Ionic liquid composition

Abstract

Provided herein are compositions or compounds comprising ionic liquids and a therapeutic protein or peptide, and methods of using them for the treatment of a disease or disorder.

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 380,125, filed October 19, 2022, U.S. Provisional Patent Application No. 63 / 334,410, filed April 25, 2022, U.S. Provisional Patent Application No. 63 / 295,197, filed December 30, 2021, and U.S. Provisional Patent Application No. 63 / 277,878, filed November 10, 2021, each of which is incorporated by reference in its entirety into this specification.

[0002] Technical Field TECHNICAL FIELD

[0002] The technology described herein relates to ionic liquids and deep eutectic liquids for the treatment of diseases including obesity, metabolic disorders, and gastrointestinal inflammation. Summary of the Invention [Problem to be solved by the invention]

[0003]

[0003] Provided herein are compositions and methods of use for the treatment of diseases or disorders. [Means for solving the problem]

[0004] The present inventors have discovered that certain modifications to proteins surprisingly improve their use with ionic liquid compositions for formulation and delivery, and these formulations can be delivered orally to patients for the purpose of treating the patients.

[0005]

[0005] In one embodiment of the present specification, a composition is described in which a protein or peptide is non-covalently conjugated to one or more ions, and such ions are also present in the ionic liquid present in the formulation.

[0006]

[0006] In one embodiment of the present specification, a composition is described in which a protein or peptide is covalently conjugated to one or more ions, and such ions are also present in the ionic liquid present in the formulation.

[0007] In certain aspects herein, inter alia, compounds of formula I:

[0008] [ka]

[0009] [In the formula, R 1 , R 2 , and R 3 are independently C1-C5 alkyl; R 4 is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a therapeutic agent] Compounds according to the formula:

[0010] In some embodiments, R 1 , R 2 , and R 3 is methyl. In some embodiments, R 1 , R 2 , and R 3 is ethyl. In some embodiments, R 1 , R 2 , and R 3 is propyl.

[0011] In some embodiments, R 1 and R 2 is methyl and R 3 is ethyl.

[0012] In some embodiments, R 1 and R 3is methyl and R 2 is ethyl.

[0012]

[0013] In some embodiments, R 1 and R 2 is ethyl, and R 3 is methyl.

[0014] In some embodiments, R 1 and R 3 is ethyl, and R 2 is methyl.

[0013]

[0015] In some embodiments, R 1 and R 2 is propyl, and R 3 is methyl.

[0016] In some embodiments, R 1 and R 3 is propyl, and R 2 is methyl.

[0014]

[0017] In some embodiments, R 4 is a C2-C5 alkyl substituted with hydroxyl.

[0018] In some embodiments, R 4 teeth,

[0015] [ka]

[0016] is.

[0019] In some embodiments, the compound has Formula Ia:

[0017] [ka]

[0018] It is a compound according to the following:

[0020] In some embodiments, the compound has Formula Ib:

[0019] [ka]

[0020] It is a compound according to the following:

[0021] In some embodiments, the compound has formula Ic:

[0021] [ka]

[0022] It is a compound according to the following:

[0022] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0023] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof.

[0024] In some embodiments, the compound comprises the structure shown in FIG.

[0024]

[0025] In some embodiments, the compound is

[0025] [ka]

[0026] of,

[0027] [ka]

[0028] The molar ratio to is about 1:1 to about 1:60. In some embodiments, the compound is

[0029] [ka]

[0030] of,

[0031] [ka]

[0032] The molar ratio of the compound to the compound is about 1:1 to about 1:30. In some embodiments, the compound is

[0033] [ka]

[0034] of,

[0035] [ka]

[0036] The molar ratio to is about 1:1. In some embodiments, the compound is

[0037] [ka]

[0038] of,

[0039] [ka]

[0040] The molar ratio to is about 1:3. In some embodiments, the compound is

[0041] [ka]

[0042] of,

[0043] [ka]

[0044] The molar ratio to is about 1:4. In some embodiments, the compound is

[0045] [ka]

[0046] The molar ratio of In some embodiments, the compound is

[0047] [ka]

[0048] The molar ratio of In some embodiments, the compound is

[0049] [ka]

[0050] The molar ratio of In some embodiments, the compound is

[0051] [ka]

[0052] The molar ratio of In some embodiments, the compound is

[0053] [ka]

[0054] The molar ratio of In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0055] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0056] In some embodiments, the therapeutic agent is an amylin analog having a structure shown in Figure 2, Figure 3, or Figure 4, or a functional variant thereof, or a mimetic or analog thereof.

