Polyesteramide compound and use thereof

Abstract

Provided are a polyesteramide compound and use thereof. Specifically provided is use of a polyesteramide compound represented by formula I or a pharmaceutically acceptable salt thereof. The use is: (1) use in the preparation of a drug for ocular administration; (2) use in the preparation of an ophthalmic drug; (3) use as a carrier for the drug for ocular administration; or (4) use in ocular administration. The polyesteramide compound represented by formula I or the pharmaceutically acceptable salt thereof can effectively improve the delivery effect of the drug for ocular administration, and has a good application prospect.

Description

A polyesteramide compound and its application

[0001] This application claims priority to Chinese patent application 2025101034111, filed on January 22, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a polyesteramide compound and its applications, specifically to an arginine polyesteramide compound, an ophthalmic drug, and its applications. Background Technology

[0003] Eye diseases are a leading cause of blindness, such as keratitis, cataracts, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), which can severely impair vision and affect quality of life. Drug treatment for eye diseases includes topical administration via eye drops or intraocular injections. However, unlike common intravenous or oral administration, ocular medications need to cross the ocular barrier to be effective. Furthermore, the therapeutic effect of conventional eye drops is largely limited by the ocular surface barrier, such as tear circulation, continuous blinking, a tight epithelial barrier, and tear drainage. These factors contribute to low bioavailability of ocular medications; traditional eye drops typically have low bioavailability in the eye, usually below 5%.

[0004] CN118903005A discloses an ophthalmic nanomedicine delivery system loaded with cyclosporine, comprising an amphiphilic polymer forming micelle particles and cyclosporine loaded in the micelle particles, wherein the amphiphilic polymer is selected from TPGS, mPEG-DSPE, mPEG-DPPE, ALC-0159, mPEG-DMG, and mPEG-DSG. WO2008070402A2 discloses an ophthalmic drug delivery system relating to a method for treating eye diseases using a biodegradable implant of controllable size suitable for implantation in the ocular region or site. CN118178671A discloses an arginine-based nanodelivery platform, providing the application of an arginine-based antigen-antibody co-delivery nanoplatform in the preparation of oral tumor drugs. Oral immunization using the arginine-based antigen-antibody co-delivery system can effectively reduce unnecessary systemic immunotoxicity. The oral therapeutic antigen-antibody co-delivery platform can produce a significant inhibitory effect on orthotopic colorectal cancer, and its anticancer activity is equivalent to or even superior to the activity provided by conventional injection of free drugs, enabling more efficient and convenient tumor treatment via oral immunization. It should be noted that oral administration and ocular administration are two completely different drug delivery methods, with significant differences in drug delivery routes and target tissues.

[0005] Despite significant efforts in research on ophthalmic treatments and ophthalmic nanomedicine delivery systems, there remains a need to develop ophthalmic drug delivery systems that improve drug bioavailability, minimize harmful side effects of treatments, and deliver drugs efficiently and conveniently. Summary of the Invention

[0006] The technical problem this invention aims to solve is to overcome the shortcomings of existing ocular drug delivery technologies, such as low delivery efficiency and limited variety. Therefore, this invention provides a polyesteramide compound and its applications. The polyesteramide compound provided by this invention can effectively improve the delivery efficiency of ocular drugs and has promising application prospects.

[0007] The present invention solves the above-mentioned technical problems through the following solution.

[0008] The present invention provides an application of a polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof, said application being (1) in the preparation of ocular drugs; (2) in the preparation of ophthalmic drugs; (3) as a carrier for ocular drugs; or (4) in ocular drug delivery.

[0009] in,

[0010] *C is marked as S configuration, R configuration or a mixture thereof;

[0011] A1 is C 1-16 Alkylene, by one or more R a Replacement C 1-16 Alkylene, C 3-10 Cycloalkylene, 3-10 member heterocycloalkylene, C 6- 10 aryl, 5-12 methyl aryl, C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene, C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene, C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene or C 1-6 Alkylene-OC 1-6 Alkylene; in the 3-10 membered heterocyclic alkylene and the 5-12 membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R a Halogens are independent of each other;

[0012] A2 is C 1-16Alkylene, C 2-12 imidene group, C 3-10 Cycloalkylene, 3-10 member heterocycloalkylene, C 6-10 aryl, 5-12 methyl aryl, C 1-6 Alkylene-OC 1-6 Alkylene, C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene, C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene, C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene or C 1-6 Alkylene-(O-CH2CH2-O) m -C 1-6 Alkylene, m is 1-6; in the 3-10 membered heterocyclic alkylene and the 5-12 membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0013] n represents the degree of polymerization, which ranges from 3 to 50.

[0014] In one possible solution, n ranges from 3 to 50.

[0015] In one embodiment, n (degree of polymerization) is 6-40 (e.g., 6-20), for example, n is approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. The number-average molecular weight of the polyesteramide compound represented by Formula I or its pharmaceutically acceptable salt is, for example, in the range of approximately 2500-20000 Da.

[0016] In one embodiment, n (degree of polymerization) is 6-12, for example, n is about 6, 7, 8, 9, 10, 11 or 12 (preferably 8). The number-average molecular weight of the polyesteramide compound of Formula I or its pharmaceutically acceptable salt is, for example, in the range of about 2500-10000 Da.

[0017] In one embodiment, * indicates C as the S configuration, and the arginine residue in the polyesteramide compound shown in Formula I is an L-arginine residue.

[0018] In one embodiment, the pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I comprises the polyesteramide compound represented by Formula I and a pharmaceutically acceptable acid, preferably comprising the polyesteramide compound represented by Formula II and a pharmaceutically acceptable anion:

[0019] Wherein, *, A1, A2 and n are as described in any embodiment of the present invention.

[0020] In one embodiment, the pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I is p-toluenesulfonate, hydrochloride, hydrobromide, or methanesulfonate.

[0021] In one embodiment, the pharmaceutically acceptable anion is conventional in the art, preferably an anion of Bronsted acids with a pKa of -7 to +5, such as an anion of strong acids, preferably p-toluenesulfonic acid. Ions, chloride ions, bromide ions, and common anions of methanesulfonic acid (p-toluenesulfonic acid is preferred).

[0022] In this invention, the pharmaceutically acceptable anionic and repeating units (polymer monomers) The molar ratio is conventional in the art, and preferably when the anion is a monovalent anion, the molar ratio of the anion to the polymer monomer of the polyester amide compound shown in Formula II is 2:1.

[0023] In one embodiment, the number-average molecular weight of the polyesteramide compound represented by Formula I is 3000-6000 Da, for example, 4136 Da.

[0024] In one embodiment, the number-average molecular weight of the polyesteramide compound represented by Formula I is 3000-8000 Da, for example 4136 Da, 6094 Da, 7933 Da, 6432 Da, 5850 Da or 6286 Da.

[0025] In one embodiment, the polydispersity index of the polyesteramide compound represented by Formula II is 1-1.5, for example, 1.05.

[0026] In one embodiment, the polydispersity index of the polyesteramide compound represented by Formula II is 1-1.8, for example, 1.05, 1.38, 1.01, 1.06, 1.58 or 1.39.

[0027] In one embodiment, the polyesteramide compound represented by Formula II has a weight-average molecular weight of 3000-6000 Da, for example, 4356 Da.

[0028] In one embodiment, the polyesteramide compound represented by Formula II has a weight-average molecular weight of 3000-10000 Da, such as 4356 Da, 8440 Da, 8016 Da, 9254 Da, or 8744 Da.

[0029] In one embodiment, the peak molecular weight (Mp) of the polyesteramide compound represented by Formula II is 3000-6000 Da, for example 4203 Da.

[0030] In one embodiment, the peak molecular weight (Mp) of the polyesteramide compound represented by Formula II is 3000-8000 Da, for example 4203 Da, 7659 Da, 8073 Da, 5301 Da or 7943 Da.

[0031] In one embodiment, the Z-average molecular weight (Mz) of the polyesteramide compound represented by Formula II is 3000-6000 Da, for example, 4608 Da.

[0032] In one embodiment, the Z-average molecular weight (Mz) of the polyesteramide compound represented by Formula II is 3000-12000 Da, for example 4608 Da, 11528 Da, 8099 Da, 14765 Da or 11947 Da.

[0033] In one embodiment, the average molecular weight (Mz+1) of the polyesteramide compound represented by Formula II is 3000-6000 Da, for example, 4889 Da.

[0034] In one embodiment, the average molecular weight (Mz+1) of the polyesteramide compound represented by Formula II is 3000-22000 Da, for example 4889 Da, 14848 Da, 8180 Da, 20764 Da or 15454 Da.

[0035] In one embodiment, the polyesteramide compound represented by Formula II is a compound represented by Formula II-1 or Formula II-2;

[0036] Where x is an integer from 1 to 9, such as 2, 4, 6 or 8;

[0037] y is an integer from 2 to 10, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0038] *, A1, A2, and n are independently as described in any embodiment of the invention.

[0039] In one embodiment, the polyesteramide compound represented by Formula II is the compound represented by Formula II-3;

[0040] Where x is an integer from 1 to 9, such as 2, 4, 6 or 8;

[0041] y is an integer from 2 to 10, such as 2, 3, 4, 5, 6, 7, 8, 9, 10;

[0042] * and n are independent as described in any embodiment of the invention.

[0043] In one embodiment, the polyesteramide compound represented by Formula I is a pharmaceutically acceptable salt, and its polymeric monomer (repeating unit) is a compound represented by Formula I-1.

[0044] Where * indicates C as the S configuration;

[0045] M is a pharmaceutically acceptable anion, for example

[0046] x and y are as described in any embodiment of the present invention.

[0047] In one embodiment, A1 and A2 may be the same or different. Preferably, A1 is n-hexylene and A2 is ethylene (in the compounds shown in formulas I-1, II-1, II-2 and II-3, x is 2 and y is 6).

[0048] In one of the schemes, A1 is C 1-16 Alkylene or C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, such as C 1-16 Alkylene, C 1-6 alkylene-cyclohexyl-C 1-6 Alkylene (e.g., methylene-cyclohexyl-methylene), preferably C 1-16 Alkylene.

[0049] In one of the schemes, A2 is C 1-16 Alkylene, C 6-10 aryl or C 1-6 Alkylene-OC 1-6 Alkylene, such as C 1-16 alkylene, phenylene or C 1-3 Alkylene-OC 1-3 Alkylene, preferably C 1-16 Alkylene.

[0050] In one scheme, the C 1-16 The alkylene group is independently a straight-chain or branched alkylene group, preferably C10. 1-10 Straight-chain or branched alkylene groups, for example, C 1-8 Straight-chain or branched alkylene groups, further for example, C 1-6 Straight-chain or branched alkylene (preferably C14) 1-6 (linear alkylene), further for example, C 1-4 Straight-chain or branched alkylene, wherein C 1-16Further examples of alkylene groups include methylene, ethylene, 1,2-dimethylethylene, n-propylene, 2-methylpropylene, 2,2-dimethylpropylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, neopentylene, tert-pentylene, 1-ethylpropylene, 1,3-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3 -Dimethylbutylene, 2-ethylbutylene, n-heptene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentanediene, 3,3-dimethylpentanediene, 2,3-dimethylpentanediene, 2,4-dimethylpentanediene, 3-ethylpentanediene, 2,2,3-trimethylbutylene, n-hexylene, isohexylene, heptanediene, n-octylene, n-nonylene, n-decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, or hexadecylene, such as ethylene, 1,2-dimethylethylene, n-propylene, 2-methylpropylene, 2,2-dimethylpropylene, 1,3-dimethylpropylene, or n-hexylene.

