Drug delivery system for treating glaucoma or ocular hypertension

Abstract

The present disclosure relates to a drug delivery system comprising an intraocular pressure lowering agent, a neurotrophic agent such as a CNTF compound, a C-type natriuretic peptide (CNP) compound, a Tie-2 agonist, a natriuretic peptide receptor-B (NPR-B) compound, or an apoptosis signaling fragment inhibitor (FAS) or a FAS-ligand (FASL) inhibitor, any combination comprising these compounds, and a sustained release component. Methods, medicaments, kits, uses and methods of manufacture for treating glaucoma or related conditions are also described.

Description

[0001] This application is a divisional application of application number 202080097040.6 filed on December 17, 2020, and the invention name is a drug delivery system for treating glaucoma or ocular hypertension, comprising an intraocular pressure reducer, a neurotrophic agent, a C-type natriuretic peptide, a natriuretic peptide receptor-B, an apoptosis signaling fragment inhibitor or a FAS-ligand inhibitor.

[0002] Sequence Listing

[0003] This application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. This ASCII copy was created on December 16, 2020, is named C4019_10001WO02_SL.txt, and is 5,282 bytes in size. Summary of the invention

[0004] The present disclosure relates to a drug delivery system, comprising: an intraocular pressure reducer, a neurotrophic agent (such as a CNTF compound), a C-type natriuretic peptide (CNP) compound, a Tie-2 agonist, a natriuretic peptide receptor-B (NPR-B) compound, a TNF-α / TNFR inhibitor, or an inhibitor of apoptosis signaling fragment (FAS) or a FAS-ligand (FASL) inhibitor, including any combination of these compounds, and a sustained-release component. This type of drug delivery system can be used to treat glaucoma or ocular hypertension.

[0005] Some embodiments include a drug delivery system comprising: a first active pharmaceutical ingredient (API) and a sustained-release component, wherein the first API is an intraocular pressure reducing agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor-B (NPR-B), a TNF-α / TNFR inhibitor, an apoptosis signaling fragment (FAS) inhibitor or a FAS-ligand (FASL) inhibitor, or a combination thereof.

[0006] Some embodiments include a method of treating glaucoma comprising administering a drug delivery system described herein to a mammal suffering from glaucoma or ocular hypertension.

[0007] Some embodiments include use of an IOP reducing agent, a neurotrophic agent, CNP, NPR-B, a TNF-α / TNFR inhibitor, a FAS inhibitor, or a FASL inhibitor, or a combination thereof in the manufacture of a drug delivery system described herein for treating glaucoma or ocular hypertension.

[0008] Some embodiments include a kit comprising a drug delivery system described herein and a label with instructions for using the drug delivery system for treating glaucoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1A IOP intraocular pressure of African green monkey B102 after administration of 100 ng and 200 ng bimatoprost acid by intravitreal injection compared to PBS in the fellow eye in relation to some examples described herein.

[0010] Figure 1B IOP intraocular pressure of African green monkey B107 after administration of 100 ng and 200 ng bimatoprost acid by intravitreal injection compared to PBS in the fellow eye in relation to some examples described herein.

[0011] Figure 1C IOP intraocular pressure of African green monkey B392 after administration of 100 ng and 200 ng bimatoprost acid by intravitreal injection compared to PBS in the fellow eye in relation to some examples described herein.

[0012] Figure 1D IOP intraocular pressure of African green monkey B300 after administration of 100 ng and 200 ng bimatoprost acid by intravitreal injection compared to PBS in the fellow eye in relation to some examples described herein.

[0013] Figure 2 % reduction in intraocular pressure (IOP) in African green monkeys following intravitreal injection administration of 100 ng and 200 ng of bimatoprost acid compared to PBS in the fellow eye in relation to some examples described herein. DETAILED DESCRIPTION

[0014] For drug delivery systems comprising an intraocular pressure reducing agent, a neurotrophic agent (such as a CNTF compound), a CNP compound, an NPR-B compound, or a FAS or FASL inhibitor and a sustained release component (referred to herein as a "subject drug delivery system"), any suitable prostaglandin receptor agonist, prostanoid receptor agonist, or any suitable prostaglandin compound can be used, including any prostaglandin acid form (e.g., an acid obtained by hydrolysis of a prostaglandin ester), any prostaglandin salt form, or any prostaglandin ester prodrug. Examples include: bimatoprost (amide) or bimatoprost acid (i.e., a carboxylic acid obtained when the amide group is hydrolyzed), travoprost, travoprost acid, latanoprost, latanoprost acid, nitrolatanoprost, tafluprost, tafluprost acid, etc., prostaglandin EP2 agonists, prostaglandin EP3 agonists, nitric oxide donor prostaglandin compounds (such as latanoprostene bunod), or combinations thereof.

[0015] Any suitable amount of a prostaglandin compound, such as bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, nitrolatanoprost, tafluprost, tafluprost acid, etc., a prostaglandin EP2 agonist, or a prostaglandin EP3 agonist, can be used in a drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90-100 μg, about 0.010-30 μg, about 30-60 μg, about 60-100 μg, about 0.01-100 μg, about 0.010-100 μg, about 100- 200μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the compound of formula 1 or formula 3 can be used to describe a kind of prostaglandin compound of formula 1 or formula 3. The compound of formula 1 or formula 3 can be used to describe a kind of prostaglandin compound of formula 1 or formula 3. The compound of formula 1 or formula 3 can be used to describe a kind of prostaglandin compound of formula 1 or formula 3.

[0016] The use of the above amounts of prostaglandin compounds (such as bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, nitrolatanoprost, tafluprost, tafluprost acid, etc., prostaglandin EP2 agonists or prostaglandin EP3 agonists) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of prostaglandin compounds for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0017]

[0018] In some embodiments, the prostaglandin receptor agonist, the prostaglandin receptor agonist or the prostaglandin compound is bimatoprost (amide) or bimatoprost acid. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is travoprost. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is travoprost acid. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is latanoprost. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is latanoprost acid. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is nitrolatanoprost. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is tafluprost. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is tafluprost acid. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is a prostaglandin EP2 receptor agonist. In some embodiments, the prostaglandin receptor agonist or the prostaglandin compound is a prostaglandin EP3 receptor agonist.

[0019] Some subject drug delivery systems may include intraocular pressure reducers, such as beta blockers, alpha receptor agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, cannabinoid receptor agonists, etc. Some subject drug delivery systems may include two or more intraocular pressure reducers, such as prostaglandin compounds, prostaglandin receptor agonists or prostanoid receptor agonists; beta blockers; alpha receptor agonists; carbonic anhydrase inhibitors; cannabinoid receptor agonists; Rho kinase inhibitors, etc. Some subject drug delivery systems contain two or more of the following: prostaglandin receptor agonists (or prostaglandin compounds or prostanoid receptor agonists), beta blockers, alpha receptor agonists, carbonic anhydrase inhibitors, cannabinoid receptor agonists, Rho kinase inhibitors, etc.

[0020] For the main drug delivery system, any suitable beta blocker or any suitable beta adrenergic antagonist can be used. Examples include timolol, betaxolol, levobunolol, metipranolol, etc., or a combination thereof. In some embodiments, the beta blocker is timolol. In some embodiments, the beta blocker is betaxolol. In some embodiments, the beta blocker is levobunolol. In some embodiments, the beta blocker is metipranolol.

[0021] Any suitable amount of beta-blockers or beta-adrenergic antagonists, such as timolol, betaxolol, levobunolol, metipranolol, can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.01-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0022] The use of the above amounts of a beta blocker or beta adrenergic antagonist (such as timolol, betaxolol, levobunolol or metipranolol) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of a beta blocker or beta adrenergic antagonist for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0023] For the main drug delivery system, any suitable alpha receptor agonist or alpha adrenergic agonist can be used. Examples include brimonidine, apraclonidine, etc., or a combination thereof. In some embodiments, the alpha receptor agonist is brimonidine. In some embodiments, the alpha receptor agonist is apraclonidine.

[0024] Any suitable amount of alpha receptor agonist or alpha adrenergic agonist, such as brimonidine, apraclonidine, etc., can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0025] The use of the above amounts of alpha receptor agonists or alpha adrenergic agonists (such as brimonidine, apraclonidine, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of alpha receptor agonists or alpha adrenergic agonists for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0026] For the main drug delivery system, any suitable carbonic anhydrase inhibitor can be used. Examples include brinzolamide, acetazolamide, dorzolamide, methazolamide, etc., or a combination thereof. In some embodiments, the carbonic anhydrase inhibitor is brinzolamide. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide. In some embodiments, the carbonic anhydrase inhibitor is dorzolamide. In some embodiments, the carbonic anhydrase inhibitor is methazolamide.

[0027] Any suitable amount of carbonic anhydrase inhibitor, such as brinzolamide, acetazolamide, dorzolamide, methazolamide, etc., can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0028] The use of the above amounts of a carbonic anhydrase inhibitor (e.g., brinzolamide, acetazolamide, dorzolamide, methazolamide, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of a carbonic anhydrase inhibitor for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years, or longer.

[0029] For the main drug delivery system, any suitable cholinergic can be used. Examples include pilocarpine, carbachol, etc., or a combination thereof. In some embodiments, the cholinergic can be pilocarpine. In some embodiments, the cholinergic can be carbachol.

[0030] Any suitable amount of cholinergic drugs, such as pilocarpine, carbachol, etc., can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0031] The use of the above amounts of cholinomimetic drugs (such as pilocarpine, carbachol, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of cholinomimetic drugs for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0032] For the subject drug delivery system, any suitable Rho kinase inhibitor may be used, such as netarsudil. In some embodiments, the Rho kinase inhibitor is netarsudil.

[0033] Any suitable amount of a Rho kinase inhibitor, such as nafacil, can be used in a drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0034] The use of the above amounts of a Rho kinase inhibitor (such as nepacidil) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of a Rho kinase inhibitor for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years, or longer.

[0035] For the subject drug delivery system, any suitable Tie-2 agonist may be used, such as angiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4, and the like.

[0036] Any suitable amount of Tie-2 agonist, such as angiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4, etc., can be used in a drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0037] The use of the above amounts of Tie-2 agonists (such as Angiopoietin-1, Angiopoietin-2, Angiopoietin-3, Angiopoietin-4, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of Tie-2 agonists for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0038] For the subject drug delivery system, the neurotrophic agent may include a CNTF compound or another neurotrophic agent, and the CNTF compound includes any compound having a structure or activity similar to ciliary neurotrophic factor (CNTF), including CNTF, a protein derivative of CNTF, or a CNTF peptide. Examples include CNTF (peptides containing a portion of the CNTF sequence), such as neurotrophic peptides containing the sequence DGGL (SEQ ID NO: 20), for example, peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1)) and peptide 21 (P21; Ac-DGGL A G-NH2 (SEQ ID NO: 2)), recombinant CNTF (rhCNTF), or the neurotrophic peptides identified in U.S. Pat. No. 8,592,374, which is incorporated herein by reference for its disclosure related to neurotrophic peptides, including neurotrophic peptides having a solid group at the C- and / or N-terminus, or any other peptide having biological activity similar to CNTF. Other neurotrophic agents include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), etc., or derivatives thereof.

[0039] Any suitable amount of neurotrophic agent, such as CNTF compound, NGF, BDNF, GDNF, etc., can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0040] The use of the above amounts of neurotrophic agents (e.g., CNTF compounds, NGF, BDNF, GDNF, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of neurotrophic agents for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years, or longer.

[0041] For the subject drug delivery system, CNP compounds include any compound having a structure or activity similar to C-type natriuretic peptide, including native C-type natriuretic peptide.

[0042] Any suitable amount of CNP compound, such as natural CNP, can be used in a drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-2 00μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.0 In some embodiments, the present invention relates to a compound of the present invention, wherein the amount of the compound is about 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0043] The use of the above amounts of CNP compounds (such as native CNP) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of CNP compounds for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0044] For the subject drug delivery system, NPR-B compounds include any compound having a structure or activity similar to that of natriuretic peptide receptor-B, including native natriuretic peptide receptor-B.

[0045] Any suitable amount of NPR-B compound, such as native NPR-B, can be used in a drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg. , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-20 0μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.00 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0046] The use of the above amounts of NPR-B compounds (such as native NPR-B) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of NPR-B compounds for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0047] Useful FAS or FASL inhibitors include: bicyclol, FLIP; MET12 (HHIYLGAVNYIY (SEQ ID NO: 3), HHIYLGATNYIY (SEQ ID NO: 4) or H 60 HIYLGATNYIY 71(SEQ ID NO: 4)), or a shorter fragment thereof, such as a tetramer having the sequence YLGA (SEQ ID NO: 5), or a fragment having sequence homology (at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% sequence homology to MET12), including compounds having the sequences shown in Table 1 below, such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 or Compound 11, MET4-8 (YLGA (SEQ ID NO: 5)), YLGAV (SEQ ID NO: 7), IYLGA (SEQ ID NO: 6), HIYLGA (SEQ ID NO: 8), IYLGAV (SEQ ID NO: 9), YLGAVN (SEQ ID NO: 16), IYLGAVN (SEQ ID NO: 11), HIYLGAV (SEQ ID NO: 12), NO: 10) or HIYLGAVN (SEQ ID NO: 17), MET4 (YLGA (SEQ ID NO: 5)), MET5 (YLGAV (SEQ ID NO: 7) and / or IYLGA (SEQ ID NO: 6)), MET6 (HIYLGA (SEQ ID NO: 8), IYLGAV (SEQ ID NO: 9), YLGAVN (SEQ ID NO: 16) and / or IYLGAVN (SEQ ID NO: 11)), MET7 (IYLGAVN (SEQ ID NO: 11) and / or HIYLGAV (SEQ ID NO: 10)), MET8 (HIYLGAVN (SEQ ID NO: 17)), (ONL1204 (e.g., a peptide comprising or consisting of the sequence HHIYLGATNYIY (SEQ ID NO: 4)); other MET12 derivatives, such as compounds having the following sequence: H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4), FAS apoptosis inhibitory molecule [FAIM]; NOL3 [nucleolar protein 3 (apoptosis inhibitor with CARD domain [ARC]) etc.]; DCR1; DCR2; or DCR3.

[0048]

[0049] Table 1

[0050] compound sequence SEQ ID NO: 1 RUN 5 2 FOR THE YEAR 6 3 RUNNING 7 4 TRICK 8 5 IYLGAV 9 6 Cunning 10 7 IYLGAVN 11 8 FOR THE DAY 12 9 FAST 13 10 HHIYLGAV 14 11 FAST 15

[0051] Any suitable amount of a FAS or FASL inhibitor, such as bicyclol, FLIP, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 or Compound 11, ONL1204, H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, DcR3, etc. can all be used in drug delivery systems. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10-20 μg , about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100μg, about 100-20 0μg, about 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 0.01-300μg, about 300-600μg, about 600-1000μg, about 0.00 0.01-1 mg, about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg or about 0.01-10 mg of one of these compounds. These amounts can also be applied to situations where the drug is present in a covalently bonded form, such as covalently bonded to another drug or a sustained release component.

[0052] The above amount of FAS or FASL inhibitor (such as bicyclol, FLIP, compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10 or compound 11, ONL1204, H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, DcR3, etc.) can provide a drug delivery system that provides therapeutic levels of NPR-B compounds for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0053] Useful TNF-α or TNFR inhibitors include etanercept, infliximab, golimumab, certolizumab, adalimumab, TNFR1 selective antagonist mutant TNF (R1antTNF), DMS5540, TNF Receptor-One Silencer (TROS), and ATROSAB.

[0054] Any suitable amount of TNF-α or TNFR inhibitor, such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, ATROSAB, etc., can be used in the drug delivery system. For example, a drug delivery system can contain about 0.01-1 μg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 0.01-3 μg, about 3-6 μg, about 6-10 μg, about 0.01-10 μg, about 10 -20μg, about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0.01-30μg, about 30-60μg, about 60-100μg, about 0.01-100μg, about 0.1-100

[0047] The present invention relates to one of the compounds of the present invention. The present invention relates to one of the compounds of the present invention. These amounts may also apply where the drug is present in a covalently bonded form, such as to another drug or to a sustained release component.

[0055] The use of the above amounts of TNF-α or TNFR inhibitors (such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, ATROSAB, etc.) in a drug delivery system can provide a drug delivery system that provides therapeutic levels of TNF-α or TNFR inhibitors for about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-5 years, about 5-10 years or longer.

[0056] Table 2 below describes drug combinations of particular interest in the subject drug delivery system.

[0057] Table 2

[0058]

[0059]

[0060]

[0061] PG: prostaglandin compound or prostaglandin receptor agonist, including acid, salt and ester or ester prodrug forms

[0062] Some drug delivery systems include a combination of bimatoprost acid and bicyclol, wherein each is covalently bonded directly, bonded to a linker, or wherein both are bonded to a polymer or silicon-based drug delivery particle. Some drug delivery systems include a combination of bimatoprost acid and bicyclol, which are not bound to each other, nor to a polymer or silicon-based drug delivery particle.

