Drug delivery systems comprising intraocular pressure lowering agent, neurotrophic agent, c-type natriuretic peptide, natriuretic peptide receptor-b, apoptosis signaling fragment inhibitor or fas-ligand inhibitor for treating glaucoma or ocular hypertension

Abstract

To provide a drug delivery system for treating glaucoma or related conditions.SOLUTION: Provided is a drug delivery system comprising (1) a prostaglandin, a CNTF compound, a TNF-α / TNFR inhibitor, a FAS or FASL inhibitor, or any combination thereof, and (2) a sustained delivery component.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on December 16, 2020, has the file name C4019_10001WO02_SL.txt and is 5,282 bytes in size. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure relates to a drug delivery system comprising an ocular hypotensive 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 (NRP-B) compound, a TNF-α / TNFR inhibitor, or a fragmentation of apoptosis signaling (FAS) inhibitor or a FAS ligand (FASL) inhibitor (including any combination of these compounds), and a sustained-delivery component. This type of drug delivery system can be used to treat glaucoma or ocular hypertension.

[0003] Some embodiments include a drug delivery system comprising a first active pharmaceutical ingredient (API) and a sustained delivery component, wherein the first API is an ocular hypotensive agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor B (NRP-B), a TNF-α / TNFR inhibitor, a fragmentation of apoptosis signaling (FAS) inhibitor or a FAS ligand (FASL) inhibitor, or a combination thereof.

[0004] 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.

[0005] Some embodiments include the use of an ocular hypotensive agent, a neurotrophic agent, a CNP, an 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 the treatment of glaucoma or ocular hypertension.

[0006] Some embodiments include a kit comprising a drug delivery system for the treatment of glaucoma described herein and a label with instructions for using the drug delivery system.

[0007] [FIG. 1A] Intraocular pressure of IOP in African green monkey B102 after administration of 100 ng and 200 ng of bimatoprost acid by intravitreal injection compared to that in PBS in the fellow eye, according to some embodiments described herein. [Figure 1B] Intraocular pressure of IOP in African green monkey B107 after administration of 100 ng and 200 ng of bimatoprost acid by intravitreal injection compared to that in PBS in the fellow eye, according to some embodiments described herein. [Figure 1C] Intraocular pressure of IOP in African green monkey B392 after administration of 100 ng and 200 ng of bimatoprost acid by intravitreal injection compared to that in PBS in the fellow eye, according to some embodiments described herein. [Figure 1D] Intraocular pressure of IOP in African green monkey B300 after administration of 100 ng and 200 ng of bimatoprost acid by intravitreal injection compared to that in PBS in the fellow eye, according to some embodiments described herein.

[0023] FIG. 2 shows the percent reduction in intraocular pressure in African green monkey IOP after administration of 100 ng and 200 ng of bimatoprost acid by intravitreal injection compared to PBS in the fellow eye for some embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0008] For a drug delivery system comprising an ocular hypotensive agent, a neurotrophic agent such as a CNTF compound, a CNP compound, an NPR-B compound, or an FAS or FASL inhibitor (herein referred to as a "subject drug delivery system"), and a sustained delivery component, any suitable prostaglandin receptor agonist, prostanoid receptor agonist, or any suitable prostaglandin compound may be used, including any prostaglandin acid form (e.g., the acid obtained by hydrolysis of a prostaglandin ester), any prostaglandin salt form, or a prodrug of a prostaglandin ester. Examples include bimatoprost (amide) or bimatoprost acid, i.e., the carboxylic acid obtained by hydrolysis of the amide group, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostene, tafluprost, tafluprost acid, etc., prostaglandin EP2 agonists, prostaglandin EP3 agonists, nitric oxide-donating prostaglandin compounds such as latanoprostene bunod, or combinations thereof.

[0009] An appropriate amount of a prostaglandin compound, such as bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprost, tafluprost, tafluprost acid, or the like, a prostaglandin EP2 agonist, or a prostaglandin EP3 agonist, can be used in the drug delivery system. For example, the drug delivery system can contain about 0.01 to 1 μg, about 1 to 2 μg, about 2 to 3 μg, about 3 to 4 μg, about 4 to 5 μg, about 5 to 6 μg, about 6 to 7 μg, about 7 to 8 μg, about 8 to 9 μg, about 9 to 10 μg, about 0.01 to 3 μg, about 3 to 6 μg, about 6 to 10 μg, about 0.01 to 10 μg, about 10 to 20 μg, about 20 to 30 μg, or the like. 0μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, Approx. 0.010~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.010~100μg, approx. 100~200μg, approx. 200-300μg, about 300-400μg, about 400-500μg, about 500-600μg, about 600-700μg, about 700-800μg, about 80 0~900μg, approx. 900~1,000μg, approx. 0.01~300μg, approx. 300~600μg, approx. 600~1,000μg, approx. 0.001~1mg, The dosage may contain 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 may also apply when the drug is present in a form covalently bound to another drug or sustained-release component, etc. For example, a compound of Formula 1 or Formula 3 may be said to contain 1 mg of the prostaglandin compound, even though the prostaglandin is covalently bound to another moiety of the drug delivery system.

[0010] Use of the above amounts of a prostaglandin compound, such as bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprost, tafluprost, tafluprost acid, or the like, a prostaglandin EP2 agonist, or a prostaglandin EP3 agonist, in a drug delivery system can provide a drug delivery system that provides therapeutic levels (concentrations) of the prostaglandin compound for about 1 to 4 weeks, about 1 to 3 months, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 to 18 months, about 18 to 24 months, about 2 to 5 years, about 5 to 10 years, or longer.

[0011] [ka]

[0012] In some embodiments, the prostaglandin receptor agonist, prostanoid receptor agonist, or prostaglandin compound is bimatoprost (amide) or bimatoprost acid. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is travoprost. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is travoprost acid. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is latanoprost. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is latanoprost acid. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is latanoprostene. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is tafluprost. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is tafluprost acid. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is a prostaglandin EP2 receptor agonist. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is a prostaglandin EP3 receptor agonist.

[0013] A subject drug delivery system can include an ocular hypotensive agent, such as a beta-blocker, an alpha-agonist, a carbonic anhydrase inhibitor, a Rho-kinase inhibitor, a cannabinoid receptor agonist, etc. Some subject drug delivery systems can include two or more ocular hypotensive agents, such as a prostaglandin compound, a prostaglandin receptor agonist, or a prostanoid receptor agonist, a beta-blocker, an alpha-agonist, a carbonic anhydrase inhibitor, a cannabinoid receptor agonist, a Rho-kinase inhibitor, etc. Some subject drug delivery systems include two or more of a prostaglandin receptor agonist (or a prostaglandin compound or a prostanoid receptor agonist), a beta-blocker, an alpha-agonist, a carbonic anhydrase inhibitor, a cannabinoid receptor agonist, a Rho-kinase inhibitor, etc.

[0014] Any suitable beta-blocker or any suitable beta-adrenergic antagonist may be used with the subject drug delivery systems. Examples include timolol, betaxolol, levobunolol, metipranolol, and the like, or combinations 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.

[0015] Any suitable amount of a beta-blocker or beta-adrenergic antagonist, such as timolol, betaxolol, levobunolol, or metipranolol, can be used in the drug delivery system. For example, the 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, or about 20-30 μg. 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 100-200μg, about 2 00~300μg, approx. 300~400μg, approx. 400~500μg, approx. 500~600μg, approx. 600~700μg, approx. 700~800μg, approx. 800 ~900μg, approx. 900~1,000μg, approx. 0.01~300μg, approx. 300~600μg, approx. 600~1,000μg, approx. 0.001~1mg, 0 The amount of one of these compounds may be 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. These amounts may also apply when the drug is present in a covalently bonded form with another agent, sustained delivery component, etc.

[0016] Use of the above amounts of a beta-blocker or beta-adrenergic antagonist, such as timolol, betaxolol, levobunolol, metipranolol, etc., in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the beta-blocker or beta-adrenergic antagonist for about 1 to 4 weeks, about 1 to 3 months, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 to 18 months, about 18 to 24 months, about 2 to 5 years, about 5 to 10 years, or longer.

[0017] Any suitable alpha agonist or alpha adrenergic agonist may be used with the subject drug delivery systems. Examples include brimonidine, apraclonidine, and the like, or combinations thereof. In some embodiments, the alpha agonist is brimonidine. In some embodiments, the alpha agonist is apraclonidine.

[0018] Any suitable amount of an alpha agonist or alpha adrenergic agonist, such as brimonidine or apraclonidine, can be used in the drug delivery system. For example, the 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, or about 30-40 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0019] Use of the above amounts of brimonidine, apraclonidine, or other alpha agonist or alpha adrenergic agonist in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the alpha agonist or alpha adrenergic agonist 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.

[0020] Any suitable carbonic anhydrase inhibitor may be used with the subject drug delivery systems. Examples include brinzolamide, acetazolamide, dorzolamide, methazolamide, and the like, or combinations 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.

[0021] Any suitable amount of a carbonic anhydrase inhibitor, such as brinzolamide, acetazolamide, dorzolamide, or methazolamide, can be used in the drug delivery system. For example, the 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, or about 20-30 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0022] Use of the above amounts of a carbonic anhydrase inhibitor, such as brinzolamide, acetazolamide, dorzolamide, or methazolamide, in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the 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.

[0023] Any suitable cholinergic agonist may be used with the subject drug delivery systems. Examples include pilocarpine, carbachol, and the like, or combinations thereof. In some embodiments, the cholinergic agonist is pilocarpine. In some embodiments, the cholinergic agonist is carbachol.

[0024] Any suitable amount of a cholinergic agonist, such as pilocarpine or carbachol, can be used in the drug delivery system. For example, the 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, or about 30-40 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0025] Use of the above amounts of pilocarpine, carbachol, or other cholinergic agonists in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the cholinergic agonist 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] Any suitable Rho kinase inhibitor, such as netarsudil, may be used with the subject drug delivery systems. In some embodiments, the Rho kinase inhibitor is netarsudil.

[0027] Any suitable amount of a Rho kinase inhibitor such as netarsudil can be used in the drug delivery system. For example, the 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, or about 20-30 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0028] Use of the above amounts of a Rho kinase inhibitor, such as netarsudil, in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the Rho kinase inhibitor for about 1 to 4 weeks, about 1 to 3 months, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 to 18 months, about 18 to 24 months, about 2 to 5 years, about 5 to 10 years, or longer.

[0029] Any suitable Tie-2 agonist may be used with the subject drug delivery systems, such as angiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4, and the like.

[0030] Any suitable amount of a Tie-2 agonist, such as angiopoietin-1, angiopoietin-2, angiopoietin-3, or angiopoietin-4, can be used in the drug delivery system. For example, the drug delivery system can contain about 0.01 to 1 μg, about 1 to 2 μg, about 2 to 3 μg, about 3 to 4 μg, about 4 to 5 μg, about 5 to 6 μg, about 6 to 7 μg, about 7 to 8 μg, about 8 to 9 μg, about 9 to 10 μg, about 0.01 to 3 μg, about 3 to 6 μg, about 6 to 10 μg, about 0.01 to 10 μg, about 10 to 20 μg, or about 20 to 3 μg. 0μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, Approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 200 The amount of one of these compounds may be about 0.0100 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.0100 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0031] Use of the above amounts of a Tie-2 agonist, such as angiopoietin-1, angiopoietin-2, angiopoietin-3, or angiopoietin-4, in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the Tie-2 agonist for about 1 to 4 weeks, about 1 to 3 months, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 to 18 months, about 18 to 24 months, about 2 to 5 years, about 5 to 10 years, or longer.

[0032] With respect to the subject drug delivery systems, the neurotrophic agent can comprise a CNTF compound or other neurotrophic agent, and CNTF compounds include any compound with a structure or activity similar to ciliary neurotrophic factor (CNTF), including CNTF, a protein derivative of CNTF, or a CNTF peptide. Examples include CNTF, neurotrophic peptides containing the sequence DGGL (SEQ ID NO:20), such as peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID NO:1)) and peptide 21 (P21; Ac-DGGL A Neurotrophic peptides include peptides containing a portion of the sequence of CNTF, such as G-NH2 (SEQ ID NO: 2), recombinant CNTF (rhCNTF), or neurotrophic peptides containing adamant groups at the C-terminus and / or N-terminus, as described in U.S. Patent No. 8,592,374, the disclosure of which related to neurotrophic peptides is incorporated herein by reference, or any other peptides with biological activity similar to CNTF. Other neurotrophic agents include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), etc., or derivatives thereof.

[0033] Any suitable amount of neurotrophic agent, such as a CNTF compound, NGF, BDNF, or GDNF, can be used in the drug delivery system. For example, the 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, or about 20-30 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0034] The use of the above amounts of neurotrophic agents, such as CNTF compounds, NGF, BDNF, GDNF, etc. in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the neurotrophic agent for periods of 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] With respect to the subject drug delivery systems, CNP compounds include any compound with a structure or activity similar to C-type natriuretic peptide, including naturally occurring C-type natriuretic peptide.