[0051] In one scheme, the C 1-6 The alkylene group is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, isopentylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, neopentylene, or n-hexylene, for example, methylene, hexylene, or ethylene.

[0052] In one scheme, the C 3-10 The cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, such as 1,3-cyclobutyl, 1,3-cyclopentyl, 1,3-cyclohexyl, and 1,4-cyclohexyl.

[0053] In one embodiment, the 3-10 membered heterocyclic alkyl group can independently be a 3-6 membered heterocyclic alkyl group, the heteroatom can be O, N or S (e.g. O), the number of heteroatoms can be 1 or 2, and it is preferably an epoxyhexyl group (e.g. 2,4-epoxyhexyl group).

[0054] In one scheme, the C 6-10The arylene group is independently arylene or naphthyl; for example, 1,3-phenylene, 1,4-phenylene, or naphthyl.

[0055] In one embodiment, the 5-12-membered heteroaryl group is independently a 5-6-membered monocyclic heteroaryl group or a 7-12-membered naphthocyclic heteroaryl group. The heteroatom can be O, N, or S, and the number of heteroatoms can be one or two, such as pyridyl, furanyl, or thiophene, for example, 3,5-pyridylene, 2,5-furanyl, or 2,5-thiophene.

[0056] In one scheme, the C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene is independently C 1-3 Alkylene-C 3-6 Cycloalkyl-C 1-3 Alkylene, for example, is methylene-1,1-propylidene-methylene, ethylidene-1,1-propylidene-ethylidene, methylene-1,3-butylidene-methylene, ethylidene-1,3-butylidene-ethylidene, methylene-1,3-pentylidene-methylene, ethylidene-1,3-pentylidene-ethylidene, methylene-1,3-hexylidene-methylene, or methylene-1,4-hexylidene-methylene.

[0057] In one scheme, the C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene is independently C 1-3 Alkylene-C 6-10 Aspartic-C 1-3 Alkylenes, such as methylene-1,3-phenyl-methylene, ethylene-1,3-phenyl-ethylene, methylene-1,4-phenyl-methylene, or ethylene-1,4-phenyl-ethylene.

[0058] In one scheme, the C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene is independently C 1-3 alkylene-5-12-membered heteroaryl-C 1-3 Alkylene, such as methylene-3,5-pyridine-methylene or ethylene-3,5-pyridine-ethylene.

[0059] In one scheme, the C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene is independently C 1-3 Alkylene-3-10-membered epoxyalkylene-C 1-3 Alkylenes, such as methylene-3,5-cyclohexylene-methylene and ethylene-3,5-cyclohexylene-ethylene.

[0060] In one scheme, the C 1-6 Alkylene-OC 1-6 Alkylene is independently C 1-3 Alkylene-OC 1-3 Alkylenes, such as methylene-O-methylene or ethylene-O-ethylene.

[0061] In one scheme, the C 1-6 Alkylene-(O-CH2CH2-O) m -C 1-6 Alkylene is C 1-3 Alkylene-(O-CH2CH2-O) m -C 1-3 Alkylene, m being 1-6, for example 1, 2, 3, 4, 5 or 6, further for example methylene-O-CH2CH2-O-methylene, methylene-(O-CH2CH2-O)2-methylene, methylene-(O-CH2CH2-O)3-methylene, methylene-(O-CH2CH2-O)4-methylene, ethylene-O-CH2CH2-O-ethylene, ethylene-(O-CH2CH2-O)2-ethylene, ethylene-(O-CH2CH2-O)3-ethylene or ethylene-(O-CH2CH2-O)4-ethylene.

[0062] In one scheme, the C 2-12 The alkenyl group is a straight-chain or branched C-chain containing one or more carbon-carbon double bonds. 6-12 imidene group, C 4-10 imide or C 2-6 alkenyl groups, such as linear vinylidene (-CH=CH-), linear propeneide (e.g., -CH=CHCH2- or -CH2-CH=CH-), branched propeneide (-C(CH3)=CH-, -CH=C(CH3)-), and branched buteneide (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH 2- , -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH- or -CH2-CH=C(CH3)-) and so on.

[0063] In a certain scheme, the one or more mentioned can be 1, 2, 3, 4, 5 or 6.

[0064] In one embodiment, the halogenation is replaced by a halogen, which is independently F, Cl, or Br, such as F.

[0065] In one scheme, * is used to mark C as the S configuration;

[0066] A1 is C 1-16 Alkylene or C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene;

[0067] A2 is C 1-16 Alkylene, C 6-10 aryl or C 1-6 Alkylene-OC 1-6 Alkylene;

[0068] n represents the degree of polymerization, which ranges from 3 to 50.

[0069] In one scheme, A1 is Propylene or hexylene.

[0070] In one embodiment, A2 is ethylene or vinylene (e.g. ),

[0071] In one embodiment, the polyesteramide compound represented by Formula II has any of the following structures:

[0072] n is as described in any embodiment of the present invention.

[0073] In one embodiment, the polyesteramide compound represented by Formula II has any of the following structures:

[0074] Wherein, * indicates C as S configuration, number average molecular weight is 4000-4200 Da, for example 4136 Da, polydispersity index (PDI) is 1-1.5, for example 1.05; preferably weight average molecular weight is 4200-4400 Da, for example 4356 Da, peak molecular weight is 4100-4300 Da, for example 4203 Da, Z average molecular weight is 4500-4700 Da, for example 4608 Da, Z+1 average molecular weight is 4700-4900 Da, for example 4889 Da;

[0075] Wherein, * indicates C as S configuration, with a number-average molecular weight of 5900-6100 Da, for example 6094 Da, and a polydispersity index (PDI) of 1-1.5, for example 1.38; preferably, a weight-average molecular weight of 8300-8600 Da, for example 8440 Da, a peak molecular weight of 7500-7700 Da, for example 7659 Da, a Z-average molecular weight of 11000-12000 Da, for example 11528 Da, and a Z+1 average molecular weight of 14000-15000 Da, for example 14848 Da;

[0076] Wherein, * indicates C as S configuration, number average molecular weight is 7800-8000 Da, for example 7933 Da, polydispersity index (PDI) is 1-1.5, for example 1.01, preferably weight average molecular weight is 7900-8100 Da, for example 8016 Da, peak molecular weight is 7900-8100 Da, for example 8073 Da, Z average molecular weight is 8000-8200 Da, for example 8099 Da, Z+1 average molecular weight is 8100-8200 Da, for example 8180 Da;

[0077] The * symbol indicates that C is the S configuration, with a number-average molecular weight of 6300-6500 Da, for example 6432 Da, and a polydispersity index (PDI) of 1-1.5, for example 1.06.

[0078] Wherein, * indicates C as S configuration, number average molecular weight is 5700-5900 Da, for example 5850 Da, polydispersity index (PDI) is 1-1.7, for example 1.58, preferably weight average molecular weight is 9100-9300 Da, for example 9254 Da, peak molecular weight is 5200-5400 Da, for example 5301 Da, Z average molecular weight is 14000-16000 Da, for example 14765 Da, Z+1 average molecular weight is 20000-22000 Da, for example 20764 Da;

[0079] Wherein, * indicates C as S configuration, number average molecular weight is 6200-6400 Da, for example 6286 Da, polydispersity index (PDI) is 1-1.5, for example 1.39, preferably weight average molecular weight is 8700-8900 Da, for example 8744 Da, peak molecular weight is 7900-8100 Da, for example 7943 Da, Z average molecular weight is 11000-13000 Da, for example 11947 Da, Z+1 average molecular weight is 14000-16000 Da, for example 15454 Da;

[0080] Preferably, the pharmaceutically acceptable salt is p-toluenesulfonate.

[0081] In this invention, depending on the synthesis process and design route used, the two ends of the polyesteramide compound shown in Formula I are... It can be connected to conventional end groups in the art. The carbonyl end group can be connected to p-nitrophenoxy, amino-alkyl, or alkoxy groups, and the NH end group can be connected to H or carbonyl-alkyl groups.

[0082] In one embodiment, the ocular medication is a liquid preparation, such as eye drops or an injection.

[0083] In one embodiment, the ophthalmic drug used in the application is an ophthalmic drug.

[0084] In one embodiment, the ophthalmic drug is administered via the eye.

[0085] In one embodiment, the polyesteramide compound of Formula I serves as a drug carrier for ocular administration.

[0086] In one embodiment, the ocular administration includes intraconjunctival sac administration, intraocular injection (e.g., intravitreal injection, subretinal injection, or anterior chamber injection), or periocular injection (e.g., subconjunctival injection, subcapsular injection, suprachoroidal injection, subfascial injection, or retrobulbar injection).

[0087] In one embodiment, the topical ocular administration delivers macromolecular biological drugs and small molecule chemical drugs to various ocular surface and intraocular tissues, including the retina, choroid, epithelial tissue, conjunctiva, and corneal tissue, via eye drops.

[0088] In this invention, those skilled in the art can administer the drug according to the condition (e.g., symptom state, location of onset, and disease behavior), including selecting appropriate ocular administration routes, dosages, and intervals. For example, the drug can be administered to the left eye, the right eye, or both eyes simultaneously or at different frequencies, as those skilled in the art can choose according to their needs.

[0089] In one embodiment, the drug further comprises pharmaceutical excipients in the application.

[0090] In one embodiment, the drug further comprises an ophthalmologically active drug. The ophthalmologically active drug includes one or more of small molecule drugs, protein antibodies, or peptides.

[0091] Examples include, but are not limited to, one or more of the following: dry eye treatment agents, glaucoma treatment agents, intraocular pressure lowering agents, vision impairment treatment agents, antibacterial agents, allergic conjunctivitis treatment agents, palpebral conjunctivitis treatment agents, night blindness treatment agents, amblyopia treatment agents, ocular inflammation treatment agents, cataract treatment agents, antiviral agents, mydriatic drugs, carbonic anhydrase inhibitors, and macular degeneration inhibitors.

[0092] Examples include, but are not limited to, one or more combinations of BMP2 drugs, TNIK inhibitors, α2-adrenergic agonists, EGFR antibodies, and anti-VEGF drugs.

[0093] Examples include, but are not limited to, neurotrophic agents (such as growth factors like CNTF, BDNF, and NGF), C-type natriuretic peptide (CNP) compounds, Tie-2 agonists, natriuretic peptide receptor-B (NPR-B) compounds, TNF-α / TNFR inhibitors, or apoptosis signaling fragment inhibitors (FAS) or FAS-ligand (FASL) inhibitors, or one or a combination thereof.

[0094] The α2-adrenergic agonist is, for example, brimonidine tartrate;

[0095] The EGFR antibody is, for example, one or more of cetuximab, nimotuzumab, panitumumab, and nexituzumab;

[0096] The anti-VEGF drug is one or more of the following: a therapeutic antibody (e.g., bevacizumab and / or ranibizumab), a VEGFR-Fc fusion protein (e.g., aflibercept), and a tyrosine kinase inhibitor that blocks the VEGF receptor (VEGF-R) (e.g., sunitinib, axitinib, pazopanib, or combinations thereof);

[0097] The antibacterial agents include one or more of levofloxacin eye drops, tobramycin eye drops, chloramphenicol eye drops, and erythromycin eye ointment;

[0098] The antiviral agents include one or more of acyclovir eye drops and ganciclovir eye drops;

[0099] The intraocular pressure-lowering agent is, for example, brinzolamide eye drops;

[0100] The dry eye treatment agents include one or more of sodium hyaluronate eye drops and pearl eye drops.