[0063] For the subject drug delivery system comprising a prostaglandin receptor agonist or a prostaglandin compound and an intraocular pressure reducing agent, in some embodiments, the prostaglandin receptor agonist is covalently bonded to the intraocular pressure reducing agent. In some embodiments, the prostaglandin receptor agonist is covalently bonded to the intraocular pressure reducing agent via a linker.

[0064] For example, some compounds containing a prostaglandin compound or a prostaglandin receptor agonist covalently bonded to an intraocular pressure reducing agent via a linker are represented by Formula 1 or 1A:

[0065] PG-L-IOP

[0066] Formula 1

[0067] IOP-L-IOP

[0068] Formula 1A

[0069] Wherein, PG-H or PG-OH is a prostaglandin receptor agonist, such as the above-mentioned prostaglandin compound or prostaglandin receptor agonist; and each IOP-H or IOP-OH is independently an intraocular pressure reducer, such as the above-mentioned intraocular pressure reducer.

[0070] For a subject drug delivery system comprising a prostaglandin receptor agonist and a neurotrophic agent (such as a CNTF compound), in some embodiments, the prostaglandin receptor agonist and the neurotrophic agent (such as a CNTF compound) are covalently bonded to each other. In some embodiments, the prostaglandin receptor agonist and the neurotrophic agent (such as a CNTF compound) are covalently bonded to each other via a linker.

[0071] Some subject drug delivery systems include an intraocular pressure reducing agent and a neurotrophic agent (e.g., a CNTF compound). In some embodiments, the intraocular pressure reducing agent and the neurotrophic agent (e.g., a CNTF compound) are covalently bonded to each other. In some embodiments, the intraocular pressure reducing agent and the neurotrophic agent (e.g., a CNTF compound) are covalently bonded to each other via a linker.

[0072] Some subject drug delivery systems include an intraocular pressure reducing agent and a CNP compound. In some embodiments, the intraocular pressure reducing agent and the CNP compound are covalently bonded to each other. In some embodiments, the intraocular pressure reducing agent and the CNP compound are covalently bonded to each other via a linker.

[0073] Some subject drug delivery systems include an intraocular pressure reducing agent and an NPR-B compound. In some embodiments, the intraocular pressure reducing agent and the NPR-B compound are covalently bonded to each other. In some embodiments, the intraocular pressure reducing agent and the NPR-B compound are covalently bonded to each other via a linker.

[0074] Some subject drug delivery systems include a neurotrophic agent (e.g., a CNTF compound) and a CNP compound. In some embodiments, the neurotrophic agent (e.g., a CNTF compound) and the CNP compound are covalently bonded to each other. In some embodiments, the neurotrophic agent (e.g., a CNTF compound) and the CNP compound are covalently bonded to each other via a linker.

[0075] Some subject drug delivery systems include a neurotrophic agent (e.g., a CNTF compound) and an NPR-B compound. In some embodiments, the neurotrophic agent (e.g., a CNTF compound) and the NPR-B compound are covalently bonded to each other. In some embodiments, the neurotrophic agent (e.g., a CNTF compound) and the NPR-B compound are covalently bonded to each other via a linker.

[0076] Some subject drug delivery systems include a CNP compound and an NPR-B compound. In some embodiments, the CNP compound and the NPR-B compound are covalently bonded to each other. In some embodiments, the CNP compound and the NPR-B compound are covalently bonded to each other via a linker.

[0077] For example, some compounds containing a prostaglandin compound or a prostaglandin receptor covalently bonded to a CNTF compound via a linker are represented by Formula 2:

[0078] PG-L-CNTF

[0079] Formula 2

[0080] Wherein, PG-H or PG-OH is a prostaglandin receptor agonist, such as the above-mentioned prostaglandin compound or prostaglandin receptor agonist; and CNTF-H or CNTF-OH is a CNTF compound, such as the above-mentioned CNTF compound.

[0081] Other covalently linked compounds include compounds represented by Formula 2A, 2B, 2C, 2D, 2E or 2F:

[0082] IOP-L-CNTF

[0083] Formula 2A

[0084] IOP-L-CNP

[0085] Formula 2B

[0086] IOP-L-NPRB

[0087] Formula 2C

[0088] CNTF-L-CNP

[0089] Formula 2D

[0090] CNTF-L-NPRB

[0091] Formula 2E

[0092] CNP-L-NPRB

[0093] Formula 2F

[0094] Among them, IOP-H is an intraocular pressure reducer, such as the above-mentioned intraocular pressure reducer; CNTF-H or CNTF-OH is a CNTF compound, such as the above-mentioned CNTF compound; CNP-H or CNP-OH is a CNP compound; and NPR-H or NPR-OH is an NPR-B compound.

[0095] For any relevant structural representation, such as Formula 1, 2, 2A, 2B, 2C, 2D, 2E, 2F, 3, 4, 5, 3D, 4D or 5D (Formulas 3-5 and 3D-5D are shown below), L is given by the empirical formula C a H b O c N d or C a H b O c Represents the connecting group.

[0096] For any L, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, a is 1-5, 5-10, 10-15, 15-20, 1-10, or 10-20.

[0097] For any L, b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43. In some embodiments, b is 1-10, 10-20, 20-30, 30-40, 40-43, 1-15, 15-30, or 30-43.

[0098] For any L, c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, c is 0-2, 2-4, 4-6, 6-8, 8-10, 0-3, 3-6, or 6-10.

[0099] For any L, d is 0, 1, or 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2.

[0100] In some embodiments, L can be represented by formula L-1, L-2, L-3, L-4, L-5, L-6, L-7 or L-8:

[0101]

[0102]

[0103] For any relevant structural representation, such as Formula L-1, L-2, L-3, L-4, L-5, L-6, L-7 or L-8, L 1 It can be obtained from the empirical formula C e H f O g N h or C e H f O g express.

[0104] For any L 1 , e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18. In some embodiments, e is 1-5, 5-10, 10-15, 15-18, 1-10 or 10-18.

[0105] For any L 1, f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38. In some embodiments, f is 1-10, 10-20, 20-30, 30-38, 1-15, 15-30, or 30-38.

[0106] For any L 1 , g is 0, 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, g is 0-2, 2-4, 4-6, 6-8, 0-3, 3-6 or 6-8.

[0107] For any L 1 , h is 0, 1 or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2.

[0108] For any relevant structural representation, such as Formula L-1, L-2, L-3, L-4, L-5, L-6, L-7 or L-8, in some embodiments, L 1 It can be:

[0109] -(CH2) i -(OCH2CH2) j -O-(CH2) k -[Formula L 1 -1],

[0110] -(CH2) i -(OCH2CH2) j -O-CONH-(CH2) k -[Formula L 1 -2],

[0111] -(C i H 2i )-(OCH2CH2) j -O-(C k H 2k )-[Formula L 1 -3],

[0112] -(C i H 2i )-(OCH2CH2) j -O-CONH-(C k H 2k )-[Formula L 1 -4],

[0113] -NH2(CH2) i-(OCH2CH2) j -O-(CH2) k -[Formula L 1 -5],

[0114] -NH2(CH2) i -(OCH2CH2) j -O-CONH-(CH2) k -[Formula L 1 -6],

[0115] -NH2(C i H 2i )-(OCH2CH2) j -O-(C k H 2k )-[Formula L 1 -7], or

[0116] -NH2(C i H 2i )-(OCH2CH2) j -O-CONH-(C k H 2k )-[Formula L 1 -8].

[0117] For any relevant structural expression, such as formula L 1 -1, L 1 -2, L 1 -3.L 1 -4, L 1 -5.L 1 -6, L 1 -7 or L 1 -8, i is 0, 1, 2, 3 or 4. In certain embodiments, i is 2.

[0118] For any relevant structural expression, such as formula L 1 -1, L 1 -2, L 1 -3.L 1 -4, L 1 -5.L 1 -6, L 1 -7 or L 1 -8, j is 0, 1, 2, 3, 4, or 5.

[0119] For any relevant structural expression, such as formula L 1 -1, L 1 -2, L 1 -3.L 1 -4, L 1 -5.L 1 -6, L1 -7 or L 1 -8, k is 0, 1, 2, 3, or 4.

[0120] For formula L 1 -1, L 1 -2, L 1 -3.L 1 -4, L 1 -5.L 1 -6, L 1 -7 or L 1 -8, any H atom in the NH or NH2 part may be substituted by a substituent, such as C 1-12 Hydrocarbon, C 1-6 Hydrocarbon or C 1-3 Hydrocarbons, including phenyl, C 1-12 Alkyl, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-6 Cycloalkyl, C 1-3 Alkyl, C 2-12 Alkenyl, C 2-6 Alkenyl, C 3-12 Cycloalkenyl, C 3-6 Cycloalkenyl, C 2-3 Alkenyl, C 2-12 Alkynyl, C 2-6 Alkynyl, C 8-12 Cycloalkynyl, C 2-3 Alkynyl, etc.

[0121] In some embodiments, HLH, HO-LH, HO-L-OH, H2N-LH, or H2N-L-NH2 or HO-L-NH2 is one or more of the following:

[0122]

[0123]

[0124] Compounds containing linkers based on O-AEEAC, O-dPEG12, LaL1 or LaL2 may be unstable in mammals or humans.

