A sustained-release drug delivery system for the treatment of glaucoma or ocular hypertension, containing a pharmaceutically active ingredient including bimatoprost acid and a sustained-release ingredient.

Abstract

The present disclosure relates to a drug delivery system comprising an intraocular pressure-lowering agent, a neurotrophic agent such as a CNTF compound, a C-type natriuretic peptide (CNP) compound, a Tie-2 agonist, a natriuretic peptide receptor B (NPR-B) compound, or an apoptosis signaling fragmentation inhibitor (FAS) or FAS ligand (FASL) inhibitor (including any combination of these compounds), and a sustained-delivery component. Methods, medicaments, kits, methods of use, and methods of manufacture for treating glaucoma or related conditions are also disclosed. [Selection diagram] None

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority based on U.S. Provisional Patent Application No. 62 / 687,172, filed on 19 June 2018, U.S. Provisional Patent Application No. 62 / 726,029, filed on 31 August 2018, and U.S. Provisional Patent Application No. 62 / 747,060, filed on 17 October 2018, the entire contents of which are incorporated herein by reference. Application C4019.10002WO01, filed on 18 June 2019, the entire contents of which are also incorporated herein by reference. A PCT application with reference number C4019.10002WO01, co-filed on 18 June 2019, with inventors M. Schiffman and Lucas Scheibler, is also incorporated herein by reference in its entirety.

[0002] (Sequence Listing) This application includes a sequence listing submitted electronically in ASCII format, which is thereby referenced in its entirety. A copy of that ASCII file, created on June 17, 2019, is filenamed V3563_10001WO01_SL.txt and has a size of 4,008 bytes. [Overview of the Initiative] [Means for solving the problem]

[0003] This disclosure includes drugs comprising intraocular pressure lowering agents, neurotrophic agents such as CNTF compounds, C-type natriuretic peptide (CNP) compounds, Tie-2 agonists, natriuretic peptide receptor B (NRP-B) compounds, or apoptosis signaling fragmentation (FAS) inhibitors or FAS ligand (FASL) inhibitors (including any combination of these compounds), and sustained-delivery components. thing Delivery system Regarding this type of drug. thing Delivery system It can be used to treat glaucoma or ocular hypertension.

[0004] Some embodiments include a drug comprising a first pharmaceutically active ingredient (API) and a sustained-delivery component. thing Delivery system These include, and the first API is an intraocular pressure lowering agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor B (NRP-B), an apoptosis signaling fragmentation (FAS) inhibitor or FAS ligand (FASL) inhibitor, or a combination thereof.

[0005] In some embodiments, the drug described herein thing Delivery system This includes methods for treating glaucoma, including administering it to mammals suffering from glaucoma or ocular hypertension.

[0006] In some embodiments, the drug described herein is used for the treatment of glaucoma or ocular hypertension. thing Delivery system This includes the use of intraocular pressure lowering agents, neurotrophic agents, CNP, NPR-B, FAS inhibitors or FASL inhibitors, or combinations thereof, in the manufacture of the product.

[0007] In some embodiments, the drug for the treatment of glaucoma described herein thing Delivery system and the drug thing Delivery system The kit includes a label with instructions for use. [Modes for carrying out the invention]

[0008] Intraocular pressure lowering agents, neurotrophic agents such as CNTF compounds, CNP compounds, NPR-B compounds, or FAS or FASL inhibitors (referred to as "subject drugs" in this specification) thing Delivery system Drugs containing sustained delivery components (as described above) thing Delivery systemIn this regard, any suitable prostaglandin compound may be used, including any suitable prostaglandin receptor agonist, prostanoid receptor agonist, or any prostaglandin acid form (e.g., an acid obtained by hydrolysis of a prostaglandin ester), any prostaglandin salt form, or any prodrug of a prostaglandin ester. Examples include bimatoprost (amide) or bimatoprost acid, i.e., carboxylic acid obtained by hydrolysis of the amide group, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprosten, tafluprost, tafluprost acid, etc., prostaglandin EP2 agonists, prostaglandin EP3 agonists, or combinations thereof.

[0009] Appropriate amounts of bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprosten, tafluprost 、 Prostaglandin compounds such as tafluprost acid, prostaglandin EP2 agonists, or prostaglandin EP3 agonists are used as drugs. thing Delivery system It can be used for medicine. thing Delivery systemApproximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg, approximately 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0 .010~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.010~100μg, approx. 100~200μg, approx. It may contain 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components. For example, the compounds of formula 1 or formula 3 are prostaglandins that are drugs thing Delivery system Although it is covalently bonded to other parts, it can be said that it contains 1 mg of prostaglandin compounds.

[0010] medicine thing Delivery systemThe use of the above amounts of prostaglandin compounds such as bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprosten, tafluprost, tafluprost acid, prostaglandin EP2 agonists, or prostaglandin EP3 agonists provides a therapeutic level (concentration) of the prostaglandin compound for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[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 latanoprosten. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is tafluprost. In some embodiments, the prostaglandin receptor agonist or prostaglandin compound is tafluprost. In some embodiments, a prostaglandin receptor agonist or prostaglandin compound is a prostaglandin EP2 receptor agonist. In some embodiments, a prostaglandin receptor agonist or prostaglandin compound is a prostaglandin EP3 receptor agonist.

[0013] The subject of medicine thing Delivery system These may include intraocular pressure-lowering agents such as beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and cannabinoid receptor agonists. thing Delivery system This may include two or more intraocular pressure-lowering agents such as prostaglandin compounds, prostaglandin receptor agonists, or prostanoid receptor agonists, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, cannabinoid receptor agonists, and Rho kinase inhibitors. thing Delivery systemThis category includes two or more of the following: prostaglandin receptor agonists (or prostaglandin compounds or prostanoid receptor agonists), beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, cannabinoid receptor agonists, Rho kinase inhibitors, etc.

[0014] The subject of medicine thing Delivery system Any suitable beta-blocker or any suitable beta-adrenergic antagonist may be used. Examples include timolol, betaxolol, levovunolol, metipranolol, etc., 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 levovunol. In some embodiments, the beta-blocker is metipranolol.

[0015] Any appropriate amount of a beta-blocker or beta-adrenergic antagonist such as timolol, betaxolol, levovunolol, or metipranolol is prescribed. thing Delivery system It can be used for medicine. thing Delivery systemThese are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.01~100μg, approx. 100~200μg, approx. 2 It may contain 00-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0016] medicine thing Delivery system The use of the above amounts of beta-blockers or beta-adrenergic antagonists such as timolol, betaxolol, levovunolol, and metipranolol in this context provides a therapeutic level of beta-blocker or beta-adrenergic antagonist for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0017] The subject of medicine thing Delivery systemAny suitable α-agonist or α-adrenergic agonist may be used. Examples include brimonidine, apraclonidine, etc., or combinations thereof. In some embodiments, the α-agonist is brimonidine. In some embodiments, the α-agonist is apraclonidine.

[0018] Any appropriate amount of an alpha-agonist or alpha-adrenergic agonist such as brimonidine or apraclonidine is taken as medication. thing Delivery system It can be used for medicine. thing Delivery system These are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0019] medicine thing Delivery systemThe use of the above amounts of alpha-agonists or alpha-adrenergic agonists such as brimonidine and apraclonidine in this context provides a therapeutic level of alpha-agonist or alpha-adrenergic agonist for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0020] The subject of medicine thing Delivery system Any suitable carbonic anhydrase inhibitor may be used. Examples include brinzolamide, acetazolamide, dorzolamide, metazolamide, etc., 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 metazolamide.

[0021] Any appropriate amount of carbonic anhydrase inhibitor such as brinzolamide, acetazolamide, dorzolamide, or metazolamide is used as a drug. thing Delivery system It can be used for medicine. thing Delivery systemThese are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0022] medicine thing Delivery system The use of carbonic anhydrase inhibitors such as brinzolamide, acetazolamide, dorzolamide, and metazolamide in the above amounts provides a therapeutic level of carbonic anhydrase inhibitors for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0023] The subject of medicine thing Delivery systemAny suitable cholinergic agent may be used. Examples include pilocarpine, carbachol, etc., or combinations thereof. In some embodiments, the cholinergic agent is pilocarpine. In some embodiments, the cholinergic agent is carbachol.

[0024] Any appropriate amount of cholinergic drugs such as pilocarpine or carbachol thing Delivery system It can be used for medicine. thing Delivery system These are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0025] medicine thing Delivery systemThe use of cholinergic agonists such as pilocarpine and carbachol in the above amounts provides a therapeutic level of cholinergic agonist for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0026] The subject of medicine thing Delivery system In this regard, any suitable Rho kinase inhibitor such as netaludil may be used. In some embodiments, the Rho kinase inhibitor is netaludil.

[0027] Any appropriate amount of a Rho kinase inhibitor such as netaludil thing Delivery system It can be used for medicine. thing Delivery systemThese are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0028] medicine thing Delivery system The use of the above amounts of Rho kinase inhibitors such as netaludil provides a therapeutic level of Rho kinase inhibitors for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0029] The subject of medicine thing Delivery system In this regard, any suitable Tie-2 agonist such as angiopoietin-1, angiopoietin-2, angiopoietin-3, or angiopoietin-4 may be used.

[0030] Any appropriate amount of Tie-2 agonist such as angiopoietin-1, angiopoietin-2, angiopoietin-3, or angiopoietin-4 is used as a drug. thing Delivery system It can be used for medicine. thing Delivery system Approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg, approximately 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90-100μg, about 0 .01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 200 It may contain one of these compounds in amounts of ~300 μg, approximately 300~400 μg, approximately 400~500 μg, approximately 500~600 μg, approximately 600~700 μg, approximately 700~800 μg, approximately 800~900 μg, approximately 900~1,000 μg, approximately 0.0100~300 μg, approximately 300~600 μg, approximately 600~1,000 μg, approximately 0.01~1 mg, approximately 0.1~1 mg, approximately 1~2 mg, approximately 2~3 mg, approximately 3~4 mg, approximately 4~5 mg, approximately 5~6 mg, approximately 6~7 mg, approximately 7~8 mg, approximately 8~9 mg, approximately 9~10 mg, approximately 0.01~3 mg, approximately 3~6 mg, approximately 6~10 mg, or approximately 0.01~10 mg. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0031] medicine thing Delivery system The use of the above amounts of Tie-2 agonists such as angiopoietin-1, angiopoietin-2, angiopoietin-3, and angiopoietin-4 provides a therapeutic level of Tie-2 agonism for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0032] The subject of medicine thing Delivery system Regarding this, neurotrophic agents may include CNTF compounds or other neurotrophic agents, and CNTF compounds include any compound having a similar structure or activity to ciliary neurotrophic factor (CNTF), including CNTF, a protein derivative of CNTF, or a CNTF peptide. Examples include CNTF, peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1)) and peptide 21 (P21; Ac-DGGL A This includes peptides containing a portion of the sequence of CNTF, such as G-NH2 (SEQ ID NO: 2), recombinant CNTF (rhCNTF), or neurotrophic peptides having adamant groups at the C-terminus and / or N-terminus, as described in U.S. Patent No. 8,592,374, which is incorporated herein by reference, or any other peptide having biological activity similar to CNTF. Other neurotrophic agents include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), etc.

