Bridge-building PLA system composite structure

Abstract

The embodiments described herein generally relate to compounds comprising allyl lactide residues. One aspect described generally relates to a compound or a pharmaceutically acceptable salt thereof comprising allyl lactide residues and lactide residues and substantially free of valerolactone residues. Another aspect relates to a method of incorporating a drug into a compound, the method comprising: (i) providing a compound or a pharmaceutically acceptable salt thereof comprising allyl lactide residues and lactide residues and substantially free of valerolactone residues; (ii) incubating the compound and the drug in the presence of a solvent for an incubation period to form a drug-loaded compound; and (iii) separating the drug-loaded compound from the solvent. TIFF2023507783000028.tif96170

Description

Technical Field

[0001] Related Application This application claims the priority and benefit of U.S. Provisional Application No. 62 / 950,281, filed December 19, 2019, entitled "CROSSLINKED PLGA-BASED COPOLYMERS", the entire content of which is incorporated herein by reference.

[0002] Field of the Disclosure The present disclosure relates to a compound comprising allyl lactide residues and lactide residues, and substantially free of valerolactone residues. Background Art

[0003] Background Controlling drug release rate is critical to ensuring adequate levels of drug exposure to patients. Achieving sufficient drug exposure requires daily or more frequent administration for many drugs. However, this requirement for frequent administration can affect patient compliance and the required frequency of consumption in many settings. When a drug is delivered via a sustained release mechanism, this can reduce the uncertainty associated with drug delivery to patients and reduce the burden of responsibility on patients. However, current technologies have limitations with respect to controlling drug release rate. Polymer matrices are not sufficiently tunable to release the drug in vivo while controlling the rate to a desired level. Accordingly, new methods and mechanisms for drug release are needed. Summary of the Invention

[0004] Summary The technology disclosed herein enables tunable release of a drug from a compound (e.g., a polymer matrix comprising allyl lactide residues, lactide residues, and optionally glycolide residues). The drug release rate can be controlled by crosslinking density. In some embodiments, the drug release rate can be controlled by the molecular weight of the compound.

[0005] The embodiments described herein generally relate to compounds containing allyl lactide residues. Controllable and predictable drug release rates can be achieved through appropriate compound development, crosslinking density, and residues as disclosed herein. For example, the precision of drug release can be finely tuned for slow, controlled release.

[0006] One aspect of the present invention generally relates to compounds or pharmaceutically acceptable salts thereof that contain allyl lactide residues and lactide residues and substantially do not contain valerolactone residues.

[0007] In some embodiments, the compound may further contain glycolide residues.

[0008] In some embodiments, the compound may include the following structure: TIFF0007924860000001.tif33128In formula, m is an integer between approximately 1 and approximately 1,000; n is an integer between approximately 1 and approximately 1,000; q is an integer between approximately 1 and approximately 100; Here, the compound or its pharmaceutically acceptable salt substantially does not contain a valerolactone residue.

[0009] In some embodiments, the compound may include the following structure: TIFF0007924860000002.tif32128In formula, p is an integer between approximately 1 and approximately 1,000; m is an integer between approximately 1 and approximately 100; n is an integer between approximately 1 and approximately 100; q is an integer between approximately 1 and approximately 100.

[0010] In some embodiments, m can be an integer between approximately 1 and approximately 25.

[0011] In some embodiments, n can be an integer between approximately 1 and approximately 25.

[0012] In some embodiments, m / (m+n) can be approximately 0.01 to 0.99, 0.2 to 0.5, 0.4 to 0.5, 0.1 to 0.19, 0.2 to 0.29, 0.3 to 0.39, 0.4 to 0.49, 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, 0.9 to 0.99, 0.02, 0.06, 0.12, 0.26, or 0.48.

[0013] In some embodiments, m / (m+n+p) can be approximately 0.01 to 0.99, 0.2 to 0.5, 0.4 to 0.5, 0.1 to 0.19, 0.2 to 0.29, 0.3 to 0.39, 0.4 to 0.49, 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, 0.9 to 0.99, 0.02, 0.06, 0.12, 0.26, or 0.48.

[0014] In some embodiments, the residues can form compounds that can be crosslinked with a crosslinking agent.

[0015] In some embodiments, the crosslinking agent may include a thiol moiety. In some embodiments, the crosslinking agent It could be TIFF0007924860000003.tif7128.

[0016] In some embodiments, the compound may be crosslinked by approximately 1% to 99%, approximately 1% to 9%, approximately 10% to 19%, approximately 20% to 29%, approximately 30% to 39%, approximately 40% to 49%, approximately 50% to 59%, approximately 60% to 69%, approximately 70% to 79%, approximately 80% to 89%, approximately 90% to 99%, approximately 2%, approximately 6%, approximately 12%, approximately 26%, and approximately 48%.

[0017] In some embodiments, the compound retains more than 90% of its initial mass after exposure to phosphate buffered saline (PBS) at about 37°C for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days.

[0018] In some embodiments, the PBS comprises about 0.5% by weight of sodium dodecyl sulfate (SDS).

[0019] In some embodiments, the drug is a small molecule drug.

[0020] In some embodiments, the drug is a macromolecular drug.

[0021] In some embodiments, macroparticles comprising any of the above compounds can be formed.

[0022] In some embodiments, microparticles comprising any of the above compounds can be formed.

[0023] In some embodiments, nanoparticles comprising any of the above compounds can be formed.

[0024] Another aspect provides a method of incorporating a drug into a compound, the method comprising (i) providing a compound or a pharmaceutically acceptable salt thereof, which comprises allyl lactide residues and lactide residues and is substantially free of valerolactone residues; (ii) incubating the compound and the drug in the presence of a solvent over an incubation period to form a drug-loaded compound; and (iii) separating the drug-loaded compound from the solvent The present disclosure relates to a method comprising the above steps.

[0025] In some embodiments, the compound may further comprise a glycolic acid residue.

[0026] In some embodiments, the compound may include the following structure: TIFF0007924860000004.tif33128In formula, m is an integer between approximately 1 and approximately 1,000; n is an integer between approximately 1 and approximately 1,000; q is an integer between approximately 1 and approximately 100; Here, the compound or its pharmaceutically acceptable salt substantially does not contain a valerolactone residue.

[0027] In some embodiments, the compound may include the following structure: TIFF0007924860000005.tif32128In formula, p is an integer between approximately 1 and approximately 1,000; m is an integer between approximately 1 and approximately 100; n is an integer between approximately 1 and approximately 100; q is an integer between approximately 1 and approximately 100.

[0028] In some embodiments, m can be an integer between approximately 1 and approximately 25.

[0029] In some embodiments, n can be an integer between approximately 1 and approximately 25.

[0030] In some embodiments, m / (m+n) can be approximately 0.01 to 0.99, 0.2 to 0.5, 0.4 to 0.5, 0.1 to 0.19, 0.2 to 0.29, 0.3 to 0.39, 0.4 to 0.49, 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, 0.9 to 0.99, 0.02, 0.06, 0.12, 0.26, or 0.48.

[0031] In some embodiments, m / (m+n+p) can be approximately 0.01 to 0.99, 0.2 to 0.5, 0.4 to 0.5, 0.1 to 0.19, 0.2 to 0.29, 0.3 to 0.39, 0.4 to 0.49, 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, 0.9 to 0.99, 0.02, 0.06, 0.12, 0.26, or 0.48.

[0032] In some embodiments, the residues can form compounds that can be crosslinked with a crosslinking agent.

[0033] In some embodiments, the crosslinking agent may include a thiol moiety. In some embodiments, the crosslinking agent It could be TIFF0007924860000006.tif7128.

[0034] In some embodiments, the compound may be crosslinked by approximately 1% to 99%, approximately 1% to 9%, approximately 10% to 19%, approximately 20% to 29%, approximately 30% to 39%, approximately 40% to 49%, approximately 50% to 59%, approximately 60% to 69%, approximately 70% to 79%, approximately 80% to 89%, approximately 90% to 99%, approximately 2%, approximately 6%, approximately 12%, approximately 26%, and approximately 48%.

[0035] In some embodiments, the compound retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

[0036] In some embodiments, the aqueous medium may include phosphate-buffered saline (PBS).

[0037] In some embodiments, PBS contains approximately 0.5% by weight of sodium dodecyl sulfate (SDS).

[0038] In some embodiments, the drug may be paclitaxel (PTX), triamcinolone acetonide (TAA), or triamcinolone hexaacetonide (TAH).

[0039] In some embodiments, the method may include a step of forming the drug-supported compound into particles.

[0040] In some embodiments, the particles can be nanoparticles.

[0041] In some embodiments, the particles can be microparticles.

[0042] In some embodiments, particles can be macroparticles.

[0043] In some embodiments, the solvent may include a hydrophobic solvent.

[0044] In some embodiments, the solvent may include a hydrophilic solvent.

[0045] In some embodiments, the solvent may include a hydrophobic solvent, and the drug may be a small molecule drug (e.g., PTX, TAH).

[0046] In some embodiments, the solvent may include a hydrophobic solvent, and the drug may be a macromolecule drug (e.g., an antibody).

[0047] In some embodiments, the solvent may include a hydrophilic solvent, and the drug may be a small molecule drug.

[0048] In some embodiments, the solvent may include a hydrophilic solvent, and the drug may be a macromolecule drug.

[0049] In some embodiments, the solvent may include dichloromethane.

[0050] In some embodiments, the solvent may include water.

[0051] In some embodiments, the solvent may include ethanol.

[0052] In some embodiments, the solvent may include methanol.

[0053] In some embodiments, the solvent may include acetic acid.

[0054] In some embodiments, the solvent may include propanol.

[0055] In some embodiments, the solvent may include carbon tetrachloride.

[0056] In some embodiments, the solvent may include hexane.

[0057] In some embodiments, the solvent may include benzene.

[0058] In some embodiments, the solvent may include tetrahydrofuran (THF).

[0059] In some embodiments, the solvent may include dimethyl sulfoxide (DMSO).

[0060] In some embodiments, the solvent may consist of a mixture of DMSO and THF in a weight ratio of approximately 50:50.

[0061] In some embodiments, the incubation period may be approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days.