[0057]

[0039] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0058] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, that comprises the N14E amino acid substitution. In some embodiments, the compound is

[0059] [ka]

[0060] of,

[0061] [ka]

[0062] The molar ratio of the compound to the compound is about 1:1 to about 1:30. In some embodiments, the compound is

[0063] [ka]

[0064] of,

[0065] [ka]

[0066] The molar ratio to is about 1:1. In some embodiments, the compound is

[0067] [ka]

[0068] of,

[0069] [ka]

[0070] The molar ratio to is about 1:3. In some embodiments, the compound is

[0071] [ka]

[0072] The molar ratio of In some embodiments, the compound is

[0073] [ka]

[0074] of,

[0075] [ka]

[0076] The molar ratio to is about 1:12. In some embodiments, the compound is

[0077] [ka]

[0078] The molar ratio of

[0047] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0048] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0079] In some embodiments, the therapeutic agent is (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0080] In some embodiments, the therapeutic agent is (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0081] In some embodiments, the therapeutic agent is (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0082]

[0052] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0053] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0083] In some embodiments, the compound is

[0084] [ka]

[0085] of,

[0086] [ka]

[0087] The molar ratio to is about 1:1 to about 1:164. In some embodiments, the compound is

[0088] [ka]

[0089] of,

[0090] [ka]

[0091] The molar ratio to is about 1:1. In some embodiments, the compound is

[0092] [ka]

[0093] of,

[0094] [ka]

[0095] The molar ratio to is about 1:33. In some embodiments, the compound is

[0096] [ka]

[0097] of,

[0098] [ka]

[0099] The molar ratio to is about 1:41. In some embodiments, the compound is

[0100] [ka]

[0101] of,

[0102] [ka]

[0103] The molar ratio to is about 1:66. In some embodiments, the compound is

[0104] [ka]

[0105] of,

[0106] [ka]

[0107] The molar ratio to is about 1:82. In some embodiments, the compound is

[0108] [ka]

[0109] of,

[0110] [ka]

[0111] The molar ratio to is about 1:132. In some embodiments, the compound is

[0112] [ka]

[0113] of,

[0114] [ka]

[0115] The molar ratio to is about 1:164.

[0062] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0063] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:3 and the sequence of SEQ ID NO:6, the sequence of SEQ ID NO:4 and the sequence of SEQ ID NO:6, or the sequence of SEQ ID NO:5 and the sequence of SEQ ID NO:7.

[0116] In some embodiments, the compound is

[0117] [ka]

[0118] of,

[0119] [ka]

[0120] The molar ratio to is about 1:1 to about 1:144.

[0065] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0066] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0121] In some embodiments, the compound is

[0122] [ka]

[0123] of,

[0124] [ka]

[0125] The molar ratio to is about 1:1 to about 1:140.

[0068] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0069] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0126] In some embodiments, the compound is

[0127] [ka]

[0128] of,

[0129] [ka]

[0130] The molar ratio of the compound to the compound is about 1:1 to about 1:80. In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0072] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:12 and the sequence of SEQ ID NO:14, or the sequence of SEQ ID NO:13 and the sequence of SEQ ID NO:15.

[0131] In some embodiments, the compound is

[0132] [ka]

[0133] of,

[0134] [ka]

[0135] The molar ratio to is about 1:1 to about 1:156.

[0074] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0075] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0136] In some embodiments, the compound is

[0137] [ka]

[0138] of,

[0139] [ka]

[0140] The molar ratio to is about 1:1 to about 1:256.

[0077] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0141]

[0078] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19. In some embodiments, the compound is

[0142] [ka]

[0143] of,

[0144] [ka]

[0145] The molar ratio to is about 1:1 to about 1:70.

[0080] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof comprising a [one or more choline or choline derivatives]-peptide salt formed at the C-terminus of the light chain, the C-terminus of the heavy chain, or a combination thereof.