[0033] Any appropriate amount of neuronutrient supplements such as CNTF compounds, NGF, BDNF, GDNF, etc. thing Delivery system It can be used for medicine. thing Delivery systemThese are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0034] medicine thing Delivery system The use of the above amounts of neuronutrient agents such as CNTF compounds, NGF, BDNF, and GDNF in this context provides therapeutic levels of neuronutrient agents for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0035] The subject of medicine thing Delivery system In this regard, CNP compounds include any compound having a structure or activity similar to that of a C-type natriuretic peptide, including the naturally occurring C-type natriuretic peptide.

[0036] Any appropriate amount of natural CNP compounds such as CNPs as medicine thing Delivery system It can be used for medicine. thing Delivery system These are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0037] medicine thing Delivery system The use of the above amounts of natural CNP compounds provides therapeutic levels of the CNP compound for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0038] The subject of medicine thing Delivery systemIn this regard, NPR-B compounds include any compound having a structure or activity similar to natriuretic peptide receptor B, including the native natriuretic peptide receptor B.

[0039] Any appropriate amount of natural NPR-B compounds or other NPR-B compounds as medicine thing Delivery system It can be used for medicine. thing Delivery system These are approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg, approximately 20-30 μg. Approx. 30-40μg, approx. 40-50μg, approx. 50-60μg, approx. 60-70μg, approx. 70-80μg, approx. 80-90μg, approx. 90-100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100~200μg, approx. 20 It may contain 0-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 0.1-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0040] medicine thing Delivery system The use of the above amounts of natural NPR-B compounds provides therapeutic levels of NPR-B compounds for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[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 Shorter fragments thereof, such as tetramers, having sequence YLGA (Sequence ID 4), or compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, or compound 11, ONL1204 (for example, containing sequence HHIYLGATNYIY (Sequence ID 4)), the Fragments having sequences such as peptides consisting of sequences, as shown in Table 1 below, having homology to MET12 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%; Sequence H 60 HIYLGATNYIY 71 -NH Other MET12 derivatives such as compounds containing 2 (SEQ ID NO: 4); FAS apoptosis inhibitor molecule [FAIM]; NOL3 [nucleolar protein 3 ( CA This includes apoptosis inhibitors mediated by the RD domain [ARC], etc.; DcR1; DcR2; or DcR3.

[0042] [ka]

[0043] [Table 1]

[0044] Any appropriate 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, H60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4), FAS or FASL inhibitors such as FAIM, NOL3, DcR1, DcR2, DcR3, etc. can be used for drug thing delivery system For example, the drug thing delivery system may contain one of these compounds in amounts of about 0.01 - 1 μg, about 1 - 2 μg, about 2 - 3 μg, about 3 - 4 μg, about 4 - 5 μg, about 5 - 6 μg, about 6 - 7 μg, about 7 - 8 μg, about 8 - 9 μg, about 9 - 10 μg, about 0.01 - 3 μg, about 3 - 6 μg, about 6 - 10 μg, about 0.01 - 10 μg, about 10 - 20 μg, about 20 - 30 μg, about 30 - 40 μg, about 40 - 50 μg, about 50 - 60 μg, about 60 - 70 μg, about 70 - 80 μg, about 80 - 90 μg, about 90 - 100 μg, about 0.01 - 30 μg, about 30 - 60 μg, about 60 - 100 μg, about 0.01 - 100 μg, about 0.1 - 100 μg, about 100 - 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 0.0100 - 300 μg, about 300 - 600 μg, about 600 - 1,000 μg, 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 can also be applicable to situations where the drug exists in a form covalently bonded to other agents or sustained - release components, etc.

[0045] drug thing delivery system The above - mentioned 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 FAS or FASL inhibitors such as -NH2 (SEQ ID NO 4), FAIM, NOL3, DcR1, DcR2, DcR3 provides therapeutic levels of NPR-B compounds for approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer. thing Delivery system It can provide.

[0046] Table 2 below shows the drug in question. thing Delivery system In this context, we will highlight particularly important drug combinations.

[0047] [Table 2-1] [Table 2-2]

[0048] several drugs thing Delivery system This includes combinations of bimatoprost acid and bicyclol, either directly covalently bonded, linked by a binding group, or both bonded to a polymer or silicon-based drug delivery particle.

[0049] The subject of drugs including prostaglandin receptor agonists or prostaglandin compounds and intraocular pressure lowering agents. thing Delivery system In some embodiments, the prostaglandin receptor agonist is covalently bound to the intraocular pressure-lowering agent.

[0050] For example, some compounds, including prostaglandin compounds or prostaglandin receptor agonists, are covalently bonded to the intraocular pressure-lowering agent by a binding group, formula 1 or 1A. PG-L-IOP formula 1 IOP-L-IOP Formula 1A Represented as , PG-H or PG-OH is a prostaglandin receptor agonist such as the aforementioned prostaglandin compound or prostaglandin receptor agonist; each IOP-H or IOP-OH is independently an intraocular pressure lowering agent such as the aforementioned intraocular pressure lowering agent.

[0051] The subject drugs include both prostaglandin receptor agonists and neurotrophic agents such as CNTF compounds. thing Delivery system In some embodiments, neurotrophic agents such as prostaglandin receptor agonists and CNTF compounds are covalently linked to each other.

[0052] Drugs on several subjects thing Delivery system This includes both an intraocular pressure-lowering agent and a neuronutrient such as a CNTF compound. In some embodiments, the intraocular pressure-lowering agent and the neuronutrient such as a CNTF compound are covalently bonded to each other. In some embodiments, the intraocular pressure-lowering agent and the neuronutrient such as a CNTF compound are covalently bonded to each other via a binding group.

[0053] Drugs on several subjects thing Delivery system This includes both an intraocular pressure-lowering agent and a CNP compound. In some embodiments, the intraocular pressure-lowering agent and the CNP compound are covalently bonded to each other. In some embodiments, the intraocular pressure-lowering agent and the CNP compound are covalently bonded to each other via a bonding group.

[0054] Drugs on several subjects thing Delivery system This includes an intraocular pressure-lowering agent and an NRP-B compound. In some embodiments, the intraocular pressure-lowering agent and the NRP-B compound are covalently bonded to each other. In some embodiments, the intraocular pressure-lowering agent and the NRP-B compound are covalently bonded to each other via a bonding group.

[0055] Drugs on several subjects thing Delivery system This includes both neurotrophic agents such as CNTF compounds and CNP compounds. In some embodiments, the neurotrophic agents such as CNTF compounds and the CNP compounds are covalently bonded to each other. In some embodiments, the neurotrophic agents such as CNTF compounds and the CNP compounds are covalently bonded to each other via binding groups.

[0056] Drugs on several subjects thing Delivery system This includes both neurotrophic agents such as CNTF compounds and NRP-B compounds. In some embodiments, the neurotrophic agents such as CNTF compounds and NRP-B compounds are covalently bonded to each other. In some embodiments, the neurotrophic agents such as CNTF compounds and NRP-B compounds are covalently bonded to each other via bonding groups.

[0057] Drugs on several subjects thing Delivery system This includes both CNP compounds and NRP-B compounds. In some embodiments, the CNP compounds and NRP-B compounds are covalently bonded to each other. In some embodiments, the CNP compounds and NRP-B compounds are covalently bonded to each other via bonding groups.

[0058] For example, some compounds that are covalently bound to CNTF by a binding group, including prostaglandin compounds or prostaglandin receptor agonists, are given by formula 2. PG-L-CNTF formula 2 Represented as , PG-H or PG-OH is a prostaglandin receptor agonist such as the aforementioned prostaglandin compound or prostaglandin receptor agonist; CNTF-H or CNTF-OH is a CNTF compound such as the aforementioned CNTF compound.

[0059] Other covalent compounds include those with formulas 2A, 2B, 2C, 2D, 2E, and 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 Represented as follows: IOP-H is an intraocular pressure-lowering agent such as the aforementioned intraocular pressure-lowering agents; CNTF-H or CNTF-OH is a CNTF compound such as the aforementioned CNTF compound; CNP-H or CNP-OH is a CNP compound; and NPR-H or NPR-OH is an NPR-B compound.

[0060] With respect to any related structural representation such as formulas 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 the empirical formula C a H b O c N d or C a H b O c This is a bonding group represented by .

[0061] 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.

[0062] For any L, b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43. In some embodiments, b is 1-10, 10-20, 20-30, 30-40, 40-43, 1-15, 15-30, or 30-43.

[0063] 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.

[0064] 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.

[0065] In some embodiments, L is 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 follows.

[0066] With respect to any related structural representation of formulas L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, L 1 This is empirical formula C e H f O g N h or C e H f O g It can be represented as follows.

[0067] Any L 1 With respect to e, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In some embodiments, e is 1-5, 5-10, 10-15, 15-18, 1-10, or 10-18.

[0068] Any L 1With respect to f, f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38. In some embodiments, f is 1-10, 10-20, 20-30, 30-38, 1-15, 15-30, or 30-38.

[0069] Any L 1 With respect to g, g is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, g is 0-2, 2-4, 4-6, 6-8, 0-3, 3-6, or 6-8.

[0070] Any L 1 With respect to this, h is 0, 1, or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2.

[0071] With respect to any related structural representation of formulas 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 L1 -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 is possible.

[0072] 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.

[0073] 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.

[0074] 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 Regarding any related structural representation such as -8 etc., k is 0, 1, 2, 3, or 4.

[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 Regarding any related structural representation such as -8 etc., any H atom of the NH or NH2 moiety is 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 including C containing alkynyl etc. 1-12 hydrocarbyl group, C 1-6 hydrocarbyl group, or C 1-3 may be substituted with a substituent such as a hydrocarbyl group etc.

[0076] In some embodiments, H-L-H, HO-L-H, HO-L-OH, H2N-L-H, or H2N-L-NH2, or HO-L-NH2 is one or more of the following.