[0125] In some embodiments, the drug delivery system comprises one of the following drug combinations: a salt; a free acid; or a free based on the drug. drugs); covalently linked, such as through a linker L, including a group represented by formula L-1, L-2, L-3, L-4, L-5, L-6, L-7 or L-8, or non-covalently linked: bimatoprost or bimatoprost acid and travoprost or travoprost acid; bimatoprost or bimatoprost acid and latanoprost or latanoprost acid; bimatoprost or bimatoprost acid and nitrolatanoprost; bimatoprost or bimatoprost acid and tafluprost or tafluprost acid; bimatoprost or bimatoprost acid and timolol; bimatoprost or bimatoprost acid and betaxolol; bimatoprost or bimatoprost acid and levobunolol; bimatoprost or bimatoprost bimatoprost or bimatoprost acid and metipranolol; bimatoprost or bimatoprost acid and brimonidine; bimatoprost or bimatoprost acid and apraclonidine; bimatoprost or bimatoprost acid and brinzolamide; bimatoprost or bimatoprost acid and acetazolamide; bimatoprost or bimatoprost acid and dorzolamide; bimatoprost or bimatoprost acid and methazolamide; bimatoprost or bimatoprost acid and pilocarpine; bimatoprost or bimatoprost acid and carbachol; bimatoprost or bimatoprost acid and nafadil; bimatoprost or bimatoprost acid and angiopoietin-1; bimatoprost or bimatoprost acid and angiopoietin-2; bimatoprost or bimatoprost acid and angiopoietin-3; Bimatoprost or bimatoprost acid and angiopoietin-4; Bimatoprost or bimatoprost acid and CNTF; Bimatoprost or bimatoprost acid and peptide 6; Bimatoprost or bimatoprost acid and peptide 21; Bimatoprost or bimatoprost acid and recombinant CNTF; Bimatoprost or bimatoprost acid and NGF; Bimatoprost or bimatoprost acid and BDNF; Bimatoprost or bimatoprost acid and GDNF; Bimatoprost or bimatoprost acid and C-type natriuretic peptide; Bimatoprost or bimatoprost acid and native C-type natriuretic peptide; Bimatoprost or bimatoprost acid and natriuretic peptide receptor-B; Bimatoprost or bimatoprost acid and bicyclol; Bimatoprost or bimatoprost bimatoprost or bimatoprost acid and FLIP; bimatoprost or bimatoprost acid and MET12; bimatoprost or bimatoprost acid and compound 1 from Table 1; bimatoprost or bimatoprost acid and compound 2 from Table 1; bimatoprost or bimatoprost acid and compound 3 from Table 1; bimatoprost or bimatoprost acid and compound 4 from Table 1; bimatoprost or bimatoprost acid and compound 5 from Table 1; bimatoprost or bimatoprost acid and compound 6 from Table 1; bimatoprost or bimatoprost acid and compound 7 from Table 1; bimatoprost or bimatoprost acid and compound 8 from Table 1; bimatoprost or bimatoprost acid and compound 9 from Table 1;Bimatoprost or bimatoprost acid and compound 10 from Table 1; Bimatoprost or bimatoprost acid and compound 11 from Table 1; Bimatoprost or bimatoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); bimatoprost or bimatoprost acid and FAIM; bimatoprost or bimatoprost acid and NOL3; bimatoprost or bimatoprost acid and DcR1; bimatoprost or bimatoprost acid and DcR2; bimatoprost or bimatoprost acid and DcR3; travoprost or travoprost acid and latanoprost or latanoprost acid; travoprost or travoprost acid and nitrolatanoprost; travoprost or travoprost acid and tafluprost or tafluprost acid; travoprost or travoprost acid and timolol; travoprost or travoprost acid and betaxolol; travoprost or travoprost acid and levobunolol; travoprost or travoprost acid and metipranolol; travoprost prostaglandins or travoprost acid and brimonidine; travoprost or travoprost acid and apraclonidine; travoprost or travoprost acid and brinzolamide; travoprost or travoprost acid and acetazolamide; travoprost or travoprost acid and dorzolamide; travoprost or travoprost acid and methazolamide; travoprost or travoprost acid and pilocarpine; travoprost or travoprost acid and carbachol; travoprost or travoprost acid and nefadil; travoprost or travoprost acid and angiopoietin-1; travoprost or travoprost acid and angiopoietin-2; travoprost or travoprost acid and angiopoietin-3; travoprost or travoprost acid and angiopoietin-4; travoprost Prostaglandins or travoprost acid and CNTF; travoprost or travoprost acid and peptide 6; travoprost or travoprost acid and peptide 21; travoprost or travoprost acid and recombinant CNTF; travoprost or travoprost acid and NGF; travoprost or travoprost acid and BDNF; travoprost or travoprost acid and GDNF; travoprost or travoprost acid and C-type natriuretic peptide; travoprost or travoprost acid and native C-type natriuretic peptide; travoprost or travoprost acid and natriuretic peptide receptor-B; travoprost or travoprost acid and bicyclol; travoprost or travoprost acid and FLIP; travoprost or travoprost acid and MET12; travoprost or travoprost acid Travoprost or travoprost acid and compound 1 from Table 1; travoprost or travoprost acid and compound 2 from Table 1; travoprost or travoprost acid and compound 3 from Table 1; travoprost or travoprost acid and compound 4 from Table 1; travoprost or travoprost acid and compound 5 from Table 1; travoprost or travoprost acid and compound 6 from Table 1; travoprost or travoprost acid and compound 7 from Table 1; travoprost or travoprost acid and compound 8 from Table 1; travoprost or travoprost acid and compound 9 from Table 1; travoprost or travoprost acid and compound 10 from Table 1; travoprost or travoprost acid and compound 11 from Table 1;Travoprost or travoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); travoprost or travoprost acid and FAIM; travoprost or travoprost acid and NOL3; travoprost or travoprost acid and DcR1; travoprost or travoprost acid and DcR2; travoprost or travoprost acid and DcR3; latanoprost or latanoprost acid and nitratelatanoprost; latanoprost or latanoprost acid and tafluprost or tafluprost acid; latanoprost or latanoprost acid and timolol; latanoprost or latanoprost acid and betaxolol; latanoprost or latanoprost acid and levobunolol; latanoprost or latanoprost acid and metipranolol; latanoprost or latanoprost acid and brimonidine; latanoprost or latanoprost acid Latanoprost or latanoprost acid and apraclonidine; Latanoprost or latanoprost acid and brinzolamide; Latanoprost or latanoprost acid and acetazolamide; Latanoprost or latanoprost acid and dorzolamide; Latanoprost or latanoprost acid and methazolamide; Latanoprost or latanoprost acid and pilocarpine; Latanoprost or latanoprost acid and carbachol; Latanoprost or latanoprost acid and nefadil; Latanoprost or latanoprost acid and angiopoietin-1; Latanoprost or latanoprost acid and angiopoietin-2; Latanoprost or latanoprost acid and angiopoietin-3; Latanoprost or latanoprost acid and angiopoietin-4; Latanoprost or latanoprost acid and CNTF; Latanoprost or latanoprost acid and peptide 6; latanoprost or latanoprost acid and peptide 21; latanoprost or latanoprost acid and recombinant CNTF; latanoprost or latanoprost acid and NGF; latanoprost or latanoprost acid and BDNF; latanoprost or latanoprost acid and GDNF; latanoprost or latanoprost acid and C-type natriuretic peptide; latanoprost or latanoprost acid and native C-type natriuretic peptide; latanoprost or latanoprost acid and natriuretic peptide receptor-B; latanoprost or latanoprost acid and bicyclol; latanoprost or latanoprost acid and FLIP; latanoprost or latanoprost acid and MET12; latanoprost or latanoprost acid and compound 1 from Table 1; latanoprost or latanoprost acid and compound 2 from Table 1; latanoprost or latanoprost acid and compound 3 from Table 1; latanoprost or latanoprost acid and compound 4 from Table 1; latanoprost or latanoprost acid and compound 5 from Table 1; latanoprost or latanoprost acid and compound 6 from Table 1; latanoprost or latanoprost acid and compound 7 from Table 1; latanoprost or latanoprost acid and compound 8 from Table 1; latanoprost or latanoprost acid and compound 9 from Table 1; latanoprost or latanoprost acid and compound 10 from Table 1; latanoprost or latanoprost acid and compound 11 from Table 1; latanoprost or latanoprost acid and H 60HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); latanoprost or latanoprost acid and FAIM; latanoprost or latanoprost acid and NOL3; latanoprost or latanoprost acid and DcR1; latanoprost or latanoprost acid and DcR2; latanoprost or latanoprost acid and DcR3; nitrolatanoprost and tafluprost or tafluprost acid; nitrolatanoprost and timolol; nitrolatanoprost and betaxolol; nitrolatanoprost and levobunolol; nitrolatanoprost and metipranolol; nitrolatanoprost and brimonidine; nitrolatanoprost prostaglandins and apraclonidine; nitrosatanoprost and brinzolamide; nitrosatanoprost and acetazolamide; nitrosatanoprost and dorzolamide; nitrosatanoprost and methazolamide; nitrosatanoprost and pilocarpine; nitrosatanoprost and carbachol; nitrosatanoprost and natridil; nitrosatanoprost and angiopoietin-1; nitrosatanoprost and angiopoietin-2; nitrosatanoprost and angiopoietin-3; nitrosatanoprost and angiopoietin-4; nitrosatanoprost and CNTF; nitrosatanoprost and angiopoietin-1; nitrosatanoprost and angiopoietin-2; nitrosatanoprost and angiopoietin-3; nitrosatanoprost and angiopoietin-4; nitrosatanoprost and CNTF; nitrosatanoprost and prostaglandin and peptide 6; nitro latanoprost and peptide 21; nitro latanoprost and recombinant CNTF; nitro latanoprost and NGF; nitro latanoprost and BDNF; nitro latanoprost and GDNF; nitro latanoprost and C-type natriuretic peptide; nitro latanoprost and native C-type natriuretic peptide; nitro latanoprost and natriuretic peptide receptor-B; nitro latanoprost and bicyclol; nitro latanoprost and FLIP; nitro latanoprost and MET12; nitro latanoprost and compound 1 from Table 1; nitro latanoprost and compound 2 from Table 1; nitro latanoprost and compound 3 from Table 1; nitro latanoprost and compound 4 from Table 1; nitro latanoprost and compound 5 from Table 1; nitro latanoprost and compound 6 from Table 1; nitro latanoprost and compound 7 from Table 1; nitro latanoprost and compound 8 from Table 1; nitro latanoprost and compound 9 from Table 1; nitro latanoprost and compound 10 from Table 1; nitro latanoprost and compound 11 from Table 1; nitro latanoprost and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); nitro latanoprost and FAIM; nitro latanoprost and NOL3; nitro latanoprost and DcR1; nitro latanoprost and DcR2; nitro latanoprost and DcR3; tafluprost or tafluprost acid and timolol; tafluprost or tafluprost acid and betaxolol; tafluprost or tafluprost acid and levobunolol; tafluprost or tafluprost acid and metipranolol; tafluprost or tafluprost acid and brimonidine; tafluprost or tafluprost acid and apraclonidine; tafluprost or tafluprost acid and brinzolamide; tafluprost or tafluprost acid and acetazolamide; tafluprost Tafluprost or tafluprost acid and dorzolamide; Tafluprost or tafluprost acid and methazolamide; Tafluprost or tafluprost acid and pilocarpine; Tafluprost or tafluprost acid and carbachol; Tafluprost or tafluprost acid and nafadil; Tafluprost or tafluprost acid and angiopoietin-1; Tafluprost or tafluprost acid and angiopoietin-2; Tafluprost or tafluprost acid and angiopoietin-3; Tafluprost or tafluprost acid and angiopoietin-4; Tafluprost or tafluprost acid and CNTF; Tafluprost or tafluprost acid and peptide 6; Tafluprost or tafluprost acid and peptide 21; Tafluprost or tafluprost acid and recombinant CNTF; tafluprost or tafluprost acid and NGF; tafluprost or tafluprost acid and BDNF; tafluprost or tafluprost acid and GDNF; tafluprost or tafluprost acid and C-type natriuretic peptide; tafluprost or tafluprost acid and natural C-type natriuretic peptide; tafluprost or tafluprost acid and natriuretic peptide receptor-B; tafluprost or tafluprost acid and bicyclol; tafluprost or tafluprost acid and FLIP; tafluprost or tafluprost acid and MET12; tafluprost or tafluprost acid and compound 1 from Table 1; tafluprost or tafluprost acid and a compound from Table 1 Compound 2; tafluprost or tafluprost acid and compound 3 from Table 1; tafluprost or tafluprost acid and compound 4 from Table 1; tafluprost or tafluprost acid and compound 5 from Table 1; tafluprost or tafluprost acid and compound 6 from Table 1; tafluprost or tafluprost acid and compound 7 from Table 1; tafluprost or tafluprost acid and compound 8 from Table 1; tafluprost or tafluprost acid and compound 9 from Table 1; tafluprost or tafluprost acid and compound 10 from Table 1; tafluprost or tafluprost acid and compound 11 from Table 1; tafluprost or tafluprost acid and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); tafluprost or tafluprost acid and FAIM; tafluprost or tafluprost acid and NOL3; tafluprost or tafluprost acid and DcR1; tafluprost or tafluprost acid and DcR2; tafluprost or tafluprost acid and DcR3; timolol and betaxolol; timolol and levobunolol; timolol and metipranolol; timolol and brimonidine; timolol and acol Clonidine; timolol and brinzolamide; timolol and acetazolamide; timolol and dorzolamide; timolol and methazolamide; timolol and pilocarpine; timolol and carbachol; timolol and natridil; timolol and angiopoietin-1; timolol and angiopoietin-2; timolol and angiopoietin-3; timolol and angiopoietin-4; timolol and CNTF; timolol and peptide 6; timolol Timolol and peptide 21; Timolol and recombinant CNTF; Timolol and NGF; Timolol and BDNF; Timolol and GDNF; Timolol and C-type natriuretic peptide; Timolol and native C-type natriuretic peptide; Timolol and natriuretic peptide receptor-B; Timolol and bicyclol; Timolol and FLIP; Timolol and MET12; Timolol and compound 1 from Table 1; Timolol and compound 2 from Table 1; Timolol and compound 3 from Table 1; Timolol and compound 4 from Table 1; Timolol and compound 5 from Table 1; Timolol and compound 6 from Table 1; Timolol and compound 7 from Table 1; Timolol and compound 8 from Table 1; Timolol and compound 9 from Table 1; Timolol and compound 10 from Table 1; Timolol and compound 11 from Table 1; Timolol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); timolol and FAIM; timolol and NOL3; timolol and DcR1; timolol and DcR2; timolol and DcR3; betaxolol and levobunolol; betaxolol and metipranolol; betaxolol and brimonidine; betaxolol and apraclonidine; betaxolol and brinzolamide; betaxolol and acetazolamide; betaxolol and dorzolamide; betaxolol and methazolamide; betaxolol and pilocarpine; betaxolol and carbachol; betaxolol and natridil; betaxolol and angiopoietin-1; betaxolol and angiopoietin-2; betaxolol and angiopoietin-3; betaxolol and angiopoietin-4; betaxolol and CNTF; betaxolol and peptide 6; betaxolol and peptide 21; betaxolol and recombinant CNTF; betaxolol and NGF; betaxolol and BDNF; betaxolol and GDNF; betaxolol and C-type natriuretic peptide; betaxolol and native C-type natriuretic peptide; betaxolol and natriuretic peptide receptor-B; betaxolol and bicyclol; betaxolol and FLIP; betaxolol and MET12; betaxolol and compound 1 from Table 1; betaxolol and compound 2 from Table 1; betaxolol and compound 3 from Table 1; betaxolol and compound 4 from Table 1; betaxolol and compound 5 from Table 1; betaxolol and compound 6 from Table 1; betaxolol and compound 7 from Table 1; betaxolol and compound 8 from Table 1; betaxolol and compound 9 from Table 1; betaxolol and compound 10 from Table 1; betaxolol and compound 11 from Table 1; betaxolol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); betaxolol and FAIM; betaxolol and NOL3; betaxolol and DcR1; betaxolol and DcR2; betaxolol and DcR3; levobunolol and metipranolol; levobunolol and brimonidine; levobunolol and apraclonidine; levobunolol and brinzolamide; levobunolol and acetazolamide; levobunolol and dorzolamide; levobunolol and methazolamide; levobunolol and Pilocarpine; levobunolol and carbachol; levobunolol and natridil; levobunolol and angiopoietin-1; levobunolol and angiopoietin-2; levobunolol and angiopoietin-3; levobunolol and angiopoietin-4; levobunolol and CNTF; levobunolol and peptide 6; levobunolol and peptide 21; levobunolol and recombinant CNTF; levobunolol and NGF; levobunolol Levobunolol and BDNF; Levobunolol and GDNF; Levobunolol and C-type natriuretic peptide; Levobunolol and native C-type natriuretic peptide; Levobunolol and natriuretic peptide receptor-B; Levobunolol and bicyclol; Levobunolol and FLIP; Levobunolol and MET12; Levobunolol and compound 1 from Table 1; Levobunolol and compound 2 from Table 1; Levobunolol and compound 3 from Table 1; Levobunolol and compound 4 from Table 1; Levobunolol and compound 5 from Table 1; Levobunolol and compound 6 from Table 1; Levobunolol and compound 7 from Table 1; Levobunolol and compound 8 from Table 1; Levobunolol and compound 9 from Table 1; Levobunolol and compound 10 from Table 1; Levobunolol and compound 11 from Table 1; Levobunolol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); levobunolol and FAIM; levobunolol and NOL3; levobunolol and DcR1; levobunolol and DcR2; levobunolol and DcR3; metipranolol and brimonidine; metipranolol and apraclonidine; metipranolol and brinzolamide; metipranolol and acetazolamide; metipranolol and dorzolamide; metipranolol and methazolamide; metipranolol and pilocarpine; metipranolol and carbachol; metipranolol and natridil; metipranolol and angiopoietin-1; metipranolol and angiopoietin-2; metipranolol and