 269 Rapa = 0.4001 g (2%) S EtOH = 0.80 g (4%) PEG 400 = 18.8 g (94%) 270 Sterile Water = 9955.8 mg (99.27%) S CMC High visc. = 47.8 mg (0.48%) Tween 80 = 25.4 mg (0.25%) 271 Sterile Water = 9947.5 mg (99.00%) S CMC Medium visc. = 75 mg (0.75%) Tween 80 = 25.1 mg (0.25%) 272 Rapa = 41 mg (2.01%) SP Form. # 270 = 2000 mg (97.99%) 273 Rapa = 40.2 mg (1.97%) SP MSF-03-172-07E = 2000 mg (98.03%) 274 NMP (Pharmasolve*I= 1280.5 mg S (65.89%) PLGA 75/25 = 662.9 mg (34.11%) 275 NMP (Pharmasolve*I= 1573.3 mg S (80.50%) PLGA 75/25 = 381.0 mg (19.50%) 276 NMP (Pharmasolve*I= 1009.7 mg S Yes, 10 pL 49.8%) PLGA 75/25 = 1001.6 mg (50.20%) 277 Sterile Water = 14934.0 mg (99.25%) S CMC Medium visc. = 112.4 mg (0.75%) 278 Propylene Glycol = 1893.7 mg S Yes, 10 pL (93.85%) EtOH = 83.8 mg (4.16%) Rapa = 40.2 mg (1.99%) 279 Propylene Glycol = 1946.2 mg S Yes, 10 pL (95.68%) Benzyl Alcohol = 47.1 mg (2.31%) Rapa = 40.8 mg (2.01%) 280 PEG 300 = 1894.1 mg (93.74%) S Yes, 10 pL EtOH = 40.1 mg (1.98%) Rapa = 86.4 mg (4.28%) 281 PEG 300 = 1925.5 mg (95.88%) S Yes, 10 pL, 30 pL EtOH = 39.8 mg (1.98%) Rapa = 43.0 mg (2.14%) 282 Rapa = 100.6 mg (2.01%) SP Yes, 10 pL, 30 pL MSF-03-176-02 = 4910.8 mg (97.99%) 283 Rapa = 11.5 mg (0.57%) S PEG 300 = 2012.5 mg (99.43%) 284 Rapa = 10.3 mg (0.51%) S PEG 400 = 2017.2 mg (99.49%) 285 Rapa = 9.8 mg (0.486%) S PEG 600 = 2005.9 mg (99.51%) 286 Tacrolimus = 42.7 mg (2.11%) S EtOH = 46.0 mg (2.27%) PG = 1938.7 mg (95.62%) 1 A'% Formulation Median particle Formation of NDM, Form. # Composition (mg), % (wlw) Type size Injection volume 287 Tacrolimus = 40.7 mg (2.01%) S EtOH = 43.0 mg (2.12%) PEG 300 = 1942.1 mg (95.87%) 288 Tacrolimus = 40.3 mg (1.99%) S EtOH = 43.8 mg (2.16%) PEG 400 = 1942.3 mg (95.85%) 289 Tacrolimus = 40.8 mg (2.03%) S EtOH = 44.5 mg (2.21%) PEG 600 = 1924.0mg (95.76%) 290 Rapa = 61.0 mg (3.17%) S NMP = 1226.54 mg (63.80%) PLGA 75/25 = 634.96 mg (33.03%) 291 Rapa = 100.2 mg (5.13%) S NMP = 1492.95 mg mg (76.37%) PLGA 75/25 = 361.65 mg (18.50%) 292 Rapa = 62.9 mg (3.04%) S NMP = 1103.8g mg (53.40%) PLGA 75/25 = 900.2 mg (43.56%) 293 Rapa = 62.4 mg (3.00%) S NMP = 1205.1 mg mg (58.11%) PLGA 75/25 = 806.4 mg (38.89%) 294 Sterile Water+1% CMC Med. = 4909.1 SP mg (97.99%) Rapa = 100.5 mg (2.01%) 295 Sterile Water+1% CMC high. = 4903.8 SP mg (97.96%) Rapa = 101.9 mg (2.04%) 296 Rapa = 40.5 mg (2.03%) S NMP = 1958.7 mg (97.97%) 297 Rapa = 20.5mg (2.0%) SP DMA = 41.4mg (4.0%) PVP = 35.0mg (3.4%) H20 = 934.7mg (90.6%) 298 Rapa = 10.6mg (2.0%) S DMA = 10.6mg (2.0%) PEG 400 = 506.1mg (96%) 299 Rapa = 5.2mg (2.0%) SP 1% DMA in PEG 