Plasma kallikrein inhibitors and methods of use thereof in ocular disorders

Abstract

To provide a method for treating a disease or condition of the eye in a subject.SOLUTION: A method for treating a disease or condition of the eye in a subject, the method comprising non-surgical administration to the suprachoroidal space (SCS) of the eye of the subject of an effective amount of a drug composition comprising an effective amount of plasma kallikrein inhibitors. The plasma kallikrein inhibitors include avoralstat.SELECTED DRAWING: Figure 1

Description

Background Art

[0001] The anterior region of the eye refers to the front part of the eye (i.e., the part of the eye in front of the lens and including the lens), and includes structures in front of the vitreous humor such as the cornea, iris, ciliary body, and lens. The posterior region of the eye refers to the rear part of the eye (i.e., the part of the eye behind the lens), and includes the vitreous humor, sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic disc, optic nerve, ciliary body, and / or trabecular meshwork. The sclera (also known as the white of the eye) is the opaque and fibrous protective outer layer of the eye. The sclera contains connective tissue that maintains the shape of the eye by providing resistance to internal and external forces. The suprachoroidal space is the region between the sclera and the choroid in the posterior region of the eye.

[0002] Drug delivery to the eye, particularly to the posterior region of the eye, is extremely difficult. Many inflammatory and proliferative diseases in the posterior region of the eye require long-term pharmacological treatment. Examples of such diseases include age-related macular degeneration, diabetic macular degeneration, diabetic retinopathy, and the like. The current long-term pharmacological treatment for such disorders can result in various adverse effects and adverse clinical symptoms both locally and systemically in the eye.

[0003] Methods for delivering drugs to the posterior segment of the eye are known, but it is often difficult to deliver an effective dose of a drug to the posterior segment of the eye using conventional delivery methods and drug formulations. Methods for delivering drug formulations to the eye include topical application, intravitreal administration (IVT), intracameral administration, systemic administration, and suprachoroidal administration. Each of these methods provides clinical utility for the treatment of certain diseases and conditions, but not all of these methods are suitable for delivering drugs to the posterior segment of the eye. Topical application, such as eye drops, is useful for treating conditions that affect the outer surface of the eye or the tissues of the anterior part of the eye, but eye drops are not sufficiently delivered to the posterior segment of the eye. Due to the limited half-life of many compounds in the vitreous humor, IVT administration generally requires multiple injections, which increases the risk of cataracts, retinal detachment, increased intraocular pressure, bleeding, and endophthalmitis. The delivery of drug formulations to the posterior segment of the eye by systemic administration is limited by the outer and inner blood-retinal barriers and the reduced therapeutic efficacy due to dilution and degradation of the drug before it reaches the posterior segment of the eye. Suprachoroidal delivery is an attractive method for delivering drugs to the posterior segment of the eye. However, even with this administration method, the half-life of many drugs requires repeated injections (e.g., every 1-2 months), and the drug concentration is below the level required for effective treatment.

[0004] For the treatment of various eye diseases and conditions, including diseases and conditions of the posterior segment of the eye, it is desirable to provide a better, safer, and more effective therapy. The present disclosure addresses these and other needs.

Summary of the Invention

[0005] The present disclosure provides a method for treating an eye disease or condition in a subject, the method including non-surgically administering a drug composition comprising an effective amount of a compound of the present disclosure to the suprachoroidal space (SCS) of the subject's eye. In some embodiments, the described method incorporates a novel drug composition comprising a compound of the present disclosure described herein.

[0006] The compounds of the present disclosure are plasma kallikrein inhibitors. In some embodiments, the compounds of the present disclosure are small molecule plasma kallikrein inhibitors. In some embodiments, the compound of the present disclosure is BCX4161. In some embodiments, the compounds of the present disclosure are inhibitory peptides or anti-plasma kallikrein antibodies. In some embodiments, the pharmaceutical composition is administered to the SCS of the eye via a piercing member such as, but not limited to, a microneedle.

[0007] In some embodiments, a method for treating an eye disease or condition in a subject includes non-surgically administering a pharmaceutical composition comprising an effective amount of a compound of the present disclosure to the SCS of the subject's eye, providing a therapeutic benefit in the treatment of the eye disease or condition without local and / or systemic side effects.

[0008] In some embodiments, a method for treating an eye disease or condition in a subject in need thereof includes non-surgically administering a pharmaceutical composition comprising an effective amount of a compound of the present disclosure to the SCS of the subject's eye, providing a favorable ocular PK profile (e.g., an increase in the concentration of the compound of the present disclosure in the SCS or ocular tissue).

[0009] In some embodiments, the compounds of the present disclosure reach the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork after administration to the SCS using the methods disclosed herein. In some embodiments, the compounds of the present disclosure reach the choroid, retinal pigment epithelium, sclera, retina, optic nerve, peripheral retinal pigment epithelium, peripheral choroid, peripheral sclera, peripheral retina, central retinal pigment epithelium, central choroid, central sclera, and / or central retina after administration using the methods disclosed herein.

[0010] In some embodiments, the high-level compounds of the present disclosure reach the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork after administration to the SCS using the methods disclosed herein. In some embodiments, the high-level compounds of the present disclosure reach the choroid, RPE, sclera, retina, and / or optic nerve after administration to the SCS using the methods disclosed herein.

[0011] In some embodiments, the compounds of the present disclosure are retained in the choroid, RPE, sclera, and / or retina for an extended period. For example, in some embodiments, the present plasma kallikrein inhibitor is retained in the choroid, RPE, sclera, and / or retina for at least about 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 90 days, or more after administration. In some embodiments, the present plasma kallikrein inhibitor is retained in the choroid, retinal pigment epithelium, sclera, retina, optic nerve, peripheral retinal pigment epithelium, peripheral choroid, peripheral sclera, peripheral retina, central retinal pigment epithelium, central choroid, central sclera, and / or central retina for at least about 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 90 days, or more after administration using the methods disclosed herein.

[0012] In some embodiments, the compounds of the present disclosure target the posterior segment of the eye. For example, in some embodiments, the compounds of the present disclosure are not retained in large amounts in the vitreous humor. For example, in some embodiments, the drug level in the vitreous humor decreases by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration. Thus, in some embodiments, the methods provided herein achieve high levels of the compounds of the present disclosure in the posterior segment of the eye with limited exposure in the anterior segment of the eye.

[0013] In some embodiments, the methods provided herein minimize or eliminate systemic exposure to the compounds of the present disclosure.

[0014] In some embodiments, a method of treating an eye disease or condition in a subject in need thereof includes non-surgically administering an effective amount of a compound of the present disclosure to the SCS of the subject's eye and administering an additional therapeutic agent to the subject's eye.

[0015] In some embodiments, the eye disease or condition is selected from the group consisting of retinopathy, macular degeneration, uveitis, macular edema, diabetic macular edema (DME), scleritis, retinitis, and choroiditis. In some embodiments, the macular degeneration is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy and age-related macular degeneration, potential without classic choroidal neovascularization (CNV) in age-related macular degeneration, Stargardt disease, subfoveal wet age-related macular degeneration, and vitreomacular adhesion associated with neovascular age-related macular degeneration.

[0016] In some embodiments, the eye disease or condition is retinopathy, and the retinopathy is selected from the group consisting of diabetic retinopathy, allergic retinopathy, sickle cell retinopathy, retinopathy of prematurity, or central serous retinopathy.

[0017] In some embodiments, the eye disease or condition is an ocular neovascular condition. In further embodiments, the ocular neovascular condition is selected from the group consisting of abnormal ocular neovascularization, ocular neovascularization, choroidal neovascularization, and polypoidal choroidal vasculopathy.

[0018] In some embodiments, the eye disease or condition affects the posterior segment of the eye. In some embodiments, the eye disease or condition is a diabetic eye disease. In some embodiments, the eye disease or condition is macular degeneration. In some embodiments, the eye disease is diabetic macular degeneration. In some embodiments, the eye disease is diabetic macular edema. In some embodiments, the eye disease is diabetic retinopathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 5

Mode for Carrying Out the Invention

[0020] Methods and pharmaceutical compositions are provided herein for treating eye diseases and conditions, particularly posterior eye diseases and conditions, in subjects in need of such treatment.

[0021] The treatment methods described herein are particularly useful for the local delivery of drugs to the posterior segment of the eye, such as, but not limited to, the choroidoretinal tissue, macula, retinal pigment epithelium (RPE), and optic nerve in the posterior segment of the eye. The novel pharmaceutical compositions described herein provide favorable PK parameters that result in high concentrations of the disclosed compounds being maintained in the SCS or ocular tissue over a long period (i.e., several months). Using the non-surgical intraocular drug delivery methods provided herein, drug delivery can be targeted to specific ocular tissues or regions within or adjacent to the posterior segment of the eye. For example, using the non-surgical intraocular drug delivery methods described herein, drug delivery can be specialized and targeted to the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic disc, optic nerve, ciliary body, trabecular meshwork, and / or other tissues in the posterior segment of the eye or adjacent tissues in the eye of a human subject. The methods provided herein can, in one embodiment, be used to target drug delivery to specific posterior eye tissues or regions within the intraocular or adjacent tissues.

[0022] One of ordinary skill in the art will understand that the suprachoroidal space expands frequently due to fluid accumulation for some eye condition or as a result of some trauma or surgical intervention. However, herein, the fluid accumulation is intentionally created by injecting a pharmaceutical composition into the suprachoroidal lamina to create a suprachoroidal space (filled with the pharmaceutical composition described herein). Without wishing to be bound by theory, the SCS region functions as a pathway for uveoscleral outflow (i.e., the natural process of the eye moving fluid from one region of the eye to another region), and is thought to become a real space when the choroid detaches from the sclera and when the pharmaceutical composition is administered as described herein.

[0023] The compounds of the present disclosure provide favorable PK parameters when administered by the non-surgical intraocular drug delivery methods described herein. Such favorable PK parameters include, but are not limited to, the drug being at a high concentration (such as above the minimum therapeutic dose) in the posterior segment of the eye over a period of several months. As a result, by using the methods and compositions of the present disclosure, a subject suffering from an eye disease or condition described herein can be treated more effectively compared to prior art treatment methods. In addition, the increased therapeutic effect is accompanied by a decrease in the number of treatments required to achieve an excellent therapeutic effect and / or a decrease in the concentration of the drug required to achieve an excellent therapeutic effect.

[0024] Accordingly, the present disclosure addresses known problems in the art and provides excellent treatment methods disclosed herein.

[0025] Definitions The articles “a” and “an” are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more than one element.

[0026] As used herein, the terms "anterior segment of the eye" or "anterior region of the eye" refer to the anterior one-third of the eye and structures anterior to the vitreous membrane including the lens, the cornea, the iris, and the ciliary body.

[0027] As used herein, the term "antibody" broadly refers to any immunological binding agent, such as, but not limited to, IgG, IgM, IgA, IgD, and IgE. Antibodies can be monoclonal or polyclonal and, in one embodiment, are humanized antibodies. The term antibody is also used to refer to any antibody-like molecule having an antigen-binding region, including but not limited to, Fab’, Fab, F(ab’)2, single domain antibodies, Fv, scFv (single-chain Fv), and engineered multivalent antibody fragments such as diabodies, tribodies, and multibodies. Techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see, e.g., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988, which is incorporated herein by reference).

[0028] As used herein, the term "compound(s) of the disclosure" refers to plasma kallikrein inhibitors. In certain embodiments, the term refers to plasma kallikrein inhibitors disclosed herein. Preferred compounds of the disclosure are plasma kallikrein inhibitors of Formula I and / or IB, including but not limited to BCX-4161. The compounds of the disclosure may exist in any pharmaceutically acceptable form.

[0029] As used herein, the term "control composition" refers to a composition having an equivalent amount of a compound of the disclosure in the same or an equivalent formulation.

[0030] As used herein, the term "dosing interval" means the period between doses. In certain embodiments, the dosing interval is monthly, every two months, every three months, every four months, every five months, every six months, or up to every twelve months. In preferred embodiments, the dosing interval is every three months, every four months, or every six months or more. When considering a concentration or other characteristic in relation to the dosing interval, this concentration / characteristic can be determined with respect to the entire dosing interval or a specified point within the dosing interval (e.g., at the end of the dosing interval).

[0031] As used herein, the term "pharmaceutical composition" refers to a formulation comprising a compound of the present disclosure, which typically includes pharmaceutically acceptable excipients and / or carriers, and in preferred embodiments, the pharmaceutical composition contains an effective amount of the compound of the present disclosure.

[0032] As used herein, the terms "effective amount", "sufficient amount", or "therapeutically effective amount" refer to an amount of a compound of the present disclosure that is sufficient to provide a therapeutic benefit or a desired result, including clinical outcomes. Thus, an effective amount may be sufficient, for example, to treat an eye disease or condition described herein. In certain embodiments, an effective amount is an amount of a compound of the present disclosure that avoids or substantially reduces undesirable side effects.

[0033] As used herein, the term "excipient" refers to any inactive component of a formulation intended to facilitate the handling, stability, dispersion, wetting, pharmacokinetics, and / or injection of a compound of the present disclosure. In one embodiment, the excipient may include, consist of, or be composed of water or saline.

[0034] As used herein, the term "exposure" refers to the concentration of a compound of the present disclosure in the subject's SCS or ocular tissue, measured over a period of time. The subject's exposure to a compound of the present disclosure can be measured by administering a composition of the present disclosure to the subject in a suitable form, collecting a sample at a predetermined time, and measuring the amount of the compound of the present disclosure in the sample using a suitable analytical technique such as, but not limited to, liquid chromatography. The amount of the compound of the present disclosure in a sample at a particular time is determined and the concentration and time data from all samples are plotted to provide a curve. Calculating the area under this curve provides the subject's exposure to the compound of the present disclosure. The terms "exposure", "area under the curve", and "area under the concentration / time curve" are intended to have the same meaning and may be used interchangeably throughout.