[0146]

[0081] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0082] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0147]

[0083] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0084] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0148]

[0085] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0086] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0149] In some embodiments, the compound is

[0150] [ka]

[0151] of,

[0152] [ka]

[0153] The molar ratio to is about 1:1 to about 1:20. In some embodiments, the compound is

[0154] [ka]

[0155] of,

[0156] [ka]

[0157] The molar ratio to is about 1:1. In some embodiments, the compound is

[0158] [ka]

[0159] of,

[0160] [ka]

[0161] The molar ratio to is about 1:2. In some embodiments, the compound is

[0162] [ka]

[0163] of,

[0164] [ka]

[0165] The molar ratio to is about 1:3. In some embodiments, the compound is

[0166] [ka]

[0167] of,

[0168] [ka]

[0169] The molar ratio to is about 1:4. In some embodiments, the compound is

[0170] [ka]

[0171] of,

[0172] [ka]

[0173] The molar ratio to is about 1:5. In some embodiments, the compound is

[0174] [ka]

[0175] of,

[0176] [ka]

[0177] The molar ratio to is about 1:10. In some embodiments, the compound is

[0178] [ka]

[0179] of,

[0180] [ka]

[0181] The molar ratio to is about 1:20. In some embodiments, the compound comprises a therapeutic agent having a modified structure.

[0096] In some embodiments, the compound comprises a therapeutic agent having a modified structure with choline or a choline derivative.

[0182] In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that comprises a choline or a choline derivative. In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that includes a choline or choline derivative-like residue.

[0183]

[0099] In some embodiments, the compound comprises a therapeutic agent comprising a [one or more choline or choline derivatives]-peptide derivative formed at a Glu residue, an Asp residue, or a combination thereof.

[0184]

[0100] In some embodiments, the compound includes a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0185]

[0101] In some embodiments, the compound comprises a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues.

[0102] In some embodiments, the compound comprises a therapeutic agent that includes a [choline or choline derivative]-peptide salt formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0186]

[0103] In some embodiments, the compound comprises a therapeutic agent that includes a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0187] In some embodiments, the compound comprises a therapeutic agent that includes a diacid that is 10, 12, 14, 16, 18, or 20 carbons in length.

[0105] In some embodiments, the diacid comprises a C10, C12, C14, C16, C18, or C20 fatty diacid.

[0188]

[0106] In some embodiments, the diacid comprises 1,20-icosane diacid. In another aspect herein, a compound of formula II:

[0189] [ka]

[0190] [In the formula, R 6 is a therapeutic agent; R 7 , R 8 , and R 9 are independently C1-C5 alkyl; n is 1, 2, 3, 4, or 5] Compounds according to the formula:

[0191] In some embodiments, R 7 , R 8 , and R 9 is methyl. In some embodiments, R 7 , R 8 , and R 9is ethyl. In some embodiments, R 7 , R 8 , and R 9 is propyl.

[0192] In some embodiments, R 7 and R 8 is methyl and R 9 is ethyl. In some embodiments, R 7 and R 9 is methyl and R 8 is ethyl.

[0193] In some embodiments, R 7 and R 8 is ethyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is ethyl, and R 8 is methyl.

[0194] In some embodiments, R 7 and R 8 is propyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is propyl, and R 8 is methyl.

[0195] In some embodiments, n is 1. In some embodiments, the compound has Formula IIa:

[0196] [ka]

[0197] It is a compound according to the following: In some embodiments, the compound has Formula IIb:

[0198] [ka]

[0199] It is a compound according to the following: In some embodiments, the compound has Formula IIc:

[0200] [ka]

[0201] It is a compound according to the following:

[0121] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0202]

[0122] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof. In some embodiments, the compound comprises the structure shown in Figure 17B.

[0203]

[0124] In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0204] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0205] In some embodiments, the therapeutic agent is an amylin analog having a structure shown in Figure 2, Figure 3, or Figure 4, or a functional variant thereof, or a mimetic or analog thereof.

[0206]

[0128] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0207]

[0129] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising the N14E amino acid substitution.

[0130] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0208]

[0131] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0209] In some embodiments, the therapeutic agent is: (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0210] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0211] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0212]

[0135] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0136] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0213]

[0137] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0138] In some embodiments, the therapeutic agent comprises the sequences of SEQ ID NO:3 and SEQ ID NO:6, the sequences of SEQ ID NO:4 and SEQ ID NO:6, or the sequences of SEQ ID NO:5 and SEQ ID NO:7.