[0036] Any suitable amount of a CNP compound, such as native CNP, can be used in the drug delivery system. For example, the 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, or about 30-40 μg. 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 100-200μg, about 20 The amount may comprise 0 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.01 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg of one of these compounds. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0037] Use of the above amounts of a CNP compound, such as native CNP, in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the CNP compound 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] With respect to the subject drug delivery systems, NPR-B compounds include any compound having a structure or activity similar to natriuretic peptide receptor B, including native natriuretic peptide receptor B.

[0039] Any suitable amount of an NPR-B compound, such as native NPR-B, can be used in the drug delivery system. For example, the 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, or about 30-40 μg. 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 100-200μg, about 20 0~300μg, approx. 300~400μg, approx. 400~500μg, approx. 500~600μg, approx. 600~700μg, approx. 700~800μg, approx. 800~ 900μg, approx. 900~1,000μg, approx. 0.01~300μg, approx. 300~600μg, approx. 600~1,000μg, approx. 0.001~1mg, approx. 0 The amount of one of these compounds may be 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. These amounts may also apply when the drug is present in a covalently bonded form with another agent, sustained delivery component, etc.

[0040] Use of the above amounts of an NPR-B compound, such as native NPR-B, in a drug delivery system can provide a drug delivery system that provides therapeutic levels of the NPR-B compound for a period of 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] 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 shorter fragments thereof, such as tetramers, having the sequence YLGA (SEQ ID NO: 5), or 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: 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 (HIYL fragments having a sequence that is 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% identical to MET12, including compounds having the sequences shown in Table 1 below, such as GA (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)); 60 HIYLGATNYIY 71 Other MET12 derivatives include compounds having -NH2 (SEQ ID NO: 4); FAS apoptosis inhibitor molecule [FAIM]; NOL3 [nucleolar protein 3 (apoptosis inhibitor with ACRD domain [ARC]), etc.]; DcR1; DcR2; or DcR3.

[0042] [ka]

[0043] [Table 1]

[0044] Any suitable amount of bicyclol, FLIP, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, ONL1204, H 60 HIYLGATNYIY 71 FAS or FASL inhibitors such as -NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, and DcR3 can be used in the drug delivery system. For example, the 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 ...0-100 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 0μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, Approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 200 The amount of one of these compounds may be about 0.0100 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, about 500 to 600 μg, about 600 to 700 μg, about 700 to 800 μg, about 800 to 900 μg, about 900 to 1,000 μg, about 0.0100 to 300 μg, about 300 to 600 μg, about 600 to 1,000 μg, about 0.001 to 1 mg, 0.01 to 1 mg, about 0.1 to 1 mg, about 1 to 2 mg, about 2 to 3 mg, about 3 to 4 mg, about 4 to 5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 0.01 to 3 mg, about 3 to 6 mg, about 6 to 10 mg, or about 0.01 to 10 mg. These amounts may also apply to situations where the drug is present in a covalently bound form, such as with another agent or sustained delivery component.

[0045] The above amounts of bicyclol, FLIP, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, ONL1204, H 60 HIYLGATNYIY 71The use of a FAS or FASL inhibitor, such as -NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, or DcR3, can provide a drug delivery system that provides therapeutic levels of an NPR-B compound 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.

[0046] Useful TNF-α or TNFR inhibitors include etanercept, infliximab, golimumab, certolizumab, adalimumab, TNFR1 selective antagonist mutant TNF (R1antTNF), DMS5540, TNF receptor-1 silencer (TROS), and ATROSAB.

[0047] An appropriate amount of a TNF-α or TNFR inhibitor, such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, or ATROSAB, can be used in the drug delivery system. For example, the drug delivery system can be used in a range of doses, including 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, or 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, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100 The compound may comprise about 200 μg, about 200-300 μg, about 300-400 μg, about 400-500 μg, about 500-600 μg, about 600-700 μg, about 700-800 μg, about 800-900 μg, about 900-1,000 μg, about 0.01-300 μg, about 300-600 μg, about 600-1,000 μg, about 0.01-1 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 may also apply when the drug is present in a covalently bound form, such as with another drug or sustained delivery component.

[0048] Use of the above-mentioned amounts of a TNF-α or TNFR inhibitor, such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, or ATROSAB, in a drug delivery system can provide a drug delivery system that provides therapeutic concentrations of the TNF-α or TNFR 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.

[0049] Table 2 below shows drug combinations of particular interest in the subject drug delivery systems.

[0050] [Table 2-1] [Table 2-2]

[0051] Some drug delivery systems include a combination of bimatoprost acid and bicyclol that are either directly covalently bonded, bonded through a linking group, or both bonded to a polymer or silicon-based drug delivery particle. Some drug delivery systems include a combination of bimatoprost acid and bicyclol that are either not bonded to each other or to a polymer or silicon-based drug delivery particle.

[0052] With respect to the subject drug delivery systems comprising a prostaglandin receptor agonist or prostaglandin compound and an ocular hypotensive agent, in some embodiments, the prostaglandin receptor agonist is covalently bonded to the ocular hypotensive agent. In some embodiments, the prostaglandin receptor agonist is covalently bonded to the ocular hypotensive agent via a linking group.

[0053] For example, some compounds, including prostaglandin compounds or prostaglandin receptor agonists, are represented by Formula 1 or 1A, covalently attached to an ocular hypotensive agent by a linking group. PG-L-IOP formula 1 IOP-L-IOP Formula 1A wherein PG-H or PG-OH is a prostaglandin compound or a prostaglandin receptor agonist, such as those described above; and each IOP-H or IOP-OH is independently an ocular hypotensive agent, such as those described above.

[0054] With respect to a subject drug delivery system comprising both 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 one another. In some embodiments, the prostaglandin receptor agonist and the neurotrophic agent, such as a CNTF compound, are covalently bonded to one another via a linking group.

[0055] Some subject drug delivery systems include both an ocular hypotensive agent and a neurotrophic agent, such as a CNTF compound. In some embodiments, the ocular hypotensive agent and the neurotrophic agent, such as a CNTF compound, are covalently bonded to each other. In some embodiments, the ocular hypotensive agent and the neurotrophic agent, such as a CNTF compound, are covalently bonded to each other via a linking group.

[0056] Some subject drug delivery systems include both an ocular hypotensive agent and a CNP compound. In some embodiments, the ocular hypotensive agent and the CNP compound are covalently bonded to each other. In some embodiments, the ocular hypotensive agent and the CNP compound are covalently bonded to each other via a linking group.

[0057] Some subject drug delivery systems include an ocular hypotensive agent and an NRP-B compound. In some embodiments, the ocular hypotensive agent and the NRP-B compound are covalently bonded to each other. In some embodiments, the ocular hypotensive agent and the NRP-B compound are covalently bonded to each other via a linking group.

[0058] Some subject drug delivery systems include both a neurotrophic agent, such as a CNTF compound, and a CNP compound. In some embodiments, the neurotrophic agent, such as a CNTF compound, and the CNP compound are covalently bonded to each other. In some embodiments, the neurotrophic agent, such as a CNTF compound, and the CNP compound are covalently bonded to each other via a linking group.

[0059] Some subject drug delivery systems include both a neurotrophic agent, such as a CNTF compound, and an NRP-B compound. In some embodiments, the neurotrophic agent, such as a CNTF compound, and the NRP-B compound are covalently linked to each other. In some embodiments, the neurotrophic agent, such as a CNTF compound, and the NRP-B compound are covalently linked to each other via a linking group.

[0060] Some subject drug delivery systems include both a CNP compound and an NRP-B compound. In some embodiments, the CNP compound and the NRP-B compound are covalently bonded to each other. In some embodiments, the CNP compound and the NRP-B compound are covalently bonded to each other via a linking group.

[0061] For example, some compounds covalently attached to CNTF by a linking group, including prostaglandin compounds or prostaglandin receptor agonists, have the formula: PG-L-CNTF formula 2 where PG-H or PG-OH is a prostaglandin compound or a prostaglandin receptor agonist such as those described above; and CNTF-H or CNTF-OH is a CNTF compound such as those described above.

[0062] Other covalent compounds include those of formula 2A, 2B, 2C, 2D, 2E, 2F IOP-L-CNTF formula 2A IOP-L-CNP formula 2B IOP-L-NPRB formula 2c CNTF-L-CNP formula 2d CNTF-L-NPRB Formula 2E CNP-L-NPRB formula 2F where IOP-H is an ocular hypotensive agent such as those described above; CNTF-H or CNTF-OH is a CNTF compound such as the CNTF compounds described above; CNP-H or CNP-OH is a CNP compound, and NPR-H or NPR-OH is an NPR-B compound.

[0063] For any related 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 a group having the empirical formula C a H b O c N d or C a H b O c It is a bonding group represented by the formula:

[0064] 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.

[0065] 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 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 43, 1 to 15, 15 to 30, or 30 to 43.

[0066] 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.

[0067] 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.

[0068] In some embodiments, L is a group of formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8: [ka] [ka] It can be expressed as:

[0069] For any related structural representation of formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, L 1 is the empirical formula C e H f O g N h or C e H f O g It can be expressed as:

[0070] Any L 1 In some embodiments, 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 to 5, 5 to 10, 10 to 15, 15 to 18, 1 to 10, or 10 to 18.

[0071] Any L 1 In some embodiments, 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 to 10, 10 to 20, 20 to 30, 30 to 38, 1 to 15, 15 to 30, or 30 to 38.

[0072] Any L 1In some embodiments, g is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, g is 0 to 2, 2 to 4, 4 to 6, 6 to 8, 0 to 3, 3 to 6, or 6 to 8.

[0073] Any L 1 In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2.

[0074] With respect to any related structural representations 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 teeth, -(CH2) i -(OCH2CH2) j -O-(CH2) k - [Formula L 1 -1], -(CH2) i -(OCH2CH2) j -O-CONH-(CH2) k - [Formula L 1 -2], -(C i H 2i )-(OCH2CH2) j -O-(C k H 2k )- [formula L 1 -3], -(C i H 2i )-(OCH2CH2) j -O-CONH-(C k H 2k )- [formula L 1 -4], -NH2(CH2) i -(OCH2CH2) j -O-(CH2) k - [Formula L 1 -5], -NH2(CH2) i -(OCH2CH2) j -O-CONH-(CH2) k - [Formula L 1 -6], -NH2(C i H 2i )-(OCH2CH2) j -O-(C k H 2k )- [formula L 1 -7], or -NH2(C i H 2i )-(OCH2CH2) j -O-CONH-(C k H 2k )- [formula L 1 -8] It could be.

[0075] 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 With respect to any related structural representation, such as -8, i is 0, 1, 2, 3, or 4. In some embodiments, i is 2.

[0076] 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 For any related structural representation such as -8, j is 0, 1, 2, 3, 4, or 5.

[0077] 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 For any related structural representation such as -8, k is 0, 1, 2, 3, or 4.

[0078] 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 With respect to the representation of any related structure, such as -8, any H atom in the NH or NH2 moiety may be substituted with 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 C including alkynyl etc. 1-12 Hydrocarbyl group, C 1-6 Hydrocarbyl group, or C 1-3 It may be substituted with a substituent such as a hydrocarbyl group.

[0079] 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: [ka]

[0080] Compounds containing O-AEEAC, O-dPEG12, LaL1, or LaL2-based linkers may be unstable in the mammalian or human body.