[0035] As used herein, the term "hollow" refers to an open pathway (i.e., a bore) that passes through or is within a piercing member of a delivery device disclosed herein, such as a micro-needle. The term includes not only a single linear bore passing through the center of the piercing member, but also multiple bores passing through the center of the piercing member, bores following a complex path through the piercing member, multiple inlet and outlet points from the bore(s), and intersecting bores or a network of bores. Thus, in some embodiments, a hollow piercing member has a structure that includes one or more continuous pathways from the base of the piercing member to an exit point (opening) within the shaft and / or the tip portion of the piercing member distal to the base.

[0036] As used herein, the term "in need of treatment" refers to a determination made by a medical professional that a subject requires or would benefit from treatment with a compound of the present disclosure. This determination is based on a variety of factors within the purview of a medical professional's expertise, such as, but not limited to, the finding that the subject is ill or will become ill as a result of a disease or condition treatable by the methods or pharmaceutical compositions of the present disclosure.

[0037] As used herein, the term "microneedle" refers to a catheter body having a base, a shaft, and a tip suitable for insertion into the sclera and other eye tissues, and having dimensions suitable for the minimally invasive insertions and drug composition injections described herein. In a preferred embodiment, the microneedle is a hollow microneedle. Suitable microneedles are described in WO2017 / 192565, WO2014 / 179698, WO2014 / 074823, WO2011 / 139713, WO2007 / 131050, and WO2007 / 004874.

[0038] As used herein, the term "microparticle" refers to particles having a number average particle size of 1 to 100 μm, most preferably 1 to 25 μm, and includes microspheres, microcapsules, microbubbles, and beads. The microparticles may or may not be spherical.

[0039] As used herein, the term "microcapsule" refers to microparticles having an outer shell surrounding a core of another material. The core can be a liquid, a gel, a solid, a gas, or a combination thereof.

[0040] As used herein, the term "microbubble" refers to a microcapsule having an outer shell surrounding a gas core, where the drug is disposed on the surface of the outer shell, within the outer shell itself, or within the core. The microbubbles may respond to acoustic vibrations as known in the art for diagnostic purposes and / or can be used to rupture the microbubbles to release their payload at / into a selected eye tissue site.

[0041] As used herein, the term "microsphere" refers to spherical microparticles that include a shell and optionally a matrix material inside the shell. The microspheres may be solid or porous. Porous microspheres may include a sponge-like or honeycomb structure formed by pores or voids in the matrix material or shell, or may include a plurality of discrete voids in the matrix material or shell. The shell or matrix material may be a polymer, amino acid, saccharide, or other material known in the art.

[0042] As used herein, the term "minimum therapeutic level" means the concentration of a compound of the present disclosure that is required to be present in the use environment (e.g., SCS or ocular tissue, particularly posterior ocular tissue) to provide effective treatment of a disease or condition. Such "minimum therapeutic levels" may vary depending on the presence of concurrent diseases or conditions, the co-use of other agents, steroid hormone levels, environmental stimuli to which the subject is exposed, and / or the lifestyle of the subject, among other factors specific to the subject, but are not limited thereto. Thus, the minimum therapeutic level may vary between subjects and / or may vary over time for a given subject. However, for subjects being treated with a compound of the present disclosure for a disease or condition described herein, generally, the minimum therapeutic level is generally in the range of 20 ng / ml to 60 ng / ml. In one embodiment, the minimum therapeutic level is at most about 40 ng / ml, about 50 ng / ml, or about 55 ng / ml. However, the minimum therapeutic level may be as low as about 20 ng / ml to about 30 ng / ml or as high as about 60 ng / ml or about 70 ng / ml. Unless otherwise specified, the "minimum therapeutic level" of a compound of the present disclosure for treating a disease or condition described herein is defined as 30 ng / ml or more and less than 70 ng / ml.

[0043] As used herein, the term "nanoparticle" refers to a particle that includes a shell and an optional matrix material inside the shell, and has a number average particle size of 1 to 1000 nm. Porous nanoparticles may include a sponge-like structure or a honeycomb structure formed by pores or voids in the matrix material or shell, or may include a plurality of discrete voids in the matrix material or shell. The shell or matrix material may be a polymer, an amino acid, a saccharide, or other materials known in the art. Nanoparticles may be spherical or non-spherical.

[0044] As used herein, the term "non-Newtonian fluid" refers to a fluid that does not follow Newton's law of viscosity, i.e., a constant viscosity independent of stress. In a non-Newtonian fluid, when a force is applied, the viscosity changes and can exhibit either a decrease in viscosity (shear-thinning fluid) or an increase in viscosity (shear-thickening fluid).

[0045] As used herein, the term "non-surgical" intravitreal drug delivery method refers to a method of drug delivery that does not require general anesthesia and / or retrobulbar anesthesia (also referred to as retrobulbar block). In certain embodiments, the "non-surgical" intravitreal drug delivery method is performed using a puncture member with a diameter of 28 gauge or less. In certain embodiments, the "non-surgical" intravitreal drug delivery method does not require an induction mechanism typically required for intravitreal drug delivery via a shunt or cannula.

[0046] As used herein, the term "pharmaceutically acceptable" refers to a compound that is compatible with the other components of the composition and is not harmful to the subject receiving the compound or composition. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal or state government regulatory authority or described in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0047] As used herein, the term "pharmaceutically acceptable form" means known forms of a compound that can be administered to a subject, including, but not limited to, solvates, hydrates, prodrugs, polymorphs, pseudomorphs, neutral forms, and salt forms of the compound.

[0048] As used herein, the term "pharmaceutically acceptable salt" is intended to include salts derived from inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may also include forms in which the ratio of the salt-containing molecule is not 1:1. For example, the salt may contain more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of the compound of the present disclosure. As another example, the salt may contain less than one inorganic or organic acid molecule per molecule of base, such as two molecules of the compound of the present disclosure per molecule of tartaric acid. The salt may also exist as a solvate or a hydrate.

[0049] As used herein, the terms "posterior segment of the eye" and "posterior region of the eye" refer to the posterior two-thirds of the eye, including the vitreous membrane and the structures behind it. Thus, "posterior eye tissues" include, but are not limited to, the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic nerve head, and optic nerve, and in certain embodiments, "posterior eye tissues" do not include vitreous humor (such as when referring to high concentrations of the compounds of the present disclosure in posterior eye tissues). For the purposes of the present disclosure, the term also optionally includes the ciliary body, trabecular meshwork, and / or iris, which are located adjacent to the SCS and may be exposed to the compounds of the present disclosure when administered as described herein.

[0050] As used herein, the terms "subject" or "patient" include, but are not limited to, all members of the animal kingdom including mammals, animals (e.g., cats, dogs, horses, pigs, etc.), and humans. In certain embodiments, the subject is a human.

[0051] As used herein, the term "substantially all" means at least 80% or more, e.g., 80%, 85%, 90%, or 95% or more, of the recited period.

[0052] As used herein, the terms "supraciliary space", "SCS", "suprachoroid", or "suprachoroidia" mean the potential space in the region of the eye located between the sclera and the choroid. This region is mainly composed of a dense layer of long pigmentation processes each derived from each of two adjacent tissues, but space can develop in this region as a result of fluid injection or accumulation of other substances in the supraciliary space and adjacent tissues.

[0053] As used herein, the term "supraciliary space" means the most anterior portion of the supraciliary space adjacent to the ciliary body, trabecular meshwork, and limbus.

[0054] As used herein, the terms "therapeutic benefit", "treatment response", or "treatment effect" refer to a decrease in the severity of the symptoms / clinical signs of the eye disease or condition being treated in a patient, or a decrease in the number of symptoms (if any) / clinical signs (if any) of the eye disease or condition being treated in a patient. Recognition of a therapeutic benefit, treatment response, or treatment effect does not require a complete decrease in the severity and / or number of clinical symptoms. In certain embodiments, the decrease in the severity of the symptoms / clinical signs may be at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 99%. In certain embodiments, the decrease in the number of symptoms (if any) / clinical signs (if any) may mean a decrease in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more symptoms (if any) / clinical signs (if any), or all symptoms (if any) / clinical signs (if any).

[0055] As used herein, the terms "treating" or "treatment" refer to improving the symptoms of a disease or condition, and may include curing the disease or condition, substantially preventing the onset of the disease or condition, improving the condition of the subject, alleviating one or more or substantially all of the symptoms resulting from the disease or condition, or curing a particular disease or condition.

[0056] As used herein, the term "alkyl" is a technical term and refers to a saturated aliphatic group that includes straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its main chain (e.g., C1-C10 for straight-chain and C3-C30 for branched-chain), alternatively about 20 or fewer carbon atoms. In one embodiment, the term "alkyl" refers to a C1-C10 straight-chain alkyl group. In one embodiment, the term "alkyl" refers to a C1-C6 straight-chain alkyl group. In one embodiment, the term "alkyl" refers to a C3-C12 branched-chain alkyl group. In one embodiment, the term "alkyl" refers to a C3-C8 branched-chain alkyl group. In one embodiment, the term "alkyl" refers to a cycloalkyl having about 3 to about 10 carbon atoms in the ring structure, alternatively about 3 to 6 carbons in the ring structure.

[0057] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical containing 2 to 10 carbons and including at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0058] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0059] As used herein, the term "alkylene" is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment, alkylene is a disubstituted alkane, i.e., at two positions, a halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), or a similar substituent. That is, in one embodiment, "substituted alkyl" is "alkylene".

[0060] As used herein, the term "acyl" is a technical term and, as used herein, refers to any group or radical of the form RCO- where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0061] As used herein, the term "aryl" is a technical term and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. The aromatic ring may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings (the rings being "fused rings") where two or more carbons are common to two adjacent rings, where at least one of the rings is an aromatic hydrocarbon, and where, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In one embodiment, the term "aryl" refers to a phenyl group.

[0062] As used herein, the term "arylalkyl" is a technical term and, as used herein, refers to an alkyl group substituted with an aryl group.

[0063] As used herein, the term "amino" is a technical term and, as used herein, refers to both unsubstituted amines and substituted amines, for example, moieties that can be represented by the following general formula. [Chemical formula] Wherein R a , R b , and R c are each independently hydrogen, alkyl, alkenyl, -(CH2) x -R d or R a and R btogether with the N to which they are attached, complete a heterocyclic ring having 4 to 8 atoms in the ring structure, and R d represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclic, and x is an integer in the range of zero or 1 to 8. In certain embodiments, R a or R b only one of them may be carbonyl. For example, R a , R b , and nitrogen do not form an imide together. In other embodiments, R a and R b (and optionally R c ) each independently represent hydrogen, alkyl, alkenyl, or -(CH2) x -R d . In one embodiment, the term "amino" refers to -NH2.

[0064] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0065] As used herein, the term "alkoxy" means an alkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0066] As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group substituted with one or more cycloalkyl groups. An example of (cycloalkyl)alkyl is the cyclopropylmethyl group.

[0067] As used herein, the term "halo" is a technical term and, as used herein, refers to -F, -Cl, -Br, or -I.

[0068] As used herein, the term "(heterocyclyl)alkyl" refers to an alkyl group substituted with one or more heterocyclyl groups.

[0069] As used herein, the term "heterocyclyl" refers to a non-aromatic ring system radical that can be fully saturated or can contain one or more units of unsaturation (to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system), having 3 to 12 atoms including at least one heteroatom such as nitrogen, oxygen, or sulfur, and including but not limited to monocyclic, bicyclic, and tricyclic rings. For purposes of illustration not to be construed as limiting the scope of the present disclosure, examples of heterocyclic rings are aziridinyl, azirinyl, oxiranyl, thiiranyl, thirenyl, dioxiranyl, diazirinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzthiadiazolyl, indolyl, benzotriazolyl, naphthyridinyl, azepin, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, and tetrahydrofuranyl.

[0070] As used herein, the term "heteroaryl" is a technical term and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having one or more heteroatoms in the ring structure, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. "Heteroaryl" may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings (the rings being "fused rings") in which two or more carbons are common to two adjacent rings, where at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, and where, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0071] As used herein, the term "heteroalkyl" or "heteroarylalkyl" is a technical term and, as used herein, refers to an alkyl group substituted with a heteroaryl group.

[0072] As used herein, the term "phosphoryl" is a technical term and, as used herein, may generally be represented by the following formula.

Chemical formula

[0073] "Substituted", "substituting", or "substituted with" includes the implicit condition that such substitution follows the acceptable valences of the substituted atoms and substituents, and it is understood that this substitution results in a stable compound, i.e., a compound that does not spontaneously undergo alteration such as rearrangement, fragmentation, decomposition, cyclization, elimination, or other reactions.

[0074] The term "substituted" is intended to include all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above herein. The acceptable substituents may be one or more, and may be the same or different, for a suitable organic compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any way by the acceptable substituents of organic compounds.

[0075] In certain embodiments, optional substituents contemplated by the present disclosure include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamide, ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

[0076] As used herein, the terms "optionally substituted" or "substituted or unsubstituted" when preceding a listing of chemical moieties mean that each of the subsequently recited chemical moieties is either substituted or unsubstituted. For example, "substituted or unsubstituted aryl, heteroaryl, and cycloalkyl" or "optionally substituted aryl, heteroaryl, and cycloalkyl" means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0077] Other chemical terms herein are used according to their conventional usage in the art as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., 1985), McGraw-Hill, San Francisco, which is incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0078] The compounds of the present disclosure The compounds of the present disclosure are plasma kallikrein inhibitors. Plasma kallikrein inhibitors include small molecule inhibitors (e.g., BCX4161, BCX7353, KDV001, KDV818, KDV824, and KDV900). Plasma kallikrein inhibitors also include inhibitory peptides (such as, but not limited to, ecallantide) and anti-plasma kallikrein antibodies (such as, but not limited to, DX-2930 which is lanadelumab), and fragments thereof.