400 = 257.4 mg (98%) 300 Rapa = 20.0mg (2.0%) S DMA = 7.8mg (0.8%) PEG 400 = 974mg (97.2%) 301 Rapa = 20.1mg (1.3%) S DMA = 19.5mg (1.3%) PEG 400 = 1449.6mg (97.3%) 302 Rapa = 20.0mg (2.0%) SP PVP = 10.8mg (1.1%) PEG 400 = 994.5mg (97.0%) 303 Rapa = 20.4mg (2.0%) SP PVP = 24.5mg (2.4%) PEG 400 = 990.7mg (95.7%) 304 Rapa = 25.5mg (2.4%) SP PVP = 51.9mg (4.8%) PEG 400 = 1000.6mg (92.8%) 305 Rapa = 22.5mg (2.3%) S BA = 27.5mg (2.7%) PEG 400 = 950.7mg (95.0%) 1 A ' Formulation Median particle Formation of NDM, Form. # Composition (mg), % (w/w) Type size Injection volume 306 Rapa = 30.2mg (2.3%) SP PVP = 240.9mg (18.6%) PEG 400 = 1021.2mg (79.0%) 307 Rapa = 8.7mg (3.1%) SP 1% PVP in H20 = 273 mg (96.9%) 308 Rapa = 12.6mg (2.53%) SP 5% PVP in H20 = 501.6 mg (97.5%) 309 Rapa = 20.3mg (3.8%) SP 10% PVP in H20 = 513.9 mg (96.2%) 310 Rapa = 100.5mg (2.0%) S Yes, 10 pL DMA = 67.8mg (1.4%) PEG 400 = 4838.3mg (96.6%) 311 Rapa = 96.8mg (1.9%) S Yes, 10 pL BA = 157.5mg (3.2%) PEG 400 = 4748.7mg (94.9%) 312 Rapa = 105.8mg (2.1%) S DMA 5.63mg (0.1%) PEG 400 = 4888.9mg (97.8%) 313 Rapa = 20.2mg (2.0%) SP PVP = 99.2mg (9.9%) H20 = 882.3mg (88.1%) 314 Rapa = 100.3mg (2.0%) SP PVP = 251.4mg (5.0%) H20 = 4662.8mg (93.0%) 315 Rapa = 20.3mg (2.0%) S DMA = 983.9mg (98%) 316 Triamcinolone = 22.8mg (2.0%) S Yes, 10 pL DMA = 12.0mg (1.1%) PEG 400 = 1104.5mg (96.9%) 317 Triamcinolone = 1.0mg (0.1%) S EtOH = 49.30mg (4.0%) PEG 400 = 1191.9mg (96.0%) 318 Triamcinolone = 18.7mg (0.9%) S PEG 400 = 959.8mg (99.1%) 319 Triamcinolone = 25.5mg (1.3%) S EtOH = 83.0mg (4.1%) I PEG 400 = 1905.6mg (94.6%) 320 Dexamethasone = 20.4mg (1.2%) S EtOH = 71.7mg (4.1%) PEG 400 = 1737.6mg (98.8%) 321 Dexamethasone = 27.5mg (2.0%) S Yes, 10 pL DMA = 5.6mg (0.4%) PEG 400 = 1347.3mg (97.6%) 322 Rapa = 9.1mg (0.152%) E EtOH = 90.9mg (1.514%) F127 = 262.8mg (4.378%) Water = 1489.1mg (24.804%) Sesame oil = 4151.5mg (69.152%) 323 Rapa = 24.4mg (0.625%) E Phosal 50PG = 203.1mg (5.201%) EtOH = 166.8mg (4.272%) Labrafac CC = 1502.8mg (38.486%) Sesame oil = 2007.7mg (51.416%) 324 Form. # 174 with 2mm beads SP 0.4929 pm 325 Form. # 175 with 2mm beads SP 0.4804 pm 1 AA Table 2 Aqueous Humor Rapa Concentration Injection of 2% Rapa-PEG-EtOH Mean Rapa concentration (ng/mL) Standard deviation Solution (ng/mL) 1.0 pL intravitreal 0.438 (1 day after injection) 0.141 3.0 pL intravitreal 0.355 (1 day after injection) 0.234 3.0 pL sub-conj 0.338 (1 day after injection) 0.122 5.0 pL into anterior chamber 0.167 (14 days after injection) 0.183 10.0 pL into anterior chamber 0.004 (14 days after injection) 0.006 1 A'|