Chemical formula

[0077] In some embodiments, the drug thing service systemThe following combinations of drugs are covalently bonded or not covalently bonded by a bonding group L, etc., which contains a salt of the drug, a free acid, or a free base, and which contains a group represented by formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8: 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 tafluprost or taflupro Bimatoprost or bimatoprost acid with timolol; bimatoprost or bimatoprost acid with betaxolol; bimatoprost or bimatoprost acid with levovunol; bimatoprost or bimatoprost acid with metipranolol; bimatoprost or bimatoprost acid with brimonidine; bimatoprost or bimatoprost acid with apraclonidine; bimatoprost or bimatoprost acid with brinzolamide; bimatoprost or bimatoprost acid with acetazolamide; bimatoprost or bimatoprost acid with dorzolamide; bimatoprost Rost or bimatoprost acid and metazolamide; bimatoprost or bimatoprost acid and pilocarpine; bimatoprost or bimatoprost acid and carbacol; bimatoprost or bimatoprost acid and netalusdil; 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; bimatopro 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 type C natriuretic peptide; bimatoprost or bimatoprost acid and natural type C natriuretic peptide; bimatoprost or bimatoprost acid and natriuretic peptide receptor B;Bimatoprost or bimatoprost acid with bicyclol; bimatoprost or bimatoprost acid with FLIP; bimatoprost or bimatoprost acid with MET12; bimatoprost or bimatoprost acid with compound 1 from Table 1; bimatoprost or bimatoprost acid with compound 2 from Table 1; bimatoprost or bimatoprost acid with compound 3 from Table 1; bimatoprost or bimatoprost acid with compound 4 from Table 1; bimatoprost or bimatoprost acid with compound 4 from Table 1; bimatoprost or bimatoprost Rost acid and compound 5 from Table 1; bimatoprost or bimatoprost acid and compound 6 from Table 1; bimatoprost or bimatoprost acid and compound 7 from Table 1; bimatoprost or bimatoprost acid and compound 8 from Table 1; bimatoprost or bimatoprost acid and compound 9 from Table 1; bimatoprost or bimatoprost acid and compound 10 from Table 1; bimatoprost or bimatoprost acid and compound 11 from Table 1; bimatoprost or bimatoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); bimatoprost or bimatoprost acid with FAIM; bimatoprost or bimatoprost acid with NOL3; bimatoprost or bimatoprost acid with DcR1; bimatoprost or bimatoprost acid with DcR2; bimatoprost or bimatoprost acid with DcR3; travoprost or travoprost acid with latanoprost or latanoprost acid; travoprost or travoprost acid with latanoprost; travoprost or travoprost acid with tafluprost or tafluprost acid; travoprost Travoprost acid and timolol; travoprost or travoprost acid and betaxolol; travoprost or travoprost acid and levovunol; 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 tra Travoprost acid and metazolamide; travoprost or travoprost acid and pilocarpine; travoprost or travoprost acid and carbacol; travoprost or travoprost acid and netalusdil; 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 also 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 natural 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 Rost acid and compound 5 from Table 1; travoprost or travoprost acid and compound 6 from Table 1; travoprost or travoprost acid and compound 7 from Table 1; travoprost or travoprost acid and compound 8 from Table 1; travoprost or travoprost acid and compound 9 from Table 1; travoprost or travoprost acid and compound 10 from Table 1; travoprost or travoprost acid and compound 11 from Table 1; travoprost or travoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); travoprost or travoprost acid with FAIM; travoprost or travoprost acid with NOL3; travoprost or travoprost acid with DcR1; travoprost or travoprost acid with DcR2; travoprost or travoprost acid with DcR3; latanoprost or latanoprost acid with latanoprosten; latanoprost or latanoprost acid with tafluprost or tafluprost acid; latanoprost or latanoprost acid with timolol; latanoprost or latanoprost acid with betaxol 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 metazolamide; latanoprost or latanoprost acid and pilocarpine; latanoprost Latanoprost or latanoprost acid and carbachol; latanoprost or latanoprost acid and netalusdil; 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 with recombinant CNTF; latanoprost or latanoprost acid with NGF; latanoprost or latanoprost acid with BDNF; latanoprost or latanoprost acid with GDNF; latanoprost or latanoprost acid with type C natriuretic peptide; latanoprost or latanoprost acid with natural type C natriuretic peptide; latanoprost or latanoprost acid with natriuretic peptide receptor B; latanoprost or latanoprost acid with bicyclol; latanoprost or latanoprost acid with FLIP;Latanoprost or latanoprost acid and MET12; Latanoprost or latanoprost acid and compound 1 from Table 1; Latanoprost and latanoprost acid and compound 2 from Table 1; Latanoprost and latanoprost acid and compound 3 from Table 1; Latanoprost and latanoprost acid and compound 4 from Table 1; Latanoprost and latanoprost acid and compound 5 from Table 1; Latanoprost and latanoprost acid and compound 6 from Table 1; Latanoprost and latanoprost acid and compound 7 from Table 1; Latanoprost and latanoprost acid and compound 8 from Table 1; Latanoprost and latanoprost acid and compound 9 from Table 1; Latanoprost and latanoprost acid and compound 10 from Table 1; Latanoprost and latanoprost acid and compound 11 from Table 1; Latanoprost and latanoprost acid and H; 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Latanoprost and latanoprost acid with FAIM; Latanoprost and latanoprost acid with NOL3; Latanoprost and latanoprost acid with DcR1; Latanoprost and latanoprost acid with DcR2; Latanoprost and latanoprost acid with DcR3; Latanoprosten and tafluprost and tafluprost acid; Latanoprosten and timolol; Latanoprosten and betaxolol; Latanoprosten and levovonol; Latanoprosten and Me Tipranolol; Latanoprosten and brimonidine; Latanoprosten and apraclonidine; Latanoprosten and brinzolamide; Latanoprosten and acetazolamide; Latanoprosten and dorzolamide; Latanoprosten and metazolamide; Latanoprosten and pilocarpine; Latanoprosten and carbachol; Latanoprosten and netalusdyl; Latanoprosten and angiopoietin-1; Latanoprosten and angiopoietin-2; Latanoprosten and angiopoietin-3; Latano Latanoprosten and angiopoietin-4; Latanoprosten and CNTF; Latanoprosten and peptide 6; Latanoprosten and peptide 21; Latanoprosten and recombinant CNTF; Latanoprosten and NGF; Latanoprosten and BDNF; Latanoprosten and GDNF; Latanoprosten and C-type natriuretic peptide; Latanoprosten and natural C-type natriuretic peptide; Latanoprosten and natriuretic peptide receptor B; Latanoprosten and bicyclol; Latanoprosten and FLIP; Latanoprosten and MET12; Latanoprosten and compound 1 from Table 1; Latanoprosten and compound 2 from Table 1; Latanoprosten and compound 3 from Table 1; Latanoprosten and compound 4 from Table 1; Latanoprosten and compound 5 from Table 1; Latanoprosten and compound 6 from Table 1; Latanoprosten and compound 7 from Table 1; Latanoprosten and compound 8 from Table 1; Latanoprosten and compound 9 from Table 1; Latanoprosten and compound 10 from Table 1; Latanoprosten and compound 11 from Table 1; Latanoprosten and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Latanoprosten and FAIM; Latanoprosten and NOL3; Latanoprosten and DcR1; Latanoprosten and DcR2; Latanoprosten and DcR3; Tafluprost or tafluprost acid and timolol; Tafluprost or tafluprost acid and betaxolol; Tafluprost or tafluprost acid and levovonol; Tafluprost or tafluprost acid and metipranolol; Tafluprost or tafluprost acid and brimonidine; Tafluprost or tafluprost acid and apraclonidine; Taflu Luprost or tafluprost acid and brinzolamide; tafluprost or tafluprost acid and acetazolamide; tafluprost or tafluprost acid and dorzolamide; tafluprost or tafluprost acid and metazolamide; tafluprost or tafluprost acid and pilocarpine; tafluprost or tafluprost acid and carbachol; tafluprost or tafluprost acid and netalusdil; tafluprost or tafluprost acid and angiopoietin-1; tafluprost or tafluprost acid and angiopoietin-2; Taflu 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 Rost acid and type C natriuretic peptide; tafluprost or tafluprost acid and natural type C 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 from Table 1; Tafluprost or tafluprost acid and compound 5 from Table 1; Tafluprost or tafluprost acid and compound 6 from Table 1; Tafluprost or tafluprost acid and compound 7 from Table 1; Tafluprost or tafluprost acid and compound 8 from Table 1; Tafluprost or tafluprost acid and compound 9 from Table 1; Tafluprost or tafluprost acid and compound 10 from Table 1; Tafluprost or tafluprost acid and compound 11 from Table 1; Tafluprost or tafluprost acid and H; 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Tafluprost or tafluprost acid and FAIM; Tafluprost or tafluprost acid and NOL3; Tafluprost or tafluprost acid and DcR1; Tafluprost or tafluprost acid and DcR2; Tafluprost or tafluprost acid and DcR3; Timolol and betaxolol; Timolol and levovonol; Timolol and metipranolol; Timolol and brimonidine; Timolol and apraclonidine; Timolol and brinzolamide; Timolol and acetazolamide; Timolol and dorzolamide; Timolol and metazolamide; Timolol and pilocarpine; Timolol and carbachol; Timolol and netalusdyl; Timolol and angiopoietin-1; Timolol and angiopoietin-2; Timolol and angiopoietin-3; Timolol and angiopoietin-1 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 natural C-type natriuretic peptide; Timolol and natriuretic peptide receptor B; Timolol and bicyclol; Timolol and FLIP; Timolol and MET12; Timolol and Compound 1 from Table 1; Timolol and Compound 2 from Table 1; Timolol and Compound 3 from Table 1; Timolol and Compound 4 from Table 1; Timolol and Compound 5 from Table 1; Timolol and Compound 6 from Table 1; Timolol and Compound 7 from Table 1; Timolol and Compound 8 from Table 1; Timolol and Compound 9 from Table 1; Timolol and Compound 10 from Table 1; Timolol and Compound 11 from Table 1; Timolol and H 60HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); Timolol and FAIM; Timolol and NOL3; Timolol and DcR1; Timolol and DcR2; Timolol and DcR3; Betaxolol and levovonol; Betaxolol and metipranolol; Betaxolol and brimonidine; Betaxolol and apraclonidine; Betaxolol and brinzolamide; Betaxolol and acetazolamide; Betaxolol and dorzolamide Betaxolol and metazolamide; Betaxolol and pilocarpine; Betaxolol and carbachol; Betaxolol and netalusdyl; 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 natural C-type natriuretic