[0101] In one embodiment, the ophthalmologically active drug may be one or more of the following: ristatin, timolol, diquafosol, dazolamide, latanoprost, zopostat, levofloxacin, pilocarpine, rebamipide, fenofibrate, olopatadine, fluometabolone, pirenoxine, acyclovir, travoprost, bimatoprost, chondroitin, cyclosporine, polymyxin B, levofloxacin, ofloxacin, tobramycin, moxifloxacin, gatifloxacin, atropine, cyclopentolate, and homatropine, but is not limited thereto.

[0102] In one embodiment, the ophthalmologically active drug may be one or more of BMP2 drugs, brimonidine tartrate, bevacizumab, ranibizumab, aflibercept, cetuximab, nimotuzumab, panitumumab, and nexituzumab, preferably BMP2 drugs or aflibercept.

[0103] In one embodiment, the ophthalmologically active drug in the drug is in a mass ratio of (50-300):1 to the polyesteramide compound of Formula I or its pharmaceutically acceptable salt, for example, 200:1.

[0104] In one embodiment, the drug is used to prevent or treat the following eye diseases, including but not limited to: refractive errors (e.g., myopia, hyperopia, or astigmatism), macular degeneration (such as acute macular degeneration (AMD), including dry AMD, wet AMD, non-exudative AMD, or exudative AMD), neovascularization (e.g., including choroidal neovascularization, treatment failure due to neovascularization such as laser coagulation, failed surgical retinal transplantation), edema (e.g., such as macular edema, cystoid macular edema, or diabetic macular edema), and retinopathy (e.g., including diabetic retinopathy, retinopathy of prematurity, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, or diabetic macular glandular tumors). Examples include neovascularization (e.g., including choroidal neovascularization), refractive errors (e.g., myopia), macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0105] This invention provides a pharmaceutical composition comprising a polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof, and an ophthalmologically active drug. Preferably, the polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof serves as a drug carrier.

[0106] In this invention, the ophthalmologically active drug in the pharmaceutical composition is preferably as described in any embodiment of this invention.

[0107] The pharmaceutical composition is preferably a pharmaceutical composition for the prevention or treatment of eye diseases as described in any embodiment of the present invention. Preferably, the ophthalmologically active drug is BMP2, and the pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of myopia and choroidal neovascularization (CNV). Alternatively, the ophthalmologically active drug is aflibercept, and the pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of choroidal neovascularization (CNV).

[0108] In this invention, the pharmaceutical composition may further comprise pharmaceutical excipients. Preferably, the pharmaceutical composition consists of a polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof, an ophthalmologically active drug, and pharmaceutical excipients.

[0109] In this invention, the pharmaceutical composition is preferably administered ocularly. Examples include intraconjunctival sac administration, intraocular injection (e.g., intravitreal injection, subretinal injection, or anterior chamber injection), or periocular injection (e.g., subconjunctival injection, subcapsular injection, suprachoroidal injection, subfascial injection, or retrobulbar injection).

[0110] In this invention, those skilled in the art can administer the drug according to the condition (e.g., symptom state, location of onset, and disease behavior), including selecting appropriate ocular administration routes, dosages, and intervals. For example, the drug can be administered to the left eye, the right eye, or both eyes simultaneously or at different frequencies, as those skilled in the art can choose according to their needs.

[0111] In this invention, the mass ratio of the ophthalmologically active drug to the polyesteramide compound of Formula I or its pharmaceutically acceptable salt may be (50-300):1, for example 200:1.

[0112] In this invention, the pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I has a polymerizable monomer (repeating unit) that is a compound represented by Formula I-1.

[0113] Where * indicates C as the S configuration;

[0114] M is a pharmaceutically acceptable anion, for example

[0115] x and y are as described in any embodiment of the present invention;

[0116] In the polyesteramide compound of Formula I or its pharmaceutically acceptable salt, the number-average molecular weight of the cation (polyesteramide compound of Formula II) is 2500-10000 Da, for example 4136 Da.

[0117] The polydispersity index of the cation (polyesteramide compound of Formula II) in the polyesteramide compound of Formula I or its pharmaceutically acceptable salt is 1-1.5, for example 1.05.

[0118] In this invention, the pharmaceutical composition preferably comprises a pharmaceutically acceptable salt of the polyesteramide compound shown in Formula I and a drug that is ophthalmologically active.

[0119] The ophthalmologically active drug may be BMP2 and / or aflibercept. Preferably, in the pharmaceutical composition, x is 2, y is 6, and n is 6-20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).

[0120] In this invention, the pharmaceutical composition is preferably prepared by mixing a polyester amide compound of Formula I or a pharmaceutically acceptable salt thereof with an ophthalmologically active drug.

[0121] In one embodiment, the polyesteramide compound represented by Formula I has any of the following structures:

[0122] * C is marked as S configuration; n is as described in any embodiment of the present invention.

[0123] This invention provides a polyesteramide compound of formula I or a pharmaceutically acceptable salt thereof;

[0124] in,

[0125] *C is marked as S configuration, R configuration or a mixture thereof;

[0126] The pharmaceutically acceptable salt is as described in any embodiment of the present invention;

[0127] Molecular weight, polydispersity index, n, A1, and A2 are as described in any embodiment of the present invention;

[0128] Furthermore, the pharmaceutically acceptable salts of the polyesteramide compounds shown in Formula I are not:

[0129] In one embodiment, the pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I is not a p-toluenesulfonate of the following compounds:

[0130] In one embodiment, the pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I is not a p-toluenesulfonate of the following compounds:

[0131] In one embodiment, the polyesteramide compound represented by Formula I is as described in any embodiment of the present invention.

[0132] Optionally, A1 is a methylene group or a branched C group. 2-6 Alkylenes (e.g., 1,2-dimethylethylene, 2-methylpropylene, 2,2-dimethylpropylene, isopropylene, isobutylene, tert-butylene, sec-butylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, neopentylene, tert-pentylene, 1-ethylpropylene, 1,3-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 1,1-dimethylbutylene, 2,2-alkylene) -Dimethylbutylene, 3,3-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n-heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, 2,2,3-trimethylbutylene, isohexylene) or C 7-16 Straight-chain or branched alkylene compounds (e.g., heptylene, n-octylene, n-nonylene, n-decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, or hexadecylene);

[0133] A2 is methylene, or C 3-16 Straight-chain or branched alkylene groups (e.g., 1,2-dimethylethylene, n-propylene, 2-methylpropylene, 2,2-dimethylpropylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, neopentylene, tert-pentylene, 1-ethylpropylene, 1,3-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, ... 1,2-Dimethylbutylene, 1,3-Dimethylbutylene, 2,3-Dimethylbutylene, 2-Ethylbutylene, n-Heptene, 2-Methylhexylene, 3-Methylhexylene, 2,2-Dimethylpentane, 3,3-Dimethylpentane, 2,3-Dimethylpentane, 2,4-Dimethylpentane, 3-Ethylpentane, 2,2,3-Trimethylbutylene, n-Hexylene, Isohexylene, Heptene, n-Octylene, n-Nonylene, n-Decanylene, Undecylene, Dodecylene, Tridecylene, Tetradecylene, Pentadecylene, or Hexadecylene).

[0134] Optionally, A1 and A2 are not both C. 1-16 Alkylene.

[0135] Alternatively, n can be 3-12, such as 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0136] For example, pharmaceutically acceptable salts of the polyesteramide compounds shown in Formula I include any of the following structures and any of the pharmaceutically acceptable anions described in any of the present invention:

[0137] * C is marked as S configuration; n is as described in any embodiment of the present invention.

[0138] This invention provides a polyesteramide composite, wherein the polymeric monomer (repeating unit) is...

[0139] Where * indicates C as the S configuration;

[0140] M is a pharmaceutically acceptable anion, for example

[0141] x is 2, y is 6 or 3;

[0142] The degree of polymerization is 3-12, for example 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0143] This invention provides a polyesteramide composite, wherein the polymeric monomer (repeating unit) is...

[0144] Where * indicates C as the S configuration;

[0145] M is a pharmaceutically acceptable anion, for example

[0146] A1 and A2 are as described in any embodiment of the present invention.

[0147] The degree of polymerization can be 3-12, for example 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0148] Preferably, in the polyesteramide composite, the polyesteramide... The number-average molecular weight is 4136 Da; and / or the polydispersity index of this fraction is 1-1.5, for example 1.05.

[0149] The present invention provides a pharmaceutical composition comprising (1) an ophthalmologically active drug according to any embodiment of the present invention; and (2) a polyesteramide complex or a pharmaceutically acceptable salt thereof, wherein the polyesteramide complex is formed by a polyesteramide compound of formula I according to any embodiment of the present invention and a pharmaceutically acceptable acid according to any embodiment of the present invention.

[0150] Wherein, *, A1, A2, and n are as described in any embodiment of the present invention. Preferably, the pharmaceutical composition further comprises pharmaceutical excipients.

[0151] Preferably, the polyesteramide complex comprises a polyesteramide compound of Formula II as described in any embodiment of the present invention and a pharmaceutically acceptable anion; more preferably, the polyesteramide complex, its molecular weight, and polydispersity index are as described in any embodiment of the present invention.

[0152] The present invention provides applications of the above-mentioned polyesteramide compound complexes, wherein the applications are (1) in the preparation of ocular drugs; (2) in the preparation of ophthalmic drugs; (3) as carriers for ocular drugs; or (4) in ocular drug delivery.

[0153] In one embodiment, the polyesteramide composite is prepared by reacting the compound of formula Ia with the compound of formula Ib in a sulfoxide solvent (e.g., DMSO) in the presence of an organic base (e.g., triethylamine) to obtain the composite.

[0154] *C is marked as S configuration; x, y, n are as described in any embodiment of the present invention.

[0155] The present invention provides a polyesteramide composite, which is prepared by the following method: in a sulfoxide solvent (e.g., DMSO) in the presence of an organic base (e.g., triethylamine), the compound shown in formula Ia above is reacted with the compound shown in formula Ib above to obtain the composite;

[0156] *C is labeled as S configuration; x, y, n are as described in any embodiment of the present invention. Preferably, the polyesteramide composite is as described in any embodiment of the present invention.

[0157] The present invention provides a polyesteramide complex, which is prepared by the following method: in a sulfoxide solvent (e.g., DMSO) in the presence of an organic base (e.g., triethylamine), the compound shown in Formula Ia above is reacted with 2,2'-oxydiester-1,1'-bis(4-nitrophenyl) ester, NSC84146 or p-nitrophenyl isophthalate to obtain the complex;

[0158] *C is labeled as S configuration; x, y, n are as described in any embodiment of the present invention. Preferably, the polyesteramide composite is as described in any embodiment of the present invention.