angiopoietin-3; metipranolol and angiopoietin-4; metipranolol and CNTF; metipranolol and peptide 6; metipranolol and peptide 21; metipranolol and recombinant CNTF; metipranolol and NGF; metipranolol and BDNF; metipranolol and GDNF; metipranolol and C-type natriuretic peptide; metipranolol and native C-type natriuretic peptide; metipranolol and natriuretic peptide receptor-B; metipranolol and bicyclol; metipranolol and FLIP; metipranolol and MET12; metipranolol and compound 1 from Table 1; metipranolol and compound 2 from Table 1; metipranolol and compound 3 from Table 1; metipranolol and compound 4 from Table 1; metipranolol and compound 5 from Table 1; metipranolol and compound 6 from Table 1; metipranolol and compound 7 from Table 1; metipranolol and compound 8 from Table 1; metipranolol and compound 9 from Table 1; metipranolol and compound 10 from Table 1; metipranolol and compound 11 from Table 1; metipranolol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); metipranolol and FAIM; metipranolol and NOL3; metipranolol and DcR1; metipranolol and DcR2; metipranolol and DcR3; brimonidine and apraclonidine; brimonidine and brinzolamide; brimonidine and acetazolamide; brimonidine and dorzolamide; brimonidine and methazolamide; brimonidine and pilocarpine; brimonidine and carbachol; brimonidine and netacidil; brimonidine and angiopoietin-1; brimonidine and angiopoietin-2; brimonidine and angiopoietin-3; brimonidine and angiopoietin-4; brimonidine and CNTF; brimonidine and peptide 6; brimonidine and peptide 21; brimonidine and recombinant CNTF; brimonidine and NGF; brimonidine and BDNF; brimonidine Brimonidine and GDNF; Brimonidine and C-type natriuretic peptide; Brimonidine and native C-type natriuretic peptide; Brimonidine and natriuretic peptide receptor-B; Brimonidine and bicyclol; Brimonidine and FLIP; Brimonidine and MET12; Brimonidine and compound 1 from Table 1; Brimonidine and compound 2 from Table 1; Brimonidine and compound 3 from Table 1; Brimonidine and compound 4 from Table 1; Brimonidine and compound 5 from Table 1; Brimonidine and compound 6 from Table 1; Brimonidine and compound 7 from Table 1; Brimonidine and compound 8 from Table 1; Brimonidine and compound 9 from Table 1; Brimonidine and compound 10 from Table 1; Brimonidine and compound 11 from Table 1; Brimonidine and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); brimonidine and FAIM; brimonidine and NOL3; brimonidine and DcR1; brimonidine and DcR2; brimonidine and DcR3; apraclonidine and brinzolamide; apraclonidine and acetazolamide; apraclonidine and dorzolamide; apraclonidine and methazolamide; apraclonidine and pilocarpine; apraclonidine and carbachol; apraclonidine and natadil; apraclonidine and angiopoietin-1; apraclonidine and angiopoietin-2; apraclonidine and angiopoietin-3; apraclonidine and angiopoietin-4; apraclonidine and CNTF; apraclonidine and peptide 6; apraclonidine and peptide 21; apraclonidine and recombinant CNTF; apraclonidine and NGF; apraclonidine and BDNF; apraclonidine and GD NF; apraclonidine and C-type natriuretic peptide; apraclonidine and native C-type natriuretic peptide; apraclonidine and natriuretic peptide receptor-B; apraclonidine and bicyclol; apraclonidine and FLIP; apraclonidine and MET12; apraclonidine and compound 1 from Table 1; apraclonidine and compound 2 from Table 1; apraclonidine and compound 3 from Table 1; apraclonidine and compound 4 from Table 1; apraclonidine and compound 5 from Table 1; apraclonidine and compound 6 from Table 1; apraclonidine and compound 7 from Table 1; apraclonidine and compound 8 from Table 1; apraclonidine and compound 9 from Table 1; apraclonidine and compound 10 from Table 1; apraclonidine and compound 11 from Table 1; apraclonidine and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); apraclonidine and FAIM; apraclonidine and NOL3; apraclonidine and DcR1; apraclonidine and DcR2; apraclonidine and DcR3; brinzolamide and acetazolamide; brinzolamide and dorzolamide; brinzolamide and methazolamide; brinzolamide and pilocarpine; brinzolamide and carbachol; brinzolamide and natridil; brinzolamide and angiopoietin-1; brinzolamide and angiopoietin-2; brinzolamide and angiopoietin-3; brinzolamide and angiopoietin-4; brinzolamide and CNTF; brinzolamide and peptide 6; brinzolamide and peptide 21; brinzolamide and recombinant CNTF; brinzolamide and NGF; brinzolamide and BDNF; brinzolamide and GDNF; brinzolamide Brinzolamide and C-type natriuretic peptide; Brinzolamide and native C-type natriuretic peptide; Brinzolamide and natriuretic peptide receptor-B; Brinzolamide and bicyclol; Brinzolamide and FLIP; Brinzolamide and MET12; Brinzolamide and compound 1 from Table 1; Brinzolamide and compound 2 from Table 1; Brinzolamide and compound 3 from Table 1; Brinzolamide and compound 4 from Table 1; Brinzolamide and compound 5 from Table 1; Brinzolamide and compound 6 from Table 1; Brinzolamide and compound 7 from Table 1; Brinzolamide and compound 8 from Table 1; Brinzolamide and compound 9 from Table 1; Brinzolamide and compound 10 from Table 1; Brinzolamide and compound 11 from Table 1; Brinzolamide and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); Brinzolamide and FAIM; Brinzolamide and NOL3; Brinzolamide and DcR1; Brinzolamide and DcR2; Brinzolamide and DcR3; Acetazolamide and Dorzolamide; Acetazolamide and Methazolamide; Acetazolamide and Pilocarpine; Acetazolamide and Carbachol; Acetazolamide and Netacidil; Acetazolamide and Angiopoietin-1; Acetazolamide and Angiopoietin-2; Acetazolamide and Angiopoietin-3; Acetazolamide and Angiopoietin-4; Acetazolamide and CNTF; Acetazolamide and Peptide 6; Acetazolamide and Peptide 21; Acetazolamide and Recombinant CNTF; Acetazolamide and NGF; Acetazolamide and BDNF; Acetazolamide and GDNF; Acetazolamide and Type C Natriuretic peptides; acetazolamide and native C-type natriuretic peptide; acetazolamide and natriuretic peptide receptor-B; acetazolamide and bicyclol; acetazolamide and FLIP; acetazolamide and MET12; acetazolamide and compound 1 from Table 1; acetazolamide and compound 2 from Table 1; acetazolamide and compound 3 from Table 1; acetazolamide and compound 4 from Table 1; acetazolamide and compound 5 from Table 1; acetazolamide and compound 6 from Table 1; acetazolamide and compound 7 from Table 1; acetazolamide and compound 8 from Table 1; acetazolamide and compound 9 from Table 1; acetazolamide and compound 10 from Table 1; acetazolamide and compound 11 from Table 1; acetazolamide and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); acetazolamide and FAIM; acetazolamide and NOL3; acetazolamide and DcR1; acetazolamide and DcR2; acetazolamide and DcR3; dorzolamide and methazolamide; dorzolamide and pilocarpine; dorzolamide and carbachol; dorzolamide and natriuretic peptide; dorzolamide and angiopoietin-1; dorzolamide and angiopoietin-2; dorzolamide and angiopoietin-3; dorzolamide and angiopoietin-4; dorzolamide and CNTF; dorzolamide and peptide 6; dorzolamide and peptide 21; dorzolamide and recombinant CNTF; dorzolamide and NGF; dorzolamide and BDNF; dorzolamide and GDNF; dorzolamide and C-type natriuretic peptide; Dorzolamide and natural C-type natriuretic peptide; Dorzolamide and natriuretic peptide receptor-B; Dorzolamide and bicyclol; Dorzolamide and FLIP; Dorzolamide and MET12; Dorzolamide and compound 1 from Table 1; Dorzolamide and compound 2 from Table 1; Dorzolamide and compound 3 from Table 1; Dorzolamide and compound 4 from Table 1; Dorzolamide and compound 5 from Table 1; Dorzolamide and compound 6 from Table 1; Dorzolamide and compound 7 from Table 1; Dorzolamide and compound 8 from Table 1; Dorzolamide and compound 9 from Table 1; Dorzolamide and compound 10 from Table 1; Dorzolamide and compound 11 from Table 1; Dorzolamide and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); Dorzolamide and FAIM; Dorzolamide and NOL3; Dorzolamide and DcR1; Dorzolamide and DcR2; Dorzolamide and DcR3; Methazolamide and pilocarpine; Methazolamide and carbachol; Methazolamide and natriuretic peptide; Methazolamide and angiopoietin-1; Methazolamide and angiopoietin-2; Methazolamide and angiopoietin-3; Methazolamide and angiopoietin-4; Methazolamide and CNTF; Methazolamide and peptide 6; Methazolamide and peptide 21; Methazolamide and recombinant CNTF; Methazolamide and NGF; Methazolamide and BDNF; Methazolamide and GDNF; Methazolamide and C-type natriuretic peptide; Methazolamide and natural C type natriuretic peptide; methazolamide and natriuretic peptide receptor-B; methazolamide and bicyclol; methazolamide and FLIP; methazolamide and MET12; methazolamide and compound 1 from Table 1; methazolamide and compound 2 from Table 1; methazolamide and compound 3 from Table 1; methazolamide and compound 4 from Table 1; methazolamide and compound 5 from Table 1; methazolamide and compound 6 from Table 1; methazolamide and compound 7 from Table 1; methazolamide and compound 8 from Table 1; methazolamide and compound 9 from Table 1; methazolamide and compound 10 from Table 1; methazolamide and compound 11 from Table 1; methazolamide and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); methazolamide and FAIM; methazolamide and NOL3; methazolamide and DcR1; methazolamide and DcR2; methazolamide and DcR3; pilocarpine and carbachol; pilocarpine and natriuretic peptide; pilocarpine and angiopoietin-1; pilocarpine and angiopoietin-2; pilocarpine and angiopoietin-3; pilocarpine and angiopoietin-4; pilocarpine and CNTF; pilocarpine and peptide 6; pilocarpine and peptide 21; pilocarpine and recombinant CNTF; pilocarpine and NGF; pilocarpine and BDNF; pilocarpine and GDNF; pilocarpine and C-type natriuretic peptide; pilocarpine and natural C-type natriuretic peptide peptide; pilocarpine and natriuretic peptide receptor-B; pilocarpine and bicyclol; pilocarpine and FLIP; pilocarpine and MET12; pilocarpine and compound 1 from Table 1; pilocarpine and compound 2 from Table 1; pilocarpine and compound 3 from Table 1; pilocarpine and compound 4 from Table 1; pilocarpine and compound 5 from Table 1; pilocarpine and compound 6 from Table 1; pilocarpine and compound 7 from Table 1; pilocarpine and compound 8 from Table 1; pilocarpine and compound 9 from Table 1; pilocarpine and compound 10 from Table 1; pilocarpine and compound 11 from Table 1; pilocarpine and H 60 HIYLGATNYIY71 -NH2 (SEQ ID NO:4); pilocarpine and FAIM; pilocarpine and NOL3; pilocarpine and DcR1; pilocarpine and DcR2; pilocarpine and DcR3; carbachol and natriuretic peptide; carbachol and angiopoietin-1; carbachol and angiopoietin-2; carbachol and angiopoietin-3; carbachol and angiopoietin-4; carbachol and CNTF; carbachol and peptide 6; carbachol and peptide 21; carbachol and recombinant CNTF; carbachol and NGF; carbachol and BDNF; carbachol and GDNF; carbachol and C-type natriuretic peptide; carbachol and native C-type natriuretic peptide; Carbachol and natriuretic peptide receptor-B; Carbachol and bicyclol; Carbachol and FLIP; Carbachol and MET12; Carbachol and compound 1 from Table 1; Carbachol and compound 2 from Table 1; Carbachol and compound 3 from Table 1; Carbachol and compound 4 from Table 1; Carbachol and compound 5 from Table 1; Carbachol and compound 6 from Table 1; Carbachol and compound 7 from Table 1; Carbachol and compound 8 from Table 1; Carbachol and compound 9 from Table 1; Carbachol and compound 10 from Table 1; Carbachol and compound 11 from Table 1; Carbachol and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); carbachol and FAIM; carbachol and NOL3; carbachol and DcR1; carbachol and DcR2; carbachol and DcR3; nepamidil and angiopoietin-1; nepamidil and angiopoietin-2; nepamidil and angiopoietin-3; nepamidil and angiopoietin-4; nepamidil and CNTF; nepamidil and peptide 6; nepamidil and peptide 21; nepamidil and recombinant CNTF; nepamidil and NGF; nepamidil and BDNF; nepamidil and GDNF; nepamidil and C-type natriuretic peptide; nepamidil and native C-type natriuretic peptide; nepamidil and natriuretic peptide Receptor-B; netadil and bicyclol; netadil and FLIP; netadil and MET12; netadil and compound 1 from Table 1; netadil and compound 2 from Table 1; netadil and compound 3 from Table 1; netadil and compound 4 from Table 1; netadil and compound 5 from Table 1; netadil and compound 6 from Table 1; netadil and compound 7 from Table 1; netadil and compound 8 from Table 1; netadil and compound 9 from Table 1; netadil and compound 10 from Table 1; netadil and compound 11 from Table 1; netadil and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); nepamidil and FAIM; nepamidil and NOL3; nepamidil and DcR1; nepamidil and DcR2; nepamidil and DcR3; angiopoietin-1 and angiopoietin-2; angiopoietin-1 and angiopoietin-3; angiopoietin-1 and angiopoietin-4; angiopoietin-1 and CNTF; angiopoietin-1 and peptide 6; angiopoietin-1 and peptide 21; angiopoietin-1 and recombinant CNTF; angiopoietin-1 and NGF; angiopoietin-1 and BDNF; angiopoietin-1 and GDNF; angiopoietin-1 and C-type natriuretic peptide; angiopoietin-1 and native C-type natriuretic peptide; angiopoietin-1 and natriuretic peptide receptor-B; angiogenesis Angiopoietin-1 and bicyclol; Angiopoietin-1 and FLIP; Angiopoietin-1 and MET12; Angiopoietin-1 and compound 1 from Table 1; Angiopoietin-1 and compound 2 from Table 1; Angiopoietin-1 and compound 3 from Table 1; Angiopoietin-1 and compound 4 from Table 1; Angiopoietin-1 and compound 5 from Table 1; Angiopoietin-1 and compound 6 from Table 1; Angiopoietin-1 and compound 7 from Table 1; Angiopoietin-1 and compound 8 from Table 1; Angiopoietin-1 and compound 9 from Table 1; Angiopoietin-1 and compound 10 from Table 1; Angiopoietin-1 and compound 11 from Table 1; Angiopoietin-1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); Angiopoietin-1 and FAIM; Angiopoietin-1 and NOL3; Angiopoietin-1 and DcR1; Angiopoietin-1 and DcR2; Angiopoietin-1 and DcR3; Angiopoietin-2 and Angiopoietin-3; Angiopoietin-2 and Angiopoietin-4; Angiopoietin-2 and CNTF; Angiopoietin-2 and peptide 6; Angiopoietin-2 and peptide 21; Angiopoietin-2 and recombinant CNTF; Angiopoietin-2 and NGF; Angiopoietin-2 and BDNF; Angiopoietin-2 and GDNF; Angiopoietin-2 and C-type natriuretic peptide; Angiopoietin-2 and native C-type natriuretic peptide; Angiopoietin-2 and natriuretic peptide receptor-B; Angiopoietin -2 and bicyclol; Angiopoietin-2 and FLIP; Angiopoietin-2 and MET12; Angiopoietin-2 and compound 1 from Table 1; Angiopoietin-2 and compound 2 from Table 1; Angiopoietin-2 and compound 3 from Table 1; Angiopoietin-2 and compound 4 from Table 1; Angiopoietin-2 and compound 5 from Table 1; Angiopoietin-2 and compound 6 from Table 1; Angiopoietin-2 and compound 7 from Table 1; Angiopoietin-2 and compound 8 from Table 1; Angiopoietin-2 and compound 9 from Table 1; Angiopoietin-2 and compound 10 from Table 1; Angiopoietin-2 and compound 11 from Table 1; Angiopoietin-2 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO:4); Angiopoietin-2 and FAIM; Angiopoietin-2 and NOL3; Angiopoietin-2 and DcR1; Angiopoietin-2 and DcR2; Angiopoietin-2 and DcR3; Angiopoietin-3 and Angiopoietin-4; Angiopoietin-3 and CNTF; Angiopoietin-3 and peptide 6; Angiopoietin-3 and peptide 21; Angiopoietin-3 and recombinant CNTF; Angiopoietin-3 and NGF; Angiopoietin-3 and BDNF; Angiopoietin-3 and GDNF; Angiopoietin-3 and C-type natriuretic peptide; Angiopoietin-3 and native C-type natriuretic peptide; Angiopoietin-3 and natriuretic peptide receptor-B; Angiopoietin-3 and bicyclol; Blood Angiopoietin-3 and FLIP; Angiopoietin-3 and MET12; Angiopoietin-3 and compound 1 from Table 1; Angiopoietin-3 and compound 2 from Table 1; Angiopoietin-3 and compound 3 from Table 1; Angiopoietin-3 and compound 4 from Table 1; Angiopoietin-3 and compound 5 from Table 1; Angiopoietin-3 and compound 6 from Table 1; Angiopoietin-3 and compound 7 from Table 1; Angiopoietin-3 and compound 8 from Table 1; Angiopoietin-3 and compound 9 from Table 1; Angiopoietin-3 and compound 10 from Table 1; Angiopoietin-3 and compound 11 from Table 1; Angiopoietin-3 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); Angiopoietin-3 and FAIM; Angiopoietin-3 and NOL3; Angiopoietin-3 and DcR1; Angiopoietin-3 and DcR2; Angiopoietin-3 and DcR3; Angiopoietin-4 and CNTF; Angiopoietin-4 and peptide 6; Angiopoietin-4 and peptide 21; Angiopoietin-4 and recombinant CNTF; Angiopoietin-4 and NGF; Angiopoietin-4 and BDNF; Angiopoietin-4 and GDNF; Angiopoietin-4 and C-type natriuretic peptide; Angiopoietin-4 and native C-type natriuretic peptide; Angiopoietin-4 and natriuretic peptide receptor-B; Angiopoietin-4 and bicyclol; Angiopoietin-4 and F LIP; Angiopoietin-4 and MET12; Angiopoietin-4 and Compound 1 from Table 1; Angiopoietin-4 and Compound 2 from Table 1; Angiopoietin-4 and Compound 3 from Table 1; Angiopoietin-4 and Compound 4 from Table 1; Angiopoietin-4 and Compound 5 from Table 1; Angiopoietin-4 and Compound 6 from Table 1; Angiopoietin-4 and Compound 7 from Table 1; Angiopoietin-4 and Compound 8 from Table 1; Angiopoietin-4 and Compound 9 from Table 1; Angiopoietin-4 and Compound 10 from Table 1; Angiopoietin-4 and Compound 11 from Table 1; Angiopoietin-4 and H 60HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); Angiopoietin-4 and FAIM; Angiopoietin-4 