[0214]

[0139] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0140] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0215]

[0141] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0142] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0216]

[0143] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0144] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:12 and the sequence of SEQ ID NO:14, or the sequence of SEQ ID NO:13 and the sequence of SEQ ID NO:15.

[0217]

[0145] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0146] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0218]

[0147] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0148] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19.

[0219]

[0149] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof comprising a [one or more choline or choline derivatives]-peptide ester formed at the C-terminus of the light chain, the C-terminus of the heavy chain, or a combination thereof.

[0220]

[0150] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof that includes a [one or more choline or choline derivatives]-peptide ester formed at a Cys residue, a Lys residue, or any combination thereof.

[0221]

[0151] In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Cys residues have a linker-to-antibody ratio of 2 to 8, and the [one or more choline or choline derivatives]-peptide esters formed at Lys residues have a linker-to-antibody ratio of 2 to 4, or a combination thereof.

[0222]

[0152] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0153] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0223]

[0154] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25. In some embodiments, the therapeutic agent is a C conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25. 20 Contains diacid-γ-Glu-(AEEA)2.

[0224] In some embodiments, the therapeutic agent is a C conjugated to a residue of the sequence of SEQ ID NO: 25. 20 Contains diacid-γ-Glu-(AEEA)2. In some embodiments, the therapeutic agent comprises a C 1 -C 2 -amino acid conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25. 20 Contains diacid-γ-Glu-(AEEA)2.

[0225]

[0158] In some embodiments, the compound comprises a therapeutic agent having a modified structure with choline or a choline derivative.

[0159] In some embodiments, the compound comprises a therapeutic agent having a salt structure modified with choline or a choline derivative.

[0226] In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that comprises a choline or a choline derivative.

[0161] In some embodiments, the compound comprises a therapeutic agent having an ester structure modified with choline or a choline derivative.

[0227] In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that includes a choline or choline derivative-like residue.

[0163] In some embodiments, the compound comprises a therapeutic agent comprising a [one or more choline or choline derivatives]-peptide ester formed at a Cys residue, a Lys residue, or any combination thereof.

[0228]

[0164] In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Cys residues have a linker to therapeutic agent ratio of 2 to 8, and the [one or more choline or choline derivatives]-peptide esters formed at Lys residues have a linker to therapeutic agent ratio of 2 to 4, or a combination thereof.

[0229]

[0165] In some embodiments, the compound comprises a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0230] In some embodiments, the compound comprises a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues.

[0167] In some embodiments, the compound comprises a therapeutic agent that includes a [choline or choline derivative]-peptide salt formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0231]

[0168] In some embodiments, the compound includes a therapeutic agent that includes a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0232] In some embodiments, the compound comprises a therapeutic agent that includes a diacid that is 10, 12, 14, 16, 18, or 20 carbons in length. In some embodiments, the diacid is C 10 , C 12 , C 14 , C 16 , C 18 , or C 20Contains fatty diacids.

[0233]

[0171] In some embodiments, the diacid comprises 1,20-icosane diacid. In another aspect herein, a compound of formula III:

[0234] [ka]

[0235] [In the formula, R 10 is a therapeutic agent; R 11 is substituted C5~C 10 , or unsubstituted C5-C 10 and; X 1 teeth,

[0236] [ka]

[0237] , -S-, or -NH-; L 1 is a covalent bond or a linker] Compounds according to the formula:

[0238] In some embodiments, L 1 is a non-cleavable linker. In some embodiments, L 1 comprises a maleimidoalkane linker or a maleimidocyclohexane linker.

[0239] In some embodiments, L 1 teeth,

[0240] [ka]

[0241] Includes. In some embodiments, L 1 is a chemically cleavable linker. In some embodiments, L 1 comprises a hydrazone linker or a disulfide linker.

[0242] In some embodiments, L 1 teeth,

[0243] [ka]

[0244] Includes. In some embodiments, R 11 is a substitution C 10 or unsubstituted C 10 is.

[0180] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0245]

[0181] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof.

[0182] In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0246]

[0183] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0247]

[0185] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0248]

[0186] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising the N14E amino acid substitution.