[0159] This invention provides a polyesteramide composite, which is prepared by the following method: in a sulfoxide solvent (e.g., DMSO) in the presence of an organic base (e.g., triethylamine), di-p-nitrobenzene succinate is reacted with tetra-p-toluenesulfonate of bis(L-arginine)cyclohexane-2-dimethyl ester, or di-p-nitrobenzene succinate is reacted with tetra-p-toluenesulfonate of bis(L-arginine)dimethylpropanediester to obtain the composite; preferably, the polyesteramide composite is as described in any embodiment of this invention.

[0160] In the preparation method, the molar ratio of the compound shown in formula Ia to the compound shown in formula Ib can be 1:1.

[0161] In the preparation method, the reaction can be carried out at 60-80°C, for example, 70°C.

[0162] In the preparation method, the molar volume ratio of the compound represented by formula Ia to the organic base can be 1:(1-3)mol / L, for example, 2mol / L.

[0163] In the preparation method, the molar volume ratio of the compound represented by formula Ia to the sulfoxide solvent can be 1.5:(5-9)mol / L, for example 1.5:7mol / L.

[0164] Terminology definition:

[0165] Unless otherwise stated, the terms used in this application have the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art to which this invention pertains.

[0166] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0167] In this invention, the term "pharmaceutical acceptable" means relatively non-toxic, safe, and suitable for patient use.

[0168] In this invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising a branched or straight chain having a specified number of carbon atoms. For example, "C1-C6 alkyl" is defined as a group comprising 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched structure, specifically including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and tert-hexyl.

[0169] In this invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, including monocyclic cycloalkyl. For example, "cycloalkyl" refers to a cycloalkyl group having 3 to 10 (e.g., 3, 4, 5 or 6) cyclic carbon atoms, including C3, C4, C5 or C6 monocyclic cycloalkyl, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0170] In this invention, the term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-10, 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S), which may be monocyclic. Heterocyclic alkyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms.

[0171] In this invention, the term "heteroaryl" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 5-10, 5-12), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic (e.g., fused rings). When polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. The heteroaryl group is attached to the rest of the molecule via a carbon atom or a heteroatom; the heteroaryl group is attached to the rest of the molecule via a ring with heteroatoms or a ring without heteroatoms.

[0172] In this invention, the term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 14 C6-C 10 An aromatic ring is a ring consisting solely of carbon atoms, which can be monocyclic or polycyclic (e.g., fused rings), and at least one ring is aromatic (following Hückel's rule). The aromatic ring is connected to other segments of the molecule via an aromatic or non-aromatic ring. Aromatic rings include, but are not limited to, benzene rings and naphthalene rings.

[0173] In this invention, the term "alkynyl" refers to a group containing an alkynyl group. It has a branched or straight alkyl group with a specified number of carbon atoms, and the number of alkynyl groups can be one or two, including but not limited to ethynyl groups.

[0174] In this invention, the term "multiple" refers to a natural number greater than 2, such as 2, 3, 4, 5, 6, 7, 8, or 9.

[0175] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0176] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise explicitly stated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0177] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...each / each independently is" used in this application should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently is" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0178] In this invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound of this invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0179] In this invention, the term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions; they are substances included in pharmaceutical preparations other than the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0180] In this application, the term “treatment” means a therapeutic therapy. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the disease or one or more biological manifestations of the condition. Attached Figure Description

[0181] Figure 1 shows the results of a four-week experiment in FDM-modeled guinea pigs after post-ball injection of polyesteramide 1 material loaded with BMP2 drug.

[0182] Figure 2 shows the results of a three-week experiment in FDM-modeled guinea pigs after post-ball injection of polyesteramide 1 material loaded with BMP2 drug.

[0183] Figure 3 shows the results of the binocular refractive difference experiment in FDM model mice after administering polyesteramide 1 material with BMP2 drug via eye drops.

[0184] Figure 4 shows the experimental results of administering BMP2 drug to the polyesteramide 1 material in the eye drops of FDM-modeled guinea pigs.

[0185] Figure 5 shows the NMR spectrum of polyesteramide 1.

[0186] Figure 6 shows the NMR spectrum of polyesteramide 2.

[0187] Figure 7 shows the NMR spectrum of polyesteramide 3.

[0188] Figure 8 shows the NMR spectrum of polyesteramide 4.

[0189] Figure 9 shows the NMR spectrum of polyesteramide 5.

[0190] Figure 10 shows the NMR spectrum of polyesteramide 6.

[0191] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0192] The reagents and raw materials used in this invention are all commercially available.

[0193] The positive and progressive effects of this invention are as follows: the polyesteramide compounds provided by this invention have one or more of the following advantages:

[0194] (1) It enhances the absorption of drugs administered through the eyes and promotes the efficacy of the drug.

[0195] (2) This invention discovers that arginine polyesteramide carriers can be used in intraocular drug delivery systems, filling a research gap in this field. The arginine polyesteramide compounds of this invention are water-soluble and non-immunogenic materials, increasing their biocompatibility. Their binding to the lipid bilayer of the corneal epithelial cell outer membrane loosens the connections between corneal epithelial cells, facilitating drug release and transport to the cornea via the paracellular pathway, overcoming the corneal barrier and increasing corneal permeability, thereby improving the ocular bioavailability of the drug.

[0196] (3) This delivery system effectively delivers drugs into the eye via an arginine-polyesteramide material carrier, improving the bioavailability of the active pharmaceutical ingredient. The novel ocular drug delivery system of this invention makes it possible to effectively deliver drugs into ocular tissues via topical administration over the ocular surface. 1) It prolongs the drug's residence time on the ocular surface; 2) It overcomes multiple ocular drug delivery barriers, enhancing the deep penetration of drugs into multiple tissues; 3) For a longer period, the drug concentration in the target tissue can be maintained above the effective therapeutic concentration. Experimental results demonstrate that, compared to direct application of ocular drugs, the intraocular drug delivery system provided by this invention can successfully deliver drugs that cannot be effectively administered alone into the eye and exhibit good therapeutic effects, or can unexpectedly enhance the therapeutic effect of ocular drugs, which is beneficial for reducing the frequency of administration and improving patient compliance.

[0197] (4) The drug delivery system of the present invention has shown better therapeutic effects than atropine in mouse and guinea pig experiments, and has similar effects when injected and dropped into the eye, and has clinical potential.

[0198] (5) The drug delivery system of the present invention showed superior performance to aflibercept in the intraglobulbar injection of polyester amide material in CNV model mice, demonstrating excellent therapeutic effect and clinical potential. Detailed Implementation

[0199] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0200] Example 1: Synthesis of Polyesteramide 1 (TM01)

[0201] (a) Synthesis of monomer I (p-nitrophenyl dicarboxylic acid ester, N2)

[0202] p-Nitrophenol (0.31 mol) and triethylamine (0.32 mol) were mixed in acetone (300 mL). Succinyl chloride (0.15 mol) was diluted with 100 mL of cold acetone and then added dropwise to the mixed p-nitrophenol / triethylamine solution. The mixture was stirred in an ice-water bath at 0°C for 2 hours. Subsequently, stirring was continued overnight at room temperature. The resulting di-p-nitrophenyl ester precipitate was collected by filtration, thoroughly washed with distilled water, dried under vacuum at room temperature, and recrystallized three times with ethyl acetate to obtain the product.

[0203] (b) Synthesis of monomer II (L-arginine diester p-toluenesulfonate, Arg-6-S)

[0204] In a three-necked flask, L-arginine (0.1 mol), 1,6-hexanediol (0.05 mol), toluene (400 mL), and p-toluenesulfonic acid monohydrate (0.22 mol) were added. The mixture was heated to 130 °C and reacted under reflux for 24 hours. During the reaction, 5.76 mL (0.32 mol) of water was generated and continuously removed. After the reaction was complete, the mixture was cooled to room temperature, and a viscous solid product was separated from the toluene. The crude product was precipitated three times in 2-propanol and dried under vacuum to obtain the final product.

[0205] (c) Synthesis of Compound 1 (Polyesteramide 1 or TM01)

[0206] N2 (1.5 mmol) and Arg-6-S (1.5 mmol) were dissolved in DMSO (7 mL), and triethylamine (3 mL) was added. The reaction mixture was stirred continuously at 70 °C for 24 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and air drying, purified polyesteramide 1 polymer (TM01) was obtained.

[0207] Characterization analysis: The obtained product was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 1 was analyzed by nuclear magnetic resonance spectroscopy (400MHz 1H-NMR, Bruker AM-400). As shown in Figure 5, the structure of the compound was successfully verified by observing the chemical shifts and integrals corresponding to the toluenesulfonate fragments.

[0208] Characterization of arginine-based poly(esteramides) (polyesteramide 1 or TM01): Mn represents the number-average molecular weight (4136 Da), Mw represents the weight-average molecular weight (4356 Da), Mp represents the peak molecular weight (4203 Da), Mz represents the Z-average molecular weight (4608 Da), and Mz+1 represents the Z+1 average molecular weight (4889 Da). The molecular weight of polyesteramide 1 was determined by gel permeation chromatography (GPC, Waters-E2695). The number-average molecular weight (Mn) of polyesteramide 1 is 4136 Da, and its polydispersity index (PDI) is 1.05, indicating that its molecular weight distribution is narrow.

[0209] (d) Synthesis of Compound 2 (Polyesteramide 2 or TM02)

[0210] 0.47 mmol of 2,2'-oxydiester-1,1'-bis(4-nitrophenyl) ester and 0.47 mmol of Arg-6-S were dissolved in 1.04 mL of DMSO, and 0.161 mL of triethylamine was added. The reaction mixture was stirred continuously at 70 °C for 72 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and vacuum drying, purified polyesteramide 2 polymer (TM02) was obtained.

[0211] Characterization analysis: The obtained product was dissolved in deuterium in dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 2 was analyzed by nuclear magnetic resonance spectroscopy (400MHz: 1H-NMR, Bruker AM-400). As shown in Figure 6, the structure of the compound was successfully verified by the observed chemical shifts corresponding to the toluenesulfonate fragments and the 1H-NMR spectrum.

[0212] Characterization of arginine-based poly(esteramide) (polyesteramide 2): The number-average molecular weight (Mn) of TM02 is 6094 Da, and its polydispersity index (PDI) is 1.38. Mw represents the weight-average molecular weight (8440 Da), Mp represents the peak molecular weight (7659 Da), Mz represents the Z-average molecular weight (11528 Da), and Mz+1 represents the Z+1 average molecular weight (14848 Da).

[0213] (e) Synthesis of Compound 3 (Polyesteramide 3 or TM03)

[0214] NSC84146 (0.47 mmol) and Arg-6-S (0.47 mmol) were dissolved in DMSO (1.04 mL), and triethylamine (0.161 mL) was added. The reaction mixture was stirred continuously at 70 °C for 72 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and vacuum drying, purified polyesteramide 3 polymer (TM03) was obtained.

[0215] Characterization analysis: The obtained product was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 3 was analyzed by nuclear magnetic resonance spectroscopy (400MHz: 1H-NMR, Bruker AM-400). As shown in Figure 7, the structure of the compound was successfully verified by the observed chemical shifts corresponding to the toluenesulfonate fragments and the 1H-NMR spectrum.

[0216] Characterization of arginine-based poly(esteramide) (polyesteramide 3): The number-average molecular weight (Mn) of polyesteramide 3 is 7933 Da, and its polydispersity index (PDI) is 1.01. Mw represents the weight-average molecular weight (8016 Da), Mp represents the peak molecular weight (8073 Da), Mz represents the Z-average molecular weight (8099 Da), and Mz+1 represents the Z+1 average molecular weight (8180 Da).