and NOL3; Angiopoietin-4 and DcR1; Angiopoietin-4 and DcR2; Angiopoietin-4 and DcR3; CNTF and peptide 6; CNTF and peptide 21; CNTF and recombinant CNTF; CNTF and NGF; CNTF and BDNF; CNTF and GDNF; CNTF and C-type natriuretic peptide; CNTF and native C-type natriuretic peptide; CNTF and natriuretic peptide receptor-B; CNTF and bicyclol; CNTF and FLIP ; CNTF and MET12; CNTF and compound 1 from Table 1; CNTF and compound 2 from Table 1; CNTF and compound 3 from Table 1; CNTF and compound 4 from Table 1; CNTF and compound 5 from Table 1; CNTF and compound 6 from Table 1; CNTF and compound 7 from Table 1; CNTF and compound 8 from Table 1; CNTF and compound 9 from Table 1; CNTF and compound 10 from Table 1; CNTF and compound 11 from Table 1; CNTF and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO:4); CNTF and FAIM; CNTF and NOL3; CNTF and DcR1; CNTF and DcR2; CNTF and DcR3; peptide 6 and peptide 21; peptide 6 and recombinant CNTF; peptide 6 and NGF; peptide 6 and BDNF; peptide 6 and GDNF; peptide 6 and C-type natriuretic peptide; peptide 6 and native C-type natriuretic peptide; peptide 6 and natriuretic peptide receptor-B; peptide 6 and bicyclol; peptide 6 and FLIP; peptide 6 and MET12; peptide 6 and compound 1 from Table 1; peptide 6 and compound 2 from Table 1; peptide 6 and compound 3 from Table 1; peptide 6 and compound 4 from Table 1; peptide 6 and compound 5 from Table 1; peptide 6 and compound 6 from Table 1; peptide 6 and compound 7 from Table 1; peptide 6 and compound 8 from Table 1; peptide 6 and compound 9 from Table 1; peptide 6 and compound 10 from Table 1; peptide 6 and compound 11 from Table 1; peptide 6 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); peptide 6 and FAIM; peptide 6 and NOL3; peptide 6 and DcR1; peptide 6 and DcR2; peptide 6 and DcR3; peptide 21 and recombinant peptide 21; peptide 21 and NGF; peptide 21 and BDNF; peptide 21 and GDNF; peptide 21 and C-type natriuretic peptide; peptide 21 and native C-type natriuretic peptide; peptide 21 and natriuretic peptide receptor-B; peptide 21 and bicyclol; peptide 21 and FLIP; peptide 21 and MET12; peptide 21 and from Table 1 Compound 1; Peptide 21 and Compound 2 from Table 1; Peptide 21 and Compound 3 from Table 1; Peptide 21 and Compound 4 from Table 1; Peptide 21 and Compound 5 from Table 1; Peptide 21 and Compound 6 from Table 1; Peptide 21 and Compound 7 from Table 1; Peptide 21 and Compound 8 from Table 1; Peptide 21 and Compound 9 from Table 1; Peptide 21 and Compound 10 from Table 1; Peptide 21 and Compound 11 from Table 1; Peptide 21 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); peptide 21 and FAIM; peptide 21 and NOL3; peptide 21 and DcR1; peptide 21 and DcR2; peptide 21 and DcR3; recombinant peptide 21 and NGF; recombinant peptide 21 and BDNF; recombinant peptide 21 and GDNF; recombinant peptide 21 and C-type natriuretic peptide; recombinant peptide 21 and native C-type natriuretic peptide; recombinant peptide 21 and natriuretic peptide receptor-B; recombinant peptide 21 and bicyclol; recombinant peptide 21 and FLIP; recombinant peptide 21 and MET12; recombinant peptide 21 and compounds from Table 1 1; recombinant peptide 21 and compound 2 from Table 1; recombinant peptide 21 and compound 3 from Table 1; recombinant peptide 21 and compound 4 from Table 1; recombinant peptide 21 and compound 5 from Table 1; recombinant peptide 21 and compound 6 from Table 1; recombinant peptide 21 and compound 7 from Table 1; recombinant peptide 21 and compound 8 from Table 1; recombinant peptide 21 and compound 9 from Table 1; recombinant peptide 21 and compound 10 from Table 1; recombinant peptide 21 and compound 11 from Table 1; recombinant peptide 21 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); recombinant peptide 21 and FAIM; recombinant peptide 21 and NOL3; recombinant peptide 21 and DcR1; recombinant peptide 21 and DcR2; recombinant peptide 21 and DcR3; NGF and BDNF; NGF and GDNF; NGF and C-type natriuretic peptide; NGF and native C-type natriuretic peptide; NGF and natriuretic peptide receptor-B; NGF and bicyclol; NGF and FLIP; NGF and MET12; NGF and compound 1 from Table 1; NGF and compound 2 from Table 1; NGF and compound 3 from Table 1; NGF and compound 4 from Table 1; NGF and compound 5 from Table 1; NGF and compound 6 from Table 1; NGF and compound 7 from Table 1; NGF and compound 8 from Table 1; NGF and compound 9 from Table 1; NGF and compound 10 from Table 1; NGF and compound 11 from Table 1; NGF and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); NGF and FAIM; NGF and NOL3; NGF and DcR1; NGF and DcR2; NGF and DcR3; BDNF and GDNF; BDNF and C-type natriuretic peptide; BDNF and native C-type natriuretic peptide; BDNF and natriuretic peptide receptor-B; BDNF and bicyclol; BDNF and FLIP; BDNF and MET12; BDNF and compound 1 from Table 1; BDNF and compound 2 from Table 1; BDNF and compound 3 from Table 1; BDNF and compound 4 from Table 1; BDNF and compound 5 from Table 1; BDNF and compound 6 from Table 1; BDNF and compound 7 from Table 1; BDNF and compound 8 from Table 1; BDNF and compound 9 from Table 1; BDNF and compound 10 from Table 1; BDNF and compound 11 from Table 1; BDNF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); BDNF and FAIM; BDNF and NOL3; BDNF and DcR1; BDNF and DcR2; BDNF and DcR3; GDNF and C-type natriuretic peptide; GDNF and native C-type natriuretic peptide; GDNF and natriuretic peptide receptor-B; GDNF and bicyclol; GDNF and FLIP; GDNF and MET12; GDNF and compound 1 from Table 1; GDNF and compound 2 from Table 1; GDNF and compound 3 from Table 1; GDNF and compound 4 from Table 1; GDNF and compound 5 from Table 1; GDNF and compound 6 from Table 1; GDNF and compound 7 from Table 1; GDNF and compound 8 from Table 1; GDNF and compound 9 from Table 1; GDNF and compound 10 from Table 1; GDNF and compound 11 from Table 1; GDNF and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); GDNF and FAIM; GDNF and NOL3; GDNF and DcR1; GDNF and DcR2; GDNF and DcR3; C-type natriuretic peptide and native C-type natriuretic peptide; C-type natriuretic peptide and natriuretic peptide receptor-B; C-type natriuretic peptide and bicyclol; C-type natriuretic peptide and FLIP; C-type natriuretic peptide and MET12; C-type natriuretic peptide and compound 1 from Table 1; C-type natriuretic peptide and compound 2 from Table 1; C-type Natriuretic peptide and compound 3 from Table 1; C-type natriuretic peptide and compound 4 from Table 1; C-type natriuretic peptide and compound 5 from Table 1; C-type natriuretic peptide and compound 6 from Table 1; C-type natriuretic peptide and compound 7 from Table 1; C-type natriuretic peptide and compound 8 from Table 1; C-type natriuretic peptide and compound 9 from Table 1; C-type natriuretic peptide and compound 10 from Table 1; C-type natriuretic peptide and compound 11 from Table 1; C-type natriuretic peptide and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); C-type natriuretic peptide and FAIM; C-type natriuretic peptide and NOL3; C-type natriuretic peptide and DcR1; C-type natriuretic peptide and DcR2; C-type natriuretic peptide and DcR3; natural C-type natriuretic peptide and natriuretic peptide receptor-B; natural C-type natriuretic peptide and bicyclol; natural C-type natriuretic peptide and FLIP; natural C-type natriuretic peptide and MET12; natural C-type natriuretic peptide and compound 1 from Table 1; natural C-type natriuretic peptide and compound 2 from Table 1; natural C-type natriuretic peptide and Compound 3 from Table 1; natural C-type natriuretic peptide and compound 4 from Table 1; natural C-type natriuretic peptide and compound 5 from Table 1; natural C-type natriuretic peptide and compound 6 from Table 1; natural C-type natriuretic peptide and compound 7 from Table 1; natural C-type natriuretic peptide and compound 8 from Table 1; natural C-type natriuretic peptide and compound 9 from Table 1; natural C-type natriuretic peptide and compound 10 from Table 1; natural C-type natriuretic peptide and compound 11 from Table 1; natural C-type natriuretic peptide and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); natural C-type natriuretic peptide and FAIM; natural C-type natriuretic peptide and NOL3; natural C-type natriuretic peptide and DcR1; natural C-type natriuretic peptide and DcR2; natural C-type natriuretic peptide and DcR3; natriuretic peptide receptor-B and bicyclol; natriuretic peptide receptor-B and FLIP; natriuretic peptide receptor-B and MET12; natriuretic peptide receptor-B and compound 1 from Table 1; natriuretic peptide receptor-B and compound 2 from Table 1; natriuretic peptide receptor-B and compound 1 from Table 1 Compound 3; natriuretic peptide receptor-B and compound 4 from Table 1; natriuretic peptide receptor-B and compound 5 from Table 1; natriuretic peptide receptor-B and compound 6 from Table 1; natriuretic peptide receptor-B and compound 7 from Table 1; natriuretic peptide receptor-B and compound 8 from Table 1; natriuretic peptide receptor-B and compound 9 from Table 1; natriuretic peptide receptor-B and compound 10 from Table 1; natriuretic peptide receptor-B and compound 11 from Table 1; natriuretic peptide receptor-B and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); natriuretic peptide receptor-B and FAIM; natriuretic peptide receptor-B and NOL3; natriuretic peptide receptor-B and DcR1; natriuretic peptide receptor-B and DcR2; natriuretic peptide receptor-B and DcR3; bicyclic alcohol and FLIP; bicyclic alcohol and MET12; bicyclic alcohol and compound 1 from Table 1; bicyclic alcohol and compound 2 from Table 1; bicyclic alcohol and compound 3 from Table 1; bicyclic alcohol and compound 4 from Table 1; bicyclic alcohol and compound 5 from Table 1; bicyclic alcohol and compound 6 from Table 1; bicyclic alcohol and compound 7 from Table 1; bicyclic alcohol and compound 8 from Table 1; bicyclic alcohol and compound 9 from Table 1; bicyclic alcohol and compound 10 from Table 1; bicyclic alcohol and compound 11 from Table 1; bicyclic alcohol and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); bicyclic alcohol and FAIM; bicyclic alcohol and NOL3; bicyclic alcohol and DcR1; bicyclic alcohol and DcR2; bicyclic alcohol and DcR3; FLIP and MET12; FLIP and compound 1 from Table 1; FLIP and compound 2 from Table 1; FLIP and compound 3 from Table 1; FLIP and compound 4 from Table 1; FLIP and compound 5 from Table 1; FLIP and compound 6 from Table 1; FLIP and compound 7 from Table 1; FLIP and compound 8 from Table 1; FLIP and compound 9 from Table 1; FLIP and compound 10 from Table 1; FLIP and compound 11 from Table 1; FLIP and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); FLIP and FAIM; FLIP and NOL3; FLIP and DcR1; FLIP and DcR2; FLIP and DcR3; MET12 and compound 1 from Table 1; MET12 and compound 2 from Table 1; MET12 and compound 3 from Table 1; MET12 and compound 4 from Table 1; MET12 and compound 5 from Table 1; MET12 and compound 6 from Table 1; MET12 and compound 7 from Table 1; MET12 and compound 8 from Table 1; MET12 and compound 9 from Table 1; MET12 and compound 10 from Table 1; MET12 and compound 11 from Table 1; MET12 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); MET12 and FAIM; MET12 and NOL3; MET12 and DcR1; MET12 and DcR2; MET12 and DcR3; Compound 1 from Table 1 and Compound 2 from Table 1; Compound 1 from Table 1 and Compound 3 from Table 1; Compound 1 from Table 1 and Compound 4 from Table 1; Compound 1 from Table 1 and Compound 5 from Table 1; Compound 1 from Table 1 and Compound 6 from Table 1; Compound 1 from Table 1 and Compound 7 from Table 1; Compound 1 from Table 1 and Compound 8 from Table 1; Compound 1 from Table 1 and Compound 9 from Table 1; Compound 1 from Table 1 and Compound 10 from Table 1; Compound 1 from Table 1 and Compound 11 from Table 1; Compound 1 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 1 and FAIM from Table 1; Compound 1 and NOL3 from Table 1; Compound 1 and DcR1 from Table 1; Compound 1 and DcR2 from Table 1; Compound 1 and DcR3 from Table 1; Compound 2 from Table 1 and Compound 3 from Table 1; Compound 2 from Table 1 and Compound 4 from Table 1; Compound 2 from Table 1 and Compound 5 from Table 1; Compound 2 from Table 1 and Compound 6 from Table 1; Compound 2 from Table 1 and Compound 7 from Table 1; Compound 2 from Table 1 and Compound 8 from Table 1; Compound 2 from Table 1 and Compound 9 from Table 1; Compound 2 from Table 1 and Compound 10 from Table 1; Compound 2 from Table 1 and Compound 11 from Table 1; Compound 2 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 2 and FAIM from Table 1; Compound 2 and NOL3 from Table 1; Compound 2 and DcR1 from Table 1; Compound 2 and DcR2 from Table 1; Compound 2 and DcR3 from Table 1; Compound 3 from Table 1 and Compound 4 from Table 1; Compound 3 from Table 1 and Compound 5 from Table 1; Compound 3 from Table 1 and Compound 6 from Table 1; Compound 3 from Table 1 and Compound 7 from Table 1; Compound 3 from Table 1 and Compound 8 from Table 1; Compound 3 from Table 1 and Compound 9 from Table 1; Compound 3 from Table 1 and Compound 10 from Table 1; Compound 3 from Table 1 and Compound 11 from Table 1; Compound 3 from Table 1 and H 60 HIYLGATNYIY 71-NH2(SEQ ID NO:4); Compound 3 and FAIM from Table 1; Compound 3 and NOL3 from Table 1; Compound 3 and DcR1 from Table 1; Compound 3 and DcR2 from Table 1; Compound 3 and DcR3 from Table 1; Compound 4 from Table 1 and Compound 5 from Table 1; Compound 4 from Table 1 and Compound 6 from Table 1; Compound 4 from Table 1 and Compound 7 from Table 1; Compound 4 from Table 1 and Compound 8 from Table 1; Compound 4 from Table 1 and Compound 9 from Table 1; Compound 4 from Table 1 and Compound 10 from Table 1; Compound 4 from Table 1 and Compound 11 from Table 1; Compound 4 from Table 1 and H 60 HIYLGATNYIY 71 -NH2(SEQ ID NO:4); Compound 4 and FAIM from Table 1; Compound 4 and NOL3 from Table 1; Compound 4 and DcR1 from Table 1; Compound 4 and DcR2 from Table 1; Compound 4 and DcR3 from Table 1; Compound 5 from Table 1 and Compound 6 from Table 1; Compound 5 from Table 1 and Compound 7 from Table 1; Compound 5 from Table 1 and Compound 8 from Table 1; Compound 5 from Table 1 and Compound 9 from Table 1; Compound 5 from Table 1 and Compound 10 from Table 1; Compound 5 from Table 1 and Compound 11 from Table 1; Compound 5 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 5 from Table 1 and FAIM; Compound 5 from Table 1 and NOL3; Compound 5 from Table 1 and DcR1; Compound 5 from Table 1 and DcR2; Compound 5 from Table 1 and DcR3; Compound 6 from Table 1 and Compound 7 from Table 1; Compound 6 from Table 1 and Compound 8 from Table 1; Compound 6 from Table 1 and Compound 9 from Table 1; Compound 6 from Table 1 and Compound 10 from Table 1; Compound 6 from Table 1 and Compound 11 from Table 1; Compound 6 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 6 from Table 1 and FAIM; Compound 6 from Table 1 and NOL3; Compound 6 from Table 1 and DcR1; Compound 6 from Table 1 and DcR2; Compound 6 from Table 1 and DcR3; Compound 7 from Table 1 and Compound 8 from Table 1; Compound 7 from Table 1 and Compound 9 from Table 1; Compound 7 from Table 1 and Compound 10 from Table 1; Compound 7 from Table 1 and Compound 11 from Table 1; Compound 7 from Table 1 and H 60 HIYLGATNYIY71 -NH2 (SEQ ID NO: 4); Compound 7 from Table 1 and FAIM; Compound 7 from Table 1 and NOL3; Compound 7 from Table 1 and DcR1; Compound 7 from Table 1 and DcR2; Compound 7 from Table 1 and DcR3; Compound 8 from Table 1 and Compound 9 from Table 1; Compound 8 from Table 1 and Compound 10 from Table 1; Compound 8 from Table 1 and Compound 11 from Table 1; Compound 8 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 8 from Table 1 and FAIM; Compound 8 from Table 1 and NOL3; Compound 8 from Table 1 and DcR1; Compound 8 from Table 1 and DcR2; Compound 8 from Table 1 and DcR3; Compound 9 from Table 1 and Compound 10 from Table 1; Compound 9 from Table 1 and Compound 11 from Table 1; Compound 9 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 9 from Table 1 and FAIM; Compound 9 from Table 1 and NOL3; Compound 9 from Table 1 and DcR1; Compound 9 from Table 1 and DcR2; Compound 9 from Table 1 and DcR3; Compound 10 from Table 1 and Compound 11 from Table 1; Compound 10 from Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 10 from Table 1 and FAIM; Compound 10 from Table 1 and NOL3; Compound 10 from Table 1 and DcR1; Compound 10 from Table 1 and DcR2; Compound 10 from Table 1 and DcR3; Compound 11 from Table 1 and H 60 HIYLGATNYIY 71 -NH2(SEQ ID NO:4); Compound 11 from Table 1 and FAIM; Compound 11 from Table 1 and NOL3; Compound 11 from Table 1 and DcR1; Compound 11 from Table 1 and DcR2; Compound 11 from Table 1 and DcR3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and FAIM; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and NOL3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DcR1; H 60HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DcR2; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO:4) and DcR3; FAIM and NOL3; FAIM and DcR1; FAIM and DcR2; FAIM and DcR3; NOL3 and DcR1; NOL3 and DcR2; NOL3 and DcR3; and DcR1 and DcR2; DcR1 and DcR3; DCR2 and DCR3.