[0081] In some embodiments, the drug delivery system includes a combination of the following drugs, covalently or non-covalently linked by a linking group L, such as a group represented by formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, including a salt, free acid, or free base of the drug: bimatoprost or bimatoprost acid and travoprost or travoprost acid; bimatoprost or bimatoprost acid and latanoprost or latanoprost acid; bimatoprost or bimatoprost acid and latanoprost; bimatoprost or bimatoprost acid and latanoprost; bimatoprost or bimatoprost acid and bimatoprost Prost 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 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 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 netarsudil; 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 acid and FLIP; Bimatoprost or bimatoprost acid and MET12; Bimatoprost or bimatoprost acid and compound 1 in Table 1; Bimatoprost or bimatoprost acid and compound 2 in Table 1; Bimatoprost or bimatoprost acid and compound 3 in Table 1; Bimatoprost or bimatoprost acid and a compound in Table 1 Compound 4; Bimatoprost or bimatoprost acid and compound 5 in Table 1; Bimatoprost or bimatoprost acid and compound 6 in Table 1; Bimatoprost or bimatoprost acid and compound 7 in Table 1; Bimatoprost or bimatoprost acid and compound 8 in Table 1; Bimatoprost or bimatoprost acid and compound 9 in Table 1; Bimatoprost or bimatoprost acid and compound 10 in Table 1; Bimatoprost or bimatoprost acid and compound 11 in 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 latanoprost; Travoprost or travoprost acid and tafluprost or tafluprost acid; Travoprost or or travoprost acid and timolol; travoprost or travoprost acid and betaxolol; travoprost or travoprost acid and levobunolol; travoprost or travoprost acid and metipranolol; travoprost 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 Travoprost or travoprost acid and methazolamide; Travoprost or travoprost acid and pilocarpine; Travoprost or travoprost acid and carbachol; Travoprost or travoprost acid and netarsudil; 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 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 and Compound 1 in Table 1; Travoprost or travoprost acid and Compound 2 in Table 1; Travoprost or travoprost acid and Compound 3 in Table 1; Travoprost or travoprost acid and Compound 4 in Table 1; Travoprost or travoprost acid Travoprost or travoprost acid and compound 5 in Table 1; travoprost or travoprost acid and compound 6 in Table 1; travoprost or travoprost acid and compound 7 in Table 1; travoprost or travoprost acid and compound 8 in Table 1; travoprost or travoprost acid and compound 9 in Table 1; travoprost or travoprost acid and compound 10 in Table 1; travoprost or travoprost acid and compound 11 in 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 latanoprost; latanoprost or latanoprost acid and tafluprost or tafluprost acid; latanoprost or latanoprost acid and timolol; latanoprost or latanoprost acid and betaxolo ol;Latanoprost or latanoprost acid and levobunolol;Latanoprost or latanoprost acid and metipranolol;Latanoprost or latanoprost acid and brimonidine;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 Latanoprost or latanoprost acid and carbachol; Latanoprost or latanoprost acid and netarsudil; 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; Latanopro 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 in Table 1; Latanoprost and Latanoprost acid and Compound 2 in Table 1; Latanoprost and Latanoprost acid and Compound 3 in Table 1; Latanoprost and Latanoprost acid and Compound 4 in Table 1; Latanoprost and Latanoprost acid and Compound 5 in Table 1; Latanoprost and Latanoprost acid and Compound 6 in Table 1; Latanoprost and Latanoprost acid and Compound 7 in Table 1; Latanoprost and Latanoprost acid and Compound 8 in Table 1; Latanoprost and Latanoprost acid and Compound 9 in Table 1; Latanoprost and Latanoprost acid and Compound 10 in Table 1; Latanoprost and Latanoprost acid and Compound 11 in Table 1; Latanoprost and Latanoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Latanoprost and Latanoprost acid and FAIM; Latanoprost and Latanoprost acid and NOL3; Latanoprost and Latanoprost acid and DcR1; Latanoprost and Latanoprost acid and DcR2; Latanoprost and Latanoprost acid and DcR3; Latanoprost and Tafluprost and Tafluprost acid; Latanoprost and Timolol; Latanoprost and Betaxolol; Latanoprost and Levobunolol; Latanoprost and Me Tipranolol;Latanoprostene and brimonidine;Latanoprostene and apraclonidine;Latanoprostene and brinzolamide;Latanoprostene and acetazolamide;Latanoprostene and dorzolamide;Latanoprostene and methazolamide;Latanoprostene and pilocarpine;Latanoprostene and carbachol;Latanoprostene and netarsudil;Latanoprostene and angiopoietin-1;Latanoprostene and angiopoietin-2;Latanoprostene and angiopoietin-3;Latano Latanoprostene and angiopoietin-4; latanoprostene and CNTF; latanoprostene and peptide 6; latanoprostene and peptide 21; latanoprostene and recombinant CNTF; latanoprostene and NGF; latanoprostene and BDNF; latanoprostene and GDNF; latanoprostene and C-type natriuretic peptide; latanoprostene and native C-type natriuretic peptide; latanoprostene and natriuretic peptide receptor B; latanoprostene and bicyclol; latanoprostene and FLIP; latanoprostene and MET12; latanoprostene and compound 1 in Table 1; latanoprostene and compound 2 in Table 1; latanoprostene and compound 3 in Table 1; latanoprostene and compound 4 in Table 1; latanoprostene and compound 5 in Table 1; latanoprostene and compound 6 in Table 1; latanoprostene and compound 7 in Table 1; latanoprostene and compound 8 in Table 1; latanoprostene and compound 9 in Table 1; latanoprostene and compound 10 in Table 1; latanoprostene and compound 11 in Table 1; latanoprostene and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); latanoprost and FAIM; latanoprost and NOL3; latanoprost and DcR1; latanoprost and DcR2; 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; taflupro Tafluprost or tafluprost acid and brinzolamide; Tafluprost or tafluprost acid and acetazolamide; 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 netarsudil; Tafluprost or tafluprost acid and angiopoietin-1; Tafluprost or tafluprost acid and angiopoietin-2; Taflupro 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 Tafluprost or Tafluprost acid and C-type natriuretic peptide; Tafluprost or Tafluprost acid and native 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 in Table 1; Tafluprost or Tafluprost acid and Compound 2 in Table 1; Tafluprost or Tafluprost acid and Compound 3 in Table 1;Tafluprost or tafluprost acid and compound 4 in Table 1; Tafluprost or tafluprost acid and compound 5 in Table 1; Tafluprost or tafluprost acid and compound 6 in Table 1; Tafluprost or tafluprost acid and compound 7 in Table 1; Tafluprost or tafluprost acid and compound 8 in Table 1; Tafluprost or tafluprost acid and compound 9 in Table 1; Tafluprost or tafluprost acid and compound 10 in Table 1; Tafluprost or tafluprost acid and compound 11 in 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 apraclonidine; Timolol and brinzolamide; Timolol and acetazolamide; Timolol and dorzolamide; Timolol and methazolamide; Timolol and pilocarpine; Timolol and carbachol; Timolol and netarsudil; Timolol and angiopoietin-1; Timolol and angiopoietin-2; Timolol and angiopoietin-3; Timolol and an Geopoietin-4; Timolol and CNTF; Timolol and Peptide 6; 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 in Table 1; Timolol and Compound 2 in Table 1; Timolol and Compound 3 in Table 1; Timolol and Compound 4 in Table 1; Timolol and Compound 5 in Table 1; Timolol and Compound 6 in Table 1; Timolol and Compound 7 in Table 1; Timolol and Compound 8 in Table 1; Timolol and Compound 9 in Table 1; Timolol and Compound 10 in Table 1; Timolol and Compound 11 in Table 1; Timolol and H 60HIYLGATNYIY 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 netarsudil;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 table Compound 1 in Table 1; Betaxolol and Compound 2 in Table 1; Betaxolol and Compound 3 in Table 1; Betaxolol and Compound 4 in Table 1; Betaxolol and Compound 5 in Table 1; Betaxolol and Compound 6 in Table 1; Betaxolol and Compound 7 in Table 1; Betaxolol and Compound 8 in Table 1; Betaxolol and Compound 9 in Table 1; Betaxolol and Compound 10 in Table 1; Betaxolol and Compound 11 in 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 netarsudil; 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 Levobunolol and recombinant CNTF; Levobunolol and NGF; 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 in Table 1; Levobunolol and compound 2 in Table 1; Levobunolol and compound 3 in Table 1; Levobunolol and compound 4 in Table 1; Levobunolol and compound 5 in Table 1; Levobunolol and compound 6 in Table 1; Levobunolol and compound 7 in Table 1; Levobunolol and compound 8 in Table 1; Levobunolol and compound 9 in Table 1; Levobunolol and compound 10 in Table 1; Levobunolol and compound 11 in 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 Metipranolol and pilocarpine; metipranolol and carbachol; metipranolol and netarsudil; 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 in Table 1; metipranolol and compound 2 in Table 1; metipranolol and compound 3 in Table 1; metipranolol and compound 4 in Table 1; metipranolol and compound 5 in Table 1; metipranolol and compound 6 in Table 1; metipranolol and compound 7 in Table 1; metipranolol and compound 8 in Table 1; metipranolol and compound 9 in Table 1; metipranolol and compound 10 in Table 1; metipranolol and compound 11 in 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 netarsudil; 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 C NTF; Brimonidine and NGF; Brimonidine and BDNF; 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 in Table 1; Brimonidine and Compound 2 in Table 1; Brimonidine and Compound 3 in Table 1; Brimonidine and Compound 4 in Table 1; Brimonidine and Compound 5 in Table 1; Brimonidine and Compound 6 in Table 1; Brimonidine and Compound 7 in Table 1; Brimonidine and Compound 8 in Table 1; Brimonidine and Compound 9 in Table 1; Brimonidine and Compound 10 in Table 1; Brimonidine and Compound 11 in 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 netarsudil; Apraclonidine and angiopoietin-1; Apraclonidine and angio Poietin-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 GDNF; 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 in Table 1; Apraclonidine and Compound 2 in Table 1; Apraclonidine and Compound 3 in Table 1; Apraclonidine and Compound 4 in Table 1; Apraclonidine and Compound 5 in Table 1; Apraclonidine and Compound 6 in Table 1; Apraclonidine and Compound 7 in Table 1; Apraclonidine and Compound 8 in Table 1; Apraclonidine and Compound 9 in Table 1; Apraclonidine and Compound 10 in Table 1; Apraclonidine and Compound 11 in 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 netarsudil; 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 Zolamide and BDNF; Brinzolamide and GDNF; 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 in Table 1; Brinzolamide and compound 2 in Table 1; Brinzolamide and compound 3 in Table 1; Brinzolamide and compound 4 in Table 1; Brinzolamide and compound 5 in Table 1; Brinzolamide and compound 6 in Table 1; Brinzolamide and compound 7 in Table 1; Brinzolamide and compound 8 in Table 1; Brinzolamide and compound 9 in Table 1; Brinzolamide and compound 10 in Table 1; Brinzolamide and compound 11 in 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 netarsudil; Acetazolamide 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 C-type natriuretic peptide; 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 in Table 1; Acetazolamide and compounds in Table 1 2; Acetazolamide and compound 3 in Table 1; Acetazolamide and compound 4 in Table 1; Acetazolamide and compound 5 in Table 1; Acetazolamide and compound 6 in Table 1; Acetazolamide and compound 7 in Table 1; Acetazolamide and compound 8 in Table 1; Acetazolamide and compound 9 in Table 1; Acetazolamide and compound 10 in Table 1; Acetazolamide and compound 11 in 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 netarsudil; 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 Dorzolamide and GDNF; Dorzolamide and C-type natriuretic peptide; Dorzolamide and native C-type natriuretic peptide; Dorzolamide and natriuretic peptide receptor B; Dorzolamide and bicyclol; Dorzolamide and FLIP; Dorzolamide and MET12; Dorzolamide and Compound 1 in Table 1; Dorzolamide and Compound 2 in Table 1; Dorzolamide and Compound 3 in Table 1; Dorzolamide and Compound 4 in Table 1; Dorzolamide and Compound 5 in Table 1; Dorzolamide and Compound 6 in Table 1; Dorzolamide and Compound 7 in Table 1; Dorzolamide and Compound 8 in Table 1; Dorzolamide and Compound 9 in Table 1; Dorzolamide and Compound 10 in Table 1; Dorzolamide and Compound 11 in 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 netarsudil; 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 native C-type natriuretic peptide; peptide receptor B; methazolamide and natriuretic peptide receptor B; methazolamide and bicyclol; methazolamide and FLIP; methazolamide and MET12; methazolamide and compound 1 in Table 1; methazolamide and compound 2 in Table 1; methazolamide and compound 3 in Table 1; methazolamide and compound 4 in Table 1; methazolamide and compound 5 in Table 1; methazolamide and compound 6 in Table 1; methazolamide and compound 7 in Table 1; methazolamide and compound 8 in Table 1; methazolamide and compound 9 in Table 1; methazolamide and compound 10 in Table 1; methazolamide and compound 11 in 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 netarsudil; 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 type C Na Tritiated diuretic peptide; Pilocarpine and native C-type natriuretic peptide; Pilocarpine and natriuretic peptide receptor B; Pilocarpine and bicyclol; Pilocarpine and FLIP; Pilocarpine and MET12; Pilocarpine and compound 1 in Table 1; Pilocarpine and compound 2 in Table 1; Pilocarpine and compound 3 in Table 1; Pilocarpine and compound 4 in Table 1; Pilocarpine and compound 5 in Table 1; Pilocarpine and compound 6 in Table 1; Pilocarpine and compound 7 in Table 1; Pilocarpine and compound 8 in Table 1; Pilocarpine and compound 9 in Table 1; Pilocarpine and compound 10 in Table 1; Pilocarpine and compound 11 in Table 1; Pilocarpine and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); pilocarpine and FAIM; pilocarpine and NOL3; pilocarpine and DcR1; pilocarpine and DcR2; pilocarpine and DcR3; carbachol and netarsudil; 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 peptide; carbachol and natural C-type natriuretic peptide; carbachol and natriuretic peptide receptor B; carbachol and bicyclol; carbachol and FLIP; carbachol and MET12; carbachol and compound 1 in Table 1; carbachol and compound 2 in Table 1; carbachol and compound 3 in Table 1; carbachol and compound 4 in Table 1; carbachol and compound 5 in Table 1; carbachol and compound 6 in Table 1; carbachol and compound 7 in Table 1; carbachol and compound 8 in Table 1; carbachol and compound 9 in Table 1; carbachol and compound 10 in Table 1; carbachol and compound 11 in 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; netarsudil and