[0217] (f) Synthesis of compound 4 (polyesteramide 4 or TM04)

[0218] Di(p-nitrobenzene) succinate (0.47 mmol) and tetra(p-toluenesulfonate) of bis(L-arginine)cyclohexane dimethyl ester (0.47 mmol) were dissolved in DMSO (1.04 mL), and triethylamine (0.161 mL) was added. The reaction mixture was stirred continuously at 70 °C for 24 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and air drying, purified polyesteramide 4 polymer (TM04) was obtained.

[0219] Characterization analysis: The obtained product was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 4 was analyzed by nuclear magnetic resonance spectroscopy (400MHz: 1H-NMR, Bruker AM-400). As shown in Figure 8, the structure of the compound was successfully verified by the observed chemical shifts corresponding to the toluenesulfonate fragments and the 1H-NMR spectrum.

[0220] Characterization of arginine-based poly(esteramide) (polyesteramide 4 or TM04): Polyesteramide 4 has a number-average molecular weight (Mn) of 6432 Da and a polydispersity index (PDI) of 1.06.

[0221] (g) Synthesis of Compound 5 (Polyesteramide 5 or TM05)

[0222] Di-p-nitrobenzene succinate (1.08 mmol) and tetra-p-toluenesulfonate of bis(L-arginine) dimethyl propylene glycol (1.08 mmol) were dissolved in DMSO (2.4 mL), and triethylamine (0.372 mL) was added. The reaction mixture was stirred continuously at 70 °C for 24 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and air drying, purified polyesteramide 5 polymer (TM05) was obtained.

[0223] Characterization analysis: The obtained product was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 5 was analyzed by nuclear magnetic resonance spectroscopy (400MHz: 1H-NMR, Bruker AM-400). As shown in Figure 9, the structure of the compound was successfully verified by the observed chemical shifts corresponding to the toluenesulfonate fragments and the 1H-NMR spectrum.

[0224] Characterization of arginine-based poly(esteramide) (polyesteramide 5 or TM05): Polyesteramide 5 has a number-average molecular weight (Mn) of 5850 Da and a polydispersity index (PDI) of 1.58. Mw represents the weight-average molecular weight (9254 Da), Mp represents the peak molecular weight (5301 Da), Mz represents the Z-average molecular weight (14765 Da), and Mz+1 represents the Z+1 average molecular weight (20764 Da).

[0225] (h) Synthesis of Compound 6 (Polyesteramide 6 or TM06)

[0226] p-Nitrophenyl isophthalate (0.47 mmol) and Arg-6-S (0.47 mmol) were dissolved in DMSO (1.04 mL), and triethylamine (0.161 mL) was added. The reaction mixture was stirred continuously at 70 °C for 72 hours. After the reaction was completed, the reaction solution was added dropwise to cold ethyl acetate to precipitate the polymer. After three repeated precipitations and vacuum drying, purified polyesteramide 6 polymer (TM06) was obtained.

[0227] Characterization analysis: The obtained product was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) to prepare a sample, and the structure of the obtained polyesteramide 6 was analyzed by nuclear magnetic resonance spectroscopy (400MHz: 1H-NMR, Bruker AM-400). As shown in Figure 10, the structure of the compound was successfully verified by the observed chemical shifts corresponding to the toluenesulfonate fragments and the 1H-NMR spectrum.

[0228] Characterization of arginine-based poly(esteramide) (polyesteramide 6 or TM06): Polyesteramide 6 has a number-average molecular weight (Mn) of 6286 Da and a polydispersity index (PDI) of 1.39. Mw represents the weight-average molecular weight (8744 Da), Mp represents the peak molecular weight (7943 Da), Mz represents the Z-average molecular weight (11947 Da), and Mz+1 represents the Z+1 average molecular weight (15454 Da).

[0229] Example 2

[0230] Polyesteramide 1 with BMP2 inhibits myopia caused by axial elongation.

[0231] To evaluate the delivery effect of the compound material on myopia drugs, a form deprivation myopia (FDM) mouse model and a guinea pig model were established for the experiment.

[0232] 1) FDM modeling

[0233] A self-made, openable, semi-transparent material was affixed to one eye of a mouse / guinea pig to completely cover the eye. An Elizabethan collar was placed around the mouse's neck to prevent the material from loosening or falling off due to scratching. The opposite eye remained normal. Mice were allowed free access to food and water during the modeling period. The modeling cycle lasted 2-4 weeks.

[0234] 2) Drug administration in FDM experiments

[0235] FDM modeling involves administration to the affected eye, but not to the contralateral eye.

[0236] The polyesteramide monotherapy group was diluted to the dosing concentration with PBS. The BMP2 monotherapy group was prepared by dissolving BMP2 powder at 100 μg / mL in 4 mM HCl + 0.1% BSA, and then diluting it to the dosing concentration with PBS. Atropine eye drops were diluted to the dosing concentration with physiological saline. The polyesteramide-loaded group was prepared as follows: Myopia eye drops BMP2 (Recombinant Human BMP-2 Protein, R&D systems, 507-BP-020) were mixed with polyesteramide 1. First, BMP2 powder was dissolved in 4 mM HCl + 0.1% BSA to obtain a 100 μg / mL BMP2 solution. Polyesteramide 1 was diluted with sterile water to 10 mg / mL to obtain a polyesteramide 1 solution. Then, the BMP2 solution and polyesteramide 1 solution were mixed in a specific ratio, resulting in a final BMP2 to polyesteramide 1 mass ratio of 200:1. Administration methods include: 1. Eye drops: Mice receive 10 μl of eye drops once daily in each eye; guinea pigs receive 25 μl of eye drops twice daily in each eye; 2. Retrobulbar injection: Guinea pigs receive 5 μl of eye drops once every three days. For eye drops, open the closable semi-transparent material attached to the eye and drop the drops directly into the eye. After the drops are applied, keep the animal in the eye-drip position for 1 minute to ensure the eyeball is completely moistened with the eye drops. For retrobulbar injection, remove the covering material and reattach it after the injection.

[0237] Method A: Three-week-old guinea pigs were randomly divided into experimental and normal groups, including four groups: FDM group (control group, n=5), FDM+na group (0.05% polyesteramide 1 injected alone, n=5), FDM+Low group (1μg / mL BMP + polyesteramide 1, n=5) and FDM+High group (3μg / mL BMP2 + polyesteramide 1, n=5). The injections were administered retrobulbarly for 1-4 weeks.

[0238] Method B: Three-week-old guinea pigs were randomly divided into experimental and normal groups, including four groups: FDM group + PBS (control group, n=10), FDM+A group (0.05% polyesteramide 1 injected alone, n=10), FDM+B group (drug delivery system blank group, used alone, 6μg / mL BMP2, n=10), FDM+C group (3μg / mL BMP2 + polyesteramide 1, n=20) and FDM+D group (6μg / mL BMP2 + polyesteramide 1, n=10). The drugs were administered via retrobulbar injection for 1-3 weeks.

[0239] Method C: Three-week-old mice were randomly divided into experimental and normal groups, including five groups: N (normal control group, n=8), A (blank group, FDM for 3 weeks, n=10), B (PBS eye drops + FDM for 3 weeks, n=16), C (positive control group, 0.05% atropine eye drops + FDM for 3 weeks, n=18), D (6μg / mL BMP2 + polyesteramide 1 eye drops + FDM for 3 weeks, n=23) and E (drug (6μg / mL BMP2 + polyesteramide 1) retrobulbar injection + FDM for 3 weeks, n=12), administered by eye drops or retrobulbar injection for 3 weeks.

[0240] Method D: Three-week-old guinea pigs were randomly divided into experimental and normal groups, including four groups: Group A (negative control group, PBS eye drops, n=5), Group B (positive control group 1, 0.05% atropine eye drops, n=7), Group C (6μg / mL BMP2 + polyesteramide 1 eye drops, n=7), and Group D (positive control group 2, 0.01% atropine eye drops, n=5). The drugs were administered via eye drops for 1-2 weeks.

[0241] 3) Curvature measurement

[0242] Mouse refractive index measurements were performed twice, at the starting and ending points. Guinea pigs underwent refractive index measurements weekly from the starting point. Refractive index measurements were also performed on the FDM-induced (drug-treated) eye and the contralateral eye. Measurements were performed using a small animal-specific EIR refractive index measuring instrument. After the readings stabilized, three readings were taken, and the average value was used as the final result. The refractive index result used for the final statistical analysis at each time point was the difference between the induced eye and the contralateral eye.

[0243] 4) Axial length measurement

[0244] Axial length measurements were performed twice in mice, at the starting and ending points. In guinea pigs, axial length measurements were performed weekly from the starting point. Axial length measurements were also performed in the FDM-induced (drug-treated) eye and the contralateral eye. Measurements were taken using an OCT scanner to photograph the animals. The specific steps were as follows: First, six interfaces were manually selected: anterior and posterior corneal surfaces, anterior and posterior lens surfaces, and anterior and posterior retinal interfaces. Second, the interface divisions were fine-tuned: the code automatically identified brightness and darkness to generate peak maps, and automatically found the interfaces near the manually selected areas in the previous step. Each interface represents the point of maximum waveform slope, with the lens interface representing the peak. If the automatic identification was inaccurate, manual fine-tuning could be performed. The code then automatically calculated the distances between each interface. If the image quality was low, it was removed from the results. The final axial length result used for each time point was the difference between the induced eye and the contralateral eye.

[0245] Experimental results

[0246] The results of the retrobulbar injection experiment in guinea pigs are shown in Figures 1 and 2. Using method A, in Figure 1, the axial length growth of the group injected alone with polyesteramide 1 (FDM+na) showed no significant difference from that of the FDM model group, and both showed an upward trend, indicating that polyesteramide 1 alone had no effect on axial length growth. However, the 1 μg / mL BMP+polyesteramide 1 (FDM+Low) group and the 3 μg / mL BMP2+polyesteramide 1 (FDM+High) group showed an inhibitory effect on axial length growth, and the 3 μg / mL BMP2+polyesteramide 1 group showed higher axial length growth in weeks 3 and 4 than the low concentration group.

[0247] Using method B, Figure 2 shows the results of further increasing the BMP2 concentration. The results showed that the 6 μg / mL BMP2 + polyesteramide 1 (FDM+D) group was more effective in inhibiting axial elongation than the 3 μg / mL BMP2 + polyesteramide 1 group (FDM+C). Meanwhile, neither the polyesteramide 1 group (FDM+A) nor the 6 μg / mL BMP2 group (FDM+B) showed any inhibitory effect on axial elongation; the inhibitory effect was only observed when BMP2 was mixed with polyesteramide 1, demonstrating that polyesteramide 1 plays a crucial delivery role.

[0248] The results of the mouse ocular or post-bulbar administration experiments are shown in Figures 3 and 4.

[0249] Using method C, the results shown in Figure 3 indicate that after 3 weeks of administration of 6 μg / mL BMP2 + polyesteramide 1 eye drops (group D), the refractive error difference between the two eyes in mice was greater than that in the FDM model group (group A), PBS eye drops group (group B), and 0.05% atropine eye drops group (group C), and was essentially consistent with that in the 6 μg / mL BMP2 + polyesteramide 1 group (group E). These results demonstrate that BMP2 + polyesteramide 1, administered via eye drops or retrobulbar administration, can still inhibit the progression of myopia, and its effect is superior to that of 0.05% atropine.