[0126] Some covalently linked combinations are represented by the following structural formulas:

[0127] Formula C-1. P6—MET12

[0128] Formula C-2. P6—MET12—P6

[0129] Formula C-3. MET12—P6—MET12

[0130] Formula C-4. P6—GGG—MET12

[0131] Formula C-5. MET12—GGG—P6

[0132] Formula C-6. P6—GGG—MET12—GGG—P6

[0133] Formula C-7. MET12—GGG—P6—GGG—MET12

[0134] Formula C-8. P6—(N—AEAc) x —MET12

[0135] Formula C-9. MET12—(N—AEEAc) x —P6

[0136] Formula C-10. MET12—(N—AEEAc) x —P6—(N—AEEAc) y —MET12

[0137] Formula C-11. P6—(N—AEEAc) x —MET12—(N—AEEAc) y —P6

[0138] Formula C-12. P6—(N—dPEG12) x —MET12

[0139] Formula C-13. P21—MET12

[0140] Formula C-14. P21—MET12—P21

[0141] Formula C-15. MET12—P21—MET12

[0142] Formula C-16. P21—GGG—MET12

[0143] Formula C-17. MET12—GGG—P21

[0144] Formula C-18. P21—GGG—MET12—GGG—P21

[0145] Formula C-19. MET12—GGG—P21—GGG—MET12

[0146] Formula C-20. P21—(N—AEAc) x —MET12

[0147] Formula C-21. MET12—(N—AEEAc) x —P21

[0148] Formula C-22. MET12—(N—AEEAc) x —P21—(N—AEEAc) y —MET12

[0149] Formula C-23. P21—(N—AEEAc) x —MET12—(N—AEEAc) y —P21

[0150] Formula C-24. P21—(N—dPEG12) x —MET12

[0151] Formula C-25. P6—(O—AEAc) x —MET12

[0152] Formula C-26. MET12—(O—AEEAc) x —P6

[0153] Formula C-27. MET12—(O—AEEAc) x —P6—(O—AEEAc) y —MET12

[0154] Formula C-28. P6—(O—AEEAc) x —MET12—(O—AEEAc) y —P6

[0155] Formula C-29. P6—(O—dPEG12) x —MET12

[0156] Formula C-30. P21—(O—AEAc) x —MET12

[0157] Formula C-31. MET12—(O—AEEAc) x —P21

[0158] Formula C-32. MET12—(O—AEEAc) x —P21—(O—AEEAc) y —MET12

[0159] Formula C-33. P21—(O—AEEAc) x —MET12—(O—AEEAc) y —P21

[0160] Formula C-34. P21—(O—dPEG12) x —MET12

[0161] Formula C-35. P6—MET12—BC

[0162] Formula C-36. P6—MET12—P6—BC

[0163] Formula C-37. MET12—P6—MET12—BC

[0164] Formula C-38. P6—GGG—MET12—BC

[0165] Formula C-39. MET12—GGG—P6—BC

[0166] Formula C-40. P6—GGG—MET12—GGG—P6—BC

[0167] Formula C-41. MET12—GGG—P6—GGG—MET12—BC

[0168] Formula C-42. P6—(N—AEAc) x —MET12—BC

[0169] Formula C-43. MET12—(N—AEEAc) x —P6—BC

[0170] Formula C-44. MET12—(N—AEEAc) x —P6—(N—AEEAc) y —MET12—BC

[0171] Formula C-45. P6—(N—AEEAc) x —MET12—(N—AEEAc) y —P6—BC

[0172] Formula C-46. P6—(N—dPEG12) x —MET12—BC

[0173] Formula C-47. P21—MET12—BC

[0174] Formula C-48. P21—MET12—P21—BC

[0175] Formula C-49. MET12—P21—MET12—BC

[0176] Formula C-50. P21—GGG—MET12—BC

[0177] Formula C-51. MET12—GGG—P21—BC

[0178] Formula C-52. P21—GGG—MET12—GGG—P21—BC

[0179] Formula C-53. MET12—GGG—P21—GGG—MET12—BC

[0180] Formula C-54. P21—(N—AEAc) x —MET12—BC

[0181] Formula C-55. MET12—(N—AEEAc) x —P21—BC

[0182] Formula C-56. MET12—(N—AEEAc) x —P21—(N—AEEAc) y —MET12—BC

[0183] Formula C-57. P21—(N—AEEAc) x —MET12—(N—AEEAc) y —P21—BC

[0184] Formula C-58. P21—(N—dPEG12) x —MET12—BC

[0185] Formula C-59. P6—(O—AEAc) x —MET12—BC

[0186] Formula C-60. MET12—(O—AEEAc) x —P6—BC

[0187] Formula C-61. MET12—(O—AEEAc) x —P6—(O—AEEAc) y —MET12—BC

[0188] Formula C-62. P6—(O—AEEAc) x —MET12—(O—AEEAc) y —P6—BC

[0189] Formula C-63. P6—(O—dPEG12) x —MET12—BC

[0190] Formula C-64. P21—(O—AEAc) x —MET12—BC

[0191] Formula C-65. MET12—(O—AEEAc) x —P21—BC

[0192] Formula C-66. MET12—(O—AEEAc) x —P21—(O—AEEAc) y —MET12—BC

[0193] Formula C-67. P21—(O—AEEAc) x —MET12—(O—AEEAc) y —P21—BC

[0194] Formula C-68. P21—(O—dPEG12) x —MET12—BC

[0195] Formula C-69. BC—P6—MET12

[0196] Formula C-70. BC—P6—MET12—P6

[0197] Formula C-71. BC—MET12—P6—MET12

[0198] Formula C-72. BC—P6—GGG—MET12

[0199] Formula C-73. BC—MET12—GGG—P6

[0200] Formula C-74. BC—P6—GGG—MET12—GGG—P6

[0201] Formula C-75. BC—MET12—GGG—P6—GGG—MET12

[0202] Formula C-76. BC—P6—(N—AEAc) x —MET12

[0203] Formula C-77. BC—MET12—(N—AEEAc) x —P6

[0204] Formula C-78. BC—MET12—(N—AEEAc) x —P6—(N—AEEAc) y —MET12

[0205] Formula C-79. BC—P6—(N—AEEAc) x —MET12—(N—AEEAc) y —P6

[0206] Formula C-80. BC—P6—(N—dPEG12) x —MET12

[0207] Formula C-81. BC—P21—MET12

[0208] Formula C-82. BC—P21—MET12—P21

[0209] Formula C-83. BC—MET12—P21—MET12

[0210] Formula C-84. BC—P21—GGG—MET12

[0211] Formula C-85. BC—MET12—GGG—P21

[0212] Formula C-86. BC—P21—GGG—MET12—GGG—P21

[0213] Formula C-87. BC—MET12—GGG—P21—GGG—MET12

[0214] Formula C-88. BC—P21—(N—AEAc) x —MET12

[0215] Formula C-89. BC—MET12—(N—AEEAc) x —P21

[0216] Formula C-90. BC—MET12—(N—AEEAc)x —P21—(N—AEEAc) y —MET12

[0217] Formula C-91. BC—P21—(N—AEEAc) x —MET12—(N—AEEAc) y —P21

[0218] Formula C-92. BC—P21—(N—dPEG12) x —MET12

[0219] Formula C-93. BC—P6—(O—AEAc) x —MET12

[0220] Formula C-94. BC—MET12—(O—AEEAc) x —P6

[0221] Formula C-95. BC—MET12—(O—AEEAc) x —P6—(O—AEEAc) y —MET12

[0222] Formula C-96. BC—P6—(O—AEEAc) x —MET12—(O—AEEAc) y —P6

[0223] Formula C-97. BC—P6—(O—dPEG12) x —MET12

[0224] Formula C-98. BC—P21—(O—AEAc) x —MET12

[0225] Formula C-99. BC—MET12—(O—AEEAc) x —P21

[0226] Formula C-100. BC—MET12—(O—AEEAc) x —P21—(O—AEEAc) y —MET12

[0227] Formula C-101. BC—P21—(O—AEEAc) x —MET12—(O—AEEAc) y —P21

[0228] Formula C-102. BC—P21—(O—dPEG12) x —MET12

[0229] Formula C-105. P6—MET4-8

[0230] Formula C-106. P6—MET4-8—P6

[0231] Formula C-107. MET4-8—P6—MET4-8

[0232] Formula C-108. P6—GGG—MET4-8

[0233] Formula C-109. MET4-8—GGG—P6

[0234] Formula C-110. P6—GGG—MET4-8—GGG—P6

[0235] Formula C-111. MET4-8—GGG—P6—GGG—MET4-8

[0236] Formula C-112. P6—(N—AEAc) x —MET4-8

[0237] Formula C-113. MET4-8—(N—AEEAc) x —P6

[0238] Formula C-114. MET4-8—(N—AEEAc) x —P6—(N—AEEAc) y —MET4-8

[0239] Formula C-115. P6—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P6

[0240] Formula C-116. P6—(N—dPEG12) x —MET4-8

[0241] Formula C-117. P21—MET4-8

[0242] Formula C-118. P21—MET4-8—P21

[0243] Formula C-119. MET4-8—P21—MET4-8

[0244] Formula C-120. P21—GGG—MET4-8

[0245] Formula C-121. MET4-8—GGG—P21

[0246] Formula C-122. P21—GGG—MET4-8—GGG—P21

[0247] Formula C-123. MET4-8—GGG—P21—GGG—MET4-8

[0248] Formula C-124. P21—(N—AEAc) x —MET4-8

[0249] Formula C-125. MET4-8—(N—AEEAc) x —P21

[0250] Formula C-126. MET4-8—(N—AEEAc) x —P21—(N—AEEAc) y —MET4-8

[0251] Formula C-127. P21—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P21

[0252] Formula C-128. P21—(N—dPEG12) x —MET4-8

[0253] Formula C-129. P6—(O—AEAc) x —MET4-8

[0254] Formula C-130. MET4-8—(O—AEEAc) x —P6

[0255] Formula C-131. MET4-8—(O—AEEAc) x —P6—(O—AEEAc) y —MET4-8

[0256] Formula C-132. P6—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P6

[0257] Formula C-133. P6—(O—dPEG12) x —MET4-8

[0258] Formula C-134. P21—(O—AEAc) x —MET4-8

[0259] Formula C-135. MET4-8—(O—AEEAc) x —P21

[0260] Formula C-136. MET4-8—(O—AEEAc) x —P21—(O—AEEAc) y —MET4-8

[0261] Formula C-137. P21—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P21

[0262] Formula C-138. P21—(O—dPEG12) x —MET4-8

[0263] Formula C-139. P6-MET4-8-BC

[0264] Formula C-140. P6-MET4-8-P6-BC

[0265] Formula C-141. MET4-8—P6—MET4-8—BC

[0266] Formula C-142. P6—GGG—MET4-8—BC

[0267] Formula C-143. MET4-8—GGG—P6—BC

[0268] Formula C-144. P6—GGG—MET4-8—GGG—P6—BC

[0269] Formula C-145. MET4-8—GGG—P6—GGG—MET4-8—BC

[0270] Formula C-146. P6—(N—AEAc) x —MET4-8—BC

[0271] Formula C-147. MET4-8—(N—AEEAc) x —P6—BC

[0272] Formula C-148. MET4-8—(N—AEEAc) x —P6—(N—AEEAc) y —MET4-8—BC

[0273] Formula C-149. P6—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P6—BC

[0274] Formula C-150. P6—(N—dPEG12)x —MET4-8—BC

[0275] Formula C-151. P21-MET4-8-BC

[0276] Formula C-152. P21-MET4-8-P21-BC

[0277] Formula C-153. MET4-8—P21—MET4-8—BC

[0278] Formula C-154. P21—GGG—MET4-8—BC

[0279] Formula C-155. MET4-8—GGG—P21—BC

[0280] Formula C-156. P21—GGG—MET4-8—GGG—P21—BC

[0281] Formula C-157. MET4-8—GGG—P21—GGG—MET4-8—BC

[0282] Formula C-158. P21—(N—AEAc) x —MET4-8—BC

[0283] Formula C-159. MET4-8—(N—AEEAc) x —P21—BC

[0284] Formula C-160. MET4-8—(N—AEEAc) x —P21—(N—AEEAc) y —MET4-8—BC

[0285] Formula C-161. P21—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P21—BC

[0286] Formula C-162. P21—(N—dPEG12) x —MET4-8—BC

[0287] Formula C-163. P6—(O—AEAc) x —MET4-8—BC

[0288] Formula C-164. MET4-8—(O—AEEAc) x —P6—BC

[0289] Formula C-165. MET4-8—(O—AEEAc) x—P6—(O—AEEAc) y —MET4-8—BC

[0290] Formula C-166. P6—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P6—BC

[0291] Formula C-167. P6—(O—dPEG12) x —MET4-8—BC

[0292] Formula C-168. P21—(O—AEAc) x —MET4-8—BC

[0293] Formula C-169. MET4-8—(O—AEEAc) x —P21—BC

[0294] Formula C-170. MET4-8—(O—AEEAc) x —P21—(O—AEEAc) y —MET4-8—BC

[0295] Formula C-171. P21—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P21—BC

[0296] Formula C-172. P21—(O—dPEG12) x —MET4-8—BC

[0297] Formula C-173. BC—P6—MET4-8

[0298] Formula C-174. BC—P6—MET4-8—P6

[0299] Formula C-175. BC—MET4-8—P6—MET4-8

[0300] Formula C-176. BC—P6—GGG—MET4-8

[0301] Formula C-177. BC—MET4-8—GGG—P6

[0302] Formula C-178. BC—P6—GGG—MET4-8—GGG—P6

[0303] Formula C-179. BC—MET4-8—GGG—P6—GGG—MET4-8

[0304] Formula C-180. BC—P6—(N—AEAc) x —MET4-8

[0305] Formula C-181. BC—MET4-8—(N—AEEAc) x —P6

[0306] Formula C-182. BC—MET4-8—(N—AEEAc) x —P6—(N—AEEAc) y —MET4-8

[0307] Formula C-183. BC—P6—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P6

[0308] Formula C-184. BC—P6—(N—dPEG12) x —MET4-8

[0309] Formula C-185. BC—P21—MET4-8

[0310] Formula C-186. BC—P21—MET4-8—P21

[0311] Formula C-187. BC—MET4-8—P21—MET4-8

[0312] Formula C-188. BC—P21—GGG—MET4-8

[0313] Formula C-189. BC—MET4-8—GGG—P21

[0314] Formula C-190. BC—P21—GGG—MET4-8—GGG—P21

[0315] Formula C-191. BC—MET4-8—GGG—P21—GGG—MET4-8

[0316] Formula C-192. BC—P21—(N—AEAc) x —MET4-8

[0317] Formula C-193. BC—MET4-8—(N—AEEAc) x —P21

[0318] Formula C-194. BC—MET4-8—(N—AEEAc) x —P21—(N—AEEAc) y —MET4-8

[0319] Formula C-195. BC—P21—(N—AEEAc) x —MET4-8—(N—AEEAc) y —P21

[0320] Formula C-196. BC—P21—(N—dPEG12) x —MET4-8

[0321] Formula C-197. BC—P6—(O—AEAc) x —MET4-8

[0322] Formula C-198. BC—MET4-8—(O—AEEAc) x —P6

[0323] Formula C-199. BC—MET4-8—(O—AEEAc) x —P6—(O—AEEAc) y —MET4-8

[0324] Formula C-200. BC—P6—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P6

[0325] Formula C-201. BC—P6—(O—dPEG12) x —MET4-8

[0326] Formula C-202. BC—P21—(O—AEAc) x —MET4-8

[0327] Formula C-203. BC—MET4-8—(O—AEEAc) x —P21

[0328] Formula C-204. BC—MET4-8—(O—AEEAc) x —P21—(O—AEEAc) y —MET4-8

[0329] Formula C-205. BC—P21—(O—AEEAc) x —MET4-8—(O—AEEAc) y —P21

[0330] Formula C-206. BC—P21—(O—dPEG12) x —MET4-8

[0331] For the above structural formulas C-1 to C-102 and C-105 to C-206, x is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In formulas C-1 to C-206, P6 or P21 includes any peptide containing the sequence DGGL (SEQ ID NO: 20). Binding can occur at either end or at any position of MET12, MET4-8, P6, P21 or BC. For example, "P6-MET12" represents P6-MET12 and MET12-P6; P6, MET12, GGG, N-AEEAc, N-dPEG12, etc. represent corresponding compounds whose structures are modified to accommodate the represented bonding. For example,

[0332] P6 is Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1).

[0333] MET12 is (SEQ ID NO: 3).

[0334] One potential structure of P6-MET12 (P6 and MET12 are disclosed as SEQ ID NOs: 1 and 3, respectively) is:

[0335]

[0336] Some of the covalently linked compounds used in drug delivery systems include:

[0337]

[0338] For any relevant structural representation, such as Formula C103 or C104, z is 0-10000, 0-1000, 1000-2000, 2000-3000, 3000-4000, 4000-5000, 5000-6000, 5000-6000, 6000-7000, 8000-9000, 9000-10000, 0-5000 or 5000-10000.

[0339] For any relevant structural representation, such as Formula C104, Y is N or O.

[0340] For any relevant structural expression, such as formula C104, A 1 is P6, P21 or a group derived from C1-C34, for example, as described above, with the relevant atoms removed to accommodate bonding.

[0341] For any relevant structural expression, such as formula C104, A 2 It is –OCH2CH2O- or –NHCH2CH2N-.

[0342] Some examples of bimatoprost acid covalently linked to MET4-8 (e.g., MET4, MET5, MET6, MET7, or MET8), MET12, P6, or P21 are represented by formula C207:

[0343]

[0344]

[0345] Wherein, n is about 2-2000, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 2-30, 30-60, 60-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000-1100, 1100-1200 , 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900, 1900-2000, 2-500, 500-1000, 2-1000, 1000-1500, 1500-2000 or 1000-2000; and RH is MET4-8 (e.g., MET4, MET5, MET6, MET7 or MET8), MET12, P6, P21, or a peptide containing the sequence DGGL (SEQ ID NO: 20).

[0346] For example, bimatoprost acid covalently linked to MET4 can be represented by formula C-208:

[0347]

[0348] The sustained-release component is a part of a drug delivery system, which allows the drug to keep a period of continuous time in vivo, for example, far exceeds the time that the drug is metabolized or excreted from the body, such as at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 5 years or longer. Usually, the sustained-release component is an implant, such as a solid implant, which plays a role by encapsulating the drug or otherwise embedding the drug in the implant. If the implant is biodegradable or bioerodible, the drug can be released along with the biodegradation or bioerosion of the implant. The implant can also be porous, so that after a period of time, the drug can diffuse out of the implant. The biodegradable or bioerodible implant can be porous or non-porous. Usually, non-biodegradable or non-bioerodible implants are porous, and the drug is released by diffusion. However, other mechanisms may also operate, such as osmotic pumps.