[0079] In one embodiment, the compound of the present disclosure is a compound of general formula I, or a pharmaceutically acceptable form thereof,

Chemical formula

[0080] In certain embodiments, the compound of formula I is X is CH, Y is N, X is N, Y is CH, W is -C(O)NH-, W is -CH2-NH-, R is CH=CH2, R 1 is hydrogen, R 1 is -C1-C4 alkoxy, R 1 is -OCH3, V is C(O)R 3 wherein V is C(O)OH, R is CH=CH2, R 1 is H, V is C(O)OH, R is CH=CH2, R 1 is -OCH3, V is C(O)OH, A is -C(O)NR 2 -(CH2) n -C3-C6 cycloalkyl, A is -C(O)NH-isobutyl, A is -C(O)NH(CH2)-cyclopropyl, B is -C(=NR 4 )NHR 5 and is defined as B being -C(=NH)NH2.

[0081] In one embodiment, W is -C(O)NH-, Z is a direct bond, B is -C(=NH)NH2, A is -C(O)NH-isobutyl or -C(O)NH(CH2)-cyclopropyl, R is CH=CH2, R 1 is H, and V is C(O)OH.

[0082] In one embodiment, W is -C(O)NH-, Z is a direct bond, B is -C(=NH)NH2, A is -C(O)NH-isobutyl or -C(O)NH(CH2)-cyclopropyl, R is CH=CH2, R 1 is -OCH3, and V is C(O)OH.

[0083] In one embodiment, X is CH, Y is N, Z is a direct bond, W is -C(O)N(R 2 )-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)R 3 and A is C(O)NR 2 -C1-C5 alkyl or -C(O)NR 2 (CH2) n -C3-C6 cycloalkyl. In certain embodiments of the foregoing, R 1 is H. In certain embodiments of the foregoing, R 1 is methoxy.

[0084] In one embodiment, X is CH, Y is N, Z is a direct bond, W is -C(O)NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)OH, and A is C(O)NH-isobutyl or -C(O)NH-CH2-cyclopropyl. In certain embodiments of the foregoing, R 1is H. In certain embodiments of those described above, R 1 is methoxy.

[0085] In one embodiment, X is CH, Y is N, Z is a direct bond, W is -CH2NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)R 3 and A is C(O)NR 2 -C1-C5 alkyl or -C(O)NR 2 (CH2) n -C3-C6 cycloalkyl. In certain embodiments of those described above, R 1 is H. In certain embodiments of those described above, R 1 is methoxy.

[0086] In one embodiment, X is CH, Y is N, Z is a direct bond, W is -CH2NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)OH, and A is C(O)NH-isobutyl or -C(O)NH-CH2-cyclopropyl. In certain embodiments of those described above, R 1 is H. In certain embodiments of those described above, R 1 is methoxy.

[0087] In one embodiment, X is N, Y is CH, Z is a direct bond, W is -C(O)N(R 2 )-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)R 3 and A is C(O)NR 2 -C1-C5 alkyl or -C(O)NR 2 (CH2) n -C3-C6 cycloalkyl. In certain embodiments of those described above, R 1 is H. In certain embodiments of those described above, R 1 is methoxy.

[0088] In one embodiment, X is N, Y is CH, Z is a direct bond, W is -C(O)NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)OH, and A is C(O)NH-isobutyl or -C(O)NH-CH2-cyclopropyl. In certain embodiments of the foregoing, R 1 is H. In certain embodiments of the foregoing, R 1 is methoxy.

[0089] In one embodiment, X is N, Y is CH, Z is a direct bond, W is -CH2NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)R 3 wherein A is C(O)NR 2 -C1-C5 alkyl or -C(O)NR 2 (CH2) n -C3-C6 cycloalkyl. In certain embodiments of the foregoing, R 1 is H. In certain embodiments of the foregoing, R 1 is methoxy.

[0090] In one embodiment, X is N, Y is CH, Z is a direct bond, W is -CH2NH-, R 1 is hydrogen or methoxy, R is CH=CH2, V is C(O)OH, and A is C(O)NH-isobutyl or -C(O)NH-CH2-cyclopropyl. In certain embodiments of the foregoing, R 1 is H. In certain embodiments of the foregoing, R 1 is methoxy.

[0091] In one embodiment, the compounds used in the present disclosure are compounds of formula (I) as defined above, provided that when X is N, Y is CH, Z is a direct bond, W is -C(O)NH-, R1 is methoxy, V is C(O)OH, B is -C(=NH)NH2, and A is C(O)NH-alkyl, the alkyl is other than isobutyl.

[0092] In one embodiment, the compound of the present disclosure is a compound of general formula IB, or a pharmaceutically acceptable form thereof,

Chemical formula

[0093] Preferably, R 10 is -(CH2)-cyclopropyl or -isobutyl. In certain embodiments of the compound of formula IB, R is -CH=CH2, V is -C(O)OH, Y is N, R 10 is -(CH2)-cyclopropyl, R 11 is =O, X is C, R 1 is -OCH3. R is -CH=CH2, V is -C(O)OH, Y is N, R 10 is -(CH2)-cyclopropyl, R 11 is =O, X is C, R 1 is H. R is -CH=CH2, V is -C(O)OH, Y is N, R 10 is -isobutyl, R 11 is =O, X is C, R 1 is H. R is -CH=CH2, V is -C(O)OH, Y is C, R 10 is -isobutyl, R 11 is H, X is N, R 1 is H.

[0094] In some embodiments, the present plasma kallikrein inhibitor is avoralstat. Avoralstat is a potent and specific inhibitor of human plasma kallikrein activity. The term "BCX4161" is used herein synonymously with the term avoralstat. The chemical structure and chemical formula of avoralstat are provided below. Table 1 provides the general properties of avoralstat.

Chemical formula

Table 1

[0095] In certain embodiments, the compounds of the present disclosure, particularly small molecule plasma kallikrein inhibitors or compounds of Formula I or IB, have a water solubility in deionized water of 0.5 mg / ml or less and greater than 0.005 mg / ml, for example, but not limited to, 0.25 mg / ml or less, 0.2 mg / ml or less, 0.15 mg / ml or less, 0.1 mg / ml or less (each determined at room temperature). In certain embodiments, the compounds of the present disclosure, particularly small molecule plasma kallikrein inhibitors or compounds of Formula I or IB, have a log D 7.4 of 1.5 or greater, 1.75 or greater, or 2.0 or greater (each in octanol phosphate buffer according to USP standards). In certain embodiments, the compounds of the present disclosure, particularly small molecule plasma kallikrein inhibitors or compounds of Formula I or IB, have a water solubility within the described range and a log D 7.4 within the described range. In certain embodiments, the compounds of the present disclosure with reduced solubility in aqueous solution surprisingly provide the favorable PK parameters described herein, resulting in the ability to maintain high concentrations of the compounds of the present disclosure in the SCS or ocular tissue for an extended period (i.e., several months). In any of the foregoing, the compounds of the present disclosure have an IC 50 for human plasma kallikrein that may range from 0.1 to 1000 ng / ml, 1 to 500 ng / ml, or 1 to 250 ng / ml.

[0096] The effect of the compounds of the present disclosure on human plasma kallikrein activity is determined by the method described by Zhang et al. (Medicinal Chemistry, 2006, No. 6, p547). Briefly, plasma kallikrein activity is determined using a chromogenic substrate (S2302). In these experiments, 2 nM of plasma kallikrein (Enzyme Research Laboratories, South Bend, IN, USA) is incubated with 80 μM of S2302 (H-D-Pro-Phe-Arg-p-nitroaniline) in a final volume of 200 μL of Tris-HCl buffer (200 mM NaCl, 2.5 mM CaCl2, 50 mM Tris-HCl, pH 7.8) in the presence or absence of increasing concentrations of the compounds of the present disclosure. The assay reaction is initiated by adding the enzyme to a pre-mixed solution of the inhibitor and the substrate (enzyme-initiated reaction). After incubation at 30°C, the activity of plasma kallikrein is measured as the change in absorbance at OD 405 nm (for example, using a BioTek PowerWave X340 Microplate Reader, Winooski, VT, USA or an equivalent device). The data are analyzed using appropriate software (for example, Four Parameter Logistic Curve, SigmaPlot software, Systat Software, Inc., San Jose, CA, USA or an equivalent).

[0097] Any of the compounds of the present disclosure can be prepared and / or administered in a pharmaceutically acceptable form. In certain embodiments, pharmaceutically acceptable forms of the compounds of the present disclosure do not include prodrugs, isomers, and / or mimetics. In certain embodiments, pharmaceutically acceptable forms of the compounds of the present disclosure are limited to pharmaceutically acceptable salts, neutral forms, solvates, and hydrates. In certain embodiments, pharmaceutically acceptable forms of the compounds of the present disclosure are limited to pharmaceutically acceptable salts and neutral forms. In certain embodiments, pharmaceutically acceptable forms of the compounds of the present disclosure are limited to pharmaceutically acceptable salts.

[0098] Furthermore, any compound of the present disclosure, including the pharmaceutically acceptable forms shown above, may be part of a composition, including a pharmaceutical composition, either alone or in combination with a compound of the prior art. Even further, any compound of the present disclosure, including the pharmaceutically acceptable forms shown above, can be used in any of the methods disclosed herein.

[0099] PK parameters As discussed herein, pharmaceutical compositions containing the compounds of the present disclosure provide favorable PK parameters when administered by the non-surgical intraocular drug delivery methods described herein. As a result, the compounds of the present disclosure can reach high concentrations in ocular tissues, particularly posterior ocular tissues, over a period of several months. The favorable PK properties enable a number of advantages described herein. As a result, using the methods and compositions of the present disclosure, subjects suffering from the ocular diseases or conditions described herein can be treated more effectively compared to prior art treatment methods.

[0100] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) of the compounds of the present disclosure when delivered to the SCS via the methods described herein is 1 / 2 longer than that of the control compositions administered intravitreally, intracamerally, topically, or systemically.

[0101] In certain aspects of this embodiment, the intraocular t 1 / 2 of the compounds of the present disclosure when administered to the SCS via the methods described herein is up to about 1.1-fold longer, up to about 2-fold longer, up to about 5-fold longer, up to about 10-fold longer, up to about 15-fold longer, up to about 20-fold longer, up to about 25-fold longer, up to about 30-fold longer, up to about 40-fold longer, or up to about 50-fold longer than the intraocular t 1 / 2 of the control compositions administered intravitreally, intracamerally, topically, or systemically. In certain aspects of this embodiment, the intraocular t 1 / 2 of the compounds of the present disclosure when administered to the SCS via the methods described herein is 1 / 2longer than that by about 1.1-fold to about 50-fold, or about 5-fold to about 50-fold, or about 10-fold to about 50-fold, or about 25-fold to about 50-fold, or about 2-fold to about 10-fold, or about 2-fold to about 20-fold, or about 2-fold to about 40-fold.

[0102] t 1 / 2 In certain aspects of the foregoing embodiments of t 1 / 2 the increase is observed for up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 2 months, up to about 3 months, up to about 4 months or more, or up to about 4 months or more. t 1 / 2 In certain aspects of the foregoing embodiments of t 1 / 2 the increase is observed for about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 4 weeks to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, or about 5 months to about 6 months after administering the compound of the present disclosure to a subject by the methods described herein.

[0103] t 1 / 2 In one aspect of any of the foregoing embodiments of t, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. t 1 / 2 In another aspect of any of the foregoing embodiments of t, the compound of the present disclosure is a compound of Formula I or a compound of Formula IB. t 1 / 2 In another aspect of any of the foregoing embodiments of t, the compound of the present disclosure is BCX4161.

[0104] In another embodiment, the intraocular C of the compound of the present disclosure when delivered to the SCS via the methods described herein max is greater than the intraocular C of a control composition administered intravitreally, intracamerally, topically, or systemically. max is greater.

[0105] In certain aspects of this embodiment, the intraocular C of the compound of the present disclosure when administered to the SCS via the methods described herein max is the intraocular C of a control composition administered topically, intracamerally, intravitreally, or systemically. maxgreater than, up to about 2-fold greater, up to about 5-fold greater, up to about 10-fold greater, up to about 15-fold greater, up to about 20-fold greater, up to about 30-fold greater, up to about 40-fold greater, up to about 50-fold greater, or up to about 60-fold greater. In certain embodiments thereof, the intraocular C of the compounds of the present disclosure when administered to SCS via the methods described herein max is the intraocular C of a control composition administered topically, intracamerally, intravitreally, or systemically max by, up to about 1.1- to about 60-fold greater, or about 5- to about 60-fold greater, or about 10- to about 60-fold greater, or about 20- to about 60-fold greater, or about 230- to about 60-fold greater, or about 2- to about 10-fold greater, or about 5- to about 15-fold greater, or about 15- to about 30-fold greater, or about 20- to about 40-fold greater, or about 30- to about 60-fold greater.

[0106] C max In certain embodiments of the foregoing embodiments of C max the increase is observed for up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 2 months, up to about 3 months, or up to about 4 months, up to about 5 months, or up to about 6 months after administering the dose of the compound of the present disclosure to a subject by the methods described herein. C max In certain embodiments of the foregoing embodiments of C max the increase is observed for about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 4 weeks to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, or about 5 months to about 6 months after administering the dose of the compound of the present disclosure to a subject by the methods described herein.

[0107] C max In one embodiment of any of the foregoing embodiments of C, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. C max In another embodiment of any of the foregoing embodiments of C, the compound of the present disclosure is a compound of formula I or a compound of formula IB. C max In another embodiment of any of the foregoing embodiments of C, the compound of the present disclosure is BCX4161.