[0250] Using method D, the results of the guinea pig eye drop experiment are shown in Figure 4. The results showed that after 2 weeks of treatment with 6 μg / mL BMP2 + polyesteramide 1 eye drops (group C in the figure), the refractive error difference between the two eyes was greater in the PBS eye drop group (group A in the figure), the 0.05% atropine eye drop group (group B in the figure), and the 0.01% atropine eye drop group (group D). The trend indicates that BMP2 + polyesteramide 1 has a better inhibitory effect on myopia than atropine. These results, along with the refractive error analysis, demonstrate that BMP2 + polyesteramide 1 eye drops have an inhibitory effect on the development of myopia.

[0251] Example 3

[0252] In Example 3, the polyesteramides are salts of polyesteramide compounds of Formula I of the present invention, namely polyesteramide 1 (TM01), polyesteramide 2 (TM02), polyesteramide 3 (TM03) and polyesteramide 6 (TM06)).

[0253] Polyesteramide nanomaterials with anti-VEGF aflibercept inhibit choroidal angiogenesis.

[0254] To evaluate the delivery effect of polyesteramide on anti-VEGF agents, a form deprivation myopia (FDM) mouse model and a guinea pig model were established for the experiment.

[0255] Fundus neovascularization (CNV) modeling

[0256] After securing the mice, fully expose the eyeballs. Using a Micron IV, observe the retinal images and guide the laser system to perform photocoagulation at four points equidistant from the optic disc in each eye, approximately 1-2 PD away from the optic disc (1120mW power, 70ms duration; laser must be correctly focused at the RPE). Immediately after laser treatment, observe the fundus for any "bubble"-like morphology. If bubbles form after laser irradiation, or the circular boundary of the impact area is unclear, resulting in a hazy appearance (successful impact areas should have clear boundaries and distinct outlines), or if hemorrhage occurs after irradiation, exclude that point. Excessive hemorrhage results in exclusion of that eye. Immediately after laser irradiation, take fundus photographs (using the same instrument), and then perform intravitreal injections.

[0257] Drug administration during retinal neovascularization (CNV) modeling

[0258] Retrobulbar injection: Mice were anesthetized using an isoflurane gas anesthesia machine. The eye patches were removed, and the mice were placed under a surgical microscope for microinjection. Using a microsyringe, the bulbar conjunctiva was punctured, and the drug was slowly injected into the posterior conjunctival muscle cone at a dose of 2 μL / eye. Aflibercept (1 μg / mL) was injected at a dose of 2 μL / eye. Aflibercept was mixed with polyesteramide (polyesteramide 1 (TM01), polyesteramide 2 (TM02), polyesteramide 3 (TM03), or polyesteramide 6 (TM06)) at a mass ratio of 200:1. After injection, an appropriate amount of ofloxacin eye ointment was applied to the ocular surface to prevent infection. Retrobulbar injection: Mice were injected every three days, with 2 μL injected into each eye.

[0259] Topical administration of eye drops: Aflibercept (1 μg / mL) was mixed with polyesteramide (polyesteramide 1 (TM01), polyesteramide 2 (TM01), polyesteramide 3 (TM03), or polyesteramide 6 (TM06)) at a mass ratio of 200:1. Mice were given 10 μL of the aflibercept-polyesteramide mixture once daily at a mass ratio of 200:1 (polyesteramide solution (polyesteramide was diluted with sterile water to 10 mg / mL)). The mixture was administered directly to the eye for one week. After each instillation, the animal was held in the instillation position for one minute to ensure complete saturation of the eyeball. One week later, the inhibitory effect of the drug on angiogenesis was assessed by staining of choroidal angiogenesis.

[0260] Intravitreal injection

[0261] Under a surgical microscope, the mouse eyeballs were exposed for a clear operating field. First, an insulin needle bevel was inserted approximately 0.5 mm behind the corneal limbus to create a tunnel. Then, under direct vision of the surgical microscope, a microinjector was slowly inserted through the tunnel into the vitreous cavity, and the drug was slowly injected. The injection was left in place for 30 seconds. Aflibercept (1 μg / mL) was injected at a dose of 2 μL / eye. 1 μg / mL aflibercept was mixed with polyesteramide (polyesteramide 1 (TM01) solution (polyesteramide was diluted with sterile water to 10 mg / mL)) at a mass ratio of 200:1. Ofloxacin eye ointment was applied after injection. One week later, the inhibitory effect of the drug on angiogenesis was assessed by staining of the choroidal neovascularization.

[0262] Method E: Mice were randomly divided into a positive control group and an experimental group, which included two groups: the aflibercept group (positive control, n=10) and the experimental group: material + aflibercept group (0.05% polyesteramide 1 + aflibercept, n=10), which were injected into the choroid cavity. After one week of continuous administration, the inhibitory effect of the drug on angiogenesis was evaluated by staining of choroidal angiogenesis.

[0263] Method F: Mice were randomly divided into experimental and normal groups, comprising 5 groups in total: PBS retrobulbar injection as a negative control group, aflibercept eye drops group, aflibercept retrobulbar injection group, aflibercept + material eye drops (0.05% polyesteramide 1 + aflibercept, n=10), and aflibercept + material retrobulbar injection group (0.05% polyesteramide 1 + aflibercept, n=10). Each mouse had two eyes, and a maximum of 4 laser points were made in each eye. If bleeding occurred, the laser treatment was discontinued. For example, if a mouse bled after the second laser point, that mouse actually only had 1 sampling point.

[0264] Method G: Mice were randomly divided into 4 control groups and 8 experimental groups. The 4 control groups were: PBS intravitreal injection group (negative control, n=20), aflibercept eye drops group (eye drops control, n=20), aflibercept retrobulbar injection group (retrobulbar control, n=20), and aflibercept intravitreal injection group (positive control, n=20). The 8 experimental groups were: polyesteramide 1 + aflibercept eye drops group (n=10), polyesteramide 1 + aflibercept retrobulbar injection group (n=10), polyesteramide 2 + aflibercept eye drops group (n=10), polyesteramide 2 + aflibercept retrobulbar injection group (n=10), polyesteramide 3 + aflibercept eye drops group (n=10), polyesteramide 3 + aflibercept retrobulbar injection group (n=10), polyesteramide 6 + aflibercept eye drops group (n=10), and polyesteramide 6 + aflibercept retrobulbar injection group (n=10).

[0265] Choroidal slide preparation, staining and photography

[0266] After euthanasia, the eyeballs were removed, excess tissue was removed, and a limbus was punctured and filled with freshly prepared 4% paraformaldehyde for fixation for 1.5 hours. After fixation, the retina was thoroughly removed under a surgical microscope to obtain the RPE-choroid-sclera complex containing the optic cup. After rinsing, 4-5 radial incisions were made centered on the optic disc to facilitate flattening. The complex was then rinsed in PBS and blocked at room temperature for 1 hour in 10% BSA-0.5% Triton X-100 blocking solution. Following blocking, it was incubated overnight with IB4 antibody (1:200 dilution). The next day, the specimen was washed three times with PBS for 10 minutes each time. After washing, the RPE layer was flattened on a glass slide with the slide facing upwards, and anti-fluorescence quenching mounting solution was added for mounting. After the mounting solution solidified, images were taken using a DM4B camera.

[0267] Statistical analysis of neovascularization

[0268] The fluorescence intensity and area of ​​FFA and immunofluorescence staining images were measured using ImageJ software. Intergroup comparisons were performed using Graph Pad Prism software (Graph Pad Software, San Diego, California). Comparisons were performed using unpaired t-tests (normally distributed data with equal standard deviations), Welch-corrected unpaired t-tests (normally distributed data with unequal standard deviations), or Mann-Whitney tests (for data not normally distributed). A p-value <0.05 was considered statistically significant.

[0269] Experimental results

[0270] (1) The experimental results of Method E are shown in Table 1. The experiment showed that the fluorescence intensity and fluorescence area of ​​neovascularization stained by intravitreal injection of polyesteramide 1 + aflibercept (polyesteramide 1 + Aflibercept) were significantly lower than those of aflibercept alone in IB4 staining. This indicates that polyesteramide 1 can enhance the inhibitory effect of aflibercept on neovascularization. The intravitreal injection data showed that aflibercept loaded with polyesteramide 1 nanomaterials was superior to intravitreal aflibercept injection, showing a statistically significant difference.

[0271] Table 1

[0272] (2) In the mouse fundus neovascularization modeling experiment of Method F, the experimental results are shown in Table 2, the results of the neovascularization fluorescence penetration intensity experiment are shown in Table 3, and the results of the neovascularization fluorescence area measurement showed that there was no significant difference between the aflibercept eye drop group and the negative control retrobulbar injection group. The aflibercept retrobulbar injection group was significantly better than the negative control, and its inhibitory effect on neovascularization was comparable to that of the polyesteramide 1 + aflibercept eye drop group (aflibercept + material eye drops). At the same time, the polyesteramide 1 + aflibercept retrobulbar injection group (aflibercept + material retrobulbar injection) was significantly better than the aflibercept retrobulbar injection group, showing a statistically significant difference. PBS retrobulbar injection was used as the negative control group, aflibercept eye drop group, aflibercept retrobulbar injection group, aflibercept + material eye drops (0.05% polyesteramide 1 + aflibercept, n=20), and aflibercept + material injection group (0.05% polyesteramide 1 + aflibercept, n=20).

[0273] Table 2

[0274] Table 3

[0275] In Figure 3-4, * represents the range of p-values ​​in pairwise comparisons: *p≤0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001. * represents the range of p-values ​​in pairwise comparisons between other groups and the model group, and ns indicates that this group is not different from the model group. Statistical data of the experimental results are expressed as mean ± standard error (SEM), and all p-values ​​were generated using a two-tailed Student's t-test.

[0276] (4) The experimental results of method G are shown in Table 4, indicating that the fluorescence intensity and fluorescence area of ​​the intravitreal injection of polyesteramide + aflibercept in IB4 staining of neovascularization were significantly lower than those of the aflibercept alone group. This indicates that polyesteramide can enhance the inhibitory effect of aflibercept on neovascularization. The intravitreal injection data showed that polyesteramide nanomaterials carrying aflibercept were superior to intravitreal aflibercept injection, showing a statistically significant difference.

[0277] In the drug administration experiment following mouse fundus neovascularization modeling, the results are shown in Table 4. The fluorescence penetration intensity of the neovascularization is shown in Table 5. The fluorescence area measurement results of the neovascularization showed no significant difference between the aflibercept eye drop group (eye drop control), the aflibercept retrobulbar injection group (retrobulbar control), and the PBS intravitreal injection group (negative control). The aflibercept intravitreal injection group (positive control) showed significantly better results than the negative control, indicating a statistically significant difference. The polyesteramide 1 (TM01) + aflibercept eye drop group, the polyesteramide 2 (TM02) + aflibercept eye drop group, and the polyesteramide 3 (TM03) + aflibercept eye drop group showed significantly better results than the negative control, indicating a statistically significant difference, and were comparable to the aflibercept intravitreal injection group (positive control). Meanwhile, the effects of the polyesteramide 1 (TM01) + aflibercept postbulbar injection group, the polyesteramide 2 (TM02) + aflibercept postbulbar injection group, and the polyesteramide 3 (TM03) + aflibercept postbulbar injection group were significantly better than those of the aflibercept postbulbar injection group, showing statistically significant differences, and were comparable to those of the aflibercept intravitreal injection group (positive control).