[0349] In some embodiments, the drug delivery system can be implanted in a mammal, such as a human, at intervals of about 1 week to about 10 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 0.1-3 years, about 3-5 years, or about 5-10 years.

[0350] In some embodiments, a therapeutic effect, such as reduced intraocular pressure or reduced vision loss, can be observed at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 5 years, from about 1 week to about 10 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 0.1-3 years, about 3-5 years, about 5-10 years, or longer after implantation of the drug delivery system in a mammal, such as a human.

[0351] The drug may be physically entrapped in the sustained release component and / or may be covalently bonded to a molecule that is part of the sustained release component.

[0352] Typical examples of biodegradable materials for porous or non-porous biodegradable implants generally include: silica-based materials, or organic biodegradable materials, such as polymers containing poly (D, L-lactic acid) (PLA) and poly (D, L-lactic-co-glycolic acid) (PLGA), polyesteramides (PEA, DSM Chemical) and polycaprolactone (PCL); hydrogels, such as polyvinyl alcohol (PVA), PEG amines, PEG-N-hydroxysuccinamide esters (such as Ocular Therapeux), etc.; collagen-based materials (e.g., Euclid Systems); or combinations thereof.

[0353] There are many suitable silicon dioxide based sustained release components.

[0354] One type of silica-based sustained-release component includes a silica hydrogel composite, which can be obtained by mixing silica particles (which contain encapsulated drugs) with silica sols, wherein the resulting hydrogel composite is shear-thinning. This type of delivery system is an injectable all-silica-based microparticle-silica hydrogel controlled-release system that uses different types of encapsulated therapeutic agents and bioactive agents to significantly reduce burst. A detailed description of such silica-based sustained-release components and their preparation methods can be found in U.S. Patent No. 9,949,922, issued to Jokinen et al. on April 24, 2018, which is incorporated herein by reference in its entirety.

[0355] Another type of silica-based sustained-release component includes a flowing silica composition and a gel containing a drug, which can be obtained by a method for preparing a flowing silica composition, including a sol-gel conversion, wherein redispersion is performed. The redispersion includes: after reaching the gel point of the sol-gel conversion, a liquid is added to the gel formed by the sol-gel conversion, and added within a sufficiently short time period after reaching the gel point, so as to produce a rheologically uniform flowing silica composition after the gel and liquid are mixed, which is injectable and remains injectable through a 22G fine needle in this way or by stirring for a short time <30 seconds. These flowing and injectable sustained-release silica compositions can increase the stability of the encapsulated therapeutic agent and maintain its activity. A detailed description of such a silica-based sustained-release component and its preparation method can be found in U.S. Patent Application No. 20140057996 of Jokinen et al., published on February 27, 2014, which is incorporated herein by reference in its entirety.

[0356] Another type of silica-based sustained-release component includes a composition comprising a bioerodible porous silica-based carrier material, wherein the carrier material carries the drug and at least one amorphous sugar, optionally also comprising a crystallization inhibitor. These delivery systems include loading the biomolecule into the pores of the silica carrier material, thereby stabilizing the biomolecule. However, these systems can also be used for small molecule therapeutic compounds. A detailed description of such silica-based sustained-release components and methods for preparing them can be found in U.S. Patent No. 9,603,801, issued to Barnett et al. on March 24, 2017, which is incorporated herein by reference in its entirety.

[0357] Another type of slow-release component based on silica comprises bioerodible equipment, such as implants for delivering medicine in a controlled manner. The equipment comprises porous carrier materials based on silica that are impregnated or loaded with medicine. These specific silica carrier materials comprise at least one macromolecular therapeutic agent that is arranged in the hole of carrier material. It is believed that large therapeutic molecules are loaded into the hole of carrier material to stabilize macromolecules. In many embodiments, macromolecules are proteins and the hole has an average size of about 15nm to about 40nm, and proteins have a molecular weight of about 100000amu to about 200000amu. However, these systems can also be used for small molecule therapeutic compounds. A detailed description of such a silicon dioxide-based sustained-release component and methods for its preparation may be found in U.S. Pat. No. 9,808,421, issued to Ashton et al. on November 7, 2017, U.S. Pat. No. 9,333,173, issued to Ashton et al. on May 10, 2016, and U.S. Patent Publication No. 20140271764, published on September 28, 2014 to Ashton et al., all of which are incorporated herein by reference in their entirety.

[0358] The sustained-release component can have any suitable mass, such as about 1 μg-100 mg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90 μg-100 μg, about 100-200 μg, about 200-300 μg, about 300-40 0μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg , about 90-100mg, about 100-200mg, about 200-300mg, about 300mg-400mg, about 400-500mg, about 500-600mg, about 600-700mg, about 700-800mg, about 800-900mg, about 900-1000mg, about 1-2g, about 2-3g, about 3-4g, about 4-5g, about 5-6g, about 6-7g, about 7-8g, about 8-9g, about 9-10g, about 10-20g, about 20-30g, about 30-40g, about 40-50g, about 50-6 In some embodiments, the present invention relates to a drug delivery system for delivering an eye to an eye. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less.

[0359] The sustained release component can be any suitable percentage of the implant, such as about 1-99wt%, about 1-10wt%, about 10-20wt%, about 20-30wt%, about 30-40wt%, about 40-50wt%, about 50-60wt%, about 60-70wt%, about 70-80wt%, about 80-90wt%, about 90-99wt%, about 1-30wt%, about 30-65wt%, about 65-99wt%, about 1-50wt% or about 50-99wt%.

[0360] The drug delivery system can have any suitable size, such as about 1 μg-100 mg, about 1-2 μg, about 2-3 μg, about 3-4 μg, about 4-5 μg, about 5-6 μg, about 6-7 μg, about 7-8 μg, about 8-9 μg, about 9-10 μg, about 10-20 μg, about 20-30 μg, about 30-40 μg, about 40-50 μg, about 50-60 μg, about 60-70 μg, about 70-80 μg, about 80-90 μg, about 90 μg-100 μg, about 100-200 μg, about 200-300 μg, about 300-400 μg. 00μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 800-900μg, about 900-1000μg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90m g, about 90-100 mg, about 100-200 mg, about 200-300 mg, about 300 mg-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1000 mg, about 1-2 g, about 2-3 g, about 3-4 g, about 4-5 g, about 5-6 g, about 6-7 g, about 7-8 g, about 8-9 g, about 9-10 g, about 10-20 g, about 20-30 g, about 30-40 g, about 40-50 g, about 50-6 In some embodiments, the present invention relates to a drug delivery system for delivering an eye to an eye. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less. In some embodiments, the drug delivery system for delivering an eye to an eye has a dosage of about 1 g or less, or about 100 mg or less.

[0361] The drug delivery system can deliver any suitable amount of drug per day, such as about 5-1000 ng, about 5-20 ng, about 20-40 ng, about 40-60 ng, about 60-80 ng, about 80-100 ng, about 100-150 ng, about 150-200 ng, about 200-300 ng, about 300-400 ng, about 400-500 ng, about 500-600 ng, about 600-800 ng, about 800-1000 ng, about 5-100 ng, about 100-300 ng, about 300-600 ng or about 600-1000 ng.

[0362] Typical examples of non-biodegradable or non-bioerodible materials for implants include silicone or PVA as a semi-permeable membrane (eg, Psivida).

[0363] Other potential sustained-release components may be based on cell-based approaches, such as encapsulated cell technology; and reservoir-type approaches (forsight4; Replenish).

[0364] The prostaglandin compound or prostaglandin receptor agonist, IOP reducing agent, and / or neurotrophic agent (eg, CNTF compound) may or may not be covalently linked to the sustained release component.

[0365] In some embodiments, the prostaglandin compound or prostaglandin receptor agonist is covalently attached to the sustained release component. In some embodiments, the prostaglandin compound or prostaglandin receptor agonist is not covalently attached to the sustained release component.

[0366] In some embodiments, the intraocular pressure reducing agent is covalently attached to the sustained release component. In some embodiments, the intraocular pressure reducing agent is not covalently attached to the sustained release component.

[0367] In some embodiments, the neurotrophic agent, such as a CNTF compound, is covalently attached to the sustained release component. In some embodiments, the neurotrophic agent, such as a CNTF compound, is not covalently attached to the sustained release component.

[0368] For example, a prostaglandin compound or prostaglandin receptor agonist may be covalently linked to the sustained release component using a compound represented by the following formula:

[0369]

[0370] Wherein, PG-H is a prostaglandin compound or a prostaglandin receptor agonist, such as the above-mentioned prostaglandin compound or prostaglandin receptor agonist.

[0371] The compound of Formula 3 can be further represented by Formula 3A and 3B:

[0372]

[0373] Among them, Prg-CO2H is a prostaglandin agonist, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0374] The intraocular pressure reducing agent can be covalently linked to the sustained release component using a compound represented by the following formula: Among them, IOP-H is an intraocular pressure lowering agent, such as the intraocular pressure lowering agent mentioned above.

[0375] The CNTF compound or another neurotrophic agent may be covalently linked to the sustained release component using a compound represented by the following formula: Wherein, CNTF-H is a CNTF compound or another neurotrophic agent, such as the CNTF compound or another neurotrophic agent mentioned above.

[0376] The CNP compound can be covalently linked to the sustained release component using a compound represented by the following formula:

[0377]

[0378] Wherein, CNP-H is a CNP compound.

[0379] The NPR-B compound can be covalently linked to the sustained release component using a compound represented by the following formula:

[0380]

[0381] Among them, NPRB-H is a NRP-B compound.

[0382] For any relevant structural representation, such as Formula 3, 3A, 3B, 4, 5, 6 or 7, or the compounds described below, R 1 independently H or C 1-6 Alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0383] For any relevant structural representation, such as Formula 3, 3A, 3B, 4, 5, 6 or 7, or the compounds described below, R 2 independently H or C 1-6 Alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0384] For any relevant structural representation, such as Formula 3, 3A, 3B, 4, 5, 6 or 7, or the compounds described below, R 3 independently H or C 1-6 Alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0385] The following compounds are examples of compounds of Formula 3, 3A or 3B:

[0386]

[0387] In vivo, the ester bond can be hydrolyzed to release the compound:

[0388]

[0389] The following table shows three compounds that are examples of compounds of Formula 4 and that can be released in vivo by hydrolysis of the ester or amide groups:

[0390]

[0391] In the above table, any Si(OH)3 group can be replaced by SiOR 1 OR 2 OR 3 replace.

[0392] Examples of compounds of Formula 5 are: VGDGGLFEKKL-PEG-Si(OH)3 (such as "VGDGGLFEKKL" disclosed in SEQ ID NO: 1) or VGDGGLFEKKL-PEG-SiOR 1 OR 2 OR 3 (such as "VGDGGLFEKKL" disclosed in SEQ ID NO: 1), wherein PEG is a polyethylene glycol chain (e.g., -(OCH2CH2) n -, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). In vivo, the ester bond can be hydrolyzed to release VGDGGLFEKKL (SEQ ID NO: 1).

[0393] SiOR of Formula 3, 3A, 3B, 4, 5, 6 or 7 1 OR 2 OR 3 The group can be covalently bonded to the silica of the silica-based drug delivery system, for example to form a compound represented by Formula 3D, 3AD, 3BD, 4D or 5D, wherein D is a SiOR comprising Formula 3, 3A, 3B, 4, 5, 6 or 7. 1 OR 2 OR 3 The slow-release component of Si.

[0394] PG-L-D

[0395] 3D

[0396]

[0397] IOP-L-D

[0398] Formula 4D

[0399] CNTF-L-D

[0400] Formula 5D

[0401] Some drug delivery systems may comprise a polymer represented by the formula:

[0402]

[0403] Where each X is independently:

[0404]

[0405]

[0406] The main drug delivery system can be administered to mammals (such as humans) by any suitable method, such as by injection or surgical implantation in any part of the body, by oral administration, or by topical application to the eye or skin. In some embodiments, the implant is injected or otherwise implanted in or around the eye, including but not limited to: anterior chamber, vitreous, posterior chamber, subconjunctival space, suprachoroidal space, or subtenon's space.

[0407] The main body drug delivery system can prolong the time amount of drug retention in vivo.For example, drug delivery system can provide the medicine of treatment level at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, at least about 2 years, at least about 3 years, at least about 4 years, about 1-6 months, about 6-12 months, about 12-18 months, about 18-24 months, about 24-36 months, up to about 2 years, up to about 3 years, up to about 4 years, up to about 5 years or up to about 10 years.Can be once injected, implanted or change drug delivery system in the above-mentioned any scope.

[0408] In some embodiments, the subject drug delivery system can be administered to a mammal (such as a human) to treat glaucoma, such as Primary Open-Angle Glaucoma (POAG), Acute Primary Angle Close Glaucoma (APACG), Chronic Angle Closure Glaucoma, Pigmentary Glaucoma, Pseudoexfoliation Glaucoma, Normal Tension Glaucoma, Pediatric Glaucoma, Secondary Glaucoma, etc., or a combination thereof.

[0409] Example

[0410] The following examples are intended to illustrate embodiments of the present disclosure but are not intended to limit the scope or underlying principles in any way.

[0411] Example 1: Solid Phase Synthesis of PG-L-CNTF Characterized by Amide Bonds:

[0412] Using methods known in the art, peptide 6 was linked to the resin at the NH2 terminus, protected with a BOC group and a tert-butyl (t-Bu) ester group, and linked to an NH2-terminated PEG at the carboxylic acid terminus to provide the resin-LK(Boc)-K(Boc)-E(tBu)-FLGGD(tBu)-GV-CO2(CH2-CH2-O) n -CH2-CH2-NH2 (SEQ ID NO: 18). The nature of the starting materials and the reaction sequence can be modified to improve efficiency and selectivity, and all reactions are carried out using methods known in the art. Bimatoprost free acid is prepared by methods known in the art, and its three hydroxyl groups are protected by tert-butyl (or other alkyl- or silyl-protecting groups, as the case may be). The free amine of the protected peptide 6 compound and the free acid of the protected prostaglandin compound can be coupled by any suitable peptide coupling method known in the art. After the coupling reaction, the protected amide can be completely deprotected using TFA or other acid-catalyzed methods known in the art to release the peptide 6-linker-bimatoprost amide derivative. As known in the art, different orthogonal protecting group strategies can be adopted as needed to optimize the efficiency of the entire process.

[0413] Example 2: Solid Phase Synthesis of PG-L-CNTF Characterized by Ester Bonds:

[0414] Peptide 6 was attached to the resin at the NH2 terminus, protected with a CBz group on the free amine group and a benzyl group on the free acid group, and coupled with polyethylene glycol at the carboxylic acid terminus to provide resin-LK(Cbz)-K(Cbz)-E(Bn)-FLGGD(Bn)-GV-CO2(CH2-CH2-O) using methods known in the art. n -CH2-CH2-OH (SEQ ID NO: 19). The properties of the starting materials and the reaction sequence can be modified to improve selectivity, and all reactions are carried out using methods known in the art. Bimatoprost free acid is prepared by methods known in the art, and its three hydroxyl groups are protected by benzyl (or other hydrogenation-unstable protecting groups, as the case may be). The free alcohol end of the protected peptide 6 compound and the free acid of the protected prostaglandin compound can be coupled by any suitable ester coupling method known in the art. After the coupling reaction, the protected ester can be completely deprotected using a hydrogenation method or other debenzylation methods known in the art to release the peptide 6-linker-bimatoprost ester derivative. As known in the art, different orthogonal protecting group strategies can be adopted as needed to optimize the efficiency of the entire process.

[0415] Embodiment 3:

[0416] Eight African green monkeys were screened to identify four animals with high normal IOP. Animals were anesthetized with ketamine 10 mg / kg and xylazine 0.5 mg / kg. 50 μl of 100 ng of bimatoprost acid was injected into the vitreous of one eye using a shelved technique through a 30-gauge syringe, and 50 μl of phosphate buffered saline (PBS) was injected into the contralateral eye at 8:30 p.m. on the 0th, 1st, and 2nd days as a concurrent control. On the 3rd day (8:30 pm) and the 4th day (5:30 pm), the dose of bimatoprost acid was gradually increased to 200 ng in 100 μl, and the same volume of PBS was given in the contralateral eye. IOP was measured with a Tonovet tonometer at 8:30am, 11:30am, and 8:30pm on day 1; at 8:30am, 11:30am, and 5:30pm on day 4; and at 8:30am on days 2, 3, and 5. The person who measured IOP was unaware of treatment assignment. Slit-lamp examination was performed on days 0, 1, and 5. OCT was performed at baseline and on day 5.