[0062] In some embodiments, the drug-carrying compound may contain about 30% to about 50% by weight of the drug.

[0063] In some embodiments, the cumulative release rate of the drug from the drug-supporting compound in an aqueous medium can be about 10% to about 20% by weight over a 35-day period.

[0064] In some embodiments, the aqueous medium may be a solution of PBS and 0.5% SDS.

[0065] In some embodiments, the cumulative release rate of the drug from the drug-supporting compound in an aqueous medium can be about 40% to about 50% by weight over a 60-day period.

[0066] In some embodiments, the aqueous medium may be a solution of PBS and 0.5% SDS.

[0067] In some embodiments, the drug-carrying compound releases approximately 10% or less, approximately 20% or less, approximately 30% or less, approximately 40% or less, approximately 50% or less, approximately 60% or less, or approximately 70% or less of the drug after 30 days.

[0068] Another aspect relates to drug-carrying compounds or pharmaceutically acceptable salts thereof that contain allyl lactide residues and lactide residues, but substantially do not contain valerolactone residues.

[0069] In some embodiments, the drug-carrying compound may contain glycolide residues.

[0070] In some embodiments, the drug-supporting compound may include the following structure: TIFF0007924860000007.tif33128In formula, m is an integer between approximately 1 and approximately 1,000; n is an integer between approximately 1 and approximately 1,000; q is an integer between approximately 1 and approximately 100; Here, the drug-carrying compound or its pharmaceutically acceptable salt substantially does not contain valerolactone residues.

[0071] In some embodiments, the drug-supporting compound may include the following structure: TIFF0007924860000008.tif32128In formula, p is an integer between approximately 1 and approximately 1,000; m is an integer between approximately 1 and approximately 100; n is an integer between approximately 1 and approximately 100; q is an integer between approximately 1 and approximately 100.

[0072] In some embodiments, m can be an integer between approximately 1 and approximately 25.

[0073] In some embodiments, n can be an integer between approximately 1 and approximately 25.

[0074] In some embodiments, m / (m+n) can be approximately 0.01 to 0.99, 0.2 to 0.5, 0.4 to 0.5, 0.1 to 0.19, 0.2 to 0.29, 0.3 to 0.39, 0.4 to 0.49, 0.5 to 0.59, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, or 0.9 to 0.99, 0.02, 0.06, 0.12, 0.26, or 0.48.

[0075] In some embodiments, m / (m+n+p) can be approximately 0.01 to approximately 0.99, approximately 0.2 to approximately 0.5, approximately 0.4 to approximately 0.5, approximately 0.1 to approximately 0.19, approximately 0.2 to approximately 0.29, approximately 0.3 to approximately 0.39, approximately 0.4 to approximately 0.49, approximately 0.5 to approximately 0.59, approximately 0.6 to approximately 0.69, approximately 0.7 to approximately 0.79, approximately 0.8 to approximately 0.89, or approximately 0.9 to approximately 0.99, approximately 0.02, approximately 0.06, approximately 0.12, approximately 0.26, or approximately 0.48.

[0076] In some embodiments, the drug-carrying compound can be crosslinked with a crosslinking agent.

[0077] In some embodiments, the crosslinking agent may include a thiol moiety. In some embodiments, the crosslinking agent It could be TIFF0007924860000009.tif7128.

[0078] In some embodiments, the drug-supported compound may be crosslinked by approximately 1% to approximately 99%, approximately 1% to approximately 9%, approximately 10% to approximately 19%, approximately 20% to approximately 29%, approximately 30% to approximately 39%, approximately 40% to approximately 49%, approximately 50% to approximately 59%, approximately 60% to approximately 69%, approximately 70% to approximately 79%, approximately 80% to approximately 89%, approximately 90% to approximately 99%, approximately 2%, approximately 6%, approximately 12%, approximately 26%, or approximately 48%.

[0079] In some embodiments, the drug-supported compound retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

[0080] In some embodiments, the aqueous medium may include PBS.

[0081] In some embodiments, PBS contains approximately 0.5% by weight of SDS.

[0082] In some embodiments, the drug-supporting compound can be supported within particles.

[0083] In some embodiments, the particles can be nanoparticles.

[0084] In some embodiments, the particles can be microparticles.

[0085] In some embodiments, particles can be macroparticles.

[0086] In some embodiments, a method for performing controlled drug release within a subject may be employed, which includes the step of administering one of the drug-carrying compounds to the subject.

[0087] In some embodiments, the drug may be a small molecule drug.

[0088] In some embodiments, drugs can be macromolecule drugs.

[0089] In some embodiments, the drug may be PTX, TAA, or TAH.

[0090] In some embodiments, the cumulative release rate of the drug from the drug-supporting compound in an aqueous medium can be about 10% to about 20% by weight over a 35-day period.

[0091] In some embodiments, the aqueous medium may be a solution of PBS and 0.5% SDS.

[0092] In some embodiments, the cumulative release rate of the drug from the drug-supporting compound in an aqueous medium can be about 40% to about 50% by weight over a 60-day period.

[0093] In some embodiments, the aqueous medium may be a solution of PBS and 0.5% SDS.

[0094] The compounds, methods, and drug-loading compounds described herein allow for precise control of drug release, enabling fine-tuning for slow, controlled release. The compounds, methods, and drug-loading compounds disclosed herein can improve drug release kinetics, thereby improving compliance with pharmaceutical regulations related to drug delivery. [Invention 1001] Allyl lactide residues; and lactide residues Includes, Substantially free of valerolactone residues, A compound or a pharmaceutically acceptable salt thereof. [Invention 1002] A compound of the present invention 1001, further comprising a glycolide residue. [Invention 1003] Compound 1001 of the present invention, comprising the following structure: TIFF0007924860000010.tif33128 During the ceremony, m is an integer between approximately 1 and approximately 1,000; n is an integer between approximately 1 and approximately 1,000; q is an integer between approximately 1 and approximately 100; Here, the compound or its pharmaceutically acceptable salt substantially does not contain a valerolactone residue. [Invention 1004] Compound 1003 of the present invention having the following structure: TIFF0007924860000011.tif32128 During the ceremony, p is an integer between approximately 1 and approximately 1,000. [Invention 1005] Compounds of the present invention 1003 or 1004, wherein m is an integer from approximately 1 to approximately 100. [Invention 1006] Compounds of the present invention 1003 or 1004, wherein m is an integer from approximately 1 to approximately 25. [Invention 1007] Compounds of the present invention 1003 or 1004, wherein n is an integer from approximately 1 to approximately 100. [Invention 1008] A compound of the present invention 1003 or 1004, wherein n is an integer from approximately 1 to approximately 25. [Invention 1009] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.01 to approximately 0.99. [Invention 1010] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.2 to approximately 0.5. [Invention 1011] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.4 to approximately 0.5. [Invention 1012] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.1 to approximately 0.19. [Invention 1013] Compound 1003 of the present invention, wherein m / (m+n) is approximately 0.2 to approximately 0.29. [Invention 1014] Compound 1003 of the present invention, wherein m / (m+n) is approximately 0.3 to approximately 0.39. [Invention 1015] Compound 1003 of the present invention, wherein m / (m+n) is approximately 0.4 to approximately 0.49. [Invention 1016] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.5 to approximately 0.59. [Invention 1017] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.6 to approximately 0.69. [Invention 1018] Compound 1003 of the present invention, wherein m / (m+n) is approximately 0.7 to approximately 0.79. [Invention 1019] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.8 to approximately 0.89. [Invention 1020] Compound 1003 of the present invention, wherein m / (m+n) is approximately 0.9 to approximately 0.99. [Invention 1021] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.02. [Invention 1022] The compound of the present invention 1003, wherein m / (m+n) is approximately 0.06. [Invention 1023] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.12. [Invention 1024] A compound of the present invention 1003, wherein m / (m+n) is approximately 0.48. [Invention 1025] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.01 to approximately 0.99. [Invention 1026] A compound of the present invention 1004, wherein m / (m+n) is approximately 0.2 to approximately 0.5. [Invention 1027] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.4 to approximately 0.5. [Invention 1028] Compound 1004 of the present invention, wherein m / (m+n+p) is approximately 0.1 to approximately 0.19. [Invention 1029] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.2 to approximately 0.29. [Invention 1030] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.3 to approximately 0.39. [Invention 1031] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.4 to approximately 0.49. [Invention 1032] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.5 to approximately 0.59. [Invention 1033] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.6 to approximately 0.69. [Invention 1034] Compound 1004 of the present invention, wherein m / (m+n+p) is approximately 0.7 to approximately 0.79. [Invention 1035] Compound 1004 of the present invention, wherein m / (m+n+p) is approximately 0.8 to approximately 0.89. [Invention 1036] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.9 to approximately 0.99. [Invention 1037] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.02. [Invention 1038] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.06. [Invention 1039] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.12. [Invention 1040] A compound of the present invention 1004, wherein m / (m+n+p) is approximately 0.48. [Invention 1041] A compound of any of the present invention 1001 to 1004, wherein the aforementioned residue is crosslinked with a crosslinking agent. [Invention 1042] A compound of the present invention 1041, wherein the crosslinking agent contains a thiol moiety. [Invention 1043] The crosslinking agents are as follows: TIFF0007924860000012.tif7128 The compound of the present invention 1042. [Invention 1044] Compound 1041 of the present invention, which is cross-linked by approximately 1% to approximately 99%. [Invention 1045] Compound 1041 of the present invention, which is cross-linked by approximately 1% to approximately 9%. [Invention 1046] Compound 1041 of the present invention, which is cross-linked by approximately 10% to approximately 19%. [Invention 1047] Compound 1041 of the present invention, which is cross-linked by approximately 20% to approximately 29%. [Invention 1048] Compound 1041 of the present invention, which is cross-linked by approximately 30% to 39%. [Invention 1049] Compound 1041 of the present invention, which is cross-linked by approximately 40% to 49%. [Invention 1050] Compound 1041 of the present invention, which is cross-linked by approximately 50% to approximately 59%. [Invention 1051] Compound 1041 of the present invention, which is cross-linked by approximately 60% to 69%. [Invention 1052] Compound 1041 of the present invention, which is cross-linked by approximately 70% to 79%. [Invention 1053] Compound 1041 of the present invention, which is cross-linked by approximately 80% to 89%. [Invention 1054] Compound 1041 of the present invention, which is cross-linked by approximately 90% to 99%. [Invention 1055] A compound of the present invention 1041 that is cross-linked by approximately 2%. [Invention 1056] A compound of the present invention 1041 that is cross-linked by approximately 6%. [Invention 1057] A compound of the present invention 1041 that is cross-linked by approximately 12%. [Invention 1058] A compound of the present invention 1041 that is approximately 48% crosslinked. [Invention 1059] A compound according to any of the present invention 1001 to 1004, which retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for one day. [Invention 1060] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for two days. [Invention 1061] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 3 days. [Invention 1062] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 4 days. [Invention 1063] A compound according to any of the present invention 1001 to 1004, which retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 5 days. [Invention 1064] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 6 days. [Invention 1065] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 7 days. [Invention 1066] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 8 days. [Invention 1067] A compound according to any of the present invention 1001 to 1004, which retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 9 days. [Invention 1068] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 10 days. [Invention 1069] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 11 days. [Invention 1070] Compounds 1001-1004 of the present invention that retain more than 90% of their initial mass after exposure to an aqueous medium at approximately 37°C for 12 days. [Invention 1071] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 13 days. [Invention 1072] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 14 days. [Invention 1073] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 15 days. [Invention 1074] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 16 days. [Invention 1075] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 17 days. [Invention 1076] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 18 days. [Invention 1077] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 19 days. [Invention 1078] A compound according to any of the present invention 1001 to 1004 that retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for 20 days. [Invention 1079] A compound according to any of invention 1045 to 1064, wherein the aqueous medium contains PBS. [Invention 1080] Compound 1079 of the present invention, wherein PBS contains approximately 0.5% by weight of sodium dodecyl sulfate (SDS). [Invention 1081] Macroparticles containing any of the compounds 1001 to 1004 of this invention. [Invention 1082] Microparticles containing any of the compounds described in invention 1001 to 1004. [Invention 1083] Nanoparticles comprising any of the compounds 1001 to 1004 of this invention. [Brief explanation of the drawing]