[0108] In another embodiment, the mean intraocular area under the curve (AUC 0-t ) of the compounds of the present disclosure when delivered to the SCS via the methods described herein 0-t is greater than the intraocular AUC

[0109] of the control composition administered intravitreally, intracamerally, topically, or systemically. 0-t In certain aspects of this embodiment, the intraocular AUC 0-t of the compounds of the present disclosure when administered to the SCS via the methods described herein is up to about 1.1-fold greater, up to about 2.5-fold greater, or up to about 5-fold greater, or up to about 10-fold greater, or up to about 15-fold greater, or up to about 20-fold greater, or up to about 30-fold greater, or up to about 50-fold greater than the intraocular AUC 0-t of the control composition administered intravitreally, intracamerally, topically, or systemically. In certain aspects of this, the intraocular AUC 0-t of the compounds of the present disclosure when administered to the SCS via the methods described herein is about 2.5-fold to about 50-fold greater, or about 5-fold to about 50-fold greater, or about 10- to about 50-fold greater, or about 15- to about 50-fold greater, or about 20- to about 50-fold greater, or about 30- to about 50-fold greater, or about 2- to about 10-fold greater, or about 5- to about 15-fold greater, or about 15- to about 30-fold greater, or about 20- to about 40-fold greater, or about 30- to about 50-fold greater than the intraocular AUC

[0110] AUC 0-t In certain aspects of the foregoing embodiments of AUC 0-t , t is up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, or up to about 6 months or more (i.e., the increase in AUC

[0111] AUC 0-tIn one aspect of any of the foregoing embodiments, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. AUC 0-t In another aspect of any of the foregoing embodiments, the compound of the present disclosure is a compound of formula I or a compound of formula IB. AUC 0-t In another aspect of any of the foregoing embodiments, the compound of the present disclosure is BCX4161.

[0112] In another embodiment, the mean intraocular area under the curve (AUC tau ) over the dosing interval of the compound of the present disclosure when delivered to the SCS via the methods described herein is greater than the intraocular AUC tau of the control composition administered intravitreally, intracamerally, topically, or systemically.

[0113] In certain aspects of this embodiment, the intraocular AUC tau of the compound of the present disclosure when administered to the SCS via the methods described herein is up to about 1.1-fold greater, up to about 2.5-fold greater, or up to about 5-fold greater, or up to about 10-fold greater, or up to about 15-fold greater, or up to about 20-fold greater, or up to about 30-fold greater, or up to about 50-fold greater than the intraocular AUC tau of the control composition administered intravitreally, intracamerally, topically, or systemically. In certain aspects of this embodiment, the intraocular AUC tau of the compound of the present disclosure when administered to the SCS via the methods described herein is about 2.5-fold to about 50-fold greater, or about 5-fold to about 50-fold greater, or about 10-fold to about 50-fold greater, or about 15-fold to about 50-fold greater, or about 20-fold to about 50-fold greater, or about 30-fold to about 50-fold greater, or about 2-fold to about 10-fold greater, or about 5-fold to about 15-fold greater, or about 15-fold to about 30-fold greater, or about 20-fold to about 40-fold greater, or about 30-fold to about 50-fold greater than the intraocular AUC tau of the control composition administered intravitreally, intracamerally, topically, or systemically.

[0114] AUC tauIn certain aspects of the foregoing embodiments, the dosing interval is about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every two months, about once every three months, about once every four months, about once every five months, or about once every six months.

[0115] AUC tau In one aspect of any of the foregoing embodiments, the compounds of the present disclosure are small molecule plasma kallikrein inhibitors, inhibitory peptides, or anti-plasma kallikrein antibodies, or fragments thereof. AUC tau In another aspect of any of the foregoing embodiments, the compounds of the present disclosure are compounds of Formula I or compounds of Formula IB. AUC tau In another aspect of any of the foregoing embodiments, the compound of the present disclosure is BCX4161.

[0116] In another embodiment, the time (T max ) to the maximum concentration of the compounds of the present disclosure when delivered to the SCS via the methods described herein is slower compared to the T max of the control composition administered intravitreally, intracamerally, topically, or systemically, and the AUC 0-t or AUC tau of the compounds of the present disclosure is greater than the AUC 0-t or AUC tau of the control composition administered intravitreally, intracamerally, topically, or systemically.

[0117] In certain aspects of this embodiment, T max is about 2 to about 20 times slower compared to the control composition administered topically, intracamerally, intravitreally, or systemically, and optionally, the AUC 0-t or AUC tau of the compounds of the present disclosure when administered to the SCS via the methods described herein is the intraocular AUC 0-t or AUC tauGreater than, up to about 1.1 times greater, up to about 2.5 times greater, or up to about 5 times greater, or up to about 10 times greater, or up to about 15 times greater, or up to about 20 times greater, or up to about 30 times greater, or up to about 50 times greater. In certain aspects of this embodiment, T max The time to T is about 2 to about 20 times slower compared to a control composition administered locally, intracamerally, intravitreally, or systemically, and the intraocular AUC of the compounds of the present disclosure when administered to the SCS via the methods described herein tau is the intraocular AUC of a control composition administered locally, intracamerally, intravitreally, or systemically 0-t or AUC tau is greater than, about 2.5 to about 50 times, or about 5 to about 50 times, or about 10 to about 50 times, or about 15 to about 50 times, or about 20 to about 50 times, or about 30 to about 50 times, or about 2 to about 10 times, or about 5 to about 15 times, or about 15 to about 30 times, or about 20 to about 40 times, or about 30 to about 50 times greater than the intraocular AUC of a control composition administered locally, intracamerally, intravitreally, or systemically.

[0118] AUC tau In certain aspects of the foregoing embodiments of AUC, the dosing interval is about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every two months, about once every three months, about once every four months, about once every five months, or about once every six months.

[0119] AUC 0-t In certain aspects of the foregoing embodiments of AUC, t is up to about one week, up to about two weeks, up to about three weeks, up to about four weeks, up to about two months, up to about three months, up to about four months, up to about five months, or up to about six months or more (i.e., the increase in AUC 0-t is observed over the period from 0 to t).

[0120] T max In one aspect of any of the foregoing embodiments of T, the compounds of the present disclosure are small molecule plasma kallikrein inhibitors, inhibitory peptides, or anti-plasma kallikrein antibodies, or fragments thereof. T maxIn another aspect of any of the foregoing embodiments, the compound of the present disclosure is a compound of Formula I or a compound of Formula IB. T max In another aspect of any of the foregoing embodiments, the compound of the present disclosure is BCX4161.

[0121] In another embodiment, administration of the drug composition comprising the compound of the present disclosure to the SCS via the methods described herein provides a dosing interval of 1 to 12 months. For example, the dosing interval may be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or up to 12 months. Preferably, the dosing interval is 3 to 6 months.

[0122] In another embodiment, administration of the compound of the present disclosure to the SCS via the methods described herein provides a dosing interval of 1 to 12 months, wherein the concentration of the compound of the present disclosure in the SCS or ocular tissue exceeds the minimum therapeutic level throughout or substantially throughout the dosing interval. For example, the dosing interval may be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months. Preferably, the dosing interval is 3 to 6 months. In certain aspects of this embodiment, the minimum therapeutic concentration is from about 20 ng / ml to about 60 ng / ml, from about 30 to about 55 ng / ml, or from about 40 ng / ml to about 50 ng / ml.

[0123] In one aspect of any of the foregoing embodiments regarding the dosing interval, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. In another aspect of any of the foregoing embodiments regarding the dosing interval, the compound of the present disclosure is a compound of Formula I or a compound of Formula IB. In another aspect of any of the foregoing embodiments regarding the dosing interval, the compound of the present disclosure is BCX4161.

[0124] In another embodiment, administration of the drug composition comprising a compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure above the minimum therapeutic level in the SCS or ocular tissue for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure is above the minimum therapeutic level in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the minimum therapeutic concentration is from about 20 ng / ml to about 60 ng / ml, from about 30 to about 55 ng / ml, or from about 40 ng / ml to about 50 ng / ml. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0125] In another embodiment, administration of the drug composition comprising a compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure above 30 ng / ml in the SCS or ocular tissue for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure is above 30 ng / ml in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0126] In another embodiment, administration of a drug composition comprising a compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure in the SCS or ocular tissue that exceeds 40 ng / ml for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure exceeds 40 ng / ml in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0127] In another embodiment, administration of a drug composition comprising a compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure in the SCS or ocular tissue that exceeds 50 ng / ml for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure exceeds 50 ng / ml in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0128] In another embodiment, administration of the drug composition comprising a compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure in the SCS or ocular tissue that exceeds 100 ng / ml for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure exceeds 100 ng / ml in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0129] In another embodiment, administration of the compound of the present disclosure to the SCS via the methods described herein provides a concentration of the compound of the present disclosure in the SCS or ocular tissue that exceeds 250 ng / ml for up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, or up to about 12 months after administration. Preferably, the concentration of the compound of the present disclosure exceeds 250 ng / ml in the SCS or ocular tissue for at least 3 to 6 months. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. In certain aspects of this embodiment, the ocular tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0130] In one aspect of any of the foregoing embodiments regarding the concentration of the compounds of the present disclosure, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. In another aspect of any of the foregoing embodiments regarding the concentration of the compounds of the present disclosure, the compound of the present disclosure is a compound of Formula I or a compound of Formula IB. In another aspect of any of the foregoing embodiments regarding the concentration of the compounds of the present disclosure, the compound of the present disclosure is BCX4161.

[0131] Device for administration into the suprachoroidal space To deliver the compound of the present disclosure or the pharmaceutical composition of the present disclosure to the SCS, a number of devices can be used. Such devices may be those known in the art or those developed in the future.

[0132] In one embodiment, the device used to deliver the compound of the present disclosure or the pharmaceutical composition of the present disclosure to the SCS is known in the art and is described, for example, in WO2017 / 192565, WO2014 / 179698, WO2014 / 074823, WO2011 / 139713, WO2007 / 131050, and WO2007 / 004874. Other suitable devices are described in US Publication No. 2018 / 0256393 or 2017 / 0273825, US Patent No. 10,226,379 or 9,084,662.

[0133] By using the SCS drug delivery methods and devices described herein (including devices incorporating microneedles), the method advantageously includes precise control of the insertion depth into the eye tissue, such that the drug composition flows into the SCS and, in some embodiments, the posterior eye tissue surrounding the SCS. In one embodiment, the insertion of the puncturing member is made into the sclera of the eye. In one embodiment, the influx of the drug into the SCS is achieved without contacting the microneedle with underlying tissues such as the choroid and retinal tissues.

[0134] In a preferred embodiment of the present disclosure, the device used to deliver the pharmaceutical composition of the present disclosure to the SCS has one or more of the following characteristics, or the combination of the device and the pharmaceutical formulation provides one or more of the following benefits. 1. The device provides a piercing member for delivering the pharmaceutical composition to the SCS. A preferred piercing member is a micro needle, more preferably a hollow micro needle. 2. The device provides precise control of the insertion depth of the piercing member into the eye tissue. 3. The device provides administration of the pharmaceutical composition to the SCS without contacting the piercing member with underlying tissues such as choroidal and retinal tissues. 4. The device provides for administration and localization of the pharmaceutical composition to one or more eye tissues, particularly posterior eye tissues such as, but not limited to, the RPE, macula, and / or subretinal space. 5. Delivery of a pharmaceutical composition comprising a compound of the present disclosure by the methods described herein provides a reduced amount of the active ingredient in the pharmaceutical composition compared to the amount of the active ingredient in a control composition administered by another method such as, but not limited to, systemic, intracameral, topical, and / or IVT. 6. Delivery of a pharmaceutical composition comprising a compound of the present disclosure by the methods described herein provides for a sustained release of the compound of the present disclosure into one or more eye tissues compared to the compound of a control composition of the disclosure administered by another method such as, but not limited to, systemic, intracameral, topical, and / or IVT. 7. Delivery of a pharmaceutical composition comprising a compound of the present disclosure by the methods described herein provides a reduction in the number of adverse side effects or clinical signs upon administration of the compound of the present disclosure compared to the number of side effects or clinical signs caused by the compound of a control composition of the disclosure administered by another method such as, but not limited to, systemic, intracameral, topical, and / or IVT.

[0135] In some embodiments, the device provides for delivery of a compound of the present disclosure or a pharmaceutical composition of the present disclosure via a piercing member. Examples of suitable piercing members include, but are not limited to, microneedles, needles, trocars, cannulas, and similar structures where the piercing member defines a hollow interior. In certain embodiments, the piercing member does not have an opening at its distal end portion. In a preferred embodiment, the piercing member is a microneedle. A microneedle refers to an object having a base, a shaft, and a tip on the opposite side of the base, and the tip is suitable for insertion into eye tissue, such as the sclera, so that a compound of the present disclosure or a pharmaceutical composition of the present disclosure is delivered to the SCS.

[0136] In a preferred embodiment, the microneedle is dimensioned to be suitable for minimally invasive insertion into eye tissue and / or injection of a compound of the present disclosure or a pharmaceutical composition of the present disclosure. Preferred dimensions are described in WO2017 / 192565, WO2014 / 179698, WO2014 / 074823, WO2011 / 139713, WO2007 / 131050, and WO2007 / 004874. In certain embodiments, the microneedle is a 28-gauge microneedle, a 32-gauge microneedle, or a 34-gauge microneedle. In certain embodiments, the shape and / or size of the microneedle may at least partially correspond to at least a portion of the target tissue. For example, in certain embodiments, the length of the microneedle may correspond to the thickness of a portion of the eye tissue such that when the microneedle is inserted into the eye tissue, at least a portion of the microneedle is disposed within the sclera or suprachoroidal space of the eye.

[0137] In certain embodiments, the microneedle has a length or effective length that does not exceed about 2000 microns and a diameter that does not exceed about 600 microns. Both the "length" and "effective length" of the microneedle encompass the length of the shaft of the microneedle and the height of the bevel angle of the microneedle. In certain embodiments, the microneedle is a hollow microneedle. In other embodiments, other types of microneedles (e.g., solid microneedles) are useful in the methods provided herein.

[0138] In one embodiment, the microneedle has an effective length of about 50 μm to about 2000 μm. In another particular embodiment, the microneedle has an effective length of about 150 μm to about 1500 μm, or about 300 μm to about 1250 μm, or about 500 μm to about 1250 μm, or about 500 μm to about 1500 μm, or about 600 μm to about 1000 μm, or about 700 μm to about 1000 μm. In one embodiment, the effective length of the microneedle is about 600 μm, or about 700 μm, or about 800 μm, or about 1000 μm. In various embodiments, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of about 50 μm to about 600 μm, or about 50 μm to about 400 μm, or about 50 μm to about 500 μm, or about 100 μm to about 400 μm, or about 200 μm to about 600 μm, or about 100 μm to about 250 μm, and an aperture diameter of about 5 μm to about 400 μm. In certain embodiments, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of about 600 μm. However, those skilled in the art will understand that in embodiments where the tip of the microneedle is beveled, the aperture diameter may be larger than the outer diameter of the proximal portion of the microneedle.