[0278] Table 4

[0279] Table 5

Claims

1. The use of a polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof, said use being (1) in the preparation of ocular medicaments; (2) in the preparation of ophthalmic medicaments; (3) as a carrier for ocular medicaments; or (4) in ocular administration; in, *C is marked as S configuration, R configuration or a mixture thereof; A1 is C 1-16 Alkylene, by one or more R a Replacement C 1-16 Alkylene, C 3-10 Cycloalkylene, 3-10 member heterocycloalkylene, C 6-10 aryl, 5-12 methyl aryl, C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene, C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene, C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene or C 1-6 Alkylene-OC 1-6 Alkylene; in the 3-10 membered heterocyclic alkylene and the 5-12 membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R a Halogens are independent of each other; A2 is C 1-16 Alkylene, C 2-12 imidene group, C 3-10 Cycloalkylene, 3-10 member heterocycloalkylene, C 6-10 aryl, 5-12 methyl aryl, C 1-6 Alkylene-OC 1-6 Alkylene, C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene, C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene, C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene or C 1-6 Alkylene-(O-CH2CH2-O) m -C 1-6 Alkylene, m is 1-6; in the 3-10 membered heterocyclic alkylene and the 5-12 membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; n represents the degree of polymerization, which ranges from 3 to 50.

2. The use of the polyesteramide compound of formula I as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) n is 3-50, for example 3-40, further for example 3-12, preferably n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; (2) *C is marked as S configuration, and the arginine residues in the polyester amide compounds shown in Formula I are L-arginine residues; (3) The pharmaceutically acceptable salt of the polyesteramide compound represented by Formula I comprises the polyesteramide compound represented by Formula I and a pharmaceutically acceptable acid, preferably comprising the polyesteramide compound represented by Formula II and a pharmaceutically acceptable anion: (4) The pharmaceutically acceptable anion is a strong acid anion or an acid radical of Brønsted acid with a pKa of -7 to +5, preferably p-toluenesulfonate ion, chloride ion, bromide ion or methanesulfonate ion. (5) The pharmaceutically acceptable anion is a monovalent anion, and the molar ratio of the anion to the polymer monomer is 2:1; (6) The C 1-16 The alkylene group is independently a straight-chain or branched alkylene group, preferably C10. 1-10 Straight-chain or branched alkylene groups, for example, C 1-6 Straight-chain or branched alkylene groups, further for example, methylene, ethylene, 1,2-dimethylethylene, n-propylene, 2-methylpropylene, 2,2-dimethylpropylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, neopentylene, tert-pentylene, 1-ethylpropylene, 1,3-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene Methylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n-heptene, 2-methylhexane, 3-methylhexane, 2,2-dimethylpentane, 3,3-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutylene, n-hexane, isohexane, heptane, n-octyl, n-nonyl, n-decyl, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, or hexadecylene; (7) The C 3-10 The cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example, 1,3-cyclobutyl, 1,3-cyclopentyl, 1,3-cyclohexyl, and 1,4-cyclohexyl; (8) The 3-10 member heterocyclic alkyl group is independently a 3-6 member heterocyclic alkyl group, the heteroatom is preferably O, N or S, the number of heteroatoms is preferably 1 or 2, and it is preferably a hexylene oxide; (9) The C 6-10 The arylene group is independently arylene or naphthyl; for example, 1,3-phenylene, 1,4-phenylene, or naphthyl; (10) The 5-12 member heteroaryl group is independently a 5-6 member monocyclic heteroaryl group or a 7-12 member denoted cyclic heteroaryl group, the heteroatom is preferably O, N or S, and the number of heteroatoms is preferably 1 or 2, such as pyridyl, furanyl or thiophene, preferably 3,5-pyridylene, 2,5-furanyl, 2,5-thiophene; (11) The C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene is independently C 1-3 Alkylene-C 3-6 Cycloalkyl-C 1-3 Alkylene, for example, is methylene-1,1-propylidene-methylene, ethylidene-1,1-propylidene-ethylidene, methylene-1,3-butylidene-methylene, ethylidene-1,3-butylidene-ethylidene, methylene-1,3-pentylidene-methylene, ethylidene-1,3-pentylidene-ethylidene, methylene-1,3-hexylidene-methylene or methylene-1,4-hexylidene-methylene; (12) The C 1-6 Alkylene-C 6-10 Aspartic-C 1-6 Alkylene is independently C 1-3 Alkylene-C 6-10 Aspartic-C 1-3 Alkylenes, such as methylene-1,3-phenylene-methylene, ethylene-1,3-phenylene-ethylene, methylene-1,4-phenylene-methylene, or ethylene-1,4-phenylene-ethylene; (13) The C 1-6 alkylene-5-12-membered heteroaryl-C 1-6 Alkylene is independently C 1-3 alkylene-5-12-membered heteroaryl-C 1-3 Alkylenes, such as methylene-3,5-pyridine-methylene or ethylene-3,5-pyridine-ethylene; (14) The C 1-6 alkylene-3-10-membered heterocyclic alkylene-C 1-6 Alkylene is independently C 1-3 Alkylene-3-10-membered epoxyalkylene-C 1-3 Alkylenes, such as methylene-3,5-cyclohexylene-methylene and ethylene-3,5-cyclohexylene-ethylene; (15) The C 1-6 Alkylene-OC 1-6 Alkylene is independently C 1-3 Alkylene-OC 1-3 Alkylenes, such as methylene-O-methylene or ethylene-O-ethylene; (16) The C 1-6 Alkylene-(O-CH2CH2-O) m -C 1-6 Alkylene is C 1-3 Alkylene-(O-CH2CH2-O) m -C 1-3 Alkylene, m being 1-6, further for example being methylene-O-CH2CH2-O-methylene, methylene-(O-CH2CH2-O)2-methylene, methylene-(O-CH2CH2-O)3-methylene, methylene-(O-CH2CH2-O)4-methylene, ethylene-O-CH2CH2-O-ethylene, ethylene-(O-CH2CH2-O)2-ethylene, ethylene-(O-CH2CH2-O)3-ethylene or ethylene-(O-CH2CH2-O)4-ethylene; (17) The C 2-12 The alkenyl group is a C-aryl group containing one or more carbon-carbon double bonds or branched groups. 6-12 imidene group, C 4-10 imide or C 2-6 Alkenyl groups, such as linear vinylene, linear propene, or branched propene; further, for example, -C(CH3)=CHCH2-, -CH=C(CH3)CH 2- , -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH- or -CH2-CH=C(CH3)-; (18) The one or more mentioned above refers to 1, 2, 3, 4, 5 or 6; (19) Halogens are independently F, Cl or Br, such as F.

3. The use of the polyesteramide compound of formula I as described in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) The C 1-6 The alkylene group is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, isopentylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, neopentylene, or n-hexylene; (2) The number average molecular weight of the polyester amide compound shown in Formula II is in the range of 2500-20000 Da, for example 2500-10000 Da, preferably 3000-6000 Da, and more preferably 4136 Da. (3) The polydispersity index of the polyesteramide compound shown in Formula II is 1-1.5, for example 1.05; (4) The weight-average molecular weight of the polyester amide compound shown in Formula II is 3000-6000 Da, for example 4356 Da; (5) The peak molecular weight of the polyester amide compound shown in Formula II is 3000-6000 Da, for example 4203 Da; (6) The average molecular weight of the polyester amide compound Z shown in Formula II is 3000-6000 Da, for example 4608 Da; (7) The average molecular weight of the polyester amide compound Z+1 shown in Formula II is 3000-6000 Da, for example 4889 Da; (8) The pharmaceutically acceptable salts of the polyesteramide compounds represented by Formula I are p-toluenesulfonate, hydrochloride, hydrobromide or methanesulfonate; The polyesteramide compounds shown in formula II and (9) are compounds shown in formula II-1 or formula II-2; Where x is an integer from 1 to 9; y is an integer between 2 and 10; *, A1, A2, and n are independently as described in claim 2; Preferably, the polyesteramide compound represented by Formula I is a pharmaceutically acceptable salt, and its repeating unit is a compound represented by Formula I-1; Where * indicates C as the S configuration; M is a pharmaceutically acceptable anion, such as p-toluenesulfonate; x is an integer from 1 to 9; y is an integer from 2 to 10; preferably, x is 2 and y is 6.

4. The use of the polyesteramide compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) The number average molecular weight of the polyester amide compound shown in Formula I is 3000-8000 Da, for example 4136 Da, 6094 Da, 7933 Da, 6432 Da, 5850 Da or 6286 Da. (2) The polydispersity index of the polyester amide compound shown in Formula II is 1-1.8, for example 1.05, 1.38, 1.01, 1.06, 1.58 or 1.39; (3) The weight-average molecular weight of the polyester amide compound shown in Formula II is 3000-10000 Da, for example 4356 Da, 8440 Da, 8016 Da, 9254 Da or 8744 Da; (4) The peak molecular weight of the polyester amide compound shown in Formula II is 3000-8000 Da, for example 4203 Da, 7659 Da, 8073 Da, 5301 Da or 7943 Da; (5) The average molecular weight of the polyester amide compound Z shown in Formula II is 3000-12000 Da, for example 4608 Da, 11528 Da, 8099 Da, 14765 Da or 11947 Da; (6) The average molecular weight of the polyester amide compound Z+1 shown in Formula II is 3000-22000 Da, for example 4889 Da, 14848 Da, 8180 Da, 20764 Da or 15454 Da; (7) A1 is C 1-16 Alkylene or C 1-6 Alkylene-C 3-10 Cycloalkyl-C 1-6 Alkylene, such as C 1-16 Alkylene, C 1-6 alkylene-cyclohexyl-C 1-6 Alkylene, preferably C 1-16 Alkylene; (8) A2 is C 1-16 Alkylene, C 6-10 aryl or C 1-6 Alkylene-OC 1-6 Alkylene, such as C 1-16 alkylene, phenylene or C 1-3 Alkylene-OC 1-3 Alkylene, preferably C 1-16 Alkylene.