peptide; Betaxolol and natriuretic peptide receptor B; Betaxolol and bicyclol; Betaxolol and FLIP; Betaxolol and MET12; Betaxolol and table Compound 1; betaxolol and Compound 2 from Table 1; betaxolol and Compound 3 from Table 1; betaxolol and Compound 4 from Table 1; betaxolol and Compound 5 from Table 1; betaxolol and Compound 6 from Table 1; betaxolol and Compound 7 from Table 1; betaxolol and Compound 8 from Table 1; betaxolol and Compound 9 from Table 1; betaxolol and Compound 10 from Table 1; betaxolol and Compound 11 from Table 1; betaxolol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Betaxolol and FAIM; Betaxolol and NOL3; Betaxolol and DcR1; Betaxolol and DcR2; Betaxolol and DcR3; Levobunorol and Metipranolol; Levobunorol and Brimonidine; Levobunorol and Apraclonidine; Levobunorol and Brinzolamide; Levobunorol and Acetazolamide; Levobunorol and Dorzolamide; Levobunorol and Metazolamide; Levobunorol and Pillocarpine; Levobunorol and Carbachol; Levobunorol and Netalusdyl; Levobunorol and Angiopoietin-1; Levobunorol and Angiopoietin-2; Levobunorol and Angiopoietin-3; Levobunorol and Angiopoietin-4; Levobunorol and CNTF; Levobunorol and Peptide 6; Levobunorol and Peptide 21; Levo Bunolol and recombinant CNTF; Levobunolol and NGF; Levobunolol and BDNF; Levobunolol and GDNF; Levobunolol and C-type natriuretic peptide; Levobunolol and natural 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 metazolamide; Metipra Methipranolol and pilocarpine; Methipranolol and carbachol; Methipranolol and netalusdil; Methipranolol and angiopoietin-1; Methipranolol and angiopoietin-2; Methipranolol and angiopoietin-3; Methipranolol and angiopoietin-4; Methipranolol and CNTF; Methipranolol and peptide-6; Methipranolol and peptide-21; Methipranolol and recombinant CNTF; Methypranolol and NGF; Methypranolol and BDNF; Methypranolol and GDNF; Methypranolol and C-type natriuretic peptide; Methypranolol and natural C-type natriuretic peptide; Methypranolol and natriuretic peptide receptor B; Methypranolol and bicyclol; Methypranolol and FLIP; Methypranolol and MET12; Methypranolol and compound 1 in Table 1; Methypranolol and compound 2 in Table 1; Methypranolol and compound 3 in Table 1; Methypranolol and compound 4 in Table 1; Methypranolol and compound 5 in Table 1; Methypranolol and compound 6 in Table 1; Methypranolol and compound 7 in Table 1; Methypranolol and compound 8 in Table 1; Methypranolol and compound 9 in Table 1; Methypranolol and compound 10 in Table 1; Methypranolol and compound 11 in Table 1; Methypranolol 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 metazolamide; Brimonidine and pilocarpine; Brimonidine and carbachol; Brimonidine and netalusdil; 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 natural 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 metazolamide; Apraclonidine and pilocarpine; Apraclonidine and carbachol; Apraclonidine and netalusdil; Apraclonidine and angiopoietin-1; Apraclonidine and angiopoietin-2; Apraclonidine and angiopoietin-3; Apraclonidine and angiopoietin-4; Apraclonidine and CNTF; Apraclonidine and peptide 6; Apraclonidine and peptide 21; Apraclonidine and recombinant CNTF; Apraclonidine and NGF; Apraclonidine and BDNF; Apraclonidine and GDNF; Apraclonidine and C-type natriuretic peptide; Apraclonidine and natural C-type natriuretic peptide; Apraclonidine and natriuretic peptide receptor B; Apraclonidine Clonidine 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 metazolamide; brinzolamide and pilocarpine; brinzolamide and carbachol; brinzolamide and netalusdyl; 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 natural 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 metazolamide; Acetazolamide and pilocarpine; Acetazolamide and carbachol; Acetazolamide and netalusdil; Acetazolamide Lamide 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 natural 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 compound 1 in Table 1 2; Acetazolamide and compounds from Table 1; 3; Acetazolamide and compounds from Table 1; 4; Acetazolamide and compounds from Table 1; 5; Acetazolamide and compounds from Table 1; 6; Acetazolamide and compounds from Table 1; 7; Acetazolamide and compounds from Table 1; 8; Acetazolamide and compounds from Table 1; 9; Acetazolamide and compounds from Table 1; 10; Acetazolamide and compounds from Table 1; 11; 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 Metazolamide; Dorzolamide and Pilocarpine; Dorzolamide and Carbachol; Dorzolamide and Netalusdyl; 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 natural 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; Metazolamide and pilocarpine; Metazolamide and carbachol; Metazolamide and netalusdyl; Metazolamide and angiopoietin-1; Metazolamide and angiopoietin-2; Metazolamide and angiopoietin-3; Metazolamide and angiopoietin-4; Metazolamide and CNTF; Metazolamide and peptide 6; Metazolamide and peptide 21; Metazolamide and recombinant CNTF; Metazolamide and NGF; Metazolamide and BDNF; Metazolamide and GDNF; Metazolamide and C-type natriuretic peptide; Metazolamide and natural C-type natriuretic peptide; Peptide receptor B; Metazolamide and natriuretic peptide receptor B; Metazolamide and bicyclol; Metazolamide and FLIP; Metazolamide and MET12; Metazolamide and compound 1 in Table 1; Metazolamide and compound 2 in Table 1; Metazolamide and compound 3 in Table 1; Metazolamide and compound 4 in Table 1; Metazolamide and compound 5 in Table 1; Metazolamide and compound 6 in Table 1; Metazolamide and compound 7 in Table 1; Metazolamide and compound 8 in Table 1; Metazolamide and compound 9 in Table 1; Metazolamide and compound 10 in Table 1; Metazolamide and compound 11 in Table 1; Metazolamide and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); Metazolamide and FAIM; Metazolamide and NOL3; Metazolamide and DcR1; Metazolamide and DcR2; Metazolamide and DcR3; Pillocarpine and Carbachol; Pillocarpine and Netalusdyl; Pillocarpine and Angiopoietin-1; Pillocarpine and Angiopoietin-2; Pillocarpine and Angiopoietin-3; Pillocarpine and Angiopoietin-4; Pillocarpine and CNTF; Pillocarpine and Peptide 6; Pillocarpine and Peptide 21; Pillocarpine and Recombinant CNTF; Pillocarpine and NGF; Pillocarpine and BDNF; Pillocarpine and GDNF; Pillocarpine and C-type na Thorium diuretic peptide; Pillocarpine and natural C-type natriuretic peptide; Pillocarpine and natriuretic peptide receptor B; Pillocarpine and bicyclol; Pillocarpine and FLIP; Pillocarpine and MET12; Pillocarpine and compound 1 in Table 1; Pillocarpine and compound 2 in Table 1; Pillocarpine and compound 3 in Table 1; Pillocarpine and compound 4 in Table 1; Pillocarpine and compound 5 in Table 1; Pillocarpine and compound 6 in Table 1; Pillocarpine and compound 7 in Table 1; Pillocarpine and compound 8 in Table 1; Pillocarpine and compound 9 in Table 1; Pillocarpine and compound 10 in Table 1; Pillocarpine and compound 11 in Table 1; Pillocarpine and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Pillocarpine and FAIM; Pillocarpine and NOL3; Pillocarpine and DcR1; Pillocarpine and DcR2; Pillocarpine and DcR3; Carbachol and netalusdil; 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 type C natriuretic peptide Butide; 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; Netalusdil and Angiopoietin-1; Netalusdil and Angiopoietin-2; Netalusdil and Angiopoietin-3; Netalusdil and Angiopoietin-4; Netalusdil and CNTF; Netalusdil and Peptide 6; Netalusdil and Peptide 21; Netalusdil and Recombinant CNTF; Netalusdil and NGF; Netalusdil and BDNF; Netalusdil and GDNF; Netalusdil and C-type natriuretic peptide; Netal Sudil and natural C-type natriuretic peptide; netalusdil and natriuretic peptide receptor B; netalusdil and bicyclol; netalusdil and FLIP; netalusdil and MET12; netalusdil and compound 1 in Table 1; netalusdil and compound 2 in Table 1; netalusdil and compound 3 in Table 1; netalusdil and compound 4 in Table 1; netalusdil and compound 5 in Table 1; netalusdil and compound 6 in Table 1; netalusdil and compound 7 in Table 1; netalusdil and compound 8 in Table 1; netalusdil and compound 9 in Table 1; netalusdil and compound 10 in Table 1; netalusdil and compound 11 in Table 1; netalusdil and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Netalusdil and FAIM; Netalusdil and NOL3; Netalusdil and DcR1; Netalusdil and DcR2; Netalusdil 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; An Geopoietin-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 natural C-type natriuretic peptide; Angiopoietin-1 and natriuretic peptide receptor B; Angiopoietin-1 and bicyclol; Angiopoietin-1 and FLIP; Angiopoietin-1 and M ET12; Angiopoietin-1 and compound 1 from Table 1; Angiopoietin-1 and compound 2 from Table 1; Angiopoietin-1 and compound 3 from Table 1; Angiopoietin-1 and compound 4 from Table 1; Angiopoietin-1 and compound 5 from Table 1; Angiopoietin-1 and compound 6 from Table 1; Angiopoietin-1 and compound 7 from Table 1; Angiopoietin-1 and compound 8 from Table 1; Angiopoietin-1 and compound 9 from Table 1; Angiopoietin-1 and compound 10 from Table 1; Angiopoietin-1 and compound 11 from Table 1; Angiopoietin-1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Angiopoietin-1 and FAIM; Angiopoietin-1 and NOL3; Angiopoietin-1 and DcR1; Angiopoietin-1 and DcR2; Angiopoietin-1 and DcR3; Angiopoietin-2 and Angiopoietin-3; Angiopoietin-2 and Angiopoietin-4; Angiopoietin-2 and CNTF; Angiopoietin-2 and Peptide 6; Angiopoietin-2 and Peptide 21; Angiopoietin-2 and Recombinant CNTF; Angiopoietin-2 and NGF; Angiopoietin-2 and BDNF; Angiopoietin-2 and GDNF; Angiopoietin-2 and C-type natriuretic peptide; Angiopoietin-2 and natural C-type natriuretic peptide Tide; 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 natural 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 natural C-type natriuretic peptide; Angiopoietin-4 and natriuretic peptide Butide receptor B; Angiopoietin-4 and bicyclol; Angiopoietin-4 and FLIP; Angiopoietin-4 and MET12; Angiopoietin-4 and compound 1 from Table 1; Angiopoietin-4 and compound 2 from Table 1; Angiopoietin-4 and compound 3 from Table 1; Angiopoietin-4 and compound 4 from Table 1; Angiopoietin-4 and compound 5 from Table 1; Angiopoietin-4 and compound 6 from Table 1; Angiopoietin-4 and compound 7 from Table 1; Angiopoietin-4 and compound 8 from Table 1; Angiopoietin-4 and compound 9 from Table 1; Angiopoietin-4 and compound 10 from Table 1; Angiopoietin-4 and compound 11 from Table 1; Angiopoietin-4 and H 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 natural C-type natriuretic peptide; CNT F and natriuretic peptide receptor B; CNTF and bicyclol; CNTF and FLIP; CNTF and MET12; CNTF and compound 1 from Table 1; CNTF