[0139] The microneedle may be manufactured such that the aspect ratio (width:length) is about 1:1.5 to about 1:10. In one embodiment, the aspect ratio of the microneedle is about 1:3 to about 1:5. In another embodiment, the aspect ratio of the microneedle is about 1:4 to about 1:10.

[0140] The microneedle can have a straight or tapered shaft. In one embodiment, the diameter of the microneedle is largest at the base of the microneedle and tapers towards the tip point distal to the base. The microneedle can also be manufactured to have a shaft that includes both a straight (i.e., non-tapered) portion and a tapered (e.g., beveled) portion. In various embodiments, the microneedle has a bevel angle where the bevel angle is from about 5 degrees to about 30 degrees, from about 5 degrees to about 25 degrees, from about 5 degrees to about 20 degrees, from about 10 degrees to about 20 degrees, and from about 10 degrees to about 30 degrees. The microneedle can be formed with a shaft having a vertically circular cross-section or the cross-section can be non-circular. The tip portion of the microneedle can be configured in various ways. The tip of the microneedle can be symmetric or asymmetric with respect to the longitudinal axis of the shaft. The tip can be beveled, tapered, square, or rounded. In various embodiments, the microneedle has a bevel height where the bevel height is from about 50 μm to 500 μm, from about 100 μm to about 500 μm, from about 100 μm to about 400 μm, from about 200 μm to about 400 μm, and from about 300 μm to about 500 μm. In certain embodiments, the microneedle may be designed such that the tip portion of the microneedle is the substantially only portion of the microneedle that is inserted into the eye tissue (i.e., the tip portion exceeds 75% of the total length of the microneedle, exceeds 85% of the total length of the microneedle, or exceeds about 95% of the total length of the microneedle). In other certain embodiments, the microneedle may be designed such that the tip portion is the only portion of the microneedle that is inserted into the eye tissue and has a length that is generally less than about 75% of the total length of the microneedle, less than about 50% of the total length of the microneedle, or less than about 25% of the total length of the microneedle. For example, in one embodiment, the microneedle has a total effective length of 500 μm to 1500 μm and the tip portion has a length of less than about 400 μm, less than about 300 μm, or less than about 200 μm.

[0141] In one embodiment, the height of the bevel is from about 100 μm to about 500 μm. In another embodiment, the height of the bevel is about 500 μm or less, about 450 μm or less, about 400 μm or less, or about 350 μm or less. In another embodiment, the height of the bevel is from about 200 μm to about 500 μm, or from about 100 μm to about 700 μm, or from about 200 μm to about 700 μm. In yet another embodiment, the height of the bevel is from about 500 μm to about 900 μm, or from about 500 μm to about 800 μm, or from about 500 μm to about 700 μm. Thus, the bevel is arranged such that the distal edge is sufficiently sharp to penetrate the target tissue and penetrate into the eye tissue without (i) substantially elastically deforming the target tissue or (ii) damaging the internal structures of the eye, such as the lens or retina.

[0142] In one embodiment, the micro-needle extends from a base. The base may be integral with or separate from the micro-needle. The base may be rigid or flexible. The base may be substantially planar, or may be curved, for example, in the shape of the surface of the eye tissue at the injection site, or may be curved away from the eye surface, for example, convex, to minimize contact between the base and the eye tissue. Desirably, the base is shaped to minimize contact with the surface of the eye at the insertion point. For example, in one embodiment, the base may extend from the micro-needle shaft at a substantially perpendicular minimum distance only. In another embodiment, the base may be shaped to lift the eye tissue towards the micro-needle to counter the deflection of the eye tissue and facilitate insertion of the micro-needle into the eye tissue (for example, the base may extend from the micro-needle towards the tip portion of the micro-needle to "pinch" the eye tissue). Some such embodiments may be based, at least in part, on the device described in U.S. Patent No. 6,743,211.

[0143] The microneedle can extend from the base of the microneedle device at any angle suitable for insertion into the eye. In certain embodiments, the microneedle extends from the base at an angle of about 90 degrees to provide a substantially perpendicular insertion of the microneedle into the surface of the eye. In another particular embodiment, the microneedle extends from the base at an angle of about 60 degrees to about 110 degrees, or about 70 degrees to about 100 degrees, or about 80 degrees to about 90 degrees, or about 85 degrees to about 95 degrees.

[0144] The device or microneedle device may comprise means for controllably inserting the microneedle into the eye tissue and optionally withdrawing it from the eye tissue. Additionally, the device or microneedle may include means for controlling the angle at which the microneedle is inserted into the eye tissue. In one embodiment, the means for such control enables the microneedle to be inserted into the surface of the eye tissue at an angle of about 90 degrees.

[0145] The insertion depth of the microneedle into the eye tissue can be controlled by the length of the microneedle and other geometric features of the microneedle. For example, a flange or other abrupt change in the microneedle width can be used to limit the depth of microneedle insertion. The insertion of the microneedle can also be controlled using a mechanical micropositioning system that includes a gear or other mechanical component that advances the microneedle a controlled distance into the eye tissue, and similarly, for example, operated in reverse to withdraw the microneedle a controlled distance. The insertion depth can also be controlled by the speed at which the microneedle is inserted into the eye tissue. The withdrawal distance can be controlled by the elastic contraction force of the eye tissue into which the microneedle is inserted or by including an elastic element within the microneedle device that pulls the microneedle back a specified distance after the insertion force is released.

[0146] The insertion angle can be directed by positioning the microneedle at a first angle relative to the microneedle base and positioning the base at a second angle relative to the surface of the eye. In one embodiment, the first angle can be about 90° and the second angle can be about 0°. The insertion angle can also be directed by protruding the microneedle from the device housing through a channel in the housing that is oriented at a specified angle.

[0147] Transport of the drug composition through the hollow microneedle can be controlled and / or monitored using, for example, one or more valves, pumps, sensors, actuators, and microprocessors. In one embodiment, the device or microneedle may include a micropump, microvalve, and positioner, and the microprocessor is programmed to control the micropump or microvalve to control the delivery rate of the drug composition to the eye tissue through the microneedle. The flow through the microneedle may be driven by diffusion, capillary action, mechanical pumps, electroosmosis, electrophoresis, convection, or other driving forces. The design of the device and microneedle can be adjusted using known pumps and other devices to utilize these driving factors. In one embodiment, the microneedle device may further include an iontophoresis device similar to that described in U.S. Patent No. 6,319,240 to enhance delivery of the drug composition to the eye tissue. In another embodiment, the device or microneedle can further include a flow meter or other means for monitoring the flow through the microneedle and coordinating the use of pumps and valves. In some embodiments, the transport of the drug composition or biological fluid through the microneedle can be controlled or monitored using the methods and devices disclosed in WO2014 / 179698, which is hereby incorporated by reference in its entirety.

[0148] However, one of ordinary skill in the art will understand that other types of microneedles (e.g., solid microneedles), and other methods of delivering the pharmaceutical composition to the suprachoroidal space, may be used instead of, or in combination with, the delivery methods described herein. Non-limiting examples of such alternative methods include at least partially dissolving a coating of the pharmaceutical composition from a microneedle inserted into the suprachoroidal space, at least partially separating a coating of the pharmaceutical composition (either as an intact sleeve or as one or more fragments) from the microneedle into the suprachoroidal space, breaking or dissolving the microneedle from a base to which the microneedle is integrally formed or connected, or any combination thereof.

[0149] Pharmaceutical composition The pharmaceutical composition delivered by the methods described herein, in one embodiment, contains an effective amount of a compound of the present disclosure. A preferred compound of the present disclosure is BCX4161. In some embodiments, the compound of the present disclosure is a small molecule plasma kallikrein inhibitor. In some embodiments, the compound of the present disclosure is an inhibitory peptide or an anti-plasma kallikrein antibody. In various embodiments, the pharmaceutical composition may be a fluid composition, a semi-solid composition, a gel composition, or a solid composition. In one embodiment, the pharmaceutical composition is a fluid composition upon injection and is converted to a gel composition of a semi-solid composition upon or after injection into the suprachoroidal space.

[0150] A pharmaceutical composition comprising a liquid pharmaceutical composition may include any biocompatible liquid formulation, and may include water or an aqueous formulation containing one or more salts. In some embodiments, the liquid formulation is Hank's Balanced Salt Solution (HBSS) or another saline solution. In some embodiments, the liquid formulation is water. The volume of the liquid formulation may be any volume that can reduce the minimum force separating the sclera and the choroid. In some embodiments, the volume of the liquid formulation is from about 50 μL to about 500 μL, from about 50 μL to about 275 μL, from about 50 μL to about 250 μL, from about 50 μL to about 225 μL, from about 50 μL to about 200 μL, from about 50 μL to about 175 μL, from about 50 μL to about 150 μL, from about 60 μL to about 140 μL, from about 70 μL to about 130 μL, from about 80 μL to about 120 μL, from about 90 μL to about 110 μL, or about 100 μL.

[0151] In certain embodiments, the pharmaceutical composition comprises an effective amount of the disclosed compound per administration. In certain embodiments, the effective amount of the disclosed compound in the pharmaceutical composition ranges from about 0.01 mg to about 20 mg. In certain embodiments, the effective amount ranges from about 0.05 mg to about 15 mg. In certain embodiments, the effective amount ranges from about 0.1 mg to about 10 mg. In certain embodiments, the effective amount ranges from about 0.2 mg to about 8 mg. In certain embodiments, the effective amount ranges from about 0.3 mg to about 7 mg. In certain embodiments, the effective amount ranges from about 0.4 mg to about 6 mg. In certain embodiments, the effective amount ranges from about 0.5 mg to about 5 mg. In certain embodiments, the effective amount ranges from about 0.6 mg to about 4 mg. In certain embodiments, the effective amount ranges from about 0.7 mg to about 3 mg. In certain embodiments, the effective amount ranges from about 0.8 mg to about 2 mg. In certain embodiments, the effective amount ranges from about 0.9 mg to about 1.5 mg. In certain embodiments, the effective amount ranges from about 0.1 mg to about 3 mg. In certain embodiments, the effective amount ranges from about 0.2 mg to about 2.5 mg. In certain embodiments, the effective amount ranges from about 0.3 mg to about 2 mg. In certain embodiments, the effective amount ranges from about 0.4 mg to about 1.5 mg. In certain embodiments, the effective amount ranges from about 0.5 mg to about 1.25 mg. In certain embodiments, the effective amount ranges from about 0.1 mg to about 1 mg.

[0152] In certain embodiments, the effective amount is less than the effective amount delivered by another method such as, but not limited to, systemic, intracameral, topical, and / or intravitreal (IVT). In certain embodiments, the SCS effective amount is about 90%, or about 75%, or about 50% or less (e.g., about half or less) compared to the effective amount delivered by another method such as, but not limited to, systemic, intracameral, topical, and / or intravitreal (IVT).

[0153] The effective amount per administration described above may be administered as a single dose or multiple doses. Preferably, the effective amount per administration is administered as a single dose.

[0154] In one embodiment, a drug composition, particularly a fluid drug composition, has a viscosity of 10 Pa·s or less at a shear rate of 100 s -1 under the conditions described herein. In another embodiment, a drug composition, particularly a fluid drug composition, has a viscosity of 1 to 5 Pa·s or less at a shear rate of 100 s -1 under the conditions described herein.

[0155] In one embodiment, a suitable drug composition comprises the compound of the present disclosure in an amount of about 0.1% to about 5% and an excipient in an amount of about 95% to 99.9%. In another embodiment, a suitable drug composition comprises the compound of the present disclosure in an amount of about 0.1% to about 5%, about 90% to 99% water, and about 1% to about 10% additional excipient. In another embodiment, a suitable drug composition comprises the compound of the present disclosure in an amount of about 0.1% to about 2.5%, about 90% to 99% water, and about 1% to about 10% additional excipient. In another embodiment, a suitable drug composition comprises the compound of the present disclosure in an amount of about 0.1% to about 1%, about 90% to 99% water, and about 1% to about 10% additional excipient. Suitable pharmaceutically acceptable excipients are known in the art. In certain aspects of the above embodiments, the excipient contains at least one polymer. Suitable polymers include, but are not limited to, polyvinylpyrrolidone (e.g., PVP K30), tyloxapol, polyethylene glycol (e.g., PEG200 - 1000), HA, MC, and CMC.

[0156] In certain embodiments, the pharmaceutical composition is used to localize delivery of the disclosed compounds to the site of administration (e.g., distribute less than 30% to the SCS) or to provide distribution to greater than 50% of the disclosed compounds. To localize delivery to the site of administration, the pharmaceutical composition may include a strongly shear-thinning non-Newtonian agent to provide a low viscosity (i.e., high shear) during injection and subsequently a higher viscosity (i.e., low shear) after injection to prevent further migration. To widely distribute the pharmaceutical composition throughout the SCS, the pharmaceutical composition may include a medium shear-thinning non-Newtonian agent to provide a low viscosity during injection but only a moderate viscosity after injection (e.g., such pharmaceutical compositions may be used in the treatment of macular degeneration, uveitis, diabetic retinopathy, macular edema, and other choroidoretinal diseases).

[0157] In one aspect of this embodiment, the agent (e.g., polymer or fluid) has a viscosity (in Pa*s) of 100 or more at a shear rate of 0.01 s -1 or more, or a viscosity of 100 Pa*s or more and 3000 Pa*s or less at a shear rate of 0.01 s -1 is considered a strongly shear-thinning non-Newtonian fluid. In one aspect of this embodiment, the polymer or other fluid has a viscosity (in Pa*s) of less than 50 at a shear rate of 1.0 s -1 or less, or a viscosity of 1 or more and less than 50 Pa*s at a shear rate of 1.0 s -1 is considered a strongly shear-thinning non-Newtonian fluid. When determining the viscosity of the polymer, the percentage (weight to weight) of the polymer in the solution may range from 1% to 50%, preferably from 1% to 20% or from 1% to 10%. Any molecular weight of the polymer may be used.