angiopoietin-1; netarsudil and angiopoietin-2; netarsudil and angiopoietin-3; netarsudil and angiopoietin-4; netarsudil and CNTF; netarsudil and peptide 6; netarsudil and peptide 21; netarsudil and recombinant CNTF; netarsudil and NGF; netarsudil and BDNF; netarsudil and GDNF; netarsudil and C-type natriuretic peptide; netarsudil Netarsudil and natural C-type natriuretic peptide; Netarsudil and natriuretic peptide receptor B; Netarsudil and bicyclol; Netarsudil and FLIP; Netarsudil and MET12; Netarsudil and compound 1 in Table 1; Netarsudil and compound 2 in Table 1; Netarsudil and compound 3 in Table 1; Netarsudil and compound 4 in Table 1; Netarsudil and compound 5 in Table 1; Netarsudil and compound 6 in Table 1; Netarsudil and compound 7 in Table 1; Netarsudil and compound 8 in Table 1; Netarsudil and compound 9 in Table 1; Netarsudil and compound 10 in Table 1; Netarsudil and compound 11 in Table 1; Netarsudil and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Netarsudil and FAIM; Netarsudil and NOL3; Netarsudil and DcR1; Netarsudil and DcR2; Netarsudil 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; angiopoietin-1 and bicyclol; angiopoietin-1 and FLIP; angiopoietin-1 and MET12; angiopoietin -1 and Compound 1 in Table 1; Angiopoietin-1 and Compound 2 in Table 1; Angiopoietin-1 and Compound 3 in Table 1; Angiopoietin-1 and Compound 4 in Table 1; Angiopoietin-1 and Compound 5 in Table 1; Angiopoietin-1 and Compound 6 in Table 1; Angiopoietin-1 and Compound 7 in Table 1; Angiopoietin-1 and Compound 8 in Table 1; Angiopoietin-1 and Compound 9 in Table 1; Angiopoietin-1 and Compound 10 in Table 1; Angiopoietin-1 and Compound 11 in 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 in Table 1; angiopoietin-2 and compound 2 in Table 1; angiopoietin-2 and compound 3 in Table 1; angiopoietin-2 and compound 4 in Table 1; angiopoietin-2 and compound 5 in Table 1; angiopoietin-2 and compound 6 in Table 1; angiopoietin-2 and compound 7 in Table 1; angiopoietin-2 and compound 8 in Table 1; angiopoietin-2 and compound 9 in Table 1; angiopoietin-2 and compound 10 in Table 1; angiopoietin-2 and compound 11 in 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 natriuretic peptide receptor B; angiopoietin-3 and bicyclol; angiopoietin-3 and FLIP; angiopoietin-3 and MET12; angiopoietin-3 and compound 1 in Table 1; angiopoietin-3 and compound 2 in Table 1; angiopoietin-3 and compound 3 in Table 1; angiopoietin-3 and compound 4 in Table 1; angiopoietin-3 and compound 5 in Table 1; angiopoietin-3 and compound 6 in Table 1; angiopoietin-3 and compound 7 in Table 1; angiopoietin-3 and compound 8 in Table 1; angiopoietin-3 and compound 9 in Table 1; angiopoietin-3 and compound 10 in Table 1; angiopoietin-3 and compound 11 in 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 peptide receptor B; angiopoietin-4 and bicyclol; angiopoietin-4 and FLIP; angiopoietin-4 and MET12; angiopoietin-4 and compound 1 in Table 1; angiopoietin-4 and compound 2 in Table 1; angiopoietin-4 and compound 3 in Table 1; angiopoietin-4 and compound 4 in Table 1; angiopoietin-4 and compound 5 in Table 1; angiopoietin-4 and compound 6 in Table 1; angiopoietin-4 and compound 7 in Table 1; angiopoietin-4 and compound 8 in Table 1; angiopoietin-4 and compound 9 in Table 1; angiopoietin-4 and compound 10 in Table 1; angiopoietin-4 and compound 11 in Table 1; angiopoietin-4 and H 60 HIYLGATNYIY 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; CNT F and natriuretic peptide receptor B; CNTF and bicyclol; CNTF and FLIP; CNTF and MET12; CNTF and compound 1 in Table 1; CNTF and compound 2 in Table 1; CNTF and compound 3 in Table 1; CNTF and compound 4 in Table 1; CNTF and compound 5 in Table 1; CNTF and compound 6 in Table 1; CNTF and compound 7 in Table 1; CNTF and compound 8 in Table 1; CNTF and compound 9 in Table 1; CNTF and compound 10 in Table 1; CNTF and compound 11 in 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 peptide 6; 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 in Table 1; peptide 6 and compound 2 in Table 1; peptide 6 and compound 3 in Table 1; peptide 6 and compound 4 in Table 1; peptide 6 and compound 5 in Table 1; peptide 6 and compound 6 in Table 1; peptide 6 and compound 7 in Table 1; peptide 6 and compound 8 in Table 1; peptide 6 and compound 9 in Table 1; peptide 6 and compound 10 in Table 1; peptide 6 and compound 11 in 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 Compound 1 in Table 1;Peptide 21 and Compound 2 in Table 1;Peptide 21 and Compound 3 in Table 1;Peptide 21 and Compound 4 in Table 1;Peptide 21 and Compound 5 in Table 1;Peptide 21 and Compound 6 in Table 1;Peptide 21 and Compound 7 in Table 1;Peptide 21 and Compound 8 in Table 1;Peptide 21 and Compound 9 in Table 1;Peptide 21 and Compound 10 in Table 1;Peptide 21 and Compound 11 in 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 Recombinant peptide 21 and MET12; recombinant peptide 21 and compound 1 in Table 1; recombinant peptide 21 and compound 2 in Table 1; recombinant peptide 21 and compound 3 in Table 1; recombinant peptide 21 and compound 4 in Table 1; recombinant peptide 21 and compound 5 in Table 1; recombinant peptide 21 and compound 6 in Table 1; recombinant peptide 21 and compound 7 in Table 1; recombinant peptide 21 and compound 8 in Table 1; recombinant peptide 21 and compound 9 in Table 1; recombinant peptide 21 and compound 10 in Table 1; recombinant peptide 21 and compound 11 in 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 in Table 1; NGF and compound 2 in Table 1; NGF and compound 3 in Table 1; NGF and compound 4 in Table 1; NGF and compound 5 in Table 1; NGF and compound 6 in Table 1; NGF and compound 7 in Table 1; NGF and compound 8 in Table 1; NGF and compound 9 in Table 1; NGF and compound 10 in Table 1; NGF and compound 11 in 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 in Table 1; BDNF and Compound 2 in Table 1; BDNF and Compound 3 in Table 1; BDNF and Compound 4 in Table 1; BDNF and Compound 5 in Table 1; BDNF and Compound 6 in Table 1; BDNF and Compound 7 in Table 1; BDNF and Compound 8 in Table 1; BDNF and Compound 9 in Table 1; BDNF and Compound 10 in Table 1; BDNF and Compound 11 in 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 in Table 1; GDNF and compound 2 in Table 1; GDNF and compound 3 in Table 1; GDNF and compound 4 in Table 1; GDNF and compound 5 in Table 1; GDNF and compound 6 in Table 1; GDNF and compound 7 in Table 1; GDNF and compound 8 in Table 1; GDNF and compound 9 in Table 1; GDNF and compound 10 in Table 1; GDNF and compound 11 in 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 in Table 1; C-type natriuretic peptide and compound 2 in Table 1; C-type natriuretic peptide and compound 3 in Table 1; C-type natriuretic peptide and compound 4 in Table 1; C-type natriuretic peptide and compound 5 in Table 1; C-type natriuretic peptide and compound 6 in Table 1; C-type natriuretic peptide and compound 7 in Table 1; C-type natriuretic peptide and compound 8 in Table 1; C-type natriuretic peptide and compound 9 in Table 1; C-type natriuretic peptide and compound 10 in Table 1; C-type natriuretic peptide and compound 11 in 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; native C-type natriuretic peptide and natriuretic peptide receptor B; native C-type natriuretic peptide and bicyclol; native C-type natriuretic peptide and FLIP; native C-type natriuretic peptide and MET12; native C-type natriuretic peptide and compound 1 in Table 1; native C-type natriuretic peptide and Table Compound 2 in Table 1; Natural C-type natriuretic peptide and compound 3 in Table 1; Natural C-type natriuretic peptide and compound 4 in Table 1; Natural C-type natriuretic peptide and compound 5 in Table 1; Natural C-type natriuretic peptide and compound 6 in Table 1; Natural C-type natriuretic peptide and compound 7 in Table 1; Natural C-type natriuretic peptide and compound 8 in Table 1; Natural C-type natriuretic peptide and compound 9 in Table 1; Natural C-type natriuretic peptide and compound 10 in Table 1; Natural C-type natriuretic peptide and compound 11 in 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 in Table 1; natriuretic peptide receptor B and compound 2 in Table 1 ;Natriuretic peptide receptor B and compound 3 in Table 1;Natriuretic peptide receptor B and compound 4 in Table 1;Natriuretic peptide receptor B and compound 5 in Table 1;Natriuretic peptide receptor B and compound 6 in Table 1;Natriuretic peptide receptor B and compound 7 in Table 1;Natriuretic peptide receptor B and compound 8 in Table 1;Natriuretic peptide receptor B and compound 9 in Table 1;Natriuretic peptide receptor B and compound 10 in Table 1;Natriuretic peptide receptor B and compound 11 in 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; bicyclol and FLIP; bicyclol and MET12; bicyclol and compound 1 in Table 1; bicyclol and compound 2 in Table 1; bicyclol and compound 3 in Table 1; bicyclol and compound 4 in Table 1; bicyclol and compound 5 in Table 1; bicyclol and compound 6 in Table 1; bicyclol and compound 7 in Table 1; bicyclol and compound 8 in Table 1; bicyclol and compound 9 in Table 1; bicyclol and compound 10 in Table 1; bicyclol and compound 11 in Table 1; bicyclol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); bicyclol and FAIM; bicyclol and NOL3; bicyclol and DcR1; bicyclol and DcR2; bicyclol and DcR3; FLIP and MET12; FLIP and compound 1 in Table 1; FLIP and compound 2 in Table 1; FLIP and compound 3 in Table 1; FLIP and compound 4 in Table 1; FLIP and compound 5 in Table 1; FLIP and compound 6 in Table 1; FLIP and compound 7 in Table 1; FLIP and compound 8 in Table 1; FLIP and compound 9 in Table 1; FLIP and compound 10 in Table 1; FLIP and compound 11 in 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 in Table 1; MET12 and Compound 2 in Table 1; MET12 and Compound 3 in Table 1; MET12 and Compound 4 in Table 1; MET12 and Compound 5 in Table 1; MET12 and Compound 6 in Table 1; MET12 and Compound 7 in Table 1; MET12 and Compound 8 in Table 1; MET12 and Compound 9 in Table 1; MET12 and Compound 10 in Table 1; MET12 and Compound 11 in 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 in Table 1 and Compound 2 in Table 1; Compound 1 in Table 1 and Compound 3 in Table 1; Compound 1 in Table 1 and Compound 4 in Table 1; Compound 1 in Table 1 and Compound 5 in Table 1; Compound 1 in Table 1 and Compound 6 in Table 1; Compound 1 in Table 1 and Compound 7 in Table 1; Compound 1 in Table 1 and Compound 8 in Table 1; Compound 1 in Table 1 and Compound 9 in Table 1; Compound 1 in Table 1 and Compound 10 in Table 1; Compound 1 in Table 1 and Compound 11 in Table 1; Compound 1 in Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 1 in Table 1 and FAIM; Compound 1 in Table 1 and NOL3; Compound 1 in Table 1 and DcR1; Compound 1 in Table 1 and DcR2; Compound 1 in Table 1 and DcR3; Compound 2 in Table 1 and Compound 3 in Table 1; Compound 2 in Table 1 and Compound 4 in Table 1; Compound 2 in Table 1 and Compound 5 in Table 1; Compound 2 in Table 1 and Compound 6 in Table 1; Compound 2 in Table 1 and Compound 7 in Table 1; Compound 2 in Table 1 and Compound 8 in Table 1; Compound 2 in Table 1 and Compound 9 in Table 1; Compound 2 in Table 1 and Compound 10 in Table 1; Compound 2 in Table 1 and Compound 11 in Table 1; Compound 2 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 2 in Table 1 and FAIM; Compound 2 in Table 1 and NOL3; Compound 2 in Table 1 and DcR1; Compound 2 in Table 1 and DcR2; Compound 2 in Table 1 and DcR3; Compound 3 in Table 1 and Compound 4 in Table 1; Compound 3 in Table 1 and Compound 5 in Table 1; Compound 3 in Table 1 and Compound 6 in Table 1; Compound 3 in Table 1 and Compound 7 in Table 1; Compound 3 in Table 1 and Compound 8 in Table 1; Compound 3 in Table 1 and Compound 9 in Table 1; Compound 3 in Table 1 and Compound 10 in Table 1; Compound 3 in Table 1 and Compound 11 in Table 1; Compound 3 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 3 in Table 1 and FAIM; Compound 3 in Table 1 and NOL3; Compound 3 in Table 1 and DcR1; Compound 3 in Table 1 and DcR2; Compound 3 in Table 1 and DcR3; Compound 4 in Table 1 and Compound 5 in Table 1; Compound 4 in Table 1 and Compound 6 in Table 1; Compound 4 in Table 1 and Compound 7 in Table 1; Compound 4 in Table 1 and Compound 8 in Table 1; Compound 4 in Table 1 and Compound 9 in Table 1; Compound 4 in Table 1 and Compound 10 in Table 1; Compound 4 in Table 1 and Compound 11 in Table 1; Compound 4 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 4 in Table 1 and FAIM; Compound 4 in Table 1 and NOL3; Compound 4 in Table 1 and DcR1; Compound 4 in Table 1 and DcR2; Compound 4 in Table 1 and DcR3; Compound 5 in Table 1 and Compound 6 in Table 1; Compound 5 in Table 1 and Compound 7 in Table 1; Compound 5 in Table 1 and Compound 8 in Table 1; Compound 5 in Table 1 and Compound 9 in Table 1; Compound 5 in Table 1 and Compound 10 in Table 1; Compound 5 in Table 1 and Compound 11 in Table 1; Compound 5 in Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 5 in Table 1 and FAIM; Compound 5 in Table 1 and NOL3; Compound 5 in Table 1 and DcR1; Compound 5 in Table 1 and DcR2; Compound 5 in Table 1 and DcR3; Compound 6 in Table 1 and Compound 7 in Table 1; Compound 6 in Table 1 and Compound 8 in Table 1; Compound 6 in Table 1 and Compound 9 in Table 1; Compound 6 in Table 1 and Compound 10 in Table 1; Compound 6 in Table 1 and Compound 11 in Table 1; Compound 6 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 6 in Table 1 and FAIM; Compound 6 in Table 1 and NOL3; Compound 6 in Table 1 and DcR1; Compound 6 in Table 1 and DcR2; Compound 6 in Table 1 and DcR3; Compound 7 in Table 1 and Compound 8 in Table 1; Compound 7 in Table 1 and Compound 9 in Table 1; Compound 7 in Table 1 and Compound 10 in Table 1; Compound 7 in Table 1 and Compound 11 in Table 1; Compound 7 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 7 in Table 1 and FAIM; Compound 7 in Table 1 and NOL3; Compound 7 in Table 1 and DcR1; Compound 7 in Table 1 and DcR2; Compound 7 in Table 1 and DcR3; Compound 8 in Table 1 and Compound 9 in Table 1; Compound 8 in Table 1 and Compound 10 in Table 1; Compound 8 in Table 1 and Compound 11 in Table 1; Compound 8 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 8 in Table 1 and FAIM; Compound 8 in Table 1 and NOL3; Compound 8 in Table 1 and DcR1; Compound 8 in Table 1 and DcR2; Compound 8 in Table 1 and DcR3; Compound 9 in Table 1 and Compound 10 in Table 1; Compound 9 in Table 1 and Compound 11 in Table 1; Compound 9 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 9 in Table 1 and FAIM; Compound 9 in Table 1 and NOL3; Compound 9 in Table 1 and DcR1; Compound 9 in Table 1 and DcR2; Compound 9 in Table 1 and DcR3; Compound 10 in Table 1 and Compound 11 in Table 1; Compound 10 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 10 in Table 1 and FAIM; Compound 10 in Table 1 and NOL3; Compound 10 in Table 1 and DcR1; Compound 10 in Table 1 and DcR2; Compound 10 in Table 1 and DcR3; Compound 11 in Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 11 and FAIM in Table 1; Compound 11 and NOL3 in Table 1; Compound 11 and DcR1 in Table 1; Compound 11 and DcR2 in Table 1; Compound 11 and DcR3 in Table 1; 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 60 HIYLGATNYIY 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.