and compound 2 from Table 1; CNTF and compound 3 from Table 1; CNTF and compound 4 from Table 1; CNTF and compound 5 from Table 1; CNTF and compound 6 from Table 1; CNTF and compound 7 from Table 1; CNTF and compound 8 from Table 1; CNTF and compound 9 from Table 1; CNTF and compound 10 from Table 1; CNTF and compound 11 from Table 1; CNTF and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); CNTF and FAIM; CNTF and NOL3; CNTF and DcR1; CNTF and DcR2; CNTF and DcR3; Peptide 6 and Peptide 21; Peptide 6 and Recombinant Peptide 6; Peptide 6 and NGF; Peptide 6 and BDNF; Peptide 6 and GDNF; Peptide 6 and C-type natriuretic peptide; Peptide 6 and natural C-type natriuretic peptide; Peptide 6 and natriuretic peptide receptor B; Peptide 6 and bicyclol; Peptide 6 and FLIP; Peptide 6 and MET12; Peptide 6 and Compound 1 from Table 1; Peptide 6 and Compound 2 from Table 1; Peptide 6 and Compound 3 from Table 1; Peptide 6 and Compound 4 from Table 1; Peptide 6 and Compound 5 from Table 1; Peptide 6 and Compound 6 from Table 1; Peptide 6 and Compound 7 from Table 1; Peptide 6 and Compound 8 from Table 1; Peptide 6 and Compound 9 from Table 1; Peptide 6 and Compound 10 from Table 1; Peptide 6 and Compound 11 from Table 1; Peptide 6 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); Peptide 6 and FAIM; Peptide 6 and NOL3; Peptide 6 and DcR1; Peptide 6 and DcR2; Peptide 6 and DcR3; Peptide 21 and recombinant Peptide 21; Peptide 21 and NGF; Peptide 21 and BDNF; Peptide 21 and GDNF; Peptide 21 and C-type natriuretic peptide; Peptide 21 and natural 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 from Table 1;Peptide 21 and Compound 2 from Table 1;Peptide 21 and Compound 3 from Table 1;Peptide 21 and Compound 4 from Table 1;Peptide 21 and Compound 5 from Table 1;Peptide 21 and Compound 6 from Table 1;Peptide 21 and Compound 7 from Table 1;Peptide 21 and Compound 8 from Table 1;Peptide 21 and Compound 9 from Table 1;Peptide 21 and Compound 10 from Table 1;Peptide 21 and Compound 11 from Table 1;Peptide 21 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); Peptide 21 and FAIM; Peptide 21 and NOL3; Peptide 21 and DcR1; Peptide 21 and DcR2; Peptide 21 and DcR3; Recombinant Peptide 21 and NGF; Recombinant Peptide 21 and BDNF; Recombinant Peptide 21 and GDNF; Recombinant Peptide 21 and C-type natriuretic peptide; Recombinant Peptide 21 and natural 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 from Table 1; Recombinant peptide 21 and compound 2 from Table 1; Recombinant peptide 21 and compound 3 from Table 1; Recombinant peptide 21 and compound 4 from Table 1; Recombinant peptide 21 and compound 5 from Table 1; Recombinant peptide 21 and compound 6 from Table 1; Recombinant peptide 21 and compound 7 from Table 1; Recombinant peptide 21 and compound 8 from Table 1; Recombinant peptide 21 and compound 9 from Table 1; Recombinant peptide 21 and compound 10 from Table 1; Recombinant peptide 21 and compound 11 from Table 1; Recombinant peptide 21 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Recombinant peptide 21 and FAIM; Recombinant peptide 21 and NOL3; Recombinant peptide 21 and DcR1; Recombinant peptide 21 and DcR2; Recombinant peptide 21 and DcR3; NGF and BDNF; NGF and GDNF; NGF and C-type natriuretic peptide; NGF and natural C-type natriuretic peptide; NGF and natriuretic peptide receptor B; NGF and bicyclol; NGF and FLIP; NGF and MET12; NGF and compound 1 from Table 1; NGF and compound 2 from Table 1; NGF and compound 3 from Table 1; NGF and compound 4 from Table 1; NGF and compound 5 from Table 1; NGF and compound 6 from Table 1; NGF and compound 7 from Table 1; NGF and compound 8 from Table 1; NGF and compound 9 from Table 1; NGF and compound 10 from Table 1; NGF and compound 11 from Table 1; NGF and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); NGF and FAIM; NGF and NOL3; NGF and DcR1; NGF and DcR2; NGF and DcR3; BDNF and GDNF; BDNF and C-type natriuretic peptide; BDNF and natural 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 natural 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 natural 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; Natural C-type natriuretic peptide and natriuretic peptide receptor B; Natural C-type natriuretic peptide and bicyclol; Natural C-type natriuretic peptide and FLIP; Natural C-type natriuretic peptide and MET12; Natural C-type natriuretic peptide and compound 1 in Table 1; Natural C-type natriuretic peptide and Table 1 Compound 1; Natural C-type natriuretic peptide and Compound 3 from Table 1; Natural C-type natriuretic peptide and Compound 4 from Table 1; Natural C-type natriuretic peptide and Compound 5 from Table 1; Natural C-type natriuretic peptide and Compound 6 from Table 1; Natural C-type natriuretic peptide and Compound 7 from Table 1; Natural C-type natriuretic peptide and Compound 8 from Table 1; Natural C-type natriuretic peptide and Compound 9 from Table 1; Natural C-type natriuretic peptide and Compound 10 from Table 1; Natural C-type natriuretic peptide and Compound 11 from Table 1; Natural C-type natriuretic peptide and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Natural C-type natriuretic peptide and FAIM; Natural C-type natriuretic peptide and NOL3; Natural C-type natriuretic peptide and DcR1; Natural C-type natriuretic peptide and DcR2; Natural C-type natriuretic peptide and DcR3; Natriuretic peptide receptor B and Bicyclol; Natriuretic peptide receptor B and FLIP; Natriuretic peptide receptor B and MET12; Natriuretic peptide receptor B and compound 1 from Table 1; Natriuretic peptide receptor B and compound 2 from Table 1 ;Natriuretic peptide receptor B and compound 3 from Table 1;Natriuretic peptide receptor B and compound 4 from Table 1;Natriuretic peptide receptor B and compound 5 from Table 1;Natriuretic peptide receptor B and compound 6 from Table 1;Natriuretic peptide receptor B and compound 7 from Table 1;Natriuretic peptide receptor B and compound 8 from Table 1;Natriuretic peptide receptor B and compound 9 from Table 1;Natriuretic peptide receptor B and compound 10 from Table 1;Natriuretic peptide receptor B and compound 11 from Table 1;Natriuretic peptide receptor B and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Natriuretic peptide receptor B and FAIM; Natriuretic peptide receptor B and NOL3; Natriuretic peptide receptor B and DcR1; Natriuretic peptide receptor B and DcR2; Natriuretic peptide receptor B and DcR3; 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 from Table 1; FLIP and Compound 2 from Table 1; FLIP and Compound 3 from Table 1; FLIP and Compound 4 from Table 1; FLIP and Compound 5 from Table 1; FLIP and Compound 6 from Table 1; FLIP and Compound 7 from Table 1; FLIP and Compound 8 from Table 1; FLIP and Compound 9 from Table 1; FLIP and Compound 10 from Table 1; FLIP and Compound 11 from Table 1; FLIP and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); FLIP and FAIM; FLIP and NOL3; FLIP and DcR1; FLIP and DcR2; FLIP and DcR3; MET12 and Compound 1 from Table 1; MET12 and Compound 2 from Table 1; MET12 and Compound 3 from Table 1; MET12 and Compound 4 from Table 1; MET12 and Compound 5 from Table 1; MET12 and Compound 6 from Table 1; MET12 and Compound 7 from Table 1; MET12 and Compound 8 from Table 1; MET12 and Compound 9 from Table 1; MET12 and Compound 10 from Table 1; MET12 and Compound 11 from Table 1; MET12 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); MET12 and FAIM; MET12 and NOL3; MET12 and DcR1; MET12 and DcR2; MET12 and DcR3; Compound 1 and Compound 2 from Table 1; Compound 1 and Compound 3 from Table 1; Compound 1 and Compound 4 from Table 1; Compound 1 and Compound 5 from Table 1; Compound 1 and Compound 6 from Table 1; Compound 1 and Compound 7 from Table 1; Compound 1 and Compound 8 from Table 1; Compound 1 and Compound 9 from Table 1; Compound 1 and Compound 10 from Table 1; Compound 1 and Compound 11 from Table 1; Compound 1 and H from Table 1 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); Compound 1 and FAIM from Table 1; Compound 1 and NOL3 from Table 1; Compound 1 and DcR1 from Table 1; Compound 1 and DcR2 from Table 1; Compound 1 and DcR3 from Table 1; Compound 2 and Compound 3 from Table 1; Compound 2 and Compound 4 from Table 1; Compound 2 and Compound 5 from Table 1; Compound 2 and Compound 6 from Table 1; Compound 2 and Compound 7 from Table 1; Compound 2 and Compound 8 from Table 1; Compound 2 and Compound 9 from Table 1; Compound 2 and Compound 10 from Table 1; Compound 2 and Compound 11 from Table 1; Compound 2 and H from Table 1 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 and FAIM in Table 1; Compound 5 and NOL3 in Table 1; Compound 5 and DcR1 in Table 1; Compound 5 and DcR2 in Table 1; Compound 5 and DcR3 in Table 1; Compound 6 and Compound 7 in Table 1; Compound 6 and Compound 8 in Table 1; Compound 6 and Compound 9 in Table 1; Compound 6 and Compound 10 in Table 1; Compound 6 and Compound 11 in Table 1; Compound 6 and H in Table 1 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Compound 6 and FAIM in Table 1; Compound 6 and NOL3 in Table 1; Compound 6 and DcR1 in Table 1; Compound 6 and DcR2 in Table 1; Compound 6 and DcR3 in Table 1; Compound 7 and Compound 8 in Table 1; Compound 7 and Compound 9 in Table 1; Compound 7 and Compound 10 in Table 1; Compound 7 and Compound 11 in Table 1; Compound 7 and H in Table 1 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 7 and FAIM in Table 1; Compound 7 and NOL3 in Table 1; Compound 7 and DcR1 in Table 1; Compound 7 and DcR2 in Table 1; Compound 7 and DcR3 in Table 1; Compound 8 and Compound 9 in Table 1; Compound 8 and Compound 10 in Table 1; Compound 8 and Compound 11 in Table 1; Compound 8 and H in Table 1 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 8 and FAIM in Table 1; Compound 8 and NOL3 in Table 1; Compound 8 and DcR1 in Table 1; Compound 8 and DcR2 in Table 1; Compound 8 and DcR3 in Table 1; Compound 9 and Compound 10 in Table 1; Compound 9 and Compound 11 in Table 1; Compound 9 and H in Table 1 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO 4); Compound 9 and FAIM in Table 1; Compound 9 and NOL3 in Table 1; Compound 9 and DcR1 in Table 1; Compound 9 and DcR2 in Table 1; Compound 9 and DcR3 in Table 1; Compound 10 and Compound 11 in Table 1; Compound 10 and H in Table 1 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4); Compound 10 and FAIM in Table 1; Compound 10 and NOL3 in Table 1; Compound 10 and DcR1 in Table 1; Compound 10 and DcR2 in Table 1; Compound 10 and DcR3 in Table 1; Compound 11 and H in Table 1 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 -Includes one of the following: NH2 (sequence number 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.