[0095] The following detailed description of specific aspects of this disclosure will be better understood when read in conjunction with the accompanying drawings. For illustrative purposes, specific aspects are shown in the drawings. However, it should be understood that this disclosure is not limited to the exact configurations and means of the aspects shown in the drawings.

[0096] [Figure 1] NMR data from a polymer containing 12% allyl lactide, referred to herein as PLA-12, are shown. [Figure 2] This shows the degradation rates of various polymers in PBS. [Figure 3] This shows the degradation rates of various polymers in PBS and 0.5% SDS. [Figure 4] This shows the disassembly of a polymer disc over a 60-day period. [Figure 5] This shows the release rates of PTX in various polymers in PBS and 0.5% SDS. [Figure 6] This shows the release rates of TAA in various polymers in PBS and 0.5% SDS. [Figure 7A] This shows the PTX release rate achieved by changing the medium every 3-4 days due to the drug's solubility limit. [Figure 7B] This shows the PTX release rate achieved by changing the medium every 3-4 days due to the drug's solubility limit. [Modes for carrying out the invention]

[0097] Detailed description of the invention This disclosure relates in part to the finding that the crosslinking density of a polymer is directly related to the rate of degradation of the polymer and, consequently, the rate of drug release from the polymer. Drug delivery is a parameter that can be finely and predictably tuned to deliver a pharmaceutical compound in a patient to achieve a desired therapeutic effect. Not only the location in the patient's body, but also the time frame in which the pharmaceutical compound is delivered are important parameters that can be manipulated to achieve a desired therapeutic effect. Often, polymers can be combined with drugs, and the structural properties of the polymer can affect the rate of drug release from the polymer. These structural properties include the type of residue, molecular weight, degree of crosslinking, and several other parameters. Specifically, since the exclusion of valerolactone residues opens the way for finer control of polymer degradation, compounds containing allyl lactide residues, lactide residues, and substantially free of valerolactone residues, or pharmaceutically acceptable salts thereof, may be beneficial for slow drug delivery to a patient. That is, the claimed compound enables a tuneable and predictable degradation and drug release profile as a function of crosslinking density. Controlled drug release may include drug release over a period of at least 30 days. In some embodiments, controlled drug release may involve the release of the drug over a period of less than 30 days (e.g., by a polymer containing lactide and / or glycolide residues).

[0098] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which the invention pertains. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but only exemplary methods and materials are described.

[0099] The following terms used herein have the meanings associated with them in this section.

[0100] As used herein, the articles “a” and “an” are used to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, “an element” means one or more elements.

[0101] The term “about” as used herein when referring to measurable values ​​such as quantity and duration is intended to include variations of ±20% or ±10% (e.g., ±5%; ±1%; and ±0.1%) from a given value, where such variations are appropriate for performing the disclosed method.

[0102] A disease or disorder is considered to be in "remission" when the severity of its symptoms, the frequency with which the patient experiences those symptoms, or both, decreases.

[0103] As used herein, the terms “alkyl,” “alkenyl,” “alkynyl,” and “alkoxy” include both linear and branched groups, as well as both unsubstituted and substituted groups. Optional substituents include, but are not limited to, halogens, C1-C6 alkoxys, CN, OH, NH2, NO2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CONH2, CO(C1-C6 alkyl), SO2NH2, and SO2(C1-C6 alkyl).

[0104] As used herein, the terms “concurrently administered” and “concurrent administration” mean administering to a subject a compound envisioned herein, or a pharmaceutically acceptable salt thereof, together with a compound capable of treating the disorder or disease envisioned herein. In some embodiments, concurrently administered compounds are administered separately as part of a single therapeutic approach. In some embodiments, concurrently administered compounds are administered in any combination as part of a single therapeutic approach. In some embodiments, concurrently administered compounds may be formulated in any combination as a mixture of solids and liquids based on various solid formulations, gel formulations, and liquid formulations, and / or as solutions.

[0105] As used herein, the terms “composition” or “pharmaceutical composition” mean a mixture of at least one compound as envisioned herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to a patient or subject. Multiple techniques exist in the art for administering compounds, including but not limited to intravenous, oral, aerosol, parenteral, intraocular, nasal, intrapulmonary, and topical administration.

[0106] The term “container” includes any container for holding a pharmaceutical composition or for adding protective effects that control stability and / or moisture absorption. For example, in some embodiments, a container is packaging that contains a pharmaceutical composition, e.g., a liquid (solution or suspension); a semi-solid; a lyophilized solid; or a solution, powder, or lyophilized preparation present in a double chamber. In some embodiments, a container is not packaging that contains a pharmaceutical composition; i.e., a container is a box or vial or similar container that contains a packaged or unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. In some embodiments, packaging techniques are well known in the art. Instructions for use of a pharmaceutical composition may be included on the packaging containing the pharmaceutical composition, thereby increasing the functional relationship between the instructions and the packaged product. However, it should be understood that the instructions may include information regarding the compound’s ability to perform a desired function, e.g., its ability to treat, prevent, or reduce respiratory distress in a patient.

[0107] As used herein, "disease" refers to a health condition in which the subject is unable to maintain homeostasis, and whose health will continue to deteriorate unless the disease goes into remission.

[0108] As used herein, “disorder” in relation to an object means a health condition in which the object is able to maintain homeostasis, but whose health condition is less desirable than that in the absence of the disorder. Leaving the disorder untreated does not necessarily lead to a further deterioration of the object’s health condition.

[0109] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” mean an amount of compound or agent that is non-toxic but sufficient to obtain the desired biological effect. The effect may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. The appropriate therapeutic dose in any individual case can be determined by a person skilled in the art using routine experiments. Therapeutic effect or improvement is not necessarily the complete disappearance of any one, most, or all symptoms, complications, consequences, or underlying causes associated with the disorder or disease. Therefore, in some embodiments, a favorable endpoint is achieved when the condition in question is temporarily, medium-term, or gradually improved over a period of time (e.g., hours, days, weeks, months, or years), or when the occurrence, frequency, severity, progression, or duration of one or more associated adverse symptoms, complications, consequences, or underlying causes, exacerbations, or progressions of the disorder or disease is partially reduced, inhibited, or reversed (e.g., one or more symptoms or complications of the condition, disorder, or disease stabilize).

[0110] As used herein, “instructional materials” include publications, records, diagrams, or any other expressive media available for use in the kit to communicate the usefulness of the compositions and / or compounds envisioned herein. The kit’s instructional materials may, for example, be attached to the container containing the compositions and / or compounds envisioned herein. The kit’s instructional materials may, for example, be transported together with the container containing the compositions and / or compounds. The instructional materials may be transported separately from the container, with the intention that the recipient use the instructional materials and compounds together. Transport of the instructional materials may be, for example, by physical transport of publications or other expressive media communicating the usefulness of the kit, or it may be carried out by electronic transmission, for example by computer, such as email, or by download from a website.

[0111] As used herein, “likelihood,” “likely to,” and similar terms generally mean an increase in the probability of an event. Therefore, when used in relation to responsiveness to cancer treatment, “likelihood,” “likely to,” and similar terms assume an increase in the probability that an individual will show a reduction in the severity or symptoms of cancer, or a delay or slowing of cancer progression. When used in relation to responsiveness to cancer treatment, “likelihood,” “likely to,” and similar terms may also mean an increase in indicators that may be evidence that the cancer is responsive to treatment.

[0112] The terms “patient,” “subject,” or “individual” are used interchangeably herein and mean any animal or its cells, whether in vitro or in situ, to which the methods herein are permitted. In some embodiments, the subject is a patient. In some embodiments, the patient is an animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the subject is a subject requiring treatment.

[0113] As used herein, “particle” means a small part of a substance. “Nanoparticle” means a particle with an average size of approximately 1 nm to approximately 999 nm. “Microparticle” means a particle with an average size of approximately 1 μm to approximately 999 μm. “Macroparticle” means a particle with an average size of approximately 1 mm to approximately 15 cm. As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not inhibit the biological activity or biological properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or harmful interactions with any components of the composition contained in the composition.