[0158] In one aspect of this embodiment, the agent (e.g., polymer or fluid) has a viscosity (in Pa*s) of less than 100 at a shear rate of 0.01 s -1 or less, or a viscosity of 0.01 s -1When the shear rate is 1 Pa·s or more and less than 100 Pa·s, it is regarded as a non-Newtonian fluid with medium shear thinning viscosity. In one aspect of this embodiment, the polymer or other fluid has a viscosity (in Pa·s) that is 50 or more at a shear rate of 1.0 s -1 or, when the viscosity is 50 Pa·s or more and less than 100 Pa·s at a shear rate of 1.0 s -1 it is regarded as a non-Newtonian fluid with medium shear thinning viscosity. When determining the viscosity of the polymer, the percentage (weight to weight) of the polymer in the solution may be in the range of 1% to 50%, preferably in the range of 1% to 20% or 1% to 10%. Any molecular weight of the polymer may be used.

[0159] In one embodiment, the medium and strong shear thinning agents preferably have a viscosity of 10 Pa·s or less at a shear rate of 100 s -1 as measured under the conditions described herein. In another embodiment, the medium and strong shear thinning agents preferably have a viscosity of 1 to 5 Pa·s or less at a shear rate of 100 s -1 as measured under the conditions described herein.

[0160] When viscosity measurement values are given herein, these are determined using an MCR300 stress-controlled rheometer (Anton Paar, Ashland, VA) equipped with a Peltier element for temperature control and an evaporation blocker that enables measurement of the polymer solution upon heating in a cone-plate configuration. The viscosity of the sample is measured at a temperature of 20 °C (sample diluted in deionized water) at a shear rate of 0.01 s -1 to 100 s -1 .

[0161] Examples of shear-thinning polymers are hyaluronic acid (HA), which is widely used in the eye and has a record of excellent safety. In one embodiment, HA is used in the pharmaceutical compositions described herein to distribute the pharmaceutical composition in more than 50% of the SCS for at least 20 days, at least 40 days, at least 60 days, or at least 90 days, or longer after administration. In one aspect of this embodiment, the HA has a molecular weight of about 300 to about 2000 kDa, about 500 to about 1500 kDa, or about 700 to about 1200 kDa. In another aspect of this embodiment, the HA has a molecular weight of about 900 to about 1000 kDa or about 950 kDa. In one aspect of this embodiment, the HA is present in the pharmaceutical composition at a concentration of about 0.5% to about 10%, about 1% to 7.5%, about 1% to about 5%, or about 2.2% (each of the foregoing is determined based on weight / volume with respect to the other components of the pharmaceutical composition). In another aspect, the HA has a molecular weight within the range specified above and is present in the pharmaceutical composition at the percentage specified above. In another aspect, the HA has a molecular weight of about 500 to about 1500 kDa and is present at a concentration of about 1% to about 5%. Such pharmaceutical compositions may further comprise a diluent such as HBSS, saline, or water.

[0162] For BCX4161, a preferred compound of the present disclosure, non-limiting and exemplary pharmaceutical compositions are shown below. [Table 2]

[0163] Examples of strongly shear-thinning polymers are carboxymethyl cellulose (CMC) or methyl cellulose (MC), which are widely used in the eye and have a record of excellent safety. In one embodiment, CMC is used in the drug composition described herein to distribute the drug composition to less than 50% of SCS over a period of at least 5 to 20 days after administration. In one aspect of this embodiment, CMC has a molecular weight of about 25 to about 1500 kDa, about 100 to about 1200 kDa, or about 500 to about 1000 kDa. In another aspect of this embodiment, CMC has a molecular weight of about 600 to about 800 kDa or about 700 kDa. In another aspect of this embodiment, CMC has a molecular weight of about 50 to about 200 kDa or about 90 kDa. In one aspect of this embodiment, CMC is present in the drug composition at a concentration of about 0.5% to about 10%, about 1% to 7.5%, about 1% to about 5%, or about 1.7% (each of the foregoing is determined based on the weight-to-volume with other components of the drug composition). In another aspect, CMC has a molecular weight within the range specified above and is present in the drug composition at the percentage specified above. In another aspect, CMC has a molecular weight of about 500 to about 1000 kDa and is present at a concentration of about 1% to about 5%. In another aspect, CMC has a molecular weight of about 50 to 200 kDa and is present at a concentration of about 1% to about 5%. Such drug compositions may further contain a diluent such as HBSS, physiological saline, or water.

[0164] Regarding BCX4161, a preferred compound of the present disclosure, a non-limiting and exemplary drug composition containing CMC is shown below.

Table 3

[0165] In one embodiment, MC may be used in the pharmaceutical composition described herein to distribute the pharmaceutical composition to less than 50% of SCS over a period of at least 5 to 20 days after administration. In one aspect of this embodiment, the MC has a molecular weight of about 25 to about 1500 kDa, about 100 to about 1200 kDa, or about 500 to about 1000 kDa. In another aspect of this embodiment, the MC has a molecular weight of about 50 to about 200 kDa or about 90 kDa. In one aspect of this embodiment, the MC is present in the pharmaceutical composition at a concentration of about 0.5% to about 10%, about 1% to 7.5%, about 1% to about 6%, or about 3.0% (each of the foregoing is determined based on weight to volume with other components of the pharmaceutical composition). In another aspect, the MC has a molecular weight within the range specified above and is present in the pharmaceutical composition at the percentage specified above. In another aspect, the MC has a molecular weight of about 50 to about 200 kDa and is present at a concentration of about 1% to about 6%. Such a pharmaceutical composition may further comprise a diluent such as HBSS, saline, or water.

[0166] Regarding BCX4161, a preferred compound of the present disclosure, a pharmaceutical composition containing a non-limiting and exemplary MC is shown below.

Table 4

[0167] In some embodiments, the fluid pharmaceutical composition comprises microparticles or nanoparticles, each of which may comprise at least one compound of the present disclosure and optionally an additional therapeutic agent. When used, the microparticles or nanoparticles may enable controlled release of the compounds of the present disclosure and optionally additional therapeutic agents to the eye tissue.

[0168] The microparticles or nanoparticles may be suspended in an aqueous or non-aqueous liquid excipient. The liquid vehicle may be a pharmaceutically acceptable aqueous solution and may optionally further contain a surfactant. The microparticles or nanoparticles themselves may contain excipient substances such as polymers, polysaccharides, surfactants, etc., which are known in the art to control the kinetics of drug release from such microparticles or nanoparticles.

[0169] In certain embodiments, the pharmaceutical composition further comprises an agent for degrading components of the eye tissue. In one embodiment, the agent degrades collagen fibers or glycosaminoglycan fibers in the sclera. Agents suitable for this purpose include, but are not limited to, hyaluronidase, collagenase, or combinations thereof. Such degradation may enhance the penetration / release of the compounds of the present disclosure of the pharmaceutical composition into the eye tissue. Alternatively, the agent for degrading components of the eye tissue may be administered to the eye tissue in a step separate from the injection of the compound or pharmaceutical composition of the present disclosure. Such a separate step may precede and / or follow the injection of the compound of the present disclosure of the pharmaceutical formulation. Preferably, the agent for degrading components of the eye tissue and the compound or pharmaceutical composition of the present disclosure are administered at the same site.

[0170] In certain embodiments, the pharmaceutical composition undergoes a phase change or after injection of the pharmaceutical composition administration (preferably within 1 hour). For example, the liquid pharmaceutical composition may be injected into the suprachoroidal space through a hollow puncture member, whereupon the liquid pharmaceutical composition subsequently gels. Subsequently, the compounds of the present disclosure diffuse or are released from the gelled pharmaceutical composition to achieve controlled release of the compounds of the present disclosure. In certain aspects of this embodiment, the phase change is induced by a chemical change such as, but not limited to, a change in pH. In certain aspects of this embodiment, the phase change is induced by an external stimulus such as, but not limited to, exposure to light containing a specific wavelength of light or sound containing a specific frequency.

[0171] The volume of the pharmaceutical composition can also affect how the pharmaceutical composition diffuses into the suprachoroidal space. Generally, the smaller the volume of the administered pharmaceutical composition, the less the pharmaceutical composition diffuses from the administration site (when compared to a pharmaceutical composition of the same formulation administered in a larger volume under the same conditions). For example, when a pharmaceutical formulation (Formulation 1) containing 5 μg / μL of the compound of the present disclosure in 50 μL of HBSS and a pharmaceutical formulation (Formulation 2) containing 5 μg / μL of the compound of the present disclosure in 150 μL of HBSS are administered into the suprachoroidal space under the same conditions, Formulation 2 is expected to be distributed in a larger portion of the suprachoroidal space compared to Formulation 1.

[0172] In one embodiment, the volume of the pharmaceutical composition administered into the suprachoroidal space by the method described herein is from about 10 μL to about 200 μL, for example, without limitation, from about 50 μL to about 150 μL, 50 μL, 100 μL, or 150 μL. In another embodiment, a pharmaceutical composition of from about 50 μL to about 500 μL, for example, without limitation, from about 50 μL to about 300 μL, 200 μL, 250 μL, or 300 μL is administered into the suprachoroidal space. Such volumes may be administered by any of the devices described herein, including but not limited to devices incorporating hollow microneedles.

[0173] Treatment method The present disclosure provides an improved method for treating an eye disease or condition in a subject. In certain embodiments, the pharmaceutical composition administered by the methods provided herein achieves delivery of a compound of the present disclosure to the suprachoroidal space of the eye, such that the drug can access eye tissues, particularly posterior eye tissues, that are not accessible by topical, systemic, intraocular, or intravitreal drug delivery. As previously discussed, it is believed that when a pharmaceutical formulation enters the SCS, it flows circumferentially from the insertion site towards the retinal choroidal tissue, macula, and optic nerve in the posterior segment of the eye, as well as anteriorly towards the uvea and ciliary body. In addition, a portion of the injected pharmaceutical formulation may remain in the SCS as a depot or in tissues covering the SCS near the administration site, such as the sclera, and function as an additional depot of the compound of the present disclosure that can later diffuse into the SCS and other adjacent eye tissues, particularly posterior eye tissues.

[0174] Furthermore, the suprachoroidal drug dose sufficient to achieve a therapeutic response in a human subject treated by the methods provided herein is less than the topical, systemic, intraocular, or intravitreal drug dose sufficient to elicit the same or a substantially similar therapeutic response.

[0175] In certain embodiments, the methods provided herein enable delivery by a single administration of a pharmaceutical formulation to defined eye tissue regions, particularly defined posterior eye tissue regions, and to tissues that are more difficult to target, compared to previously known methods.

[0176] In a first embodiment, the present disclosure provides a method for treating an eye disease or condition in a subject, the method comprising non-surgically administering to the suprachoroidal space (SCS) of the subject's eye a pharmaceutical composition comprising an effective amount of a plasma kallikrein inhibitor.

[0177] In certain aspects of this embodiment, the eye disease or condition is selected from the group consisting of retinopathy, macular degeneration, uveitis, macular edema, diabetic macular edema, scleritis, retinitis, and choroiditis.

[0178] In some embodiments, macular degeneration is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy and age-related macular degeneration, potential ones without classical choroidal neovascularization (CNV) in age-related macular degeneration, Stargardt's disease, subfoveal wet age-related macular degeneration, and vitreomacular adhesion associated with neovascular age-related macular degeneration.

[0179] In certain aspects of this embodiment, retinopathy is selected from the group consisting of diabetic retinopathy, allergic retinopathy, sickle cell retinopathy, retinopathy of prematurity, or central serous retinopathy.

[0180] In certain aspects of this embodiment, the neovascular state is selected from the group consisting of abnormal ocular angiogenesis, ocular neovascularization, choroidal neovascularization, and polypoidal choroidal vasculopathy.

[0181] In certain aspects of this embodiment, the eye disease or condition is a disease or condition of the posterior eye tissue.

[0182] In certain aspects of this embodiment, the eye disease or condition is a diabetic eye disease or condition.

[0183] In a second embodiment, the present disclosure provides a method for treating a neovascular state in a subject, the method comprising non-surgically administering to the SCS of the subject's eye a pharmaceutical composition comprising an effective amount of a plasma kallikrein inhibitor.

[0184] In certain aspects of this embodiment, the neovascular state is selected from the group consisting of abnormal ocular angiogenesis, ocular neovascularization, choroidal neovascularization, and polypoidal choroidal vasculopathy.

[0185] In a third embodiment, the present disclosure provides a method for treating retinopathy in a subject, the method including non-surgically administering to the SCS of the subject's eye a drug composition comprising an effective amount of a plasma kallikrein inhibitor.

[0186] In certain aspects of this embodiment, the retinopathy is selected from the group consisting of diabetic retinopathy, hypertensive retinopathy, sickle cell retinopathy, retinopathy of prematurity, or central serous chorioretinopathy.

[0187] In a fourth embodiment, the present disclosure provides a method for treating macular degeneration in a subject, the method including non-surgically administering to the SCS of the subject's eye a drug composition comprising an effective amount of a plasma kallikrein inhibitor.

[0188] In a fifth embodiment, the present disclosure provides a method for treating diabetic retinopathy in a subject, the method including non-surgically administering to the SCS of the subject's eye a drug composition comprising an effective amount of a plasma kallikrein inhibitor.

[0189] In a sixth embodiment, the present disclosure provides a method for treating macular edema in a subject, the method including non-surgically administering to the SCS of the subject's eye a drug composition comprising an effective amount of a plasma kallikrein inhibitor.

[0190] In a seventh embodiment, the present disclosure provides a method for inhibiting plasma kallikrein activity in a subject, the method including non-surgically administering to the SCS of the subject's eye an effective amount of a drug composition comprising a plasma kallikrein inhibitor. In one aspect of the seventh embodiment, the inhibiting step is used to treat the eye disease or condition specified in the first embodiment.