Claims (20)

1. A method for treating an ocular disease comprising administering to a subject by intraocular or periocular delivery a volume of a liquid formulation comprising 5 rapamycin at a concentration of between 0.5% and 10% by weight, polyethylene glycol and ethanol, to treat an ocular disease in a subject, wherein the liquid formulation is a liquid solution that forms a non-dispersed mass when injected into the vitreous.

2. The method of claim 1, wherein non-dispersed mass is in a form of a solid 10 depot.

3. The method of claim 1 or claim 2, wherein the liquid formulation has a viscosity of between 40 centipoise and 120 centipoise. 15

4. The method of claim 3, wherein the liquid formulation has a viscosity of between 60 centipoise and 80 centipoise.

5. The method of any one of the preceding claims, wherein the liquid formulation contains a concentration of rapamycin between 1% and 5% by weight. 20

6. The method of any one of the preceding claims, wherein the ethanol is present at a concentration between 0.1% and 10% by weight.

7. The method of any one of the preceding claims, wherein the ocular disease is 25 selected from the group consisting of choroidal neovascularization, dry aged-related macular degeneration, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, dry eye, and uveitis.

8. The method of claim 1, wherein the non-dispersed mass is not in a form of a gel 30 or gel-like substance.

9. The method of any one of the preceding claims, wherein the liquid formulation comprises about 2% (w/w) rapamycin, about 94% (w/w/) polyethylene glycol 400, and about 4% (w/w) ethanol. 35 147

10. The method of any one of claims I to 8, wherein the liquid formulation comprises about 4% (w/w) rapamycin, about 92% (w/w/) polyethylene glycol 400, and about 4% (w/w) ethanol. 5

11. The method of any one of the preceding claims, wherein the intraocular delivery comprises injection of the liquid formulation into the vitreous of an eye of the subset.

12. The method of any one of claims I to 10, wherein the periocular delivery comprises injection of the liquid formulation between the sclera and conjunctiva of an 10 eye of the subject.

13. A method for treating an ocular disease comprising administering to a subject by intraocular or periocular delivery a volume of a liquid formulation consisting of rapamycin at a concentration of between 0.5% and 10% by weight, polyethylene 15 glycol, and ethanol at a concentration between 0.1% and 10% by weight, to treat an ocular disease in a subject, wherein the liquid formulation is a liquid solution that forms a non-dispersed mass when injected into the vitreous, and wherein the ocular disease is selected from the group consisting of choroidal neovascularization, dry aged-related macular degeneration, wet age-related macular degeneration, diabetic macular edema, 20 diabetic retinopathy, dry eye, and uveitis.

14. The method of claim 13, wherein non-dispersed mass is in a form of a solid depot. 25

15. The method of claim 13 or claim 14, wherein the liquid formulation contains a concentration of rapamycin between 1% and 5% by weight.

16. The method of claim 13, wherein the non-dispersed mass is not in a form of a gel or gel-like substance. 30

17. The method of any one of claims 13 to 16, wherein the liquid formulation comprises about 2% (w/w) rapamycin, about 94% (w/w/) polyethylene glycol 400, and about 4% (w/w) ethanol or; 35 wherein the liquid formulation comprises about 4% (w/w) rapamycin, about 92% (w/w/) polyethylene glycol 400, and about 4% (w/w) ethanol. 148

18. The method of any one of claims 13 to 17, wherein the intraocular delivery comprises injection of the liquid formulation into the vitreous of an eye of the subset. 5

19. The method of any one of claims 13 to 17, wherein the periocular delivery comprises injection of the liquid formulation between the sclera and conjunctiva of an eye of the subject.

20. The method of any one of claims 13 to 19, wherein the ocular disease is uveitis 10 and the uveitis is chronic uveitis or; wherein the ocular disease is wet age-related macular degeneration.