[0114] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting the compound disclosed herein. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting the compound disclosed herein to its target so that it can perform its intended function. In some embodiments, these constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of a formulation containing the compound disclosed herein and is not harmful to the patient. In some embodiments, examples of materials that can serve as pharmaceutically acceptable carriers include sugars (e.g., lactose, glucose, and sucrose); starches (e.g., corn starch and potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository wax; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols (e.g., propylene glycol); polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol hereafter referred to as "PEG"); esters (e.g., ethyl oleate and ethyl laurate); agar; buffers (e.g., magnesium hydroxide and aluminum hydroxide); surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic and suitable substances used in pharmaceutical formulations.

[0115] As used herein, “pharmaceutically acceptable carriers” include, for example, coatings, antimicrobial and antifungal agents, and absorption retarders that are compatible with the activity and suitability of the compounds disclosed herein and are physiologically acceptable to patients. Supplementary active compounds may be incorporated into the composition.

[0116] "Pharmacologically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional components that may be included in the pharmaceutical compositions disclosed herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0117] As used herein, the term “pharmaceutically acceptable salt” means a salt, solvate, hydrate, or clathrate of the compounds of this disclosure, prepared, for example, from a pharmaceutically acceptable, non-toxic acid, including inorganic acids and organic acids.

[0118] As used herein, the terms “prevent,” “prevent,” or “prevention” mean to avoid or delay the onset of symptoms associated with a disease or condition in a subject who does not have such symptoms at the time administration of the agent or compound is initiated.

[0119] As used herein, the term “prodrug” means a compound that, after administration, is metabolized or otherwise converted into a compound (e.g., a drug) that is biologically active or more active in at least one property. A prodrug is a drug that has been chemically modified to be less active or inactive than the drug, such that the corresponding drug is produced by metabolic or other biological processes after the prodrug is administered. Prodrugs may have altered metabolic stability, altered transportability, fewer side effects, lower toxicity, or improved flavor compared to the active drug (see, for example, Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388–392, incorporated herein by reference). Prodrugs can be synthesized using reactants other than the corresponding compound (e.g., the drug).

[0120] A "therapeutic" treatment is a procedure performed on an individual exhibiting signs of a disease with the aim of reducing or eliminating those signs.

[0121] When used in reference to a treatment, the terms “responsiveness” or “responsive” mean the degree of effectiveness of the treatment in reducing or diminishing the symptoms of the disease, disorder, or condition being treated. For example, when used in reference to the treatment of cells or subjects, the term “increased responsiveness” means an increase in effectiveness in reducing or diminishing the symptoms of the disease, as measured using any method known in the art. In some embodiments, the increase in effectiveness is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.

[0122] As used herein, the terms “treatment” or “to treat” are defined as a therapeutic agent applied to, cured, alleviated, mitigated, altered, remedyed, reduced, improved or affected by, a therapeutic agent applied to, or administered to, a subject capable of developing, a therapeutic agent, i.e., a compound disclosed herein (alone or in combination with another pharmaceutical agent), or applied to, or administered to, a tissue or cell line isolated from such subject (e.g., for diagnostic or ex vivo purposes). In some embodiments, the terms “treatment” or “to treat” are defined as a therapeutic agent to an object having the condition or symptoms of the condition as described herein, i.e., the application or administration (alone or in combination with another pharmaceutical agent) of the compounds disclosed herein, for the purpose of curing, healing, reducing, mitigating, altering, remedying, improving, or influencing the condition, symptoms of the condition as described herein, or the possibility of causing the condition as described herein, or the application or administration of the therapeutic agent to tissue or cell lines isolated from such object (e.g., for diagnostic or ex vivo use). In some embodiments, the terms “treatment” or “treatment” are defined as a therapeutic agent, i.e., the application or administration (alone or in combination with another pharmaceutical agent) to a subject having the condition, symptoms of the condition, or the condition described herein, for the purpose of reducing, mitigating, altering, remedying, improving or influencing the condition, symptoms of the condition described herein, or the possibility of causing the condition described herein, or the application or administration (e.g., for diagnostic or ex vivo purposes) of a therapeutic agent to tissue or cell lines isolated from such subject.These measures can be specifically adjusted or modified based on knowledge gained from the field of pharmacological genomics.

[0123] In some embodiments, the term “treatment” or “treatment” means an action that occurs while an individual is suffering from a particular disease that reduces the severity or symptoms of the disease and / or slows or slows the progression of the disease. For example, in some embodiments, “treatment” or “treatment” means a reduction of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the rate of disease progression. In some aspects, “treatment” means a reduction of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of any physical symptom of the disease. In some embodiments, “treatment” means an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the overall health of the individual, as determined by any preferred means, e.g., cell count, assay results, or other preferred means.

[0124] Throughout this disclosure, various aspects of the disclosure can be presented in the form of scope. It should be understood that descriptions in the form of scope are for convenience and conciseness only and should not be interpreted as rigid limitations on the disclosures herein. Accordingly, scope descriptions should be considered as specifically disclosing all possible sub-scopes and the individual numbers within those scopes. For example, a scope description such as about 1 to about 6 should be considered as specifically disclosing sub-scopes such as about 1 to about 3, about 1 to about 4, about 1 to about 5, about 2 to about 4, about 2 to about 6, about 3 to about 6, and the individual numbers within those scopes, such as about 1, about 2, about 2.7, about 3, about 4, about 5, about 5.1, about 5.3, about 5.5, and about 6. Therefore, for example, references to the 90-100% range include approximately 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91-94%, 91-93%, etc. References to the 90-100% range also include approximately 91%, 92%, 93%, 94%, 95%, 96%, 97%, etc., as well as approximately 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., and approximately 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc. A range is disclosed throughout this disclosure. Use of a range includes combinations of high and low ranges that represent different ranges. This interpretation applies in all contexts throughout this disclosure, regardless of the width of the range. Therefore, for example, references to ranges such as 5-10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, and 100-150 include ranges such as 5-20, 5-30, 5-40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, and 20-150. This applies regardless of the width of the range.

[0125] Polymers containing allyl-lactide residues and lactide residues The embodiments described herein generally relate to compounds comprising lactide residues and allyl lactide residues and substantially free of valerolactone residues, methods for producing such compounds, methods for supporting drugs in such compounds, and drug-supported compounds comprising lactide residues and allyl lactide residues and substantially free of valerolactone residues. One aspect of the present invention generally relates to compounds comprising allyl lactide residues and lactide residues and substantially free of valerolactone residues, or pharmaceutically acceptable salts thereof. Technical advantages of compounds comprising allyl lactide residues and lactide residues and substantially free of valerolactone residues include, but are not limited to, fine control of crosslinking density, fine control of compound degradation, and fine control of the drug release rate contained in the compound. The drug release rate from the polymer is a function of crosslinking density. Compound degradation is also a function of crosslinking density. Since allyl groups are often the primary sites that react with crosslinking agents, the crosslinking density can correlate with the proportion of allyls.

[0126] In some embodiments, the compound may contain a glycolide residue. In some embodiments, the compound may contain a PEG residue. In some embodiments, the compound may contain a benzyl residue. In some embodiments, benzene can be used as an initiator. In some embodiments, the compound may contain a benzyl residue and a PEG residue. In some embodiments, the compound may contain a glycolide residue and a PEG residue. In some embodiments, the compound may contain a glycolide residue and a benzyl residue. In some embodiments, the compound may contain a glycolide residue, a PEG residue, and a benzyl residue. In some embodiments, the compound may not contain a benzyl residue.

[0127] In some embodiments, a catalyst can be used to produce the compound. In some embodiments, the catalyst may be a tin-based catalyst. In some embodiments, the catalyst may include tin(II) trifluoromethanesulfonate. In some embodiments, the catalyst may include 4-dimethylaminopyridine (DMAP). In some embodiments, the compound can be produced without the use of a catalyst.

[0128] In some embodiments, the compound may contain lactide residues in amounts of about 1% to about 99% by weight, about 1% to about 9% by weight, about 10% to about 19% by weight, about 20% to about 29% by weight, about 30% to about 39% by weight, about 40% to about 49% by weight, about 50% to about 59% by weight, about 60% to about 69% by weight, about 70% to about 79% by weight, about 80% to about 89% by weight, about 90% to about 99% by weight, or about 100% by weight of lactide residues. These include all values ​​and ranges between the two ends.

[0129] In some embodiments, the compound may contain about 1% to about 100% by weight, about 1% to about 99% by weight, about 1% to about 9% by weight, about 10% to about 19% by weight, about 20% to about 29% by weight, about 30% to about 39% by weight, about 40% to about 49% by weight, about 50% to about 59% by weight, about 60% to about 69% by weight, about 70% to about 79% by weight, about 80% to about 89% by weight, about 90% to about 99% by weight of allyl-lactide residues, about 100% by weight of allyl-lactide residues, about 2% by weight of allyl-lactide residues, about 6% by weight of allyl-lactide residues, about 12% by weight of allyl-lactide residues, about 26% by weight of allyl-lactide residues, or about 48% by weight of allyl-lactide residues. These include all values ​​and ranges between the two ends.

[0130] In some embodiments, the compound may contain glycolide residues in amounts of about 1% to about 99% by weight, about 1% to about 9% by weight, about 10% to about 19% by weight, about 20% to about 29% by weight, about 30% to about 39% by weight, about 40% to about 49% by weight, about 50% to about 59% by weight, about 60% to about 69% by weight, about 70% to about 79% by weight, about 80% to about 89% by weight, or about 90% to about 99% by weight. These include all values ​​and ranges between the two ends.

[0131] In some embodiments, the compound may contain PEG residues in amounts of about 1% to about 99% by weight, about 1% to about 9% by weight, about 10% to about 19% by weight, about 20% to about 29% by weight, about 30% to about 39% by weight, about 40% to about 49% by weight, about 50% to about 59% by weight, about 60% to about 69% by weight, about 70% to about 79% by weight, about 80% to about 89% by weight, or about 90% to about 99% by weight. These include all values ​​and ranges between the two ends.