[0191] In one aspect of any of the foregoing first through seventh embodiments, the subject is determined to be in need of treatment.

[0192] In one aspect of any of the first to seventh embodiments described above, the pharmaceutical composition is administered once to twelve times a year, preferably two to six times a year, more preferably two or three times a year.

[0193] In one aspect of any of the first to seventh embodiments described above, the pharmaceutical composition is administered at a dosing interval. Suitable dosing intervals include monthly, every two months, every three months, every four months, every five months, every six months, or up to every twelve months. In one aspect of any of the first to seventh embodiments described above, the pharmaceutical composition is administered at a dosing interval of three months, four months, five months, or six months (i.e., the pharmaceutical composition is administered two to four times a year).

[0194] In one aspect of any of the first to seventh embodiments described above, administration of the pharmaceutical composition provides a concentration of the disclosed compound in the SCS or ocular tissue (such as posterior ocular tissue) that exceeds the minimum therapeutic level throughout or substantially throughout the dosing interval. Such dosing intervals may be monthly, every two months, every three months, every four months, every five months, every six months, or up to every twelve months. Such minimum therapeutic levels may be from about 20 ng / ml to about 60 ng / ml, from about 30 to about 55 ng / ml, or from about 40 ng / ml to about 50 ng / ml.

[0195] In one aspect of any of the first to seventh embodiments described above, administration of the pharmaceutical composition provides a concentration of the disclosed compound in the SCS or ocular tissue (such as posterior ocular tissue) that exceeds 20 ng / ml for at least three months after administration, at least four months after administration, or at least six months after administration.

[0196] In one aspect of any of the first to seventh embodiments described above, administration of the pharmaceutical composition provides a concentration of the disclosed compound in the SCS or ocular tissue (such as posterior ocular tissue) that exceeds 30 ng / ml for at least three months after administration, at least four months after administration, or at least six months after administration.

[0197] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in SCS or eye tissue (such as posterior eye tissue) exceeding 40 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0198] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in SCS or eye tissue (such as posterior eye tissue) exceeding 50 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0199] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in SCS or eye tissue (such as posterior eye tissue) exceeding 100 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0200] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in SCS or eye tissue (such as posterior eye tissue) exceeding 250 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0201] In one aspect of the first to seventh embodiments, the present drug composition includes a polymer having moderately shear-thinning viscosity, such as but not limited to HA. In one aspect of the first to seventh embodiments, the present drug composition provides a distribution of the present drug composition that covers at least about 50%, at least about 70%, or at least about 90% of the SCS. In another aspect of the first to seventh embodiments, such a distribution occurs within 10 days of administration and is maintained for at least 20 days, at least 40 days, at least 60 days, or at least 90 days, or more after administration. In one aspect of the first to seventh embodiments, the present drug composition is as described in Table 2.

[0202] In one aspect of the first to seventh embodiments, the pharmaceutical composition includes a polymer with strong shear-thinning viscosity, such as but not limited to CMC or MC. In one aspect of the first to seventh embodiments, the pharmaceutical composition provides a distribution of the pharmaceutical composition that covers less than 50% of the SCS, less than about 35% of the SCS, or less than about 25% of the SCS. In another aspect of the first to seventh embodiments, such a distribution is limited to the period from administration to 20 days after administration. In one aspect of the first to seventh embodiments, the pharmaceutical composition is as described in Table 3 or Table 4.

[0203] In one aspect of the first to seventh embodiments, the administration of the pharmaceutical composition provides a therapeutic benefit in the treatment of eye diseases or conditions without local and / or systemic side effects.

[0204] In one aspect of the first to seventh embodiments, the compounds of the present disclosure target the posterior segment of the eye. In one aspect of the first to seventh embodiments, the compounds of the present disclosure are present at least 10 to 100 times higher in the posterior tissues of the eye compared to aqueous humor 14, 28, 56, or 84 days after administration.

[0205] In any of the foregoing aspects of the embodiments, the eye tissue is the sclera, choroid, Bruch's membrane, RPE, subretinal space, retina, macula, optic nerve head, optic nerve, ciliary body, and / or trabecular meshwork. More preferably, in any of the foregoing embodiments or aspects of the embodiments, the eye tissue is the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina.

[0206] In one aspect of any of the foregoing first to seventh embodiments, the administration of the pharmaceutical composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 20 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0207] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 30 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0208] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 40 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0209] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 50 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0210] In one aspect of any of the first to seventh embodiments described above, the administration of the present drug composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 100 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0211] In one aspect of any of the first to seventh embodiments described above, administration of the present drug composition provides a concentration of the compound of the present disclosure in the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina that exceeds 250 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

[0212] In one aspect of the first to seventh embodiments, the compound of the present disclosure is retained in eye tissues such as, but not limited to, the sclera, choroid, Bruch's membrane, RPE, retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, and / or central retina over a long period of time. For example, in some aspects, the compound of the present disclosure is retained in the eye tissue for at least about 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 90 days, or more after administration.

[0213] In one aspect of the first to seventh embodiments, the present plasma kallikrein inhibitor is a small molecule plasma kallikrein inhibitor, an inhibitory peptide, or an anti-plasma kallikrein antibody, or a fragment thereof. In one aspect of the first to seventh embodiments, the present plasma kallikrein inhibitor is a compound of formula I or a compound of formula IB. In one aspect of the first to seventh embodiments, the present plasma kallikrein inhibitor is BCX4161.

[0214] For the treatment of one or more eye diseases and conditions, the plasma kallikrein inhibitor delivered to the SCS via the methods described herein, particularly the methods of the first to seventh embodiments, can be administered together with one or more additional therapeutic agents. The one or more additional therapeutic agents may be present in the same drug composition as the present plasma kallikrein inhibitor or may be delivered in separate formulations. The one or more additional therapeutic agents may be delivered to the SCS or may be delivered to the subject intravitreally, intracamerally, topically, or systemically. In one embodiment, an angiogenesis inhibitor such as, but not limited to, a VEGF antagonist is administered to the SCS of the subject's eye in combination with the compound of the present disclosure.

[0215] Determination of Therapeutic Effect The therapeutic effect of the pharmaceutical composition delivered by the method described herein and the therapeutic response of the subject can be assayed by standard means in the art, as is known to those skilled in the art. Generally, the therapeutic effect of the pharmaceutical composition and / or compound of the present disclosure can be evaluated by measuring the response of the subject after administration of the pharmaceutical composition and / or compound of the present disclosure. The pharmaceutical composition and / or compound of the present disclosure with a high therapeutic effect will show greater symptom improvement and / or cessation than the pharmaceutical composition and / or compound of the present disclosure with a lower therapeutic effect. The therapeutic effect depends not only on the pharmaceutical formulations and compounds of the present disclosure, but also on the condition being treated and the severity of the condition being treated. In non-limiting examples, the effects of the pharmaceutical compositions provided herein can be measured, for example, by observing the intensity of pain, eye lesions (size or number), cell death, intraocular pressure, changes in inflammation (e.g., by measuring changes in the Hackett / McDonald eye score), ocular hypertension, edema, changes in retinal thickness (e.g., changes in optical coherence tomography (OCT) measurements of retinal thickness and volume), photophobia, time between flares, corneal ulcers, and / or visual acuity.

Examples

[0216] Example 1: Evaluation of PK and Ocular Tolerance of BCX4161 Suspension after Suprachoroidal Administration In this study, Dutch Belted rabbits from the Netherlands were used. A 0.5% w / v suspension of BCX4161 was prepared as shown in Table 5 below.

Table 5

[0217] A 100 μL suspension was administered to both eyes into the suprachoroidal space of the eye at a dose of 0.5 mg / eye. Except for day 28 in which 3 rabbits were treated, 2 rabbits (4 eyes) were treated at each time point. Plasma was collected at 3 hours, 1 day, 3 days, 7 days, 10 days, 14 days, 21 days, 28 days, 56 days, and 84 days after dosing. Punch tissues of aqueous humor, vitreous humor, peripheral retina, peripheral sclera / choroid / RPE, central retina, and central sclera / choroid / RPE were collected at 1 day, 7 days, 14 days, 28 days, 56 days, and 84 days after dosing. Ophthalmoscopy and intraocular pressure (IOP) were also evaluated in the anterior and posterior segments at 1 day, 7 days, 14 days, 28 days, 56 days, and 84 days after dosing. Lesions of hyperemia, conjunctival edema, secretion, turbidity, aqueous flare, cell flare, vitreous flare, retinal vasculature, retina, and choroid were evaluated at these time points.

[0218] The results of the study indicated that the 0.5% suspension of BCX4161 had good tolerability and a very favorable PK profile for at least 3 months after a single SCS injection, demonstrating that SCS administration of a plasma kallikrein inhibitor is a safe and durable treatment for the treatment of various eye diseases and conditions.

[0219] Mild conjunctival hyperemia and conjunctival edema were observed on day 1 after dosing. No adverse events were observed on days 7, 14, 28, 56, or 84 after dosing. The ophthalmoscopy score was 0 in all observations.

[0220] BCX4161 administered via SCS injection showed a favorable ocular PK profile as shown in Figures 1 - 5. High drug levels were achieved in both central and peripheral RPE / choroid / sclera (Figure 1). BCX4161 reached the optic nerve area near the macula (central RPE / choroid / sclera) and was present at high drug levels in both central and peripheral RPE / choroid / sclera for at least 84 days after SCS injection.

[0221] High levels of BCX4161 were achieved in both the central and peripheral retina (Figure 2). BCX4161 was present at high drug levels in both the central and peripheral retina for at least 84 days after SCS injection. The dotted line in Figure 2 represents the IC 99 value for the inhibition of plasma kallikrein by BCX4161 in vitro, indicating that the concentrations obtained far exceed the levels necessary for effective inhibition of plasma kallikrein. Concentrations of plasma kallikrein inhibitors that exceed the IC 99 value have previously been shown to correlate with effective treatment in vivo.

[0222] Figures 3A - C show the drug concentration of BCX4161 in the whole and selected parts of the fundus tissue. Figure 3A shows the concentration of BCX4161 in the fundus tissue, Figure 3B shows the concentration of BCX4161 in the peripheral and central RPE / choroid / sclera, and Figure 3C shows the concentration of BCX4161 in the peripheral and central retina.

[0223] BCX4161 in the vitreous humor was at moderate to low levels (Figures 4A and 4B). In addition, BCX4161 in the aqueous humor was at low levels (Figure 4C), indicating that drug exposure to the anterior segment (front) of the eye was limited. Figure 4B shows the individual data points used to generate the graph in Figure 4A, showing two outlier values on day 84. BCX4161 also showed a favorable systemic PK profile (Figure 5). Since systemic exposure was minimal or absent, the risk of systemic effects was reduced or eliminated (note that in humans, the dilution factor is much larger than that in rabbits).

[0224] All patent applications, patents, and printed publications cited in this specification are hereby incorporated by reference in their entirety, except for any definitions, disclaimers, or denials, and except where the incorporated material is inconsistent with the explicit disclosure of this specification (in which case the language of this disclosure shall govern). The described invention has been described with reference to specific embodiments, but those skilled in the art should understand that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the present disclosure. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step(s) to the purpose and scope of the described disclosure. Such modifications are intended to be within the scope of the patent claims appended hereto.

Claims

**Claim 1** A method for treating an eye disease or condition in a subject, the method comprising non-surgically administering to the suprachoroidal space (SCS) of the subject's eye an effective amount of a drug composition comprising an effective amount of a plasma kallikrein inhibitor. **Claim 2** The method of claim 1, further comprising determining that the subject is in need of treatment. **Claim 3** The method of claim 1, wherein the drug composition is administered once to twelve times per year. **Claim 4** The method of claim 1, wherein the drug composition is administered two to six times per year, or two or three times per year. **Claim 5** The method of claim 1, wherein administration of the drug composition provides a concentration of the plasma kallikrein inhibitor in the SCS or eye tissue that exceeds a minimum therapeutic level throughout or substantially throughout the dosing interval. **Claim 6** The method of claim 5, wherein the dosing interval is monthly, every two months, every three months, every four months, every five months, every six months, or up to every twelve months, and the minimum therapeutic level is from about 20 ng / ml to about 60 ng / ml. **Claim 7** The method of claim 5, wherein the eye tissue is posterior eye tissue. **Claim 8** The method of claim 8, wherein the posterior eye tissue is sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, central retina, or a combination of the foregoing. **Claim 9** The method of claim 1, wherein administration of the drug composition provides a concentration of the plasma kallikrein inhibitor in the SCS or eye tissue that exceeds 20 ng / ml for at least three months, at least four months, or at least six months after administration. **Claim 10** The method of claim 9, wherein the eye tissue is posterior eye tissue. **Claim 11** The method of claim 10, wherein the posterior eye tissue is sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, central retina, or a combination of the foregoing. **Claim 12** The method of claim 1, wherein administration of the drug composition provides a concentration of the plasma kallikrein inhibitor in the SCS or eye tissue that exceeds 50 ng / ml for at least three months, at least four months, or at least six months after administration. **Claim 13** The method according to claim 12, wherein the eye tissue is posterior eye tissue.

14. The method according to claim 13, wherein the posterior eye tissue is sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, central retina, or a combination of the foregoing.

15. The method according to claim 1, wherein administration of the pharmaceutical composition provides a concentration of the plasma kallikrein inhibitor in the SCS or eye tissue that exceeds 100 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

16. The method according to claim 15, wherein the eye tissue is posterior eye tissue.

17. The method according to claim 16, wherein the posterior eye tissue is sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, central retina, or a combination of the foregoing.

18. The method according to claim 1, wherein administration of the pharmaceutical composition provides a concentration of the plasma kallikrein inhibitor in the SCS or eye tissue that exceeds 250 ng / ml for at least 3 months, at least 4 months, or at least 6 months after administration.