[0082] Some covalently bonded combinations are represented by the following structural formulas: Formula C-1 P6-MET12 Formula C-2 P6-MET12-P6 Formula C-3 MET12-P6-MET12 Formula C-4 P6-GGG-MET12 Formula C-5 MET12-GGG-P6 Formula C-6 P6-GGG-MET12-GGG-P6 Formula C-7 MET12-GGG-P6-GGG-MET12 Formula C-8 P6-(N-AEAc) x -MET12 Formula C-9 MET12-(N-AEEAc) x -P6 Formula C-10 MET12-(N-AEEAc) x -P6-(N-AEEAc) y -MET12 Formula C-11 P6-(N-AEEAc) x -MET12-(N-AEEAc)y -P6 Formula C-12 P6-(N-dPEG12) x -MET12 Formula C-13 P21-MET12 Formula C-14 P21-MET12-P21 Formula C-15 MET12-P21-MET12 Formula C-16 P21-GGG-MET12 Formula C-17 MET12-GGG-P21 Formula C-18 P21-GGG-MET12-GGG-P21 Formula C-19 MET12-GGG-P21-GGG-MET12 Formula C-20 P21-(N-AEAc) x -MET12 Formula C-21 MET12-(N-AEEAc) x -P21 Formula C-22 MET12-(N-AEEAc) x -P21-(N-AEEAc) y -MET12 Formula C-23 P21-(N-AEEAc) x -MET12-(N-AEEAc) y -P21 Formula C-24 P21-(N-dPEG12) x -MET12 Formula C-25 P6-(O-AEAc) x -MET12 Formula C-26 MET12-(O-AEEAc) x -P6 Formula C-27 MET12-(O-AEEAc) x -P6-(O-AEEAc) y -MET12 Formula C-28 P6-(O-AEEAc) x -MET12-(O-AEEAc) y -P6 Formula C-29 P6-(O-dPEG12) x -MET12 Formula C-30 P21-(O-AEAc) x -MET12 Formula C-31 MET12-(O-AEEAc) x -P21 Formula C-32 MET12-(O-AEEAc) x -P21-(O-AEEAc) y -MET12 Formula C-33 P21-(O-AEEAc) x -MET12-(O-AEEAc) y -P21 Formula C-34 P21-(O-dPEG12) x -MET12 Formula C-35 P6-MET12-BC Formula C-36 P6-MET12-P6-BC Formula C-37 MET12-P6-MET12-BC Formula C-38 P6-GGG-MET12-BC Formula C-39 MET12-GGG-P6-BC Formula C-40 P6-GGG-MET12-GGG-P6-BC Formula C-41 MET12-GGG-P6-GGG-MET12-BC Formula C-42 P6-(N-AEAc) x -MET12-BC Formula C-43 MET12-(N-AEEAc) x -P6-BC Formula C-44 MET12-(N-AEEAc) x -P6-(N-AEEAc) y -MET12-BC Formula C-45 P6-(N-AEEAc) x -MET12-(N-AEEAc) y -P6-BC Formula C-46 P6-(N-dPEG12) x -MET12-BC Formula C-47 P21-MET12-BC Formula C-48 P21-MET12-P21-BC Formula C-49 MET12-P21-MET12-BC Formula C-50 P21-GGG-MET12-BC Formula C-51 MET12-GGG-P21-BC Formula C-52 P21-GGG-MET12-GGG-P21-BC Formula C-53 MET12-GGG-P21-GGG-MET12-BC Formula C-54 P21-(N-AEAc) x -MET12-BC Formula C-55 MET12-(N-AEEAc) x -P21-BC Formula C-56 MET12-(N-AEEAc) x -P21-(N-AEEAc) y -MET12-BC Formula C-57 P21-(N-AEEAc) x -MET12-(N-AEEAc) y -P21-BC Formula C-58 P21-(N-dPEG12) x -MET12-BC Formula C-59 P6-(O-AEAc) x -MET12-BC Formula C-60 MET12-(O-AEEAc) x -P6-BC Formula C-61 MET12-(O-AEEAc) x -P6-(O-AEEAc) y -MET12-BC Formula C-62 P6-(O-AEEAc) x -MET12-(O-AEEAc) y -P6-BC Formula C-63 P6-(O-dPEG12) x -MET12-BC Formula C-64 P21-(O-AEAc) x -MET12-BC Formula C-65 MET12-(O-AEEAc) x -P21-BC Formula C-66 MET12-(O-AEEAc) x -P21-(O-AEEAc) y -MET12-BC Formula C-67 P21-(O-AEEAc) x -MET12-(O-AEEAc) y-P21-BC Formula C-68 P21-(O-dPEG12) x -MET12-BC Formula C-69 BC-P6-MET12 Formula C-70 BC-P6-MET12-P6 Formula C-71 BC-MET12-P6-MET12 Formula C-72 BC-P6-GGG-MET12 Formula C-73 BC-MET12-GGG-P6 Formula C-74 BC-P6-GGG-MET12-GGG-P6 Formula C-75 BC-MET12-GGG-P6-GGG-MET12 Formula C-76 BC-P6-(N-AEAc) x -MET12 Formula C-77 BC-MET12-(N-AEEAc) x -P6 Formula C-78 BC-MET12-(N-AEEAc) x -P6-(N-AEEAc) y -MET12 Formula C-79 BC-P6-(N-AEEAc) x -MET12-(N-AEEAc) y -P6 Formula C-80 BC-P6-(N-dPEG12) x -MET12 Formula C-81 BC-P21-MET12 Formula C-82 BC-P21-MET12-P21 Formula C-83 BC-MET12-P21-MET12 Formula C-84 BC-P21-GGG-MET12 Formula C-85 BC-MET12-GGG-P21 Formula C-86 BC-P21-GGG-MET12-GGG-P21 Formula C-87 BC-MET12-GGG-P21-GGG-MET12 Formula C-88 BC-P21-(N-AEAc) x -MET12 Formula C-89 BC-MET12-(N-AEEAc) x-P21 Formula C-90 BC-MET12-(N-AEEAc) x -P21-(N-AEEAc) y -MET12 Formula C-91 BC-P21-(N-AEEAc) x -MET12-(N-AEEAc) y -P21 Formula C-92 BC-P21-(N-dPEG12) x -MET12 Formula C-93 BC-P6-(O-AEAc) x -MET12 Formula C-94 BC-MET12-(O-AEEAc) x -P6 Formula C-95 BC-MET12-(O-AEEAc) x -P6-(O-AEEAc) y -MET12 Formula C-96 BC-P6-(O-AEEAc) x -MET12-(O-AEEAc) y -P6 Formula C-97 BC-P6-(O-dPEG12) x -MET12 Formula C-98 BC-P21-(O-AEAc) x -MET12 Formula C-99 BC-MET12-(O-AEEAc) x -P21 Formula C-100 BC-MET12-(O-AEEAc) x -P21-(O-AEEAc) y -MET12 Formula C-101 BC-P21-(O-AEEAc) x -MET12-(O-AEEAc) y -P21 Formula C-102 BC-P21-(O-dPEG12) x -MET12 Formula C-105 P6-MET4~8 Formula C-106 P6-MET4~8-P6 Formula C-107 MET4~8-P6-MET4~8 Formula C-108 P6-GGG-MET4~8 Formula C-109 MET4~8-GGG-P6 Formula C-110 P6-GGG-MET4~8-GGG-P6 Formula C-111 MET4~8-GGG-P6-GGG-MET4~8 Formula C-112 P6-(N-AEAc) x -MET4~8 Formula C-113 MET4~8-(N-AEEAc) x -P6 Formula C-114 MET4~8-(N-AEEAc) x -P6-(N-AEEAc) y -MET4~8 Formula C-115 P6-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P6 Formula C-116 P6-(N-dPEG12) x -MET4~8 Formula C-117 P21-MET4~8 Formula C-118 P21-MET4~8-P21 Formula C-119 MET4~8-P21-MET4~8 Formula C-120 P21-GGG-MET4~8 Formula C-121 MET4~8-GGG-P21 Formula C-122 P21-GGG-MET4~8-GGG-P21 Formula C-123 MET4~8-GGG-P21-GGG-MET4~8 Formula C-124 P21-(N-AEAc) x -MET4~8 Formula C-125 MET4~8-(N-AEEAc) x -P21 Formula C-126 MET4~8-(N-AEEAc) x -P21-(N-AEEAc) y -MET4~8 Formula C-127 P21-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P21 Formula C-128 P21-(N-dPEG12) x -MET4~8 Formula C-129 P6-(O-AEAc) x -MET4~8 Formula C-130 MET4~8-(O-AEEAc) x -P6 Formula C-131 MET4~8-(O-AEEAc) x -P6-(O-AEEAc) y -MET4~8 Formula C-132 P6-(O-AEEAc) x -MET4~8-(O-AEEAc) y -P6 Formula C-133 P6-(O-dPEG12) x -MET4~8 Formula C-134 P21-(O-AEAc) x -MET4~8 Formula C-135 MET4~8-(O-AEEAc) x -P21 Formula C-136 MET4~8-(O-AEEAc) x -P21-(O-AEEAc) y -MET4~8 Formula C-137 P21-(O-AEEAc) x -MET4~8-(O-AEEAc) y -P21 Formula C-138 P21-(O-dPEG12) x -MET4~8 Formula C-139 P6-MET4~8-BC Formula C-140 P6-MET4~8-P6-BC Formula C-141 MET4~8-P6-MET4~8-BC Formula C-142 P6-GGG-MET4~8-BC Formula C-143 MET4~8-GGG-P6-BC Formula C-144 P6-GGG-MET4~8-GGG-P6-BC Formula C-145 MET4~8-GGG-P6-GGG-MET4~8-BC Formula C-146 P6-(N-AEAc) x -MET4~8-BC Formula C-147 MET4~8-(N-AEEAc) x -P6-BC Formula C-148 MET4~8-(N-AEEAc) x -P6-(N-AEEAc) y -MET4~8-BC Formula C-149 P6-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P6-BC Formula C-150 P6-(N-dPEG12) x -MET4~8-BC Formula C-151 P21-MET4~8-BC Formula C-152 P21-MET4~8-P21-BC Formula C-153 MET4~8-P21-MET4~8-BC Formula C-154 P21-GGG-MET4~8-BC Formula C-155 MET4~8-GGG-P21-BC Formula C-156 P21-GGG-MET4~8-GGG-P21-BC Formula C-157 MET4~8-GGG-P21-GGG-MET4~8-BC Formula C-158 P21-(N-AEAc) x -MET4~8-BC Formula C-159 MET4~8-(N-AEEAc) x -P21-BC Formula C-160 MET4~8-(N-AEEAc) x -P21-(N-AEEAc) y -MET4~8-BC Formula C-161 P21-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P21-BC Formula C-162 P21-(N-dPEG12) x -MET4~8-BC Formula C-163 P6-(O-AEAc) x -MET4~8-BC Formula C-164 MET4~8-(O-AEEAc) x -P6-BC Formula C-165 MET4~8-(O-AEEAc) x -P6-(O-AEEAc) y -MET4~8-BC Formula C-166 P6-(O-AEEAc) x -MET4~8-(O-AEEAc) y -P6-BC Formula C-167 P6-(O-dPEG12) x -MET4~8-BC Formula C-168 P21-(O-AEAc) x -MET4~8-BC Formula C-169 MET4~8-(O-AEEAc) x -P21-BC Formula C-170 MET4~8-(O-AEEAc) x -P21-(O-AEEAc) y -MET4~8-BC Formula C-171 P21-(O-AEEAc) x -MET4~8-(O-AEEAc) y -P21-BC Formula C-172 P21-(O-dPEG12) x -MET4~8-BC Formula C-173 BC-P6-MET4~8 Formula C-174 BC-P6-MET4~8-P6 Formula C-175 BC-MET4~8-P6-MET4~8 Formula C-176 BC-P6-GGG-MET4~8 Formula C-177 BC-MET4~8-GGG-P6 Formula C-178 BC-P6-GGG-MET4~8-GGG-P6 Formula C-179 BC-MET4~8-GGG-P6-GGG-MET4~8 Formula C-180 BC-P6-(N-AEAc) x -MET4~8 Formula C-181 BC-MET4~8-(N-AEEAc) x -P6 Formula C-182 BC-MET4~8-(N-AEEAc) x -P6-(N-AEEAc)y -MET4~8 Formula C-183 BC-P6-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P6 Formula C-184 BC-P6-(N-dPEG12) x -MET4~8 Formula C-185 BC-P21-MET4~8 Formula C-186 BC-P21-MET4~8-P21 Formula C-187 BC-MET4~8-P21-MET4~8 Formula C-188 BC-P21-GGG-MET4~8 Formula C-189 BC-MET4~8-GGG-P21 Formula C-190 BC-P21-GGG-MET4~8-GGG-P21 Formula C-191 BC-MET4~8-GGG-P21-GGG-MET4~8 Formula C-192 BC-P21-(N-AEAc) x -MET4~8 Formula C-193 BC-MET4~8-(N-AEEAc) x -P21 Formula C-194 BC-MET4~8-(N-AEEAc) x -P21-(N-AEEAc) y -MET4~8 Formula C-195 BC-P21-(N-AEEAc) x -MET4~8-(N-AEEAc) y -P21 Formula C-196 BC-P21-(N-dPEG12) x -MET4~8 Formula C-197 BC-P6-(O-AEAc) x -MET4~8 Formula C-198 BC-MET4~8-(O-AEEAc) x -P6 Formula C-199 BC-MET4~8-(O-AEEAc) x -P6-(O-AEEAc) y -MET4~8 Formula C-200 BC-P6-(O-AEEAc)x -MET4~8-(O-AEEAc) y -P6 Formula C-201 BC-P6-(O-dPEG12) x -MET4~8 Formula C-202 BC-P21-(O-AEAc) x -MET4~8 Formula C-203 BC-MET4~8-(O-AEEAc) x -P21 Formula C-204 BC-MET4~8-(O-AEEAc) x -P21-(O-AEEAc) y -MET4~8 Formula C-205 BC-P21-(O-AEEAc) x -MET4~8-(O-AEEAc) y -P21 Formula C-206 BC-P21-(O-dPEG12) x -MET4~8