[0132] In some embodiments, the compound may contain benzyl residues in amounts of about 1% to about 99% by weight, about 1% to about 9% by weight, about 10% to about 19% by weight, about 20% to about 29% by weight, about 30% to about 39% by weight, about 40% to about 49% by weight, about 50% to about 59% by weight, about 60% to about 69% by weight, about 70% to about 79% by weight, about 80% to about 89% by weight, or about 90% to about 99% by weight, encompassing all values ​​and ranges between the two ends.

[0133] In some embodiments, the compound may have the following structure. TIFF0007924860000013.tif33128

[0134] In some embodiments, m can be an integer between approximately 1 and 1,000, approximately 1 and 900, approximately 1 and 800, approximately 1 and 700, approximately 1 and 600, approximately 1 and 500, approximately 1 and 400, approximately 1 and 300, approximately 1 and 200, approximately 1 and 100, approximately 1 and 75, approximately 1 and 50, approximately 1 and 25, approximately 1 and 20, approximately 1 and 15, approximately 5 and 15, approximately 10 and 15, approximately 10 and 20, approximately 1 and 10, approximately 5 and 10, approximately 20 and 25, approximately 20 and 30, approximately 25 and 30, or approximately 15 and 20. These include all values ​​and ranges between the two ends.

[0135] In some aspects, n is approximately 0 to approximately 1,000, approximately 1 to approximately 1,000, approximately 1 to approximately 900, approximately 1 to approximately 800, approximately 1 to approximately 700, approximately 1 to approximately 600, approximately 1 to approximately 500, approximately 1 to approximately 400, approximately 1 to approximately 300, approximately 1 to approximately 200, approximately 1 to approximately 100, approximately 1 to approximately 75, approximately 1 to approximately 50, approximately 1 to approximately 25, approximately 100 to approximately 900, approximately 100 to approximately 800, approximately 100 to approximately 700, approximately 100 to approximately 600, approximately 100 to approximately 500, approximately 100 to approximately 4 It can be an integer between 00, approximately 100-300, approximately 100-200, approximately 100-150, approximately 150-200, approximately 200-250, approximately 200-225, approximately 125-150, approximately 150-175, approximately 140-150, approximately 135-145, approximately 135-140, approximately 140-145, approximately 50-75, approximately 50-60, approximately 55-60, approximately 60-65, approximately 65-70, or approximately 65-75. These include all values ​​and ranges between the two ends.

[0136] In some embodiments, q can be an integer between approximately 1 and approximately 1,000, approximately 1 and approximately 900, approximately 1 and approximately 800, approximately 1 and approximately 700, approximately 1 and approximately 600, approximately 1 and approximately 500, approximately 1 and approximately 400, approximately 1 and approximately 300, approximately 1 and approximately 200, approximately 1 and approximately 100, approximately 1 and approximately 75, approximately 1 and approximately 50, approximately 1 and approximately 25, approximately 1 and approximately 15, approximately 1 and approximately 10, approximately 9, approximately 8, approximately 7, approximately 6, approximately 5, approximately 4, approximately 3, approximately 2, or approximately 1. These include all values ​​and ranges between the two ends.

[0137] In some embodiments, the compound may have the following structure. TIFF0007924860000014.tif32128

[0138] In some embodiments, m can be an integer between approximately 1 and 1,000, approximately 1 and 900, approximately 1 and 800, approximately 1 and 700, approximately 1 and 600, approximately 1 and 500, approximately 1 and 400, approximately 1 and 300, approximately 1 and 200, approximately 1 and 100, approximately 1 and 75, approximately 1 and 50, approximately 1 and 25, approximately 1 and 20, approximately 1 and 15, approximately 5 and 15, approximately 10 and 15, approximately 10 and 20, or approximately 15 and 20. These include all values ​​and ranges between the two ends.

[0139] In some aspects, n is approximately 1 to 1,000, approximately 1 to 900, approximately 1 to 800, approximately 1 to 700, approximately 1 to 600, approximately 1 to 500, approximately 1 to 400, approximately 1 to 300, approximately 1 to 200, approximately 1 to 100, approximately 1 to 75, approximately 1 to 50, approximately 1 to 25, approximately 100 to 900, approximately 100 to 800, and approximately 100 to 70. It can be an integer between 0, approximately 100-600, approximately 100-500, approximately 100-400, approximately 100-300, approximately 100-200, approximately 100-150, approximately 150-200, approximately 125-150, approximately 150-175, approximately 140-150, approximately 135-145, approximately 135-140, or approximately 140-145. These include all values ​​and ranges between the two ends.

[0140] In some embodiments, p can be an integer between approximately 1 and approximately 1,000, approximately 1 and approximately 900, approximately 1 and approximately 800, approximately 1 and approximately 700, approximately 1 and approximately 600, approximately 1 and approximately 500, approximately 1 and approximately 400, approximately 1 and approximately 300, approximately 1 and approximately 200, approximately 1 and approximately 100, approximately 1 and approximately 75, approximately 1 and approximately 50, approximately 1 and approximately 25, approximately 25 and approximately 1,000, approximately 25 and approximately 900, approximately 25 and approximately 800, approximately 25 and approximately 700, approximately 25 and approximately 600, approximately 25 and approximately 500, approximately 25 and approximately 40, approximately 30 and approximately 40, approximately 30 and approximately 35, or approximately 35 and approximately 40. These include all values ​​and ranges between the two ends.

[0141] In some embodiments, p can be an integer between approximately 1 and 1,000, approximately 1 and 900, approximately 1 and 800, approximately 1 and 700, approximately 1 and 600, approximately 1 and 500, approximately 1 and 400, approximately 1 and 300, approximately 1 and 200, approximately 1 and 100, approximately 1 and 75, approximately 1 and 50, approximately 1 and 25, approximately 1 and 15, approximately 1 and 10, approximately 9, approximately 8, approximately 7, approximately 6, approximately 5, approximately 4, approximately 3, approximately 2, and approximately 1. These include all values ​​and ranges between the two ends.

[0142] In some aspects, q can be an integer between approximately 1 and 1,000, 1 and 900, 1 and 800, 1 and 700, 1 and 600, 1 and 500, 1 and 400, 1 and 300, 1 and 200, 1 and 100, 1 and 75, 1 and 50, 1 and 25, 1 and 15, 1 and 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1. These include all values ​​and ranges between the two ends.

[0143] In some aspects, m / (m+n) can be approximately 0.01 to 1, approximately 0.01 to 0.99, approximately 0.2 to 0.5, approximately 0.4 to 0.5, approximately 0.1 to 0.19, approximately 0.2 to 0.29, approximately 0.3 to 0.39, approximately 0.4 to 0.49, approximately 0.5 to 0.59, approximately 0.6 to 0.69, approximately 0.7 to 0.79, approximately 0.8 to 0.89, and approximately 0.9 to 0.99. These include all values ​​and ranges between the two extremes.

[0144] In some embodiments, m / (m+n+p) can be approximately 0.01 to 1, approximately 0.01 to 0.99, approximately 0.2 to 0.5, approximately 0.4 to 0.5, approximately 0.1 to 0.19, approximately 0.2 to 0.29, approximately 0.3 to 0.39, approximately 0.4 to 0.49, approximately 0.5 to 0.59, approximately 0.6 to 0.69, approximately 0.7 to 0.79, approximately 0.8 to 0.89, and approximately 0.9 to 0.99. These include all values ​​and ranges between the two extremes.

[0145] In some embodiments, the compound may be crosslinked. In some embodiments, the compound may contain a crosslinkable compound. In some embodiments, residues of the compound may be crosslinked with a crosslinking agent. In some embodiments, the crosslinking agent may contain a thiol moiety. In some embodiments, the crosslinking agent may have the following structure. TIFF0007924860000015.tif11128

[0146] In some embodiments, f can be approximately 0, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 15, approximately 20, approximately 25, and approximately 30. These include all values ​​and ranges between the two ends.

[0147] In some aspects, the crosslinking agent may be a cleavable crosslinking agent. In some aspects, the crosslinking agent may comprise PEG.

[0148] In some aspects, the crosslinking agent may have the structure below. TIFF0007924860000016.tif76128

[0149] In some aspects, the polymer backbones can be linked by a plurality of crosslinking agents.

[0150] In some aspects, p may be an integer from about 0 to about 5. In some aspects, t may be an integer from about 0 to about 5.

[0151] In some aspects, the crosslinking agent may have the structure below. TIFF0007924860000017.tif66128

[0152] In some aspects, p may be an integer from about 0 to about 5. In some aspects, t may be an integer from about 0 to about 5.

[0153] In some aspects, the crosslinking agent may have the structure below. TIFF0007924860000018.tif75128

[0154] In some aspects, p may be an integer from about 0 to about 5. In some aspects, t may be an integer from about 0 to about 5.

[0155] In some aspects, the crosslinking agent may have the structure below. TIFF0007924860000019.tif74128

[0156] In some aspects, p may be an integer from about 0 to about 5. In some aspects, t may be an integer from about 0 to about 5.

[0157] In some aspects, the crosslinking agent may have the structure below. TIFF0007924860000020.tif122128

[0158] In some embodiments, p can be an integer between approximately 0 and approximately 5. In some embodiments, t can be an integer between approximately 0 and approximately 5.

[0159] In some embodiments, the crosslinking agent may have the following structure. TIFF0007924860000021.tif93128

[0160] In some embodiments, p can be an integer between approximately 0 and approximately 5. In some embodiments, t can be an integer between approximately 0 and approximately 5.

[0161] In some embodiments, the crosslinking agent may have the following structure. TIFF0007924860000022.tif64128

[0162] In some embodiments, p can be an integer between approximately 0 and approximately 5. In some embodiments, t can be an integer between approximately 0 and approximately 5.

[0163] In some embodiments, the compound may be crosslinked to about 1% to about 100%, about 1% to about 99%, about 1% to about 9%, about 10% to about 19%, about 20% to about 29%, about 30% to about 39%, about 40% to about 49%, about 50% to about 59%, about 60% to about 69%, about 70% to about 79%, about 80% to about 89%, about 90% to about 99%, about 100%, about 2%, about 6%, about 12%, about 26%, or about 48%. These include all values ​​and ranges between the two ends.