[0078] Several covalent bond 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

[0079] In the above structural formulas C-1 to C100, 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. The bond can occur at either end or at any site of Met12, P6, P12, or BC. P6, Met12, GGG, N-AEEAc, N-dPEG12, etc. represent the corresponding compounds whose structures are modified to correspond to the indicated bond. For example, P6 is Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1). Met12 is

Chemical formula

Chemical formula

[0080] Drug delivery system For use in, some of the covalently linked compounds include

Chemical formula

[0081] Regarding the representation of any related structures 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.

[0082] Regarding the representation of any related structures such as formula C104, Y is N or O.

[0083] Regarding the representation of any related structures such as formula C104, A 1This is a group derived from P6, P21, or C1-C34, for example, a state in which the relevant atoms corresponding to the bond have been removed, as explained above.

[0084] Regarding the representation of any related structure such as formula C104, A 2 It is -OCH2CH2O- or -NHCH2CH2N-.

[0085] Sustained-delivery components allow a drug to remain in the body for a sustained period, for example, longer than the time it takes for the drug to be metabolized or eliminated from the body. thing Delivery system It is part of this. Typically, the sustained delivery component is a graft, such as a solid graft, which functions by encapsulating or otherwise capturing the drug within the graft. If the graft is biodegradable or bioerosive, the drug may be released as the graft biodegrades or bioerodes. The graft may also be porous to allow the drug to diffuse from the graft over a period of time. Biodegradable or bioerosive grafts may be porous or non-porous. Typically, non-biodegradable or non-bierosive grafts are porous, and the drug is released by diffusion. However, other mechanisms, such as osmotic pumps, may be at work.

[0086] The drug may be physically captured by the sustained delivery component and / or covalently bonded to a molecule that is part of the sustained delivery component.

[0087] Typical examples of biodegradable materials for porous or non-porous biodegradable grafts include silica-based materials and organic biodegradable materials such as polymers containing poly(D,L-lactic acid) (PLA) and poly(D,L-glycolic acid copolymer) (PLGA), polyesteramides (PEA, DSM Chemical), and polycaprolactone (PCL); hydrogels such as polyvinyl alcohol (PVA), PEGamines, and PEG-N-hydroxysuccinate esters (Ocular Therapeutix, etc.); collagen-based materials (Euclid Systems); or combinations thereof.

[0088] There are many suitable silica-based sustained-delivery components available.

[0089] One type of silica-based sustained delivery component involves a silica hydrogel complex obtained by mixing silica particles containing encapsulated drugs with a silica sol, the resulting hydrogel complex being shear-thinning. This type of delivery system is an injectable, all-silica-based microparticle-silica hydrogel controlled-release system that significantly reduces bursts of different types of encapsulated therapeutic and bioactive drugs. A detailed description of this type of silica-based sustained delivery component and its manufacturing method can be found in U.S. Patent No. 9,949,922 by Jokinen et al., issued April 24, 2018, the entire contents of which are incorporated herein by reference.

[0090] Another type of silica-based sustained delivery component includes drug-containing fluid silica compositions and gel compositions obtained by a method for producing fluid silica compositions involving a sol-gel transition in which redispersion occurs. The redispersion involves adding a liquid to the gel formed by the sol-gel transition after it has reached its gel point, with this addition occurring within a sufficiently short time after the gel point is reached, and after mixing the gel and liquid, a viscoelastically homogeneous fluid silica composition is obtained that is injectable and remains injectable, either directly through a fine 22G needle or by short-duration stirring of less than 30 seconds. Fluid and injectable sustained delivery silica compositions can enhance the stability and maintain the activity of encapsulated therapeutic agents. A detailed description of this type of silica-based sustained delivery component and a method for producing the same can be found in U.S. Patent Application No. 20140057996 by Jokinen et al., published February 27, 2014, which is incorporated herein by reference in its entirety.

[0091] Another type of silica-based sustained delivery component includes compositions comprising a bio-erosive, porous, silicon-based carrier material that delivers a drug and at least one amorphous sugar, optionally further comprising a crystallization inhibitor. These delivery systems involve loading biomolecules into the pores of the silica carrier material, thereby stabilizing the biomolecules. 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 methods for producing the same can be found in U.S. Patent No. 9,603,801 by Barnett et al., issued March 28, 2017, which is incorporated herein by reference in its entirety.

[0092] Another type of silica-based sustained delivery component includes bio-erosive devices, such as grafts, for controlled drug delivery. These devices include porous silicon-based carrier materials impregnated with or loaded with the drug. These specific silicon carrier materials contain at least one large molecule therapeutic agent positioned within the pores of the carrier material. It is believed that the large molecule is stabilized by loading it into the pores of the carrier material. In many embodiments, this large molecule is a protein, with pores having an average size of approximately 15 nm to 40 nm, and the protein having a molecular weight of approximately 100,000 amu to 200,000 amu. However, these systems may also be used with small molecule therapeutic compounds. Detailed descriptions of this type of silica-based sustained delivery component and methods for producing the same can be found in U.S. Patent No. 9,808,421, issued November 7, 2017; U.S. Patent No. 9,333,173, issued May 10, 2016; and U.S. Patent Publication No. 20140271764, published September 28, 2014, all of which are incorporated herein by reference.

[0093] The sustained-delivery component is available in doses of approximately 10 μg to 100 mg, 10 to 20 μg, 20 to 30 μg, 30 to 40 μg, 40 to 50 μg, 50 to 60 μg, 60 to 70 μg, 70 to 80 μg, 80 to 90 μg, 90 to 100 μg, 100 to 200 μg, 200 to 300 μg, 300 to 400 μg, 400 to 500 μg, 500 to 600 μg, 600 to 700 μg, 700 to 800 μg, 800 to 900 μg, and 90 0-1,000 μg, approx. 1-2 mg, approx. 2-3 mg, approx. 3-4 mg, approx. 4-5 mg, approx. 5-6 mg, approx. 6-7 mg, approx. 7-8 mg, approx. 8-9 mg, approx. 9-10 mg, approx. 10-20 mg, approx. 20-30 mg, approx. 30-40 mg, approx. 40-50 mg, approx. 50-60 mg, approx. 60-70 mg, approx. 70-80 mg, approx. 80-90 mg, approx. 90-100 mg, approx. 100-200 mg, approx. 200-300 mg, approx. 300-400 mg, approx. 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 6-7 g, 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 80-90g, about 90-100g, about 10 It can have any appropriate mass such as 0-200g, approximately 200-300g, approximately 300-400g, approximately 400-500g, approximately 500-600g, approximately 600-700g, approximately 700-800g, approximately 800-900g, approximately 900-1,000g, approximately 10-100μg, approximately 100-1,000μg, approximately 1-10mg, approximately 10-100mg, approximately 100-1,000mg, approximately 1-10g, approximately 10-100g, or approximately 100-1,000g. The above range of approximately 1g or less, or approximately 100mg or less, is for drugs delivered onto or into the eyeball. thing Delivery system This might be of interest to them.

[0094] The sustained delivery component may be any suitable percentage of the graft, such as about 1 to 99 wt%, about 1 to 10 wt%, about 10 to 20 wt%, about 20 to 30 wt%, about 30 to 40 wt%, about 40 to 50 wt%, about 50 to 60 wt%, about 60 to 70 wt%, about 70 to 80 wt%, about 80 to 90 wt%, about 90 to 99 wt%, about 1 to 30 wt%, about 30 to 65 wt%, about 65 to 99 wt%, about 1 to 50 wt%, or about 50 to 99 wt%, etc.

[0095] Drug thing Delivery systemThis includes approximately 10μg-100mg, approximately 10-20μg, approximately 20-30μg, approximately 30-40μg, approximately 40-50μg, approximately 50-60μg, approximately 60-70μg, approximately 70-80μg, approximately 80-90μg, approximately 90-100μg, approximately 100-200μg, approximately 200-300μg, approximately 300-400μg, approximately 400-500μg, approximately 500-600μg, approximately 600-700μg, approximately 700-800μg, approximately 800-900μg, and approximately 900-1. 000μg, approx. 1-2mg, approx. 2-3mg, approx. 3-4mg, approx. 4-5mg, approx. 5-6mg, approx. 6-7mg, approx. 7-8mg, approx. 8-9mg, approx. 9-10mg, approx. 10-20mg, approx. 20-30mg, approx. 30-40mg, approx. 40-50mg, approx. 50-60mg, approx. 60-70mg, approx. 70-80mg, approx. 80-90mg, approx. 90-100mg, approx. 100-200mg, approx. 200-300mg, approx. 300-400mg, approx. 400-50 0mg, 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 80-90g, about 90-100g, about 10 Any appropriate size is acceptable, such as 0-200g, approximately 200-300g, approximately 300-400g, approximately 400-500g, approximately 500-600g, approximately 600-700g, approximately 700-800g, approximately 800-900g, approximately 900-1,000g, approximately 10-100μg, approximately 100-1,000μg, approximately 1-10mg, approximately 10-100mg, approximately 100-1,000mg, approximately 1-10g, approximately 10-100g, or approximately 100-1,000g. The above range of approximately 1g or less, or approximately 100mg or less, is for drugs delivered onto or into the eyeball. thing Delivery system This might be of interest to them.

[0096] Typical examples of non-biodegradable or non-biodegradable materials for grafts include silicone or PVA (Psivida, et al.) as a semipermeable membrane.

[0097] Other possible sustained-delivery components may be based on cell-based approaches such as encapsulated cell technology; and reservoir-type approaches (forsight4; Replenish).

[0098] Prostaglandin compounds or prostaglandin receptor agonists, intraocular pressure lowering agents, and / or neurotrophic agents such as CNTF compounds may or may not be covalently bound to the sustained delivery component.

[0099] 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.

[0100] In some embodiments, the intraocular pressure-lowering agent is covalently bonded to the sustained-delivery component. In some embodiments, the intraocular pressure-lowering agent is not covalently bonded to the sustained-delivery component.

[0101] In some embodiments, neuronutrient agents such as CNTF compounds are covalently bonded to the sustained delivery component. In some embodiments, neuronutrient agents such as CNTF compounds are not covalently bonded to the sustained delivery component.

[0102] For example, prostaglandin compounds or prostaglandin receptor agonists are formulated as follows: [ka] The compound represented by PG-H may be covalently bonded to the sustained delivery component, and PG-H is a prostaglandin compound or prostaglandin receptor agonist, such as the aforementioned prostaglandin compound or prostaglandin receptor agonist.

[0103] The compounds of formula 3 are further divided into formulas 3A and 3B [ka] Represented as Prg-CO2H, Prg-CO2H is a prostaglandin agonist, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0104] Intraocular pressure lowering agents are, formula [ka] The compound represented by [the formula] may be covalently bonded to the sustained delivery component, and IOP-H is an intraocular pressure lowering agent such as the aforementioned intraocular pressure lowering agent.

[0105] CNTF compounds or other neurotrophic agents are formulated as follows: [ka] The compound represented by CNTF-H may be covalently bonded to the sustained delivery component, and CNTF-H is the aforementioned CNTF compound or other neurotrophic agent.

[0106] CNP compounds are formulated with the formula [ka] The sustained delivery component may be covalently bonded to a compound represented by , and CNP-H is a CNP compound.