[0083] In 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 the structural formulas C-1 to C-206, P6 or P21 includes any peptide containing the sequence DGGL (SEQ ID NO: 20). The bond can occur at either end or at any position of MET12, MET4-MET8, P6, P21, or BC. For example, "P6-MET12" represents both P6-MET12 and MET12-P6. P6, MET12, GGG, N-AEEAc, N-dPEG12, etc. represent corresponding compounds whose structures have been modified to accommodate the depicted bond. For example, P6 is Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1). Met12 is [ka] is. One possible structure for P6-MET12 (P6 and MET12 disclosed as SEQ ID NOs: 1 and 3) is: [ka] is.

[0084] Some covalently bonded compounds for use in drug delivery systems include: [ka] Includes:

[0085] With respect to any related structural representation, such as formula C103 or C104, z is 0 to 10,000, 0 to 1,000, 1,000 to 2,000, 2,000 to 3,000, 3,000 to 4,000, 4,000 to 5,000, 5,000 to 6,000, 6,000 to 7,000, 8,000 to 9,000, 9,000 to 10,000, 0 to 5,000, or 5,000 to 10,000.

[0086] For any related structural representation such as formula C104, Y is N or O.

[0087] For any relevant structural representation such as formula C104, A 1 is a group derived from P6, P21, or C1-C34, eg, as described above, with the relevant atom removed to accommodate the bond.

[0088] For any relevant structural representation such as formula C104, A 2 is -OCH2CH2O- or -NHCH2CH2N-.

[0089] Some examples of bimatoprost acids covalently linked to MET4-8 (e.g., MET4, MET5, MET6, MET7, or MET8), MET12, P6, or P21 are represented by the formula C207 [ka] is expressed by During the ceremony, n is approximately 2-2000, e.g., 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, 900-1,000, 1,000-1,100, 1,100-1,200, 1,200-1,300, 1,300-1,400, RH is 00, 1,400-1,500, 1,500-1,600, 1,600-1,700, 1,700-1,800, 1,800-1,900, 1,900-2,000, 2-500, 500-1,000, 2-1,000, 1,000-1,500, 1,500-2,000, or 1,000-2,000; 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).

[0090] For example, bimatoprost acid covalently bound to MET4 has the formula C-208 [ka] It can be expressed as:

[0091] The sustained delivery component is a part of a drug delivery system that allows a drug to remain in the body for a sustained period of time, e.g., longer than the time it takes for the drug to be metabolized or exit the body, e.g., 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. Typically, the sustained delivery component is an implant, such as a solid implant, that functions by encapsulating or otherwise entrapping the drug within the implant. If the implant is biodegradable or bioerodible, the drug can be released as the implant biodegrades or bioerodes. The implant may also be porous to allow the drug to diffuse out of the implant over a period of time. Biodegradable or bioerodible implants may be porous or non-porous. Typically, non-biodegradable or non-bioerodible implants are porous and the drug is released by diffusion, although other mechanisms such as osmotic pumps may also work.

[0092] In some embodiments, the drug delivery system may be implanted into a mammal, such as a human, at intervals of about 1 week to about 10 years, about 1 to 12 weeks, about 3 to 6 months, about 6 to 9 months, about 9 to 12 months, about 12 to 18 months, about 18 to 24 months, about 0.1 to 3 years, about 3 to 5 years, or about 5 to 10 years.

[0093] In some embodiments, a therapeutic effect, such as a reduction in intraocular pressure or a reduction in vision loss, may be observed for 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, from about 1 to 12 weeks, from about 3 to 6 months, from about 6 to 9 months, from about 9 to 12 months, from about 12 to 18 months, from about 18 to 24 months, from about 0.1 to 3 years, from about 3 to 5 years, from about 5 to 10 years, or longer, after the drug delivery system is implanted in a mammal, such as a human.

[0094] The agent may be physically entrapped in the sustained delivery component and / or may be covalently bound to a molecule that is part of the sustained delivery component.

[0095] Typical examples of biodegradable materials for porous or non-porous biodegradable implants generally include silica-based materials and organic biodegradable materials such as polymers including poly(D,L-lactic acid) (PLA) and poly(D,L-lactic-co-glycolic acid) (PLGA), polyesteramide (PEA, DSM Chemical), and polycaprolactone (PCL); hydrogels such as polyvinyl alcohol (PVA), PEG amine, PEG-N-hydroxysuccinamide ester (Ocular Therapeutix, etc.); collagen-based materials (Euclid systems); or combinations thereof.

[0096] There are many suitable silica-based sustained delivery compositions.

[0097] One type of silica-based sustained-release component includes a silica hydrogel composite obtained by mixing silica particles containing an encapsulated drug with a silica sol, and 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 significantly reduces burst release of different types of encapsulated therapeutic and biologically active agents. A detailed description of this type of silica-based sustained-release component and its method of manufacture can be found in U.S. Patent No. 9,949,922 to Jokinen et al., issued April 24, 2018, the entire contents of which are incorporated herein by reference.

[0098] Another type of silica-based sustained delivery component includes drug-containing flowable silica compositions and gel compositions obtained by a method for producing a flowable silica composition that includes a sol-gel transition followed by redispersion. The redispersion involves adding a liquid to the gel formed by the sol-gel transition after the gel point of the sol-gel transition is reached, the addition occurring within a sufficiently short time after the gel point is reached, such that the gel and liquid are mixed together to form a viscoelastically homogeneous flowable silica composition that is injectable directly through a thin 22G needle or with brief agitation of less than 30 seconds, and remains injectable. The flowable, injectable sustained delivery silica composition can enhance the stability and maintain activity of the encapsulated therapeutic agent. A detailed description of this type of silica-based sustained delivery component and its method of production can be found in U.S. Patent Application No. 20140057996 to Jokinen et al., published February 27, 2014, the entire contents of which are incorporated herein by reference.

[0099] Another type of silica-based sustained delivery component includes a composition comprising a bioerodible porous silicon-based carrier material carrying a drug and at least one amorphous sugar, optionally further comprising a crystallization inhibitor. These delivery systems involve loading a biomolecule into the pores of the silica carrier material, resulting in stabilization of the biomolecule. However, these systems may also be used for small molecule therapeutic compounds. A detailed description of this type of silica-based sustained delivery component and its manufacturing method can be found in U.S. Patent No. 9,603,801 to Barnett et al., issued March 28, 2017, the entire contents of which are incorporated herein by reference.

[0100] Another type of silica-based sustained-delivery component includes bioerodible devices, such as implants, for controlled drug delivery. These devices include porous silicon-based carrier materials impregnated with or loaded with a drug. These particular silicon carrier materials contain at least one large molecule therapeutic agent disposed within the pores of the carrier material. Loading the therapeutic large molecule into the pores of the carrier material is believed to stabilize the large molecule. In many embodiments, the large molecule is a protein, the pores have an average size of about 15 nm to about 40 nm, and the protein has a molecular weight of about 100,000 amu to about 200,000 amu. However, these systems may also be used with small molecule therapeutic compounds. A detailed description of this type of silica-based sustained delivery component and methods for its manufacture can be found in U.S. Pat. No. 9,808,421 to Ashton et al., issued November 7, 2017, U.S. Pat. No. 9,333,173 to Ashton et al., issued May 10, 2016, and U.S. Patent Publication No. 20140271764 to Ashton et al., published September 28, 2014, the entire contents of all of which are incorporated herein by reference.

[0101] The sustained delivery component may be about 1 μg to 100 mg, about 1 to 2 μg, about 2 to 3 μg, about 3 to 4 μg, about 4 to 5 μg, about 5 to 6 μg, about 6 to 7 μg, about 7 to 8 μg, about 8 to 9 μg, about 9 to 10 μg, about 10 to 20 μg, about 20 to 30 μg, about 30 to 40 μg, about 40 to 50 μg, about 50 to 60 μg, about 60 to 70 μg, about 70 to 80 μg, about 80 to 90 μg, about 90 to 100 μg, about 100 to 200 μg, about 200 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, Approximately 500-600μg, approximately 600-700μg, approximately 700-800μg, approximately 800-900μg, approximately 900-1,000μg, approximately 1-2mg, approximately 2-3mg, approximately 3-4mg, approximately 4-5mg, approximately 5-6mg, approximately 6-7mg, approximately 7-8mg , about 8-9 mg, about 9-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-20 0mg, about 200-300mg, about 300-400mg, about 400-500mg, about 500-600mg, about 600-700mg, about 700-800mg, about 800-900mg, about 900-1,000mg, about 1-2g, about 2-3 g, 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 50-60g, about 60-70g, about 70-80g, about 80- The drug may have any suitable mass, such as 90 g, about 90-100 g, about 100-200 g, about 200-300 g, about 300-400 g, about 400-500 g, about 500-600 g, about 600-700 g, about 700-800 g, about 800-900 g, about 900-1,000 g, about 10-100 μg, about 100-1,000 μg, about 1-10 mg, about 10-100 mg, about 100-1,000 mg, about 1-10 g, about 10-100 g, or about 100-1,000 g. The above ranges of about 1 g or less, or about 100 mg or less, may be of interest for drug delivery systems delivered onto or into the eye.