[0164] In some embodiments, the compound is approximately 5kDa to 50kDa, approximately 5kDa to 45kDa, approximately 5kDa to 40kDa, approximately 5kDa to 35kDa, approximately 5kDa to 30kDa, approximately 5kDa to 25kDa, approximately 5kDa to 20kDa, approximately 5kDa to 15kDa, approximately 5kDa to 10kDa, approximately 10kDa to 50kDa, approximately 10kDa to 45kDa, approximately 10kDa to about 40kDa, about 10kDa to about 35kDa, about 10kDa to about 30kDa, about 10kDa to about 25kDa, about 10kDa to about 20kDa, about 10kDa to about 15k Da, about 15kDa - about 50kDa, about 15kDa - about 45kDa, about 15kDa - about 35kDa, about 15kDa - about 30kDa, about 15kDa - about 25kDa, about 15kDa - Approximately 20kDa, approximately 20kDa to approximately 50kDa, approximately 20kDa to approximately 45kDa, approximately 20kDa to approximately 40kDa, approximately 20kDa to approximately 35kDa, approximately 20kDa to approximately 30kDa, approximately 20 kDa ~ about 25kDa, about 25kDa - about 50kDa, about 25kDa - about 45kDa, about 25kDa - about 40kDa, about 25kDa - about 35kDa, about 25kDa - about 30kDa It may have a weight-average molecular weight (Mw) of approximately 30kDa to 50kDa, approximately 30kDa to 45kDa, approximately 30kDa to 40kDa, approximately 30kDa to 35kDa, approximately 35kDa to 50kDa, approximately 35kDa to 45kDa, approximately 35kDa to 40kDa, approximately 40kDa to 50kDa, approximately 40kDa to 45kDa, or approximately 45kDa to 50kDa. These include all values ​​and ranges between the two ends.

[0165] In some embodiments, the compound is approximately 5kDa to 50kDa, approximately 5kDa to 45kDa, approximately 5kDa to 40kDa, approximately 5kDa to 35kDa, approximately 5kDa to 30kDa, approximately 5kDa to 25kDa, approximately 5kDa to 20kDa, approximately 5kDa to 15kDa, approximately 5kDa to 10kDa, approximately 10kDa to 50kDa, approximately 10kDa to 45kDa, approximately 10kDa to about 40kDa, about 10kDa to about 35kDa, about 10kDa to about 30kDa, about 10kDa to about 25kDa, about 10kDa to about 20kDa, about 10kDa to about 15k Da, about 15kDa - about 50kDa, about 15kDa - about 45kDa, about 15kDa - about 35kDa, about 15kDa - about 30kDa, about 15kDa - about 25kDa, about 15kDa - Approximately 20kDa, approximately 20kDa to approximately 50kDa, approximately 20kDa to approximately 45kDa, approximately 20kDa to approximately 40kDa, approximately 20kDa to approximately 35kDa, approximately 20kDa to approximately 30kDa, approximately 20 kDa ~ about 25kDa, about 25kDa - about 50kDa, about 25kDa - about 45kDa, about 25kDa - about 40kDa, about 25kDa - about 35kDa, about 25kDa - about 30kDa It may have a number-average molecular weight (Mn) of approximately 30kDa to 50kDa, approximately 30kDa to 45kDa, approximately 30kDa to 40kDa, approximately 30kDa to 35kDa, approximately 35kDa to 50kDa, approximately 35kDa to 45kDa, approximately 35kDa to 40kDa, approximately 40kDa to 50kDa, approximately 40kDa to 45kDa, or approximately 45kDa to 50kDa. These include all values ​​and ranges between the two ends.

[0166] In some embodiments, the compounds are approximately 1 to approximately 2, approximately 1 to approximately 1.9, approximately 1 to approximately 1.8, approximately 1 to approximately 1.7, approximately 1 to approximately 1.6, approximately 1 to approximately 1.5, approximately 1 to approximately 1.4, approximately 1 to approximately 1.3, approximately 1 to approximately 1.2, approximately 1 to approximately 1.1, approximately 1.1 to approximately 2, approximately 1.1 to approximately 1.9, approximately 1.1 to approximately 1.8, approximately 1.1 to approximately 1.7, approximately 1.1 to approximately 1.6, approximately 1.1-1.5, approximately 1.1-1.4, approximately 1.1-1.3, approximately 1.1-1.2, approximately 1.2-2, approximately 1.2-1.9, approximately 1.2-1.8, approximately 1.2-1.7, approximately 1.2-1.6, approximately 1.2-1.5, approximately 1.2-1.4, approximately 1.2-1.3, approximately 1.3-2, approximately 1.3- 1.9, approximately 1.3-1.8, approximately 1.3-1.7, approximately 1.3-1.6, approximately 1.3-1.5, approximately 1.3-1.4, approximately 1.4-2, approximately 1.4-1.9, approximately 1.4-1.8, approximately 1.4-1.7, approximately 1.4-1.6, approximately 1.4-1.5, approximately 1.5-2, approximately 1.5-1.9, approximately 1.5- It may have a polyvariance index (PDI) of 1.8, approximately 1.5–1.7, approximately 1.5–1.6, approximately 1.6–2, approximately 1.6–1.9, approximately 1.6–1.8, approximately 1.6–1.7, approximately 1.7–2, approximately 1.7–1.9, approximately 1.7–1.8, approximately 1.8–2, approximately 1.8–1.9, or approximately 1.9–2. These include all values ​​and ranges between the two ends.

[0167] In some embodiments, the compound retains more than 90% of its initial mass after exposure to PBS at approximately 37°C for an exposure period. In some embodiments, the compound retains more than 99%, more than 98%, more than 97%, more than 96%, more than 95%, more than 94%, more than 93%, more than 92%, more than 91%, more than 90%, more than 85%, more than 80%, more than 75%, more than 70%, more than 65%, more than 60%, more than 55%, or more than 50% of its initial mass after exposure to PBS at approximately 37°C for 20 days. These include all values ​​and ranges between the two extremes. In some embodiments, PBS may include SDS in amounts of approximately 0.1% by weight, approximately 0.2% by weight, approximately 0.3% by weight, approximately 0.4% by weight, approximately 0.5% by weight, approximately 0.6% by weight, approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, approximately 2% by weight, approximately 3% by weight, approximately 4% by weight, approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, or approximately 10% by weight. These include all values ​​and ranges between the two ends.

[0168] In some embodiments, the exposure period may be approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days. These include all values ​​and ranges between the two extremes.

[0169] In some embodiments, the compound may be contained in particles. In some embodiments, the compound may be contained in nanoparticles. In some embodiments, the compound may be contained in microparticles. In some embodiments, the compound may be contained in microparticles. In some embodiments, the particles are approximately 1 nm to 500 nm, approximately 1 nm to 400 nm, approximately 1 nm to 300 nm, approximately 1 nm to 200 nm, approximately 1 nm to 100 nm, approximately 1 nm to 50 nm, approximately 1 μm to 500 μm, approximately 1 μm to 400 μm, approximately 1 μm to 300 μm, approximately 1 μm to 200 μm, approximately 1 μm to 100 μm, approximately 1 μm to 50 μm, approximately 1 μm to 40 μm, and approximately 1 μm to 30 μm. They may have average dimensions of approximately 1 μm to 20 μm, 1 μm to 10 μm, 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 500 μm to 5 mm, 500 μm to 4 mm, 500 μm to 3 mm, 500 μm to 2 mm, 500 μm to 1 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, or 1 mm to 2 mm. These include all values ​​and ranges between the two ends.

[0170] In some embodiments, the compound may be contained in macroparticles. In some embodiments, the macroparticles may be disks. In some embodiments, the macroparticles may be depots. In some embodiments, the macroparticles may be implants. In some embodiments, the macroparticles may have average dimensions of approximately 1 mm to 2 mm, 1 mm to 3 mm, 1 mm to 4 mm, 1 mm to 5 mm, 1 mm to 6 mm, 1 mm to 7 mm, 1 mm to 8 mm, 1 mm to 9 mm, 1 mm to 1 cm, 1 mm to 2 cm, 1 mm to 3 cm, 1 mm to 4 cm, 1 mm to 5 cm, 1 mm to 6 cm, 1 mm to 7 cm, 1 mm to 8 cm, 1 mm to 9 cm, 1 mm to 10 cm, 1 mm to 11 cm, 1 mm to 12 cm, 1 mm to 13 cm, 1 mm to 14 cm, or 1 mm to 15 cm. These include all values ​​and ranges between the two ends.

[0171] In some embodiments, a drug can be incorporated into a compound. In some embodiments, the incorporation of a drug into a compound may include: (i) A step of providing a compound or a pharmaceutically acceptable salt thereof; (ii) the step of incubating the compound and the drug in the presence of a solvent over an incubation period in order to form a drug-supported compound; and (iii) A step of separating the drug-supported compound from the solvent.

[0172] In some embodiments, the solvent may include a hydrophobic solvent. In some embodiments, the solvent may include a hydrophilic solvent. In some embodiments, the solvent may include a hydrophobic solvent. In some embodiments, the solvent may include a hydrophilic solvent. In some embodiments, the solvent may include a hydrophilic solvent. In some embodiments, the solvent may include a hydrophilic solvent. In some embodiments, the solvent may include dichloromethane. In some embodiments, the solvent may include water. In some embodiments, the solvent may include ethanol. In some embodiments, the solvent may include methanol. In some embodiments, the solvent may include acetic acid. In some embodiments, the solvent may include propanol. In some embodiments, the solvent may include carbon tetrachloride. In some embodiments, the solvent may include dimethyl chloride. In some embodiments, the solvent may include hexane. In some embodiments, the solvent may include benzene. In some embodiments, the solvent may include THF. In some embodiments, the solvent may include DMSO. In some embodiments, the solvent may include THF and DMSO. In some embodiments, the solvent may be a mixture of THF and DMSO at approximately 50:50 wt%. In some embodiments, the solvent may be a mixture of THF:DMSO in a ratio of approximately 10:90% by weight, approximately 20:80% by weight, approximately 30:70% by weight, approximately 40:60% by weight, approximately 60:40% by weight, approximately 70:30% by weight, approximately 80:20% by weight, or approximately 90:10% by weight.