19. The method according to claim 18, wherein the eye tissue is posterior eye tissue.

20. The method according to claim 19, wherein the posterior eye tissue is sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), retina, macula, peripheral RPE, peripheral choroid, peripheral sclera, peripheral retina, central RPE, central choroid, central sclera, central retina, or a combination of the foregoing.

21. The method according to claim 1, wherein the volume of the pharmaceutical composition administered is from about 10 μL to about 200 μL.

22. The method according to claim 1, wherein administration of the pharmaceutical composition provides a therapeutic benefit in the treatment of the eye disease or condition without local or systemic side effects.

23. The drug composition has a viscosity of less than 100 Pa·s at a shear rate of 0.01 s －１ The method according to claim 1, wherein the viscosity is less than 100 Pa·s at a shear rate of 0.01 s

24. The drug composition has a viscosity of less than 100 Pa·s at a shear rate of 0.01 s －１ and is 50 Pa·s or more at a shear rate of 1.0 s －１ The method according to claim 23.

25. The method according to claim 23, wherein the pharmaceutical composition provides an extension of the pharmaceutical composition that covers at least about 50% of the SCS.

26. The drug composition has a viscosity of 100 Pa·s or more at a shear rate of 0.01 s －１ according to the method of claim 1.

27. The method according to claim 26, wherein the pharmaceutical composition provides an extension of the pharmaceutical composition that covers at least about 50% of the SCS.

28. The method according to claim 1, wherein the effective amount of the plasma kallikrein inhibitor in the drug composition is in the range of about 0.01 mg to about 20 mg.

29. The method according to claim 1, wherein the effective amount of the plasma kallikrein inhibitor in the drug composition is in the range of about 0.1 mg to about 10 mg.

30. The method according to claim 1, wherein the effective amount of the plasma kallikrein inhibitor in the drug composition is in the range of about 0.1 mg to about 1 mg.

31. The method according to claim 1, wherein the eye disease or condition affects the posterior segment of the eye.

32. The method according to claim 1, wherein the eye disease or condition is a diabetic eye disease.

33. The method according to claim 1, wherein the eye disease or condition consists of diabetic retinopathy or diabetic macular edema.

34. The method according to claim 1, wherein the eye disease or condition is retinopathy, macular degeneration, uveitis, macular edema, diabetic macular edema, scleritis, retinitis, or choroiditis.

35. The method according to claim 1, wherein the macular degeneration is age-related macular degeneration, dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular macular degeneration and age-related macular degeneration, potential ones without classical choroidal neovascularization in age-related macular degeneration, Stargardt's disease, subfoveal wet age-related macular degeneration, or vitreomacular adhesion associated with neovascular age-related macular degeneration.

36. The method according to claim 1, wherein the retinopathy is diabetic retinopathy, allergic retinopathy, sickle cell retinopathy, retinopathy of prematurity, or central serous chorioretinopathy.

37. The method according to claim 1, wherein the neovascular state is selected from the group consisting of abnormal ocular neovascularization, ocular neovascularization, choroidal neovascularization, or polypoidal choroidal vasculopathy.

38. The method according to claim 1, wherein the eye disease or condition consists of diabetic retinopathy or diabetic macular edema.

39. The method according to claim 1, wherein the drug composition is administered to the SCS of the eye via a hollow microneedle.

40. The method according to claim 1, further comprising administering an additional therapeutic agent.

41. The plasma kallikrein inhibitor is a compound of formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 【Chemical 1】 wherein, X is CH or N, Y is CH or N, A is -H, -R, -NO ２ , -CN, -halo, -N ３ , -C １－８ alkyl, -(CH ２ ) ｎ CO ２ R ２ , -C ２－８ alkenyl-CO ２ R ２ , -O(CH ２ ) ｎ CO ２ R ２ , -C(O)NR ２ R ３ , -C(O)NH-(CH ２ ) ｎ -cycloalkyl, -C(O)NH-alkyl, -C(O)NR ２ -C １ -C ５ alkyl, -C(O)NR ２ -(CH ２ ) ｎ -C ３ -C ６ cycloalkyl, -P(O)(OR ２ ) ２ , -(CH ２ ) ｎ O(CH ２ ) ｎ aryl, -NR ２ R ３ , -(CH ２ ) ｎ OR ２ , -(CH ２ ) ｎ SR ２ , -N(R ２ )C(O)R ３ , -S(O ２ )NR ２ R ３ , -N(R ２ )S(O ２ )R ３ , -(CHR ２ ) ｎ NR ２ R ３ , -C(O)R ３ , -(CH ２ ) ｎ N(R ３ )C(O)R ３ , -N(R ２ )CR ２ R ３ , or substituted or unsubstituted (CH ２ ) ｎ -cycloalkyl, and B is H, -halo, -CN, -NH ２ , -(CH ２ ) ｎ -C(=NR ４ )NHR ５ , -C(=NH)NH ２ , -(CH ２ ) ｎ -NHR ４ , -(CH ２ ) ｎ NH-C(=NR ４ )NR ５ , -(CH ２ )n-OR ４ , C １－８ substituted or C １－８ unsubstituted alkyl, and Z is a direct bond, O, S, NR ２ , S(O), S(O ２ ), or N(O) containing one or two C １－４ substituted or unsubstituted methylene chains or substituted or unsubstituted C １－４ methylene chains, and W is a direct bond, -CHR ２ -, -CH=CR ２ -, -CR ２ =CH-, -CR ２ =CR ２ -, -C≡C-, -O-CHR ２ -, -CHR ２ -O-, -N(R ２ ), -C(O)-, -C(O)-N(R ２ ), -C(O)-NH-, -N(R ２ ), -N(R ３ )-CH-(R ２ )-NH-, -CH ２ -NH-, -CH ２ )-N(R １ ), -CH(R ２ ), -N(R ２ )-, -CHR ２ )-S-, -S(O ２ ), -N(R ２ ), -C(O)N(R ２ )-(CHR ２ ) ｎ )-, -C(R １ R ２ ) ｎ -NR ２ )-, -N(R ２ ), -S(O ２ ), -R ２ C(O)NR ２ ), -R ２ NC(O)NR ２ ), -CONR ２ CO-, -C(=NR ２ ), -NR ２ ), -NR ２ C(=NR ２ ), -NR ２ ), -NR ２ O, -N=NCHR ２ ), or -C(O)NR ２ SO ２ -, and V is R １ selected from R is -CH=CH-R ２ , -C≡C-R ２ , -C(R ２ )=CH ２ , -CH=CH ２ , -C(R ２ )=C(R ３ ), -CH=NR ２ , or -C(R ２ )=N-R ３ wherein R １ is -H, -R, -NO ２ , -CN, -halo, -N ３ , -C １－８ alkyl, -(CH ２ ) ｎ CO ２ R ２ , -C ２－８ alkenyl-CO ２ R ２ , -O(CH ２ ) ｎ CO ２ R ２ , -C(O)NR ２ R ３ , -P(O)(OR ２ ) ２ , -(CH ２ ) ｎ O(CH ２ ) ｎ aryl, -NR ２ R ３ , -(CH ２ ) ｎ OR ２ , -O-C １ -C ４ alkyl, -C １－４ alkoxy, -OCH ３ , -(CH ２ ) ｎ SR ２ , -N(R ２ )C(O)R ３ , -S(O ２ )NR ２ R ３ , -N(R ２ )S(O ２ )R ３ , -(CHR ２ ) ｎ NR ２ R ３ , -C(O)R ３ , -C(O)OH, -(CH ２ ) ｎ N(R ３ )C(O)R ３ , or -N(R ２ )CR ２ R ３ and R ２ is H, -halo, -alkyl, -haloalkyl, -CO(CHR １ ) ｎ -OR １ , -(CHR １ ) ｎ -NH-CO-R １ , -(CHR １ ) ｎ -NH-SO ２ R １ , -(CHR １ ) ｎ -C(O)(CHR １ )-NHR １ , -(CHR １ ) ｎ -C(S)(CHR １ )-NHR １ , -(CH ２ ) ｎ O(CH ２ ) ｎ CH ３ , -CF ３ , -C ２－５ acyl, -(CHR １ ) ｎ OH, -(CHR １ ) ｎ CO ２ R １ , -(CHR １ ) ｎ -O-alkyl, -O(CHR １ ) ｎ -O-(CH ２ ) ｎ -O-alkyl, -(CHR １ ) ｎ -S-alkyl, -(CHR １ ) ｎ -S(O)-alkyl, -(CHR １ ) ｎ -S(O ２ )-alkyl, -(CHR １ ) ｎ -S(O ２ )-NHR ３ , -(CHR ３ ) ｎ -N ３ , -(CHR ３ ) ｎ NHR ４ , an alkene chain having 2 to 8 carbon atoms with 1 to 5 double bonds, an alkyne chain having 2 to 8 carbon atoms with 1 to 5 triple bonds, or a substituted or unsubstituted -(CHR ３ ) ｎ which is cycloalkyl, R ３ is -H, -OH, -CN, substituted alkyl, -C ２－８ alkenyl, -(CH ２ ) ｎ -cycloalkyl, substituted or unsubstituted cycloalkyl, -N(R １ )R ２ or a 5- to 6-membered saturated substituted or unsubstituted heterocyclic ring, R ４ and R ５ are each, independently, H, -(CH ２ ) ｎ OH, -C(O)OR ６ , -C(O)SR ６ , -(CH ２ ) ｎ C(O)NR ７ R ８ , or -O-C(O)-O-R ７ and each R ６ is H, R ７ , -C(R ７ )(R ８ )-(CH ２ ) ｎ - -O-C(O)-R ９ ,-(CH ２ ) ｎ -C(R ７ )(R ８ )-O-C(O)R ９ ,-(CH ２ ) ｎ -C(R ７ )(R ８ )-O-C(O)-O-R ９ or -C(R ７ )(R ８ )-(CH ２ ) ｎ -O-C(O)-O-R ９ and Each R ７ , R ８ , and R ９ is, individually, H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, or CH ２ CO ２ alkyl, The method according to any one of claims 1 to 40, wherein n is an integer from 0 to 4.

42. R is CH=CH ２ The method according to claim 41, wherein R is CH=CH and V is C(O)OH.

43. R １ is H or -OCH ３ The method according to claim 42, wherein

44. The plasma kallikrein inhibitor is a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [Chemical Formula 2] wherein X is CH or N, Y is CH or N, R is -CH=CH-R ２ , -C≡C-R ２ , -C(R ２ )=CH ２ , -CH=CH ２ , -C(R ２ )=C(R ３ ), -CH=NR ２ , or -C(R ２ )=N-R ３ wherein R １ is -H, -R, -NO ２ , -CN, -halo, -N ３ , -C １－８ alkyl, -(CH ２ ) ｎ CO ２ R ２ , -C ２－８ alkenyl-CO ２ R ２ , -C ２－４ alkoxy, -O(CH ２ ) ｎ CO ２ R ２ , -C(O)NR ２ R ３ , -NR ２ R ３ , -(CH ２ ) ｎ OR ２ , -C(O)OH, -O-C １ -C ３ alkyl, -OCH ３ , N(R ２ )C(O)R ３ , or -(CHR ２ ) ｎ and V is independently selected from R １ and R １０ is -(CH ２ )-cyclopropyl or -isobutyl, and R １１ is hydrogen or =O, R ２ is H, -halo, -alkyl, -haloalkyl, -CO(CHR １ ), ｎ -OR, １ -(CHR １ ), ｎ -NH-CO-R, １ -(CHR １ ), ｎ -NH-SO ２ R, １ -(CHR １ ), ｎ -C(O)(CHR １ )-NHR, １ -(CHR １ ), ｎ -C(S)(CHR １ )-NHR, １ -(CH ２ ), ｎ O(CH ２ ), ｎ CH, ３ -CF, ３ -C, ２－５ acyl, -(CHR １ ), ｎ OH, -(CHR １ ), ｎ CO, ２ R, １ -(CHR １ ), ｎ -O-alkyl, -O(CHR １ ), ｎ -O-(CH ２ ), ｎ -O-alkyl, -(CHR １ ), ｎ -S-alkyl, -(CHR １ ), ｎ -S(O)-alkyl, -(CHR １ ), ｎ -S(O ２ )-alkyl, -(CHR １ ), ｎ -S(O ２ )-NHR, ３ -(CHR ３ ), ｎ -N, ３ -(CHR ３ ), ｎ NHR, ４ , an alkene chain having 2 to 8 carbon atoms and 1 to 5 double bonds, an alkyne chain having 2 to 8 carbon atoms and 1 to 5 triple bonds, or a substituted or unsubstituted -(CHR ３ ) ｎ which is cycloalkyl, R ３ is -H, -OH, -CN, substituted alkyl, -C ２－８ alkenyl, -(CH ２ ) ｎ -cycloalkyl, substituted or unsubstituted cycloalkyl, -N(R １ )R ２ or a 5- to 6-membered saturated substituted or unsubstituted heterocyclic ring, The method according to any one of claims 1 to 40, wherein n is an integer from 0 to 4.

45. R is -CH=CH ２ where V is -C(O)OH, Y is N, R １０ is -(CH ２ )-cyclopropyl, R １１ is =O, X is C, R １ is -OCH ３ and the method according to claim 44.

46. R is -CH=CH ２ where V is -C(O)OH, Y is N, R １０ is -(CH ２ )-cyclopropyl, R １１ is =O, X is C, R １ is H, the method according to claim 44.

47. R is -CH=CH ２ wherein V is -C(O)OH, Y is N, R １０ is -isobutyl, R １１ is =O, X is C, R １ is H, the method according to claim 44.

48. R is -CH=CH ２ wherein V is -C(O)OH, Y is C, R １０ is -isobutyl, R １１ is H, X is N, R １ is H, the method according to claim 44.

49. The method according to any one of claims 1 to 40, wherein the plasma kallikrein inhibitor is an inhibitory peptide.

50. The method according to any one of claims 1 to 40, wherein the plasma kallikrein inhibitor is an anti-kallikrein antibody or a fragment thereof.

51. The method according to any one of claims 1 to 40, wherein the plasma kallikrein inhibitor is a small molecule.

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