[0102] The sustained delivery component may be any suitable percentage of the implant, such as about 1-99% by weight, about 1-10% by weight, about 10-20% by weight, about 20-30% by weight, about 30-40% by weight, about 40-50% by weight, about 50-60% by weight, about 60-70% by weight, about 70-80% by weight, about 80-90% by weight, about 90-99% by weight, about 1-30% by weight, about 30-65% by weight, about 65-99% by weight, about 1-50% by weight, or about 50-99% by weight.

[0103] The drug delivery system may be administered in a range of dosages from about 1 μg to 100 mg, about 1 to 2 μg, about 2 to 3 μg, about 3 to 4 μg, about 4 to 5 μg, about 5 to 6 μg, about 6 to 7 μg, about 7 to 8 μg, about 8 to 9 μg, about 9 to 10 μg, about 10 to 20 μg, about 20 to 30 μg, about 30 to 40 μg, about 40 to 50 μg, about 50 to 60 μg, about 60 to 70 μg, about 70 to 80 μg, about 80 to 90 μg, about 90 to 100 μg, about 100 to 200 μg, about 200 to 300 μg, about 300 to 400 μg, about 400 to 500 μg, Approximately 500-600μg, approximately 600-700μg, approximately 700-800μg, approximately 800-900μg, approximately 900-1,000μg, approximately 1-2mg, approximately 2-3mg, approximately 3-4mg, approximately 4-5mg, approximately 5-6mg, approximately 6-7mg, approximately 7-8m g, about 8-9 mg, about 9-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-2 00mg, about 200-300mg, about 300-400mg, about 400-500mg, about 500-600mg, about 600-700mg, about 700-800mg, about 800-900mg, about 900-1,000mg, 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 50-60g, about 60-70g, about 70-80g, about 80 The dosage may be any suitable size, such as about 90 g, about 90-100 g, about 100-200 g, about 200-300 g, about 300-400 g, about 400-500 g, about 500-600 g, about 600-700 g, about 700-800 g, about 800-900 g, about 900-1,000 g, about 10-100 μg, about 100-1,000 μg, about 1-10 mg, about 10-100 mg, about 100-1,000 mg, about 1-10 g, about 10-100 g, or about 100-1,000 g. The above ranges of about 1 g or less, or about 100 mg or less, may be of interest for drug delivery systems delivered onto or into the eye.

[0104] The drug delivery system may deliver any suitable amount of drug per day, such as about 5 to 1,000 ng, about 5 to 20 ng, about 20 to 40 ng, about 40 to 60 ng, about 60 to 80 ng, about 80 to 100 ng, about 100 to 150 ng, about 150 to 200 ng, about 200 to 300 ng, about 300 to 400 ng, about 400 to 500 ng, about 500 to 600 ng, about 600 to 800 ng, about 800 to 1,000 ng, about 5 to 100 ng, about 100 to 300 ng, about 300 to 600 ng, or about 600 to 1,000 ng.

[0105] Typical examples of non-biodegradable or non-bioerodible materials for implants include silicone or PVA (Psivida, etc.) as a semi-permeable membrane.

[0106] Other possible sustained delivery components may be based on cell-based approaches such as encapsulated cell technology; and reservoir-based approaches (foresight4; Replenish).

[0107] The neurotrophic agent, such as a prostaglandin compound or prostaglandin receptor agonist, an ocular hypotensive agent, and / or a CNTF compound, may or may not be covalently bound to a sustained delivery component.

[0108] In some embodiments, the prostaglandin compound or prostaglandin receptor agonist is covalently bound to the sustained delivery component. In some embodiments, the prostaglandin compound or prostaglandin receptor agonist is not covalently bound to the sustained delivery component.

[0109] In some embodiments, the ocular hypotensive agent is covalently attached to the sustained delivery component. In some embodiments, the ocular hypotensive agent is not covalently attached to the sustained delivery component.

[0110] In some embodiments, the neurotrophic agent, such as the CNTF compound, is covalently attached to a sustained delivery component. In some embodiments, the neurotrophic agent, such as the CNTF compound, is not covalently attached to a sustained delivery component.

[0111] For example, a prostaglandin compound or prostaglandin receptor agonist may be represented by the formula [ka] wherein PG-H is a prostaglandin compound or prostaglandin receptor agonist, such as the prostaglandin compounds or prostaglandin receptor agonists described above.

[0112] Compounds of formula 3 may further be represented by formulas 3A and 3B [ka] where Prg-CO2H is a prostaglandin agonist and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0113] The intraocular pressure lowering agent is [ka] and the IOP-H is an intraocular pressure lowering agent, such as those described above.

[0114] The CNTF compound or other neurotrophic agent may be [ka] wherein CNTF-H is a CNTF compound or other neurotrophic agent, such as the CNTF compounds described above or other neurotrophic agents.

[0115] The CNP compound has the formula [ka] and CNP-H is the CNP compound.

[0116] The NPR-B compound has the formula [ka] and NPRB-H is an NPR-B compound.

[0117] With respect to representations of formula 3, 3A, 3B, 4, 5, 6, or 7, or related structures such as the compounds shown below, R 1 are independently H or C alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1-6 It is alkyl.

[0118] With respect to representations of formula 3, 3A, 3B, 4, 5, 6, or 7, or related structures such as the compounds shown below, R 2 are independently H or C alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1-6 It is alkyl.

[0119] With respect to representations of formula 3, 3A, 3B, 4, 5, 6, or 7, or related structures such as the compounds shown below, R 3 are independently H or C alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1-6 It is alkyl.

[0120] The compounds are examples of compounds of formula 3, 3A or 3B. [ka]

[0121] In the body, the ester bond can be hydrolyzed to release the compound. [ka]

[0122] The table below shows three examples of compounds of formula 4 and three compounds that can be released in the body by hydrolysis of the ester or amide group. [Table 3]

[0123] In the table above, any Si(OH)3 group is SiOR 1 OR 2 OR 3 may be substituted with

[0124] Examples of compounds of Formula 5 are VGDGGLFEKKL-PEG-Si(OH)3 ("VGDGGLFEKKL" is disclosed as SEQ ID NO: 1) or VGDGGLFEKKL-PEG-SiOR 1 OR 2 OR 3 ("VGDGGLFEKKL" is disclosed as SEQ ID NO: 1), and PEG is a polyethylene glycol chain (e.g., -(OCH2CH2) n - and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. In the body, the ester bond can be hydrolyzed to release VGDGGLFEKKL (SEQ ID NO: 1).

[0125] 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 a silica-based drug delivery system to form, for example, a compound represented by formula 3D, 3AD, 3BD, 4D, or 5D, where D is SiOR of formula 3, 3A, 3B, 4, 5, 6, or 7. 1 OR 2 OR 3 It is a sustained delivery component containing Si.

[0126] [ka]

[0127] Some drug delivery systems are [ka] The polymer may include a polymer represented by Each X is independently [ka] is.

[0128] The subject drug delivery systems can be administered to a mammal, such as a human, by any suitable method, such as injection or surgery into a body part, oral administration, or topical application to the eye or skin. In some embodiments, the implant is injected or otherwise implanted within or around the eye, including, but not limited to, the anterior chamber, vitreous body, posterior chamber, subconjunctival space, suprachoroidal space, or sub-Tenon's space.

[0129] The subject drug delivery systems can extend the time a drug remains in the body. For example, the drug delivery systems can provide therapeutic levels of a drug for 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. The drug delivery systems may be injected, implanted, or modified for a period within any of the above ranges.

[0130] In some embodiments, the subject drug delivery systems may be administered to a mammal, such as a human, to treat glaucoma, such as primary open-angle glaucoma (POAG), acute primary angle-closure glaucoma (APACG), chronic angle-closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, normal-tension glaucoma, pediatric glaucoma, secondary glaucoma, etc., or combinations thereof.

[0131] (Example) The following examples are intended to illustrate embodiments of the present disclosure, but are not intended to limit its scope or underlying principles.

[0132] Example 1: Solid-phase synthesis of PG-L-CNTF featuring an amide bond Using methods known in the art, peptide 6 was coupled to a resin at the NH2 terminus, protected with a BOC group and a t-Bu ester group, and coupled to NH2-PEG at the carboxylic acid terminus, forming resin-LK(Boc)-K(Boc)-E(tBu)-FLGGD(tBu)-GV-CO2(CH2-CH2-O). n The formula is -CH2-CH2-NH2 (SEQ ID NO: 18). The nature of the starting materials and the order of the reactions may be varied to improve efficiency and selectivity, and all reactions are carried out using methods known in the art. Bimatoprost free acid, which has three hydroxyl groups protected with t-butyl groups (or other alkyl or silyl protecting groups, as appropriate), is prepared by methods known in the art. 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 fully 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 may be employed as needed to optimize the efficiency of the overall procedure.

[0133] Example 2: Solid-phase synthesis of PG-L-CNTF featuring an ester bond Using methods known in the art, peptide 6 was linked to a resin at the NH2 terminus, protected on the free amine groups with CBz groups and on the free acid groups with benzyl groups, and coupled to polyethylene glycol at the carboxylic acid terminus, yielding resin-LK(Cbz)-K(Cbz)-E(Bn)-FLGGD(Bn)-GV-CO2(CH2-CH2-O).n The formula provides -CH2-CH2-OH (SEQ ID NO: 19). The nature of the starting materials and the order of the reactions may be varied to improve selectivity, and all reactions are carried out using methods known in the art. Bimatoprost free acid, which has three hydroxyl groups protected with benzyl groups (or other hydrogenation-labile protecting groups, as appropriate), is prepared by methods known in the art. The free alcohol terminus 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 fully deprotected using hydrogenation 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 may be employed as needed to optimize the efficiency of the overall procedure.

[0134] Example 3 Eight African green monkeys were screened and four animals with normal-high IOP were identified. Animals were anesthetized with 10 mg / kg ketamine and 0.5 mg / kg xylazine. At 8:30 PM on days 0, 1, and 2, 100 ng of bimatoprost acid in 50 μl was injected intravitreally into one eye using a 30-gauge syringe using conventional techniques. 50 μl of phosphate-buffered saline (PBS) was injected into the fellow eye as a concurrent control. On days 3 (8:30 PM) and 4 (5:30 PM), the bimatoprost acid dose was increased to 200 ng in 100 μl, and the same volume of PBS was administered to the fellow eye. IOP was measured with a Tonovet tonometer at 8:30 AM, 11:30 AM, and 8:30 PM on day 1; 8:30 AM, 11:30 AM, and 5:30 PM on day 4; and 8:30 AM on days 2, 3, and 5. The IOP measurers were masked to treatment assignment. Slit-lamp examinations were performed on days 0, 1, and 5. Optical coherence tomography (OCT) was performed at baseline and on day 5.

[0135] One of four animals (B392) responded to the 100 ng dose and showed a ≥30% reduction in IOP at one time point compared to the fellow eye (typical effect of prostaglandin analogs on IOP). Three of four animals responded to the 200 ng dose and showed a ≥30% reduction in IOP at one or more time points in the treated eye compared to the fellow eye receiving PBS, with one animal (B392) showing a 52% reduction in IOP at 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 intraocularly by bolus injection. One animal (B300) did not respond to either dose. Actual IOP measurements and percentage IOP reduction are shown in Figures 1 and 2, respectively.

[0136] No ocular inflammation occurred in clinical trials, although one animal developed corneal edema that was thought to be treatment-related and not drug-related. OCT showed no cystoid macular edema in any of the animals.

[0137] These results demonstrate a clear IOP-lowering effect of intravitreal bimatoprost acid in a dose-response manner between the 100 ng and 200 ng doses. Because no ocular inflammation was observed, this is unlikely to be the cause of the IOP reduction in the treated eye. Furthermore, this study was masked, and the same volume of vehicle was simultaneously injected into the fellow eye as a control. Therefore, since significant IOP reductions were only observed in the treated eye, the IOP results are unlikely to be procedure-related (e.g., wound leakage). Further dose escalation is expected to result in even greater IOP-lowering effects. The test article was well tolerated.

[0138] Based on these results, sustained-release intravitreal bimatoprost acid is expected to safely achieve clinically meaningful IOP reduction and be well tolerated in patients, with known caveats for retinal exposure to prostaglandins or prostaglandin agonists.

[0139] The following embodiments are particularly contemplated by the inventors.

[0140] Embodiment 1. A drug delivery system comprising an ocular hypotensive agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor B (NPR-B), or an apoptosis signaling fragmentation inhibitor (FAS) or FAS ligand (FASL) inhibitor, and a sustained delivery component.