[0173] In some aspects, the incubation period may be from about 1 day to about 30 days, from about 1 day to about 25 days, from about 1 day to about 20 days, from about 1 day to about 15 days, from about 1 day to about 10 days, from about 1 day to about 5 days, from about 5 days to about 30 days, from about 5 days to about 25 days, from about 5 days to about 20 days, from about 5 days to about 15 days, from about 5 days to about 10 days, from about 10 days to about 30 days, from about 10 days to about 25 days, from about 10 days to about 20 days, from about 10 days to about 15 days, from about 15 days to about 20 days, from about 20 days to about 30 days, from about 20 days to about 25 days, or from about 25 days to about 30 days, and may be about 1 day, about 2 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. These include all values and ranges between the two endpoints.

[0174] In some aspects, the incubation may be performed at a temperature of from about 20°C to about 50°C, from about 20°C to about 40°C, from about 20°C to about 30°C, from about 30°C to about 50°C, from about 30°C to about 40°C, or from about 40°C to about 50°C.

[0175] In some aspects, the drug may be a small molecule drug. In some aspects, the drug may be a macromolecular drug. In some aspects, the drug may include PTX, TAA, or TAH.

[0176] In some aspects, the step of separating the drug-loaded compound from the solvent may include vacuum filtration, centrifugal filtration, gravity filtration, cold filtration, hot filtration, multi-layer filtration, or any other suitable separation process or combination of processes.

[0177] In some aspects, the drug-loaded compound may include the drug in an amount of from about 10 wt% to about 60 wt%, from about 10 wt% to about 50 wt%, from about 10 wt% to about 40 wt%, from about 10 wt% to about 30 wt%, from about 10 wt% to about 20 wt%, from about 20 wt% to about 60 wt%, from about 20 wt% to about 50 wt%, from about 20 wt% to about 40 wt%, from about 20 wt% to about 30 wt%, from about 30 wt% to about 60 wt%, from about 30 wt% to about 50 wt%, from about 30 wt% to about 40 wt%, from about 40 wt% to about 60 wt%, from about 40 wt% to about 50 wt%, or from about 50 wt% to about 60 wt%.

[0178] In some embodiments, the drug-supporting compound releases approximately 5% or less, approximately 10% or less, approximately 15% or less, approximately 20% or less, approximately 25% or less, approximately 30% or less, approximately 35% or less, approximately 40% or less, approximately 45% or less, approximately 50% or less, approximately 55% or less, approximately 60% or less, approximately 65% ​​or less, approximately 70% or less, approximately 75% or less, approximately 80% or less, approximately 85% or less, approximately 90% or less, or approximately 95% or less of the drug after a release period in a solution at a temperature of approximately 37°C.

[0179] In some embodiments, the solution may contain PBS with about 0% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of SDS.

[0180] In some embodiments, the release period can be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days, approximately 15 days, approximately 20 days, approximately 25 days, approximately 30 days, approximately 35 days, approximately 40 days, approximately 45 days, approximately 50 days, approximately 55 days, or approximately 60 days. These include all values ​​and ranges between the two extremes.

[0181] In some embodiments, the drug-carrying compound retains more than 90% of its initial mass after exposure to an aqueous medium at approximately 37°C for an exposure period. In some embodiments, the compound retains more than 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of its initial mass after exposure to an aqueous medium at approximately 37°C for 20 days. These include all values ​​and ranges between the two extremes.

[0182] In some embodiments, the aqueous medium may include PBS. In some embodiments, PBS may include about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of SDS. These include all values ​​and ranges between the two ends.

[0183] In some embodiments, the exposure period may be approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days. These include all values ​​and ranges between the two extremes.

[0184] Those skilled in the art will recognize numerous equivalents to the specific procedures, embodiments, claims, and examples described herein, or will be able to verify them using mere routine experiments. These equivalents are considered to be covered by the claims appended herein, within the scope of this disclosure. For example, it should be understood that it is within the scope of this disclosure to modify reaction conditions, including but not limited to reaction time, reaction size / volume, experimental reagents such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents, using substitutes recognized in the art and using mere routine experiments.

[0185] Wherever values ​​and ranges are shown herein, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are intended to be included within the scope of this disclosure. Furthermore, all values ​​within those ranges, as well as any upper or lower limits on the ranges of values, are also assumed by this disclosure.

[0186] The following examples further illustrate aspects of the present disclosure. However, they do not in any way limit the teachings or disclosures relating to the present disclosure as described herein. As described in the following examples, the disclosed compounds (e.g., compounds including lactides, allyl lactides, and optionally glycolides) exhibited tunable degradation profiles and tunable drug release profiles, for example, slower drug release profiles compared to compounds containing valerolactone (e.g., allyl valerolactone) in the polymer backbone. Although it is undesirable to be constrained by theory, excluding valerolactone from the polymer backbone can allow for greater control over the crosslinking density of the resulting compounds, thereby allowing for greater control over degradation and drug release properties. [Examples]

[0187] The following is a non-limiting set of examples relating to compounds synthesized by the methods described herein. Compounds containing valerolactone residues are shown in the examples solely for comparison with compounds not containing valerolactone residues and should not be construed as being included in the subject matter of the claims.

[0188] Abbreviation AVL Allyl-Valerolactone Da, kDa Dalton, Kilodalton DCM Dichloromethane EtOH Ethanol NMR, H NMR, C NMR nuclear magnetic resonance, proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance PBS (Phosphate-buffered Saline) PLA (polylactic acid) PLGA Poly(allyl-lactic acid-lactic acid-co-glycolic acid) V-PLGA Poly(allyl-δ-valerolactone-co-lactic acid-co-glycolic acid) PTX Paclitaxel PVL-AL Poly(allyl-lactic-co-valerolactone) SDS Sodium Dodecyl Sulfate Sn(OTf)2 Tin(II) Trifluoromethanesulfonate TAA Triamcinolone Acetonide TAH Triamcinolone Hexaacetonide THF (Tetrahydrofuran)

[0189] Example 1. Synthesis of a polymer having 12% allyl lactide, referred to herein as PLA-12. A polymer having the following structure was synthesized. TIFF0007924860000023.tif67155

[0190] A stock solution of anhydrous ethanol in anhydrous methylene chloride was prepared in a 25 mL flame-dried and argon-swept round-bottom flask (1.0 mL of ethanol diluted 1:20 in 19 mL of CH2Cl2). A flame-dried 50 mL round-bottom flask was fitted with a stirring bar, sealed with a rubber septum, and swept with argon for 10 minutes. Next, 3.6 mL of anhydrous methylene chloride was added to the reaction flask by syringe under argon to counteract the generated pressure. 1.24 mL of the stock ethanol solution (1.06 mmol) was added to the reaction flask by syringe under argon.

[0191] The initiator / catalyst solution was stirred at room temperature for 30 minutes. L-lactide (37.15 g) in DCM and benzyl alcohol (0.33 mL) solution was added to the stirred solution by syringe, and then allyl lactide (13.03 g) was added by syringe under an argon balloon to counteract the pressure. The reaction system was vigorously stirred under argon at room temperature for 48 hours. 4-dimethylaminopyridine (1.57 g) was weighed and placed in anhydrous DCM.

[0192] The obtained polymer (almost solidified) was diluted with 5 mL of methylene chloride and purified by adding it dropwise to 100 mL of cold methanol, and cooled overnight in a freezer. The precipitate was rinsed with ice-cold methanol (100 mL x 3) and collected by centrifugation. After drying under reduced pressure overnight, the final polymer product was prepared as a white waxy solid. Colorless crystals (95% yield) were obtained with EtOH. 1¹H NMR (500 MHz, CDCb / TMS, ppm) δ: 5.2 (lactide), 5.7 (allyl-lactide), 7.4 (benzyl alcohol).

[0193] Figure 1 shows the NMR data from Example 1.

[0194] Example 2. Synthesis of a polymer having 6% allyl lactide, referred to herein as PLA-6. A polymer having the following structure was synthesized. TIFF0007924860000024.tif67155

[0195] A stock solution of anhydrous ethanol in anhydrous methylene chloride was prepared in a 25 mL flame-dried and argon-swept round-bottom flask (1.0 mL of ethanol diluted 1:20 in 19 mL of CH2Cl2). A flame-dried 50 mL round-bottom flask was fitted with a stirring bar, sealed with a rubber septum, and swept with argon for 10 minutes. Next, 3.6 mL of anhydrous methylene chloride was added to the reaction flask by syringe under argon to counteract the generated pressure. 1.24 mL of the stock ethanol solution (1.06 mmol) was added to the reaction flask by syringe under argon.

[0196] The initiator / catalyst solution was stirred at room temperature for 30 minutes. L-lactide (37.15 g) in DCM and benzyl alcohol (0.33 mL) solution was added to the stirred solution by syringe, and then allyl lactide (13.03 g) was added by syringe under an argon balloon to counteract the pressure. The reaction system was vigorously stirred under argon at room temperature for 48 hours. 4-dimethylaminopyridine (1.46 g) was weighed and placed in anhydrous DCM.

[0197] The obtained polymer (almost solidified) was diluted with 5 mL of methylene chloride and purified by adding it dropwise to 100 mL of cold methanol, and cooled overnight in a freezer. The precipitate was rinsed with ice-cold methanol (100 mL x 3) and collected by centrifugation. After drying under reduced pressure overnight, the final polymer product was prepared as a white waxy solid. Colorless crystals (95% yield) were obtained with EtOH.1 ¹H NMR (500 MHz, CDCb / TMS, ppm) δ: 5.2 (lactide), 5.7 (allyl-lactide), 7.4 (benzyl alcohol).