5. The use of the polyesteramide compound of formula I as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)A1 is Propylene or hexylene; (2) A2 is ethyl, vinyl, (3) The polyesteramide compounds shown in Formula I have two ends Preferably, the terminal carbonyl group is connected to p-nitrophenoxy, amino-alkyl, or alkoxy groups, and the terminal NH group is connected to H or carbonyl-alkyl groups. (4) In the application described, the ocular medication is a liquid preparation, such as eye drops or injection; (5) In the application described, the ophthalmic drug is an ophthalmic drug; (6) In the application described, the ophthalmic drug is administered via the eye; (7) In the drug, the polyesteramide compound of Formula I serves as a drug carrier for ocular administration; (8) In the application described, the ocular administration includes intraconjunctival sac administration, intraocular injection or periocular injection, the intraocular injection being, for example, intravitreal injection, subretinal injection or anterior chamber injection, the periocular injection being, for example, subconjunctival injection, subcapsular injection, suprachoroidal injection, subfascial injection or retrobulbar injection. Preferably, ocular administration delivers the drug to the surface and intraocular tissues of the eye, including the retina, choroid, epithelial tissue, conjunctiva, and corneal tissue, via eye drops. (9) The drug is administered to the left eye, the right eye, or both eyes. (10) The drug may be administered at the same frequency or at different frequencies; (11) In the application described, the drug further comprises pharmaceutical excipients; (12) In the application, the drug further includes a drug that is active in ophthalmic pharmaceuticals, preferably, the drug that is active in ophthalmic pharmaceuticals includes one or more of small molecule drugs or protein antibodies and peptides; Examples include: dry eye treatment agents, glaucoma treatment agents, intraocular pressure lowering agents, vision impairment treatment agents, antibacterial agents, allergic conjunctivitis treatment agents, palpebral conjunctivitis treatment agents, night blindness treatment agents, amblyopia treatment agents, ocular inflammation treatment agents, cataract treatment agents, antiviral agents, mydriatic drugs, carbonic anhydrase inhibitors, and macular degeneration inhibitors; Examples include one or more of BMP2 drugs, TNIK inhibitors, α2-adrenergic agonists, EGFR antibodies, and anti-VEGF drugs; Examples include one or more of the following: neurotrophic agents, C-type natriuretic peptide compounds, Tie-2 agonists, natriuretic peptide receptor-B compounds, TNF-α / TNFR inhibitors, or apoptosis signaling fragment inhibitors or FAS-ligand inhibitors. The neurotrophic agent is one or more of CNTF, BDNF, and NGF factor; the α2-adrenergic agonist is, for example, brimonidine tartrate; the EGFR antibody is one or more of cetuximab, nimotuzumab, panitumumab, and nexituzumab; the anti-VEGF drug is one or more of a therapeutic antibody, VEGFR-Fc fusion protein, and tyrosine kinase inhibitors that block VEGF receptors; the therapeutic antibody is, for example, bevacizumab and / or ranibizumab; the VEGFR -Fc fusion proteins such as aflibercept; tyrosine kinase inhibitors that block VEGF receptors such as sunitinib, axitinib, and pazopanib, or one or more; antibacterial agents such as levofloxacin eye drops, tobramycin eye drops, chloramphenicol eye drops, and erythromycin eye ointment, or one or more; antiviral agents such as acyclovir eye drops and ganciclovir eye drops, or one or more; intraocular pressure lowering agents such as brinzolamide eye drops; dry eye treatment agents such as sodium hyaluronate eye drops and pearl eye drops, or one or more. Preferably, the ophthalmologically active drug is one or more of the following: ristatin, timolol, diquafosol, dazolamide, latanoprost, zopostatin, levofloxacin, pilocarpine, rebamipide, fenofibrate, olopatadine, fluocinolone, pirenoidin, acyclovir, travoprost, bimatoprost, chondroitin, cyclosporine, polymyxin B, levofloxacin, ofloxacin, tobramycin, moxifloxacin, gatifloxacin, atropine, cyclopentolate, and homatropine. Preferably, the ophthalmologically active drug is one or more of BMP2, brimonidine tartrate, bevacizumab, ranibizumab, aflibercept, cetuximab, nimotuzumab, panitumumab, and nexituzumab, preferably BMP2 or aflibercept. (13) In the drug, the ophthalmologically active drug and the polyesteramide compound of Formula I or its pharmaceutically acceptable salt are in a mass ratio of (50-300):1, for example 200:1; The medicine described in (14) is used to prevent or treat the following eye diseases: refractive errors, macular degeneration, neovascularization, edema, or retinopathy; the refractive errors include myopia, hyperopia, or astigmatism; the macular degeneration includes acute macular degeneration, preferably dry AMD, wet AMD, non-exudative AMD, or exudative AMD; the neovascularization includes choroidal neovascularization, treatment failure caused by neovascularization such as laser coagulation, and failed surgical retinal transplantation; the edema includes macular edema, cystoid macular edema, or diabetic macular edema; the retinopathy includes diabetic retinopathy, retinopathy of prematurity, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, or diabetic macular glandular tumors.

6. The use of the polyesteramide compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The polyesteramide compound represented by Formula I has any of the following structures: *C is marked as S configuration; n is as described in claim 1 or 2; Alternatively, the polyesteramide compound represented by Formula II may have any of the following structures: *C is marked as S configuration; n is as described in claim 1 or 2.

7. The use of the polyesteramide compound of formula I as described in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The polyesteramide compound represented by Formula II has any of the following structures: Wherein, * indicates C as S configuration, number average molecular weight is 4000-4200 Da, for example 4136 Da, polydispersity index is 1-1.5, for example 1.05; preferably weight average molecular weight is 4200-4400 Da, for example 4356 Da, peak molecular weight is 4100-4300 Da, for example 4203 Da, Z average molecular weight is 4500-4700 Da, for example 4608 Da, Z+1 average molecular weight is 4700-4900 Da, for example 4889 Da; Wherein, * indicates C as S configuration, number average molecular weight is 5900-6100 Da, for example 6094 Da, polydispersity index is 1-1.5, for example 1.38; preferably weight average molecular weight is 8300-8600 Da, for example 8440 Da, peak molecular weight is 7500-7700 Da, for example 7659 Da, Z average molecular weight is 11000-12000 Da, for example 11528 Da, Z+1 average molecular weight is 14000-15000 Da, for example 14848 Da; Wherein, * indicates C as S configuration, number average molecular weight is 7800-8000 Da, for example 7933 Da, polydispersity index is 1-1.5, for example 1.01, preferably weight average molecular weight is 7900-8100 Da, for example 8016 Da, peak molecular weight is 7900-8100 Da, for example 8073 Da, Z average molecular weight is 8000-8200 Da, for example 8099 Da, Z+1 average molecular weight is 8100-8200 Da, for example 8180 Da; Wherein, * indicates C is the S configuration, the number average molecular weight is 6300-6500 Da, for example 6432 Da, and its polydispersity index is 1-1.5, for example 1.06; Wherein, * indicates C as S configuration, number average molecular weight is 5700-5900 Da, for example 5850 Da, polydispersity index is 1-1.7, for example 1.58, preferably weight average molecular weight is 9100-9300 Da, for example 9254 Da, peak molecular weight is 5200-5400 Da, for example 5301 Da, Z average molecular weight is 14000-16000 Da, for example 14765 Da, Z+1 average molecular weight is 20000-22000 Da, for example 20764 Da; Wherein, * indicates C as S configuration, number average molecular weight is 6200-6400 Da, for example 6286 Da, polydispersity index is 1-1.5, for example 1.39, preferably weight average molecular weight is 8700-8900 Da, for example 8744 Da, peak molecular weight is 7900-8100 Da, for example 7943 Da, Z average molecular weight is 11000-13000 Da, for example 11947 Da, Z+1 average molecular weight is 14000-16000 Da, for example 15454 Da; Preferably, the pharmaceutically acceptable salt is p-toluenesulfonate, and the molar ratio of p-toluenesulfonic acid to the polymer monomer is 2:

1.

8. A pharmaceutical composition, characterized in that, It comprises a polyesteramide compound of Formula I as described in any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and an ophthalmologically active drug as described in claim 5.

9. The pharmaceutical composition according to claim 8, characterized in that, It satisfies one or more of the following conditions: (1) The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of an eye disease as described in claim 5; Preferably, the ophthalmologically active drug is BMP2, and the drug composition is a drug composition for the prevention or treatment of myopia and choroidal neovascularization; or, the ophthalmologically active drug is aflibercept, and the drug composition is a drug composition for the prevention or treatment of choroidal neovascularization. (2) The pharmaceutical composition further comprises pharmaceutical excipients. Preferably, the pharmaceutical composition consists of a polyester amide compound of Formula I or a pharmaceutically acceptable salt thereof, an ophthalmologically active drug and pharmaceutical excipients. (3) The pharmaceutical composition is administered via the eye; the ocular administration includes, for example, intraconjunctival sac administration, intraocular injection or periocular injection, the intraocular injection includes, for example, intravitreal injection, subretinal injection or anterior chamber injection, the periocular injection includes, for example, subconjunctival injection, subtenonian sac injection, suprachoroidal injection, subfascial injection or retrobulbar injection. Preferably, ocular administration delivers the drug to the surface and intraocular tissues of the eye, including the retina, choroid, epithelial tissue, conjunctiva, and corneal tissue, via eye drops. (4) The pharmaceutical composition is administered via the left eye, the right eye, or both eyes. (5) The drug composition may be administered at the same frequency or at different frequencies; (6) The ophthalmologically active drug and the polyesteramide compound of Formula I or its pharmaceutically acceptable salt are in a mass ratio of (50-300):1, for example 200:1; The pharmaceutical composition described in (7) is prepared by mixing a polyester amide compound of formula I or a pharmaceutically acceptable salt thereof with an ophthalmologically active drug.

10. A polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof; in, Molecular weight, polydispersity index, *, n, A 1 A 2 The polyesteramide compound of Formula I is preferably as described in claim 6; Furthermore, the pharmaceutically acceptable salts of the polyesteramide compounds shown in Formula I are not: For example, pharmaceutically acceptable salts of the polyesteramide compounds represented by Formula I are not p-toluenesulfonates of the following compounds: For example, pharmaceutically acceptable salts of the polyesteramide compounds represented by Formula I are not p-toluenesulfonates of the following compounds: Preferably, the polyesteramide compound of Formula I or a pharmaceutically acceptable salt thereof satisfies any of the following conditions: (1) A1 is a methylene, branched C 2-6 Alkylene or C 7-16 Straight-chain or branched alkylene; or, A2 is methylene or C 3-16 Straight-chain or branched alkylene groups; (2) A1 and A2 are not both C 1-16 Alkylene; (3) n is 3-12, for example 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

11. The polyesteramide compound of formula I as described in claim 10, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts of the polyesteramide compounds represented by Formula I comprise any of the following structures and the pharmaceutically acceptable anion of claim 2: *C is marked as S configuration; n is as described in any one of claims 1-7.

12. A polyesteramide composite, wherein the repeating unit is: in, *C is marked as S configuration; M is a pharmaceutically acceptable anion, such as p-toluenesulfonic acid; A1 and A2 are as described in any one of claims 1-7; The degree of polymerization can be 3-12, for example 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M is a pharmaceutically acceptable anion, such as p-toluenesulfonic acid; Preferably, *C is marked as S configuration; M is a pharmaceutically acceptable anion, such as p-toluenesulfonic acid; x is 2, y is 6 or 3; Its degree of polymerization is 3-12, for example 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Preferably, the number-average molecular weight of the polyesteramide complex, excluding the anionic portion, is 4136 Da; and / or the polydispersity index is 1-1.5, for example 1.

05.

13. A polyesteramide composite, characterized in that, The polyesteramide complex is prepared by the following method: in a sulfoxide solvent, in the presence of an organic base, the compound shown in formula Ia is reacted with the compound shown in formula Ib to obtain the complex. *C is marked as S configuration; x is 2, y is 6 or 3; The reaction preferably satisfies one or more of the following conditions: (1) The molar ratio of the compound shown in formula Ia to the compound shown in formula Ib is 1:1; (2) The reaction is carried out at 60-80°C, for example, 70°C; (3) The molar volume ratio of the compound shown in formula Ia to the organic base is 1:(1-3)mol / L, for example 2mol / L; (4) The molar volume ratio of the compound shown in Formula Ia to the sulfoxide solvent is 1.5:(5-9)mol / L, for example 1.5:7mol / L; (5) The polyesteramide compound is the polyesteramide compound as described in claim 12.

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