[0141] Embodiment 2. 2. The drug delivery system of embodiment 1, comprising an ocular hypotensive agent.

[0142] Embodiment 3. 3. The drug delivery system of embodiment 2, wherein the ocular hypotensive agent is a prostaglandin compound.

[0143] Embodiment 4. 4. The drug delivery system of embodiment 2 or 3, further comprising a second ocular hypotensive agent.

[0144] Embodiment 5. The drug delivery system of embodiment 2, 3, or 4, wherein the intraocular pressure-reducing agent comprises a beta-blocker.

[0145] Embodiment 6. The drug delivery system of embodiment 2, 3, 4, or 5, wherein the intraocular pressure-reducing agent comprises timolol.

[0146] Embodiment 7. The drug delivery system of embodiment 2, 3, 4, 5, or 6, wherein the intraocular pressure-reducing agent comprises betaxolol.

[0147] Embodiment 8. The drug delivery system of embodiment 2, 3, 4, 5, 6, or 7, wherein the intraocular pressure-reducing agent comprises levobunolol.

[0148] Embodiment 9. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, or 8, wherein the intraocular pressure-reducing agent comprises metipranolol.

[0149] 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.

[0150] 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.

[0151] Embodiment 12. The drug delivery system of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the intraocular pressure-reducing agent comprises apraclonidine.

[0152] Embodiment 13. 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.

[0153] Embodiment 14. 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.

[0154] Embodiment 15. 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.

[0155] Embodiment 16. 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.

[0156] Embodiment 17. 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.

[0157] Embodiment 18. 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 cholinergic agonist.

[0158] Embodiment 19. 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.

[0159] Embodiment 20. 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.

[0160] Embodiment 21. 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.

[0161] Embodiment 22. 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 netarsudil.

[0162] Embodiment 23. 23. 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, or 22, comprising a neurotrophic agent.

[0163] Embodiment 24. 24. 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, or 23, comprising both a prostaglandin receptor agonist and a neurotrophic agent.

[0164] Embodiment 25. 25. The drug delivery system of embodiment 24, wherein the prostaglandin receptor agonist and the neurotrophic agent are covalently bonded to each other.

[0165] Embodiment 26. 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 linking group.

[0166] Embodiment 27. 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.

[0167] Embodiment 28. 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 travoprost.

[0168] Embodiment 29. 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 latanoprost.

[0169] Embodiment 30. 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 latanoprostene.

[0170] Embodiment 31. 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 tafluprost.

[0171] Embodiment 32. 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 a prostaglandin EP-2 receptor agonist.

[0172] Embodiment 33. 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 a prostaglandin EP-3 receptor agonist.

[0173] Embodiment 34. 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.

[0174] Embodiment 35. 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.

[0175] Embodiment 36. 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.

[0176] Embodiment 37. 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.

[0177] Embodiment 38. 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 both an ocular hypotensive agent and a neurotrophic agent.

[0178] Embodiment 39. The drug delivery system of embodiment 38, wherein the ocular hypotensive agent and the neurotrophic agent are covalently bonded to each other.

[0179] Embodiment 40. 40. The drug delivery system of embodiment 39, wherein the ocular hypotensive agent and the neurotrophic agent are covalently bonded to each other via a linking group.

[0180] Embodiment 41. 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 both an ocular hypotensive agent and a CNP compound.

[0181] Embodiment 42. The drug delivery system of embodiment 41, wherein the ocular hypotensive agent and the CNP compound are covalently bonded to one another.

[0182] Embodiment 43. The drug delivery system of embodiment 42, wherein the ocular hypotensive agent and the CNP compound are covalently bonded to each other via a linking group.

[0183] Embodiment 44. 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 both an ocular hypotensive agent and an NPR-B compound.

[0184] Embodiment 45. The drug delivery system of embodiment 44, wherein the ocular hypotensive agent and the NPR-B compound are covalently bonded to each other.

[0185] Embodiment 46. The drug delivery system of embodiment 45, wherein the ocular hypotensive agent and the NPR-B compound are covalently bonded to each other via a linking group.

[0186] Embodiment 47. 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 both a neurotrophic agent and a CNP compound.

[0187] Embodiment 48. The drug delivery system of embodiment 47, wherein the neurotrophic agent and the CNP compound are covalently bonded to each other.

[0188] 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 linking group.

[0189] Embodiment 50. 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 both a neurotrophic agent and an NPR-B compound.

[0190] Embodiment 51. The drug delivery system of embodiment 50, wherein the neurotrophic agent and the NPR-B compound are covalently bonded to each other.

[0191] 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 linking group.

[0192] Embodiment 53. 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 both a CNP compound and an NPR-B compound.

[0193] Embodiment 54. The drug delivery system of embodiment 53, wherein the CNP compound and the NPR-B compound are covalently bonded to each other.

[0194] Embodiment 55. 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 linking group.

[0195] Embodiment 56. 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.

[0196] Embodiment 57. 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 delivery component is silica-based.

[0197] Embodiment 58. 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 delivery component is porous.

[0198] Embodiment 59. 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 delivery component is non-porous.

[0199] Embodiment 60. 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, 46, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein the sustained delivery component is of the type described in U.S. Patent No. 9,949,922 to Jokinen et al., issued April 24, 2018.

[0200] Embodiment 61. 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 delivery component is of the type described in U.S. Patent Application No. 20140057996 to Jokinen et al., published February 27, 2014.

[0201] Embodiment 62. 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 delivery component is of the type described in U.S. Patent No. 9,603,801 to Barnett et al., issued March 28, 2017.

[0202] Embodiment 63. 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 delivery component is of the type described in U.S. Pat. No. 9,808,421 to Ashton et al., issued November 7, 2017.

[0203] Embodiment 64. 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 delivery component is of the type described in U.S. Patent No. 9,333,173 to Ashton et al., issued May 10, 2016.

[0204] Embodiment 65. 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 delivery component is of the type described in U.S. Patent Publication No. 20140271764 to Ashton et al., published September 28, 2014.

[0205] Embodiment 66. 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 attached to the sustained delivery component.

[0206] Embodiment 67. 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 delivery component.

[0207] Embodiment 68. 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 delivery component.

[0208] Embodiment 69. 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 delivery component.

[0209] Embodiment 70. 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.

[0210] Embodiment 71. 71. The method of embodiment 70, wherein the drug delivery system is administered to the affected eye of the mammal by intravitreal injection.

[0211] Embodiment 72. 71. The method of embodiment 70, wherein said drug delivery system is implanted into the anterior chamber, subconjunctival space, suprachoroidal space, or subtenon space of the affected eye of the mammal.

[0212] Embodiment 73. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises primary open-angle glaucoma (POAG).

[0213] Embodiment 74. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises acute primary angle-closure glaucoma (APACG).

[0214] Embodiment 75. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises chronic angle-closure glaucoma.

[0215] Embodiment 76. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises pigmentary glaucoma.

[0216] Embodiment 77. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises pseudoexfoliation glaucoma.

[0217] Embodiment 78. The method of embodiment 70, 71, or 72, wherein said glaucoma comprises normal tension glaucoma.

[0218] Embodiment 79. The method of embodiment 70, 71, or 72, wherein said glaucoma includes pediatric glaucoma.

[0219] Embodiment 80. The method of embodiment 70, 71, or 72, wherein said glaucoma includes secondary glaucoma.

[0220] Embodiment 81. 1. A drug delivery system comprising a first active pharmaceutical ingredient (API) and a sustained delivery component, wherein the first API is an ocular hypotensive agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor B (NPR-B), a fragmentation of apoptosis signaling (FAS) inhibitor, or a FAS ligand (FASL) inhibitor, or a combination thereof.

[0221] Embodiment 82. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is an ocular hypotensive agent and said second API is a neurotrophic agent.

[0222] Embodiment 83. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is an ocular hypotensive agent and said second API is CNP.

[0223] Embodiment 84. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is an ocular hypotensive agent and said second API is NPR-B.

[0224] Embodiment 85. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is an ocular hypotensive agent and said second API is a FAS inhibitor or a FASL inhibitor.

[0225] 86. 82. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is a neurotrophic agent and said second API is CNP.

[0226] Embodiment 87. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is a neurotrophic agent and said second API is NPR-B.

[0227] Embodiment 88. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is a neurotrophic agent and said second API is a FAS inhibitor or a FASL inhibitor.

[0228] Embodiment 89. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is CNP and said second API is NPR-B.

[0229] Embodiment 90. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is CNP and said second API is a FAS inhibitor or a FASL inhibitor.

[0230] Embodiment 91. The drug delivery system of embodiment 81, further comprising a second API, wherein said first API is NPR-B and said second API is a FAS inhibitor or a FASL inhibitor.

[0231] 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.

[0232] Embodiment 93. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, or 91, wherein the first API is covalently bonded to the second API.

[0233] 94. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, or 93, wherein said first API is covalently bonded to said sustained delivery component.

[0234] 95. The drug delivery system of embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, or 94, wherein said second API is covalently bonded to said sustained delivery component.

[0235] 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 said first API.

[0236] 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 said second API.

[0237] 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 weight of the implant is from about 300 μg to about 10 mg.

[0238] 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.

[0239] Embodiment 100. 100. The method of embodiment 99, wherein the drug delivery system is injected intraocularly into the mammal.

[0240] Embodiment 101. The method of embodiment 99 or 100, wherein the mammal is a human.

[0241] Embodiment 102. 1. Use of an ocular hypotensive 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 the treatment of glaucoma or ocular hypertension, further comprising a sustained delivery component.

[0242] Embodiment 103. The use of embodiment 102, wherein the drug delivery system is injected into the eye of the mammal.

[0243] Embodiment 104. The use according to embodiment 102 or 103, wherein the mammal is a human.

[0244] Embodiment 105. 97. A kit comprising a drug delivery system according to embodiment 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, or 98 for the treatment of glaucoma, and a label with instructions for use of said drug delivery system.

[0245] Embodiment 106. The kit of embodiment 105, wherein the drug delivery system is injected into the eye of the mammal.

[0246] (Addendum) (Appendix 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 delivery component.

[0247] (Appendix 2) 2) a CNTF compound, a FAS or FASL inhibitor, or a combination thereof; and 3) a sustained delivery component.

[0248] (Appendix 3) 3. The drug delivery system of claim 2, wherein the CNTF compound is a peptide comprising the amino acid sequence DGGL (SEQ ID NO: 20), or a salt thereof.

[0249] (Appendix 4) 3. The drug delivery system of claim 2, wherein the prostaglandin is bimatoprost acid or a salt thereof.

[0250] (Appendix 5) 5. The drug delivery system of claim 4, comprising a prostaglandin and a CNTF compound, wherein the CNTF compound is peptide 6 or a salt thereof.

[0251] (Appendix 6) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is bicyclol.

[0252] (Appendix 7) The drug delivery system described in Appendix 2, wherein the FAS or FASL inhibitor is a peptide comprising the amino acid sequence YLGA (SEQ ID NO: 5), or a salt thereof.

[0253] (Appendix 8) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is MET4.

[0254] (Appendix 9) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is MET5.

[0255] (Appendix 10) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is MET6.

[0256] (Appendix 11) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is MET7.

[0257] (Appendix 12) The drug delivery system of claim 2, wherein the FAS or FASL inhibitor is MET8.

[0258] (Appendix 13) 3. The drug delivery system of claim 2, wherein the prostaglandin is not covalently bound or covalently linked to the CNTF compound, the FAS or FASL inhibitor, or the combination thereof.

[0259] (Appendix 14) 3. The drug delivery system of claim 2, wherein the prostaglandin is covalently bound or covalently linked to the CNTF compound, the FAS or FASL inhibitor, or the combination thereof.

[0260] (Appendix 15) 2. The drug delivery system of claim 1, wherein the prostaglandin, the CNTF compound, the FAS or FASL inhibitor, or the combination thereof is covalently bound or linked to the sustained delivery component.

[0261] (Appendix 16) 10. A method of treating glaucoma or ocular hypertension, comprising administering the drug delivery system of claim 1 to an eye of a mammal in need of treatment, wherein administering the drug delivery system to the eye of the mammal results in a decrease in intraocular pressure in the eye of the mammal.

[0262] (Appendix 17) 17. The method of claim 16, wherein the mammal is a human.

[0263] (Appendix 18) 17. The method of claim 16, wherein the CNTF compound is peptide 6 or peptide 21.

[0264] (Appendix 19) 17. The method of claim 16, wherein the prostaglandin is bimatoprost acid or a salt thereof.

[0265] (Appendix 20) The method of claim 16, wherein the FAS or FASL inhibitor is MET4-8.

[0266] (Appendix 21) 17. The method of claim 16, wherein the CNTF compound is a peptide comprising the amino acid sequence DGGL (SEQ ID NO: 20), or a salt thereof.

[0267] (Appendix 22) 17. The method of claim 16, wherein the reduction in intraocular pressure in the eye of the mammal occurs for a period of at least one month after the drug delivery system is administered to the eye of the mammal.

Claims

[Claim 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 delivery component.

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