[0198] Example 3. Synthesis of poly(allyl-lactic acid-lactic acid-co-glycolic acid), referred to herein as PLGA. A polymer having the following structure was synthesized. TIFF0007924860000025.tif101128

[0199] A stock solution of anhydrous ethanol in anhydrous methylene chloride was prepared in a 25 mL flame-dried and argon-swept round-bottom flask (1.0 mL of ethanol diluted 1:20 in 19 mL of CH2Cl2). A stirring bar was fitted to a flame-dried 50 mL round-bottom flask, sealed with a rubber septum, and swept with argon for 10 minutes. Sn(OTf)2 (8.2 mL, 10% wt / vol solution with toluene) was added directly to the flask. The reaction flask was restopped with a septum and swept with argon again for 10 minutes. Next, 3.6 mL of anhydrous methylene chloride was added to the reaction flask by syringe under argon to counteract the generated pressure. 1.24 mL of stock ethanol solution (1.06 mmol) was added to the reaction flask by syringe under argon.

[0200] The initiator / catalyst solution was stirred at room temperature for 30 minutes. Allyl lactide (8.3 g) was added to the stirred solution by syringe, followed by D,L-lactic acid (32.737 g) by syringe, and then 50:50 lactic acid:glycolic acid premix (18.57 g) was added under argon balloon pressure to counteract the pressure. The reaction system was vigorously stirred under argon at room temperature for 48 hours.

[0201] The obtained polymer (almost solidified) was diluted with 5 mL of methylene chloride and purified by adding it dropwise to 100 mL of cold methanol, and cooled overnight in a freezer. The precipitate was rinsed with ice-cold methanol (100 mL x 3) and collected by centrifugation. After drying under reduced pressure overnight, the final polymer product was prepared as a white waxy solid. Yield: 7.90 g / 90.0%, (purity 98.8% / NMR). NMR data analysis showed a polymer molecular weight of 14.9 kDa and an allyl-lactide content of 13.3 mol%. NMR (500 MHz, CDCb / TMS, ppm) δ: 4.8 (glycolide), 5.2 (lactide), 5.7 (allyl-lactide).

[0202] Example 4. Synthesis of drug-carrying polymer Paclitaxel (PTX), triamcinolone acetonide (TAA), or triamcinolone hexaacetonide (TAH) were supported on the polymer synthesized in Example 1 by the following process.

[0203] Drug loading was performed onto pre-formed cross-linked microparticles and disks by immersion in a drug solution in prepared tetrahydrofuran or dichloromethane for only 4 hours. For example, paclitaxel was loaded onto cross-linked microparticles. A drug solution was prepared by dissolving 30 mg of paclitaxel in 0.5 mL of THF, and this was used to achieve post-drug loading by a swelling equilibrium approach, in which purified microparticles (16 ± 0.5 mg) were suspended overnight in a glass tube. Next, the THF was evaporated at room temperature in a fume hood, and the paclitaxel-loaded microparticles were freeze-dried. The resulting mixture was vortexed with 10 mL of PBS, sonicated for 1 minute (until the microparticles were well suspended), and centrifuged for 1 minute. After decanting the supernatant, the microparticles were retained, replaced with 10 mL of fresh PBS, vortexed without sonication, and centrifuged for 1 minute. Next, after decanting the supernatant, the microparticles were freeze-dried overnight before the release test.

[0204] Comparative Example 1. Synthesis of poly(allyl-δ-valerolactone-co-lactic acid-co-glycolic acid), referred to herein as AV-PLGA. A polymer having the following structure was synthesized. TIFF0007924860000026.tif106151

[0205] A stock solution of anhydrous ethanol in anhydrous methylene chloride was prepared in a 25 mL flame-dried and argon-swept round-bottom flask (1.0 mL of ethanol diluted 1:20 in 19 mL of CH2Cl2). A stirring bar was fitted to a flame-dried 50 mL round-bottom flask, sealed with a rubber septum, and argon was swept for 10 minutes. Sn(OTf)2 (98.6 mg, 0.237 mmol) was added directly to the flask. The reaction flask was re-stopped with a septum and swept again with argon for another 10 minutes. Next, 3.6 mL of anhydrous methylene chloride was added to the reaction flask by syringe under argon to counteract the generated pressure. 1.24 mL of stock ethanol solution (1.06 mmol) was added to the reaction flask by syringe under argon.

[0206] The initiator / catalyst solution was stirred at room temperature for 30 minutes. δ-allyl (valerolactone) (2.1 ml, 16.2 mmol) was added to the stirred solution by syringe, followed by L-lactic acid (6.05 ml, 65.3 mmol) by syringe, and then glycolic acid (6.05 ml, 65.3 mmol) was added under an argon balloon to counteract the pressure. The reaction system was vigorously stirred under argon at room temperature for 48 hours.

[0207] The obtained polymer (almost solidified) was diluted with 5 mL of methylene chloride and purified by adding it dropwise to 100 mL of cold methanol, and cooled overnight in a freezer. The precipitate was rinsed with ice-cold methanol (100 mL x 3) and collected by centrifugation. After drying under reduced pressure overnight, the final polymer product was prepared as a white waxy solid. Yield: 7.90 g / 90.0% (purity 98.8% / NMR). NMR data analysis showed a polymer molecular weight of 14.9 kDa and an avl content of 13.3 mol%. 1¹H NMR (500 MHz, CDCb / TMS, ppm) δ: 4.8 (glycolide), 5.2 (lactide), 5.7 (allyl-valerolactone).

[0208] Comparative Example 2. Synthesis of poly(allyl-lactic acid-co-valerolactone), referred to herein as PVL-AL. PVL-AL polymer was synthesized and purified. NMR data analysis showed a polymer molecular weight of 14.9 kDa and an avl content of 13.3 mol%. NMR (500 MHz, CDCb / TMS, ppm) δ: 4.2 (valerolactone), 5.7 (allyl-lactide).

[0209] Example 5. Degradation in PBS and in PBS containing 0.5% by weight of sodium dodecyl sulfate (SDS). The above PLA-6, PLGA, and V-PLGA were placed in a PBS solution and a PBS solution with 0.5 wt% SDS and allowed to stand for 25 days. Figures 2 and 3 show their residual weight percentages measured at various points throughout the process. Figure 4 shows the disintegration of the disks over 60 days. After 20 days in PBS, PLA-6 retained approximately 98% of its initial mass, PLGA retained approximately 82% of its initial mass, and V-PLGA retained approximately 74% of its initial mass. After 21 days in PBS with 0.5 wt% SDS, PLA-6 retained approximately 99% of its initial mass, PLGA retained approximately 82% of its initial mass, and V-PLGA retained approximately 9% of its initial mass.

[0210] Example 6. Drug release rate in PBS and 0.5 wt% SDS. Drugs were loaded onto V-PLGA, PLGA, and PLA-6 discs. The PTX (paclitaxel) content of the loaded discs ranged from 33.81% to 37.79% by weight. The TAA (triamcinolone acetonide) content of the loaded discs ranged from 32.95% to 35.02% by weight. The loaded discs were left standing for 100 days. The following cumulative drug release rates were observed. Figure 5 shows the release rate of PTX in these polymers in PBS and 0.5% SDS. Figure 6 shows the release rate of TAA in these polymers in PBS and 0.5% SDS. Figures 7A and 7B show the PTX release rate achieved by changing the medium every 3-4 days due to the drug's solubility limit. After 60 days in PBS containing 0.5 wt% SDS, PLA-6 releases approximately 50% of its initial PTX mass, PLGA releases approximately 60% of its initial PTX mass, and V-PLGA releases approximately 90% of its initial PTX mass. After approximately 50 days in PBS containing 0.5 wt% SDS, PLA-6 releases approximately 50% of its initial TAA mass. After approximately 32 days in PBS containing 0.5 wt% SDS, PLGA releases approximately 50% of its initial TAA mass. After approximately 23 days in PBS containing 0.5 wt% SDS, V-PLGA releases approximately 50% of its initial TAA mass. After 50 days, due to changes in the medium every 3-4 days based on the drug's solubility limit, PLA-6 releases approximately 15% of the initial PTX mass, PLGA releases approximately 40% of the initial PTX mass, and V-PLGA releases approximately 65% ​​of the initial PTX mass.

[0211] Equivalents Details of one or more aspects of this disclosure are described in the accompanying descriptions above. Other features, purposes, and advantages of this disclosure will be apparent from this specification and the claims. In this specification and the accompanying claims, unless otherwise clearly indicated by the context, the singular refers to multiple subjects. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0212] The above description is provided for illustrative purposes only and is not intended to limit the disclosure to the exact form disclosed, and the disclosure is limited by the claims appended to this specification.

Claims

1. Allyl lactide residues; and lactide residues Includes, The aforementioned residue is crosslinked with a crosslinking agent, It does not contain valerolactone residues. A compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further comprising a glycolide residue.

3. The compound according to claim 1, comprising the following structure: During the ceremony, m is an integer between 1 and 1,000; n is an integer between 1 and 1,000; q is an integer between 1 and 100; Here, the compound or its pharmaceutically acceptable salt does not contain a valerolactone residue.

4. The compound according to claim 3, having the following structure: During the ceremony, p is an integer between 1 and 1,000.

5. The compound according to claim 3 or 4, wherein m is an integer from 1 to 100.

6. The compound according to claim 3 or 4, wherein m is an integer from 1 to 25.

7. The compound according to claim 3 or 4, wherein n is an integer from 1 to 100.

8. The compound according to claim 3 or 4, wherein n is an integer from 1 to 25.

9. The compound according to claim 3, wherein m / (m+n) is 0.2 to 0.

5.

10. The compound according to claim 3, wherein m / (m+n) is 0.4 to 0.

5.

11. The compound according to claim 1, wherein the crosslinking agent includes a thiol moiety.

12. The crosslinking agents are as follows: The compound according to claim 1.

13. The compound according to claim 1, wherein 1% to 9% of the compound is crosslinked.

14. The compound according to claim 1, wherein 10% to 19% of the compound is crosslinked.

15. The compound according to claim 1, wherein 40% to 49% of the compound is crosslinked.

16. The compound according to any one of claims 1 to 4, which retains more than 90% of its initial mass after exposure to an aqueous medium at 37°C for one day.

17. Macroparticles comprising the compound according to any one of claims 1 to 4.

18. Microparticles comprising the compound according to any one of claims 1 to 4.

19. Nanoparticles comprising the compound according to any one of claims 1 to 4.

Images