[0107] NPR-B compounds are, formula [ka] The sustained delivery component may be covalently bonded to a compound represented by , and NPRB-H is an NPR-B compound.

[0108] Regarding the representation of the structures of formulas 3, 3A, 3B, 4, 5, 6, or 7, or related compounds shown below, R 1 These are independently H or CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl, etc. 1-6 It is alkyl.

[0109] Regarding the representation of the structures of formulas 3, 3A, 3B, 4, 5, 6, or 7, or related compounds shown below, R 2 These are independently H or CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl, etc. 1-6 It is alkyl.

[0110] Regarding the representation of the structures of formulas 3, 3A, 3B, 4, 5, 6, or 7, or related compounds shown below, R 3 These are independently H or CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl, etc. 1-6 It is alkyl.

[0111] The compounds are examples of compounds of formula 3, 3A, or 3B. [ka]

[0112] Within the body, ester bonds can be hydrolyzed to release compounds. [ka]

[0113] The following table shows three example compounds of formula 4, and three compounds that can be released in the body by hydrolysis of the ester or amide group. [Table 3]

[0114] In the table above, any three Si(OH) groups are SiOR 1 Ure 2 Ure 3 It may be replaced with this.

[0115] Examples of compounds of formula 5 are VGDGGLFEKKL-PEG-Si(OH)3 (where "VGDGGLFEKKL" is disclosed as Sequence ID No. 1) or VGDGGLFEKKL-PEG-SiOR1 Ure 2 Ure 3 ("VGDGGLFEKKL" is disclosed as Sequence ID No. 1), and PEG is a polyethylene glycol chain (e.g., -(OCH2CH2) n - where 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).

[0116] OSIOR of formulas 3, 3A, 3B, 4, 5, 6, or 7 1 Ure 2 Ure 3 The base is silica-based medicine thing Delivery system It can covalently bond with silica to form compounds represented by formulas such as 3D, 3AD, 3BD, 4D, or 5D, where D is SiOR of formula 3, 3A, 3B, 4, 5, 6, or 7. 1 Ure 2 Ure 3 It is a sustained-delivery component containing Si.

[0117] [ka]

[0118] several drugs thing Delivery system is, formula [ka] The polymer represented by may be included, Each X is independent [ka] That is the case.

[0119] The subject drug delivery system can be administered to mammals such as humans by appropriate methods such as injection into a part of the body or surgical procedure, oral administration, or topical application to the eye or skin. In some embodiments, the graft is injected into or around the eye, including but not limited to the anterior chamber, vitreous humor, posterior chamber, subconjunctival space, suprachoroidal space, or sub-Tenon's space, or is otherwise implanted.

[0120] The subject of medicine thing Delivery system This can extend the time that drugs remain in the body. For example, thing Delivery system The drug can provide therapeutic levels of medication for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, at least approximately 8 weeks, at least approximately 3 months, at least approximately 4 months, at least approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 1 year, at least approximately 1.5 years, at least approximately 2 years, at least approximately 3 years, at least approximately 4 years, approximately 1 to 6 months, approximately 6 to 12 months, approximately 12 to 18 months, approximately 18 to 24 months, approximately 24 to 36 months, up to approximately 2 years, up to approximately 3 years, up to approximately 4 years, up to approximately 5 years, or up to approximately 10 years. thing Delivery system It may be injected, implanted, or modified within any period within the above range.

[0121] In some embodiments, the subject drug is used 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, childhood glaucoma, secondary glaucoma, or combinations thereof. thing Delivery system It may be administered to mammals such as humans.

[0122] (Examples) The following embodiments are intended to illustrate embodiments of the present disclosure, but are not intended to limit their scope or underlying principles.

[0123] Example 1: Solid-phase synthesis of PG-L-CNTF characterized by amide bonds Using methods known in the art, peptide 6 is linked to the resin at its NH2 terminus, protected with a BOC group and a t-Bu ester group, and linked to the NH2 terminus-PEG at its carboxylic acid terminus, resulting in the resin-LK(Boc)-K(Boc)-E(tBu)-FLGGD(tBu)-GV-CO2(CH2-CH2-O) n -CH2-CH2-NH2 is provided. The properties of the starting materials and the order of the reactions may be changed to improve efficiency and selectivity, and all reactions are carried out using methods known in the art. Bimatoprost free acid having three hydroxyl groups protected with a t-butyl group (or optionally other alkyl or silyl protecting group) 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 completely deprotected using TFA or other acid-catalyzed methods known in the art to release the peptide 6-linker-bimatoprostamide derivative. As known in the art, different orthogonal protecting strategies may be employed as needed to optimize the efficiency of the overall procedure.

[0124] Example 2: Solid-phase synthesis of PG-L-CNTF characterized by ester bonds Using methods known in the art, peptide 6 is linked to the resin at its NH2 terminus, protected with a CBz group over the free amine group and a benzyl group over the free acid group, and bonded to polyethylene glycol at its carboxylic acid terminus, forming the resin-LK(Cbz)-K(Cbz)-E(Bn)-FLGGD(Bn)-GV-CO2(CH2-CH2-O) n-CH2-CH2-OH is provided. To improve selectivity, the properties of the starting materials and the order of the reactions may be changed, and all reactions are carried out using methods known in the art. The bimatoprost free acid having three hydroxyl groups protected with a benzyl group (or, as appropriate, other hydrogenation-unstable protecting group) 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 completely deprotected using a hydrogenation method or other debenzylation method known in the art to release the peptide-6-linker-bimatoprost ester derivative. As known in the art, different orthogonal protecting strategies may be employed as needed to optimize the efficiency of the overall procedure.

[0125] The following embodiments are those that the inventor particularly anticipates.

[0126] Embodiment 1. Drugs containing intraocular pressure lowering agents, neurotrophic agents, C-type natriuretic peptide (CNP), natriuretic peptide receptor B (NPR-B), or apoptosis signaling fragmentation inhibitors (FAS) or FAS ligand (FASL) inhibitors, and sustained-delivery components. thing Delivery system .

[0127] Embodiment 2. The drug according to Embodiment 1, which includes an intraocular pressure lowering agent. thing Delivery system .

[0128] Embodiment 3. The intraocular pressure lowering agent is a prostaglandin compound, as described in Embodiment 2. thing Delivery system .

[0129] Embodiment 4. The drug according to Embodiment 2 or 3, further comprising a second intraocular pressure lowering agent. thing Delivery system .

[0130] Embodiment 5. The drug according to Embodiment 2, 3, or 4, wherein the intraocular pressure lowering agent includes a beta-blocker. thing Delivery system .

[0131] Embodiment 6. The drug according to Embodiments 2, 3, 4, or 5, wherein the intraocular pressure lowering agent contains timolol. thing Delivery system .

[0132] Embodiment 7. The drug according to Embodiments 2, 3, 4, 5, or 6, wherein the intraocular pressure lowering agent contains betaxolol. thing Delivery system .

[0133] Embodiment 8. The drug according to Embodiment 2, 3, 4, 5, 6, or 7, wherein the intraocular pressure lowering agent includes levobunolol. thing Delivery system .

[0134] Embodiment 9. The drug according to Embodiment 2, 3, 4, 5, 6, 7, or 8, wherein the intraocular pressure lowering agent includes metipranolol. thing Delivery system .

[0135] Embodiment 10. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, or 9, wherein the intraocular pressure lowering agent contains an alpha-adrenergic agonist. thing Delivery system .

[0136] Embodiment 11. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the intraocular pressure lowering agent contains brimonidine. thing Delivery system .

[0137] Embodiment 12. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the intraocular pressure lowering agent contains apraclonidine. thing Delivery system .

[0138] Embodiment 13. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the intraocular pressure lowering agent includes a carbonic anhydrase inhibitor. thing Delivery system .

[0139] Embodiment 14. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the intraocular pressure lowering agent contains brinzolamide. thing Delivery system .

[0140] Embodiment 15. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the intraocular pressure lowering agent contains acetazolamide. thing Delivery system .

[0141] Embodiment 16. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the intraocular pressure lowering agent contains dorzolamide. thing Delivery system .

[0142] Embodiment 17. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the intraocular pressure lowering agent contains metazolamide. thing Delivery system .

[0143] Embodiment 18. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the intraocular pressure lowering agent includes a cholinergic agent. thing Delivery system .

[0144] Embodiment 19. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the intraocular pressure lowering agent contains pilocarpine. thing Delivery system .

[0145] Embodiment 20. The drug according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the intraocular pressure lowering agent contains carbacol. thing Delivery system .

[0146] Embodiment 21. The intraocular pressure lowering agent includes a Rho kinase (ROCK) inhibitor, according to Embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. thing Delivery system .

[0147] Embodiment 22. The drug according to Embodiments 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 lowering agent contains netaludil. thing Delivery system .

[0148] Embodiment 23. A drug according to Embodiments 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 neuronutrient agent. thing Delivery system .

[0149] Embodiment 24. A drug according to Embodiments 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. thing Delivery system .

[0150] Embodiment 25. The prostaglandin receptor agonist and the neurotrophic agent are covalently bound to each other, according to Embodiment 24. thing Delivery system .

[0151] Embodiment 26. The prostaglandin receptor agonist and the neurotrophic agent are covalently bonded to each other via a binding group, according to Embodiment 25. thing Delivery system .

[0152] Embodiment 27. The drug according to Embodiments 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 includes bimatoprost. thing Delivery system .

[0153] Embodiment 28. The drug according to Embodiments 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 includes travoprost. thing Delivery system .

[0154] Embodiment 29. The prostaglandin receptor agonist includes latanoprost, according to the drug according to Embodiments 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. thing Delivery system.

[0155] Embodiment 30. The drug according to Embodiments 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 includes latanoprosten. thing Delivery system .

[0156] Embodiment 31. The drug according to Embodiments 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 includes tafluprost. thing Delivery system .

[0157] Embodiment 32. The drug according to Embodiments 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 includes a prostaglandin EP-2 receptor agonist. thing Delivery system .

[0158] Embodiment 33. The drug according to Embodiments 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 includes a prostaglandin EP-3 receptor agonist. thing Delivery system .

[0159] Embodiment 34. The neurotrophic agent contains CNTF peptide 6, according to the drug according to Embodiments 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. thing Delivery system .

[0160] Embodiment 35. The neurotrophic agent contains CNTF peptide 21, according to the drug according to Embodiments 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. thing Delivery system .

[0161] Embodiment 36. A drug according to Embodiments 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. thing Delivery system .

[0162] Embodiment 37. A drug according to Embodiments 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 thing Delivery system .

[0163] Embodiment 38. A drug according to Embodiments 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 intraocular pressure lowering agent and a neuronutrition agent. thing Delivery system .

[0164] Embodiment 39. The drug according to Embodiment 38, wherein the intraocular pressure lowering agent and the neuronutrient agent are covalently bonded to each other. thing Delivery system.

[0165] Embodiment 40. The intraocular pressure lowering agent and the neuronutrient agent are covalently bonded to each other via a binding group, according to Embodiment 39. thing Delivery system .