[0417] One of four animals (B392) responded to the 100 ng dose with a ≥30% reduction in IOP at 1 time point compared to the fellow eye (a typical effect of a prostaglandin analog on IOP). Three of four animals responded to the 200 ng dose with a ≥30% reduction in IOP at 1 or more time points compared to the fellow eye receiving PBS, and one animal (B392) had a 52% reduction in IOP in the treated eye on Day 5. Notably, this was the same animal that responded to the 100 ng dose, suggesting that this animal was more responsive to bimatoprost acid than the other animals. The time course of IOP reduction is consistent with the short half-life of bimatoprost when injected into the eye by bolus injection. One animal (B300) did not respond to either dose. The actual IOP measurements and the percent reduction in IOP are shown in Figures 1 and , respectively. Figure 2 middle.

[0418] Clinical examination revealed no ocular inflammation, but one animal experienced corneal edema, which was thought to be related to the multiple surgeries and not medication. OCT showed no cystoid macular edema in any animal.

[0419] These results show the obvious IOP lowering effect of bimatoprost acid in the vitreous, with dose response between the dosage of 100ng and 200ng.Due to no observation of ocular inflammation, this is unlikely to be the reason for the IOP reduction of the eye for treatment.Further, this research is covered and controlled, and the same volume is used to carry out vehicle injection in the contralateral eye.Therefore, the IOP result is unlikely to be related to surgery (for example, wound leakage), because only in the eye for treatment, significant IOP reduction is seen.It is expected that further dosage increase will have the effect of even greater IOP reduction.The test article has good tolerance.

[0420] Based on these results, an extended-release form of intravitreal bimatoprost acid is expected to safely achieve clinically meaningful IOP reductions and be well tolerated by patients with the known caveats of prostaglandin or prostaglandin agonist exposure to the retina.

[0421] The inventors specifically contemplate the following embodiments:

[0422] Example 1. A drug delivery system comprising: an intraocular pressure reducing agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor-B (NPR-B) or an inhibitor of apoptosis signaling fragment (FAS) or a FAS-ligand (FASL) inhibitor, and a sustained-release component.

[0423] Example 2. The drug delivery system of Example 1, comprising an intraocular pressure reducing agent.

[0424] Embodiment 3. The drug delivery system of embodiment 2, wherein the intraocular pressure reducing agent is a prostaglandin compound.

[0425] Embodiment 4. The drug delivery system of embodiment 2 or 3, further comprising a second intraocular pressure reducing agent.

[0426] Embodiment 5. The drug delivery system of embodiment 2, 3 or 4, wherein the intraocular pressure reducing agent comprises a beta-blocker.

[0427] Embodiment 6. The drug delivery system of embodiment 2, 3, 4 or 5, wherein the intraocular pressure reducing agent comprises timolol.

[0428] Embodiment 7. The drug delivery system of embodiment 2, 3, 4, 5 or 6, wherein the intraocular pressure reducing agent comprises betaxolol.

[0429] Embodiment 8. The drug delivery system of embodiment 2, 3, 4, 5, 6 or 7, wherein the intraocular pressure reducing agent comprises levobunolol.

[0430] Embodiment 9. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7 or 8, wherein the intraocular pressure reducing agent comprises metipranolol.

[0431] Embodiment 10. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8 or 9, wherein the intraocular pressure reducing agent comprises an alpha adrenergic agonist.

[0432] Embodiment 11. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the intraocular pressure reducing agent comprises brimonidine.

[0433] Embodiment 12. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 or 10, wherein the intraocular pressure reducing agent comprises apraclonidine.

[0434] Embodiment 13. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the intraocular pressure reducing agent comprises a carbonic anhydrase inhibitor.

[0435] Embodiment 14. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein the intraocular pressure reducing agent comprises brinzolamide.

[0436] Embodiment 15. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the intraocular pressure reducing agent comprises acetazolamide.

[0437] Embodiment 16. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the intraocular pressure reducing agent comprises dorzolamide.

[0438] Embodiment 17. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the intraocular pressure reducing agent comprises methazolamide.

[0439] Embodiment 18. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein the intraocular pressure reducing agent comprises a cholinomimetic drug.

[0440] Embodiment 19. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the intraocular pressure reducing agent comprises pilocarpine.

[0441] Embodiment 20. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein the intraocular pressure reducing agent comprises carbachol.

[0442] Embodiment 21. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the intraocular pressure reducing agent comprises a Rho kinase (ROCK) inhibitor.

[0443] Embodiment 22. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the intraocular pressure reducing agent comprises natriuretic acid.

[0444] Embodiment 23. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, comprising a neurotrophic agent.

[0445] Embodiment 24. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, comprising a prostaglandin receptor agonist and a neurotrophic agent.

[0446] Embodiment 25. The drug delivery system of embodiment 24, wherein the prostaglandin receptor agonist and the neurotrophic agent are covalently bonded to each other.

[0447] Embodiment 26. The drug delivery system of embodiment 25, wherein the prostaglandin receptor agonist and the neurotrophic agent are covalently bonded to each other via a linker.

[0448] Embodiment 27. The drug delivery system of embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises bimatoprost.

[0449] Embodiment 28. The drug delivery system of embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises travoprost.

[0450] Embodiment 29. The drug delivery system of embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises latanoprost.

[0451] Embodiment 30. The drug delivery system of embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises nitrolatanoprost.

[0452] Embodiment 31. The drug delivery system of embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises tafluprost.

[0453] Example 32. The drug delivery system of Example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises a prostaglandin EP2 receptor agonist.

[0454] Example 33. The drug delivery system of Example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the prostaglandin receptor agonist comprises a prostaglandin EP3 receptor agonist.

[0455] Embodiment 34. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33, wherein the neurotrophic agent comprises CNTF peptide 6.

[0456] Embodiment 35. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34, wherein the neurotrophic agent comprises CNTF peptide 21.

[0457] Embodiment 36. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, comprising a CNP compound.

[0458] Embodiment 37. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36, comprising an NPR-B compound.

[0459] Embodiment 38. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or 37, comprising an intraocular pressure reducing agent and a neurotrophic agent.

[0460] Embodiment 39. The drug delivery system of Embodiment 38, wherein the intraocular pressure reducing agent and the neurotrophic agent are covalently bonded to each other.

[0461] Embodiment 40. The drug delivery system of Embodiment 39, wherein the intraocular pressure reducing agent and the neurotrophic agent are covalently bonded to each other via a linker.

[0462] Embodiment 41. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, comprising an intraocular pressure reducing agent and a CNP compound.

[0463] Embodiment 42. The drug delivery system of Embodiment 41, wherein the IOP reducing agent and the CNP compound are covalently bonded to each other.

[0464] Embodiment 43. The drug delivery system of Embodiment 42, wherein the IOP reducing agent and the CNP compound are covalently bonded to each other via a linker.

[0465] Embodiment 44. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 or 43, comprising an intraocular pressure reducing agent and an NPR-B compound.

[0466] Embodiment 45. The drug delivery system of Embodiment 44, wherein the intraocular pressure reducing agent and the NPR-B compound are covalently bonded to each other.

[0467] Embodiment 46. The drug delivery system of Embodiment 45, wherein the intraocular pressure reducing agent and the NPR-B compound are covalently bonded to each other via a linker.

[0468] Embodiment 47. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46, comprising a neurotrophic agent and a CNP compound.

[0469] Embodiment 48. The drug delivery system of Embodiment 47, wherein the neurotrophic agent and the CNP compound are covalently bonded to each other.

[0470] Embodiment 49. The drug delivery system of Embodiment 48, wherein the neurotrophic agent and the CNP compound are covalently bonded to each other via a linker.

[0471] Embodiment 50. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, comprising a neurotrophic agent and an NPR-B compound.

[0472] Embodiment 51. The drug delivery system of Embodiment 50, wherein the neurotrophic agent and the NPR-B compound are covalently bonded to each other.

[0473] Embodiment 52. The drug delivery system of Embodiment 51, wherein the neurotrophic agent and the NPR-B compound are covalently bonded to each other via a linker.

[0474] Embodiment 53. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52, comprising a CNP compound and a NPR-B compound.

[0475] Embodiment 54. The drug delivery system of Embodiment 53, wherein the CNP compound and the NPR-B compound are covalently bonded to each other.

[0476] Embodiment 55. The drug delivery system of Embodiment 54, wherein the CNP compound and the NPR-B compound are covalently bonded to each other via a linker.

[0477] Embodiment 56. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55, wherein the neurotrophic agent is a CNTF compound.

[0478] Embodiment 57. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is based on silicon dioxide.

[0479] Embodiment 58. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is porous.

[0480] Embodiment 59. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is non-porous.

[0481] Example 60. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Patent No. 9,949,922 issued to Jokinen et al. on April 24, 2018.

[0482] Example 61. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Patent Application No. 20140057996 to Jokinen et al., published on February 27, 2014.

[0483] Example 62. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Patent No. 9,603,801 issued to Barnett et al. on March 28, 2017.

[0484] Example 63. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Patent No. 9,808,421 issued to Ashton et al. on November 7, 2017.

[0485] Example 64. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Pat. No. 9,333,173 issued to Ashton et al. on May 10, 2016. Example 65. The drug delivery system of Example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the sustained release component is of the type described in U.S. Patent Publication No. 20140271764 to Ashton et al., published on September 28, 2014.

[0486] Embodiment 66. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65, wherein the prostaglandin receptor agonist is covalently linked to the sustained release component.

[0487] Embodiment 67. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 or 66, wherein the neurotrophic agent is covalently attached to the sustained release component.

[0488] Embodiment 68. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 or 67, wherein the prostaglandin receptor agonist is not covalently attached to the sustained release component. Embodiment 69. The drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 or 68, wherein the neurotrophic agent is not covalently attached to the sustained release component.

[0489] Embodiment 70. A method of treating glaucoma or ocular hypertension, comprising: administering the drug delivery system of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69 to a mammal suffering from glaucoma or ocular hypertension.

[0490] Embodiment 71. The method of Embodiment 70, wherein the drug delivery system is administered to the affected eye of the mammal by intravitreal injection.

[0491] Embodiment 72. The method of Embodiment 70, wherein the drug delivery system is implanted in the anterior chamber, subconjunctival space, suprachoroidal space, or subfascial space of the affected eye of the mammal.

[0492] Embodiment 73. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises primary open angle glaucoma (POAG).

[0493] Embodiment 74. The method of embodiment 70, 71 or 72, wherein the glaucoma comprises acute primary angle-closure glaucoma (APACG).

[0494] Embodiment 75. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises chronic angle-closure glaucoma.

[0495] Embodiment 76. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises pigmentary glaucoma.

[0496] Embodiment 77. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises pseudoexfoliation glaucoma.

[0497] Embodiment 78. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises normal-tension glaucoma.

[0498] Embodiment 79. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises childhood glaucoma.

[0499] Embodiment 80. The method of Embodiment 70, 71 or 72, wherein the glaucoma comprises secondary glaucoma.

[0500] Example 81. A drug delivery system comprising: a first active pharmaceutical ingredient (API) and a sustained-release component, wherein the first API is an intraocular pressure reducer, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor-B (NPR-B), an apoptosis signaling fragment (FAS) inhibitor or a FAS-ligand (FASL) inhibitor, or a combination thereof.

[0501] Embodiment 82. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is an intraocular pressure reducing agent and the second API is a neurotrophic agent.

[0502] Embodiment 83. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is an intraocular pressure reducing agent and the second API is CNP.

[0503] Embodiment 84. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is an intraocular pressure reducing agent and the second API is NPR-B.

[0504] Embodiment 85. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is an intraocular pressure reducing agent, and the second API is a FAS inhibitor or a FASL inhibitor.

[0505] Embodiment 86. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is a neurotrophic agent and the second API is CNP.

[0506] Embodiment 87. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is a neurotrophic agent and the second API is NPR-B.

[0507] Embodiment 88. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is a neurotrophic agent and the second API is a FAS inhibitor or a FASL inhibitor.

[0508] Embodiment 89. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is CNP and the second API is NRP-B.

[0509] Embodiment 90. The drug delivery system of Embodiment 81, further comprising a second API, wherein the first API is CNP, and the second API is a FAS inhibitor or a FASL inhibitor.

[0510] Example 91. The drug delivery system of Example 81, further comprising a second API, wherein the first API is NRP-B, and the second API is a FAS inhibitor or a FASL inhibitor.

[0511] Embodiment 92. The drug delivery system of Embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 or 91, wherein the first API and the second API are not covalently bonded to each other.

[0512] Embodiment 93. The drug delivery system of Embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 or 91, wherein the first API and the second API are covalently bonded.

[0513] Embodiment 94. The drug delivery system of Embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 or 93, wherein the first API is covalently bonded to the sustained release component.

[0514] Embodiment 95. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 or 94, wherein the second API is covalently bonded to the sustained release component.

[0515] Embodiment 96. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 or 95 having about 100 μg to about 1 mg of the first API.

[0516] Embodiment 97. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96 having about 100 μg to about 1 mg of the second API.

[0517] Embodiment 98. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 or 97, wherein the implant has a weight of about 300 μg to about 10 mg.

[0518] Embodiment 99. A method of treating glaucoma comprising administering the drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 or 98 to a mammal suffering from glaucoma or ocular hypertension.

[0519] Embodiment 100. The method of Embodiment 99, wherein the drug delivery system is injected into the eye of the mammal.

[0520] Embodiment 101. The method of Embodiment 99 or 100, wherein the mammal is a human.

[0521] Embodiment 102. Use of an intraocular pressure reducing agent, a neurotrophic agent, CNP, NPR-B, a FAS inhibitor or a FASL inhibitor, or a combination thereof in the manufacture of a drug delivery system for treating glaucoma or ocular hypertension, wherein the drug delivery system further comprises a sustained release component.

[0522] Embodiment 103. The use of Embodiment 102, wherein the drug delivery system is injected into the eye of a mammal.

[0523] Embodiment 104. The use of Embodiment 102 or 103, wherein the mammal is a human.

[0524] Embodiment 105. A kit comprising the drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 or 98 and a label with instructions for using the drug delivery system for treating glaucoma.

[0525] Embodiment 106. The kit of embodiment 105, wherein the drug delivery system is injected into the eye of a mammal.

Claims

1. A drug delivery system comprising: 1) a prostaglandin, a CNTF compound, a TNF-α / TNFR inhibitor, a FAS or FASL inhibitor, or a combination thereof, and 2) a sustained release component.

2. The drug delivery system according to claim 1, comprising: 1) the prostaglandin, 2) the CNTF compound, the FAS or FASL inhibitor, or a combination thereof, and 3) the sustained-release component.

3. The drug delivery system according to claim 2, wherein: The CNTF compound is a peptide comprising the amino acid sequence DGGL (SEQ ID NO: 20) or a salt thereof.

4. The drug delivery system according to claim 2, wherein: The prostaglandin is bimatoprost acid or a salt thereof.

5. The drug delivery system according to claim 4, comprising: the prostaglandin and the CNTF compound, wherein: The CNTF compound is peptide 6 or a salt thereof.

6. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is bicyclic alcohol.

7. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is a peptide comprising the amino acid sequence YLGA (SEQ ID NO: 5) or a salt thereof.

8. The drug delivery system according to claim 2, wherein The FAS or FASL inhibitor is MET4.

9. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is MET5.

10. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is MET6.

11. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is MET7.

12. The drug delivery system according to claim 2, wherein: The FAS or FASL inhibitor is MET8.

13. The drug delivery system according to claim 2, wherein: The prostaglandin is not covalently bonded or covalently linked to the CNTF compound, the FAS or FASL inhibitor, or a combination thereof.

14. The drug delivery system according to claim 2, wherein: The prostaglandin is covalently bonded or covalently linked to the CNTF compound, the FAS or FASL inhibitor, or a combination thereof.

15. The drug delivery system according to claim 1, wherein: The prostaglandin, the CNTF compound, the FAS or FASL inhibitor, or a combination thereof is covalently bonded or covalently linked to the sustained release component.

16. Use of the drug delivery system according to claim 1 in preparing a drug for treating glaucoma or ocular hypertension, comprising: The medicament is administered to an eye of a mammal in need thereof, wherein administering the medicament to the eye of the mammal results in a decrease in intraocular pressure in the eye of the mammal.

17. The use according to claim 16, wherein The CNTF compound is peptide 6 or peptide 21.

18. The use according to claim 16, wherein The prostaglandin is bimatoprost acid or a salt thereof.

19. The use according to claim 16, wherein The FAS or FASL inhibitor is MET4-8.

20. The use according to claim 16, wherein The CNTF compound is a peptide comprising the amino acid sequence DGGL (SEQ ID NO: 20) or a salt thereof.

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