[0166] Embodiment 41. The drug according to Embodiments 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 intraocular pressure lowering agent and a CNP compound. thing Delivery system .

[0167] Embodiment 42. The drug according to Embodiment 41, wherein the intraocular pressure lowering agent and the CNP compound are covalently bonded to each other. thing Delivery system .

[0168] Embodiment 43. The intraocular pressure lowering agent and the CNP compound are covalently bonded to each other via a bonding group, according to Embodiment 42 of the drug thing Delivery system .

[0169] Embodiment 44. A drug according to Embodiments 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 intraocular pressure lowering agent and an NPR-B compound. thing Delivery system .

[0170] Embodiment 45. The drug according to Embodiment 44, wherein the intraocular pressure lowering agent and the NPR-B compound are covalently bonded to each other. thing Delivery system .

[0171] Embodiment 46. The intraocular pressure lowering agent and the NPR-B compound are covalently bonded to each other via a bonding group, according to Embodiment 45 of the drug thing Delivery system .

[0172] Embodiment 47. The drug according to Embodiments 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. thing Delivery system .

[0173] Embodiment 48. The drug according to Embodiment 47, wherein the neurotrophic agent and the CNP compound are covalently bonded to each other. thing Delivery system .

[0174] Embodiment 49. The neurotrophic agent and the CNP compound are covalently bonded to each other via a binding group, as described in Embodiment 48. thing Delivery system .

[0175] Embodiment 50. The drug according to Embodiments 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. thing Delivery system .

[0176] Embodiment 51. The drug according to Embodiment 50, wherein the neurotrophic agent and the NPR-B compound are covalently bonded to each other. thing Delivery system .

[0177] Embodiment 52. The neurotrophic agent and the NPR-B compound are covalently bonded to each other via a binding group, as described in Embodiment 51. thing Delivery system .

[0178] Embodiment 53. The drug according to Embodiments 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. thing Delivery system .

[0179] Embodiment 54. The drug according to Embodiment 53, wherein the CNP compound and the NPR-B compound are covalently bonded to each other. thing Delivery system .

[0180] Embodiment 55. The CNP compound and the NPR-B compound are covalently bonded to each other via a bonding group, as described in Embodiment 54 of the drug thing Delivery system .

[0181] Embodiment 56. The neurotrophic agent is a CNTF compound, as described in Embodiments 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. thing Delivery system .

[0182] Embodiment 57. The drug according to Embodiments 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. thing Delivery system .

[0183] Embodiment 58. The drug according to Embodiments 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. thing Delivery system .

[0184] Embodiment 59. The sustained delivery component is nonporous, as described in Embodiments 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 of the drug. thing Delivery system .

[0185] Embodiment 60. The sustained delivery component is of the type described in U.S. Patent No. 9,949,922 by Jokinen et al., issued on April 24, 2018, and is the drug described in Embodiments 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. thing Delivery system .

[0186] Embodiment 61. The sustained delivery component is of the type described in U.S. Patent Application No. 20140057996 by Jokinen et al., published on February 27, 2014, and is the drug described in Embodiments 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. thing Delivery system .

[0187] Embodiment 62. The sustained delivery component is of the type described in U.S. Patent No. 9,603,801 by Barnett et al., issued on March 28, 2017, and is the drug described in Embodiments 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. thing Delivery system .

[0188] Embodiment 63. The sustained delivery component is of the type described in U.S. Patent No. 9,808,421 by Ashton et al., issued on November 7, 2017, and is the drug described in Embodiments 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. thing Delivery system .

[0189] Embodiment 64. The sustained delivery component is of the type described in U.S. Patent No. 9,333,173 by Ashton et al., issued on May 10, 2016, and is the drug described in Embodiments 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. thing Delivery system .

[0190] Embodiment 65. The sustained delivery component is of the type described in U.S. Patent Publication No. 20140271764 by Ashton et al., published on September 28, 2014, and is the drug described in Embodiments 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. thing Delivery system .

[0191] Embodiment 66. The drug according to Embodiments 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 bound to the sustained delivery component. thing Delivery system .

[0192] Embodiment 67. The drug according to Embodiments 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 neuronutrient is covalently bonded to the sustained delivery component. thing Delivery system .

[0193] Embodiment 68. The drug according to Embodiments 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 bound to the sustained delivery component. thing Delivery system .

[0194] Embodiment 69. The drug according to Embodiments 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 neuronutrient is not covalently bound to the sustained delivery component. thing Delivery system .

[0195] Embodiment 70. The drug according to Embodiments 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 thing Delivery system A method for treating glaucoma or ocular hypertension, comprising administering to a mammal suffering from glaucoma or ocular hypertension.

[0196] Embodiment 71. The drug is administered by intravitreal injection. thing Delivery system The method according to Embodiment 70, wherein the substance is administered to the affected eye of a mammal.

[0197] Embodiment 72. The drug thing Delivery system The method according to Embodiment 70, wherein the implant is implanted in the anterior chamber, subconjunctival space, suprachoroidal space, or subtenon's space of an affected eye in a mammal.

[0198] Embodiment 73. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes primary open-angle glaucoma (POAG).

[0199] Embodiment 74. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes acute primary angle-closure glaucoma (APACG).

[0200] Embodiment 75. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes chronic angle-closure glaucoma.

[0201] Embodiment 76. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes pigmentary glaucoma.

[0202] Embodiment 77. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes pseudoexfoliation glaucoma.

[0203] Embodiment 78. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes normal-tension glaucoma.

[0204] Embodiment 79. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes pediatric glaucoma.

[0205] Embodiment 80. The method according to embodiment 70, 71, or 72, wherein the glaucoma includes secondary glaucoma.

[0206] (Note) (Note 1) A drug containing a first active pharmaceutical ingredient (API) and a sustained-delivery component. thing Delivery system The first API is an intraocular pressure lowering agent, a neurotrophic agent, a C-type natriuretic peptide (CNP), a natriuretic peptide receptor B (NPR-B), an apoptosis signaling fragmentation (FAS) inhibitor or a FAS ligand (FASL) inhibitor, or a combination thereof. thing Delivery system .

[0207] (Note 2) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is an intraocular pressure lowering agent and the second API is a neurotrophic agent. thing Delivery system .

[0208] (Note 3) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is an intraocular pressure lowering agent and the second API is CNP. thing Delivery system .

[0209] (Note 4) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is an intraocular pressure lowering agent and the second API is NPR-B. thing Delivery system .

[0210] (Note 5) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is an intraocular pressure lowering agent and the second API is a FAS inhibitor or a FASL inhibitor. thing Delivery system .

[0211] (Note 6) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is a neurotrophic agent and the second API is CNP. thing Delivery system .

[0212] (Note 7) Drugs containing a second API thing Delivery systemThe drug described in Appendix 1, wherein the first API is a neurotrophic agent and the second API is NPR-B. thing Delivery system .

[0213] (Note 8) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is a neurotrophic agent and the second API is a FAS inhibitor or a FASL inhibitor. thing Delivery system .

[0214] (Note 9) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is CNP and the second API is NPR-B. thing Delivery system .

[0215] (Note 10) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is CNP and the second API is a FAS inhibitor or a FASL inhibitor. thing Delivery system .

[0216] (Note 11) Drugs containing a second API thing Delivery system The drug described in Appendix 1, wherein the first API is NPR-B and the second API is a FAS inhibitor or a FASL inhibitor. thing Delivery system .

[0217] (Note 12) The drug described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the first API and the second API are not covalently bonded to each other. thing Delivery system .

[0218] (Note 13) The drug described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the first API is covalently bonded to the second API. thing Delivery system .

[0219] (Note 14) The drug according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the first API is covalently bound to the sustained delivery component. thing Delivery system .

[0220] (Note 15) The drug according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the second API is covalently bound to the sustained delivery component. thing Delivery system .

[0221] (Note 16) A drug having approximately 100 μg to approximately 1 mg of the first API, as described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. thing Delivery system .

[0222] (Note 17) A drug having approximately 100 μg to approximately 1 mg of the second API, as described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. thing Delivery system .

[0223] (Note 18) The graft weight is approximately 300 μg to approximately 10 mg, and the drugs are those described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17. thing Delivery system .

[0224] (Note 19) The drugs listed in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 thing Delivery system A method for treating glaucoma, including administering to mammals suffering from glaucoma or ocular hypertension.

[0225] (Note 20) The aforementioned drug thing Delivery system The method described in Appendix 19, wherein the substance is injected into the eye of the mammal.

[0226] (Note 21) The method according to Appendix 19 or 20, wherein the mammal is a human.

[0227] (Note 22) Drug delivery for the treatment of glaucoma or ocular hypertension, further containing sustained-delivery components. system The use of intraocular pressure lowering agents, neurotrophic agents, CNP, NPR-B, FAS inhibitors or FASL inhibitors, or combinations thereof, in the manufacture of [the product / service].

[0228] (Note 23) The aforementioned drug thing Delivery system It is used as described in Appendix 22, when injected into the eye of a mammal.

[0229] (Note 24) The use described in Appendix 22 or 23, wherein the mammal is a human.

[0230] (Note 25) Drugs for the treatment of glaucoma as described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 thing Delivery system , and the drug thing Delivery system A kit including a label with instructions for use.

[0231] (Note 26) The aforementioned drug thing Delivery systemThe kit described in Appendix 25 is injected into the eye of a mammal.

Claims

1. A drug delivery system comprising a first pharmaceutically active ingredient (API) containing bimatoprost acid, a sustained delivery component, and a second API containing a neurotrophic peptide, The second API is covalently bonded to the sustained delivery component. The drug delivery system is injected into the vitreous body of a mammal, wherein the mammal is a human.

2. The drug delivery system according to claim 1, wherein the neurotrophic peptide is a CNTF peptide.

3. The drug delivery system according to claim 1, wherein the first API and the second API are not covalently bonded to each other.

4. The drug delivery system according to claim 1 or 2, wherein the first API is covalently bonded to the second API.

5. The drug delivery system according to claim 1 or 2, wherein the first API is covalently bonded to the sustained delivery component.

6. A drug delivery system according to any one of claims 1 to 5, comprising approximately 100 μg to approximately 1 mg of the first API.

7. A drug delivery system according to any one of claims 1 to 4, comprising approximately 100 μg to approximately 1 mg of the second API.

8. The drug delivery system according to any one of claims 1 to 7, wherein the weight of the drug delivery system is approximately 300 μg to approximately 10 mg.

9. Sustained delivery components and, The first active pharmaceutical ingredient (API) contains bimatoprost acid, A second API containing neurotrophic peptides, A drug delivery system for the treatment of glaucoma or ocular hypertension, including, The second API is covalently bonded to the sustained delivery component. The drug delivery system is injected into the vitreous body of a mammal, wherein the mammal is a human.

10. The drug delivery system according to claim 9, wherein the second API is a CNTF peptide.

11. The drug delivery system according to claim 9 or 10, wherein the first API and the second API are not covalently bonded to each other.

12. The drug delivery system according to claim 9 or 10, wherein the first API is covalently bonded to the second API.

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