[0187] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0249]

[0188] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0250] In some embodiments, the therapeutic agent is: (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0251] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0252] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0253]

[0192] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0193] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0254]

[0194] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0195] In some embodiments, the therapeutic agent comprises the sequences of SEQ ID NO:3 and SEQ ID NO:6, the sequences of SEQ ID NO:4 and SEQ ID NO:6, or the sequences of SEQ ID NO:5 and SEQ ID NO:7.

[0255]

[0196] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0197] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0256]

[0198] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0199] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0257]

[0200] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0201] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:12 and the sequence of SEQ ID NO:14, or the sequence of SEQ ID NO:13 and the sequence of SEQ ID NO:15.

[0258]

[0202] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0203] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0259]

[0204] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0205] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19.

[0260] In some embodiments, the therapeutic agent comprises one or more R linked to the C-terminus of the light chain, the C-terminus of the heavy chain, or a combination thereof. 11 or an antibody fragment thereof comprising:

[0261]

[0207] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0208] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0262]

[0209] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0210] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0263]

[0211] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0212] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0264]

[0213] In some embodiments, the compound comprises a therapeutic agent having a modified structure with choline or a choline derivative.

[0214] In some embodiments, the compound comprises a therapeutic agent having a salt structure modified with choline or a choline derivative.

[0265]

[0215] In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that comprises a choline or a choline derivative.

[0216] In some embodiments, the compound comprises a therapeutic agent having an ester structure modified with choline or a choline derivative.

[0266]

[0217] In some embodiments, the compound comprises a therapeutic agent having a cationic moiety that includes a choline or choline derivative-like residue. In some embodiments, the compound comprises one or more R linked to a Lys residue, a Cys residue, or any combination thereof. 11 Therapeutic agents include:

[0267] In some embodiments, R 11 is linked to a Lys residue with a linker to therapeutic agent ratio of 2-4, or R 11 is linked to a Cys residue at a linker to therapeutic agent ratio of 2-8, or at a linker to therapeutic agent ratio of 4, or a combination thereof.

[0268]

[0220] In some embodiments, the compound comprises a therapeutic agent that comprises a dual conjugation.

[0221] In some embodiments, the dual conjugation has a linker to therapeutic agent ratio of 1-2.

[0269]

[0222] In some embodiments, the compound comprises a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0270]

[0223] In some embodiments, the compound comprises a therapeutic agent that includes a linker that includes one or more gamma glutamic acid (γGlu) residues.

[0224] In some embodiments, the compound includes a therapeutic agent that includes a [choline or choline derivative]-peptide salt formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0271]

[0225] In some embodiments, the compound comprises a therapeutic agent that includes a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0272]

[0226] In some embodiments, the compound comprises a therapeutic agent that includes a diacid that is 10, 12, 14, 16, 18, or 20 carbons in length. In some embodiments, the diacid is C 10 , C 12 , C 14 , C 16 , C 18 , or C 20 Contains fatty diacids.

[0273]

[0228] In some embodiments, the diacid comprises 1,20-icosane diacid.

[0229] In another aspect, provided herein are compositions comprising the compounds provided herein and one or more ionic liquids.

[0274]

[0230] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0275]

[0231] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0276]

[0233] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydroxycinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0277]

[0234] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0278]

[0235] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0279]

[0236] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0280]

[0237] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0281]

[0238] In some embodiments, the compositions presented herein further comprise at least one penetration enhancer. In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0282]

[0240] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0283]

[0241] In some embodiments, the compositions presented herein further comprise at least one pharmaceutically acceptable excipient.

[0242] Another aspect of the present invention is a method for treating a pulmonary arthritis, comprising: (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof A composition is presented in which:

[0284]

[0243] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0285]

[0244] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0286]

[0246] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydroxycinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0287]

[0247] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0288]

[0248] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0289]

[0249] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0290]

[0250] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0291]

[0251] In some embodiments, the solubility of the therapeutic agent is increased compared to the therapeutic agent in the composition without the ionic liquid.

[0252] In some embodiments, the delivery efficiency of the therapeutic agent in a subject in need thereof is enhanced or improved when administered to a subject compared to the therapeutic agent in a composition without the ionic liquid.

[0292]

[0253] In some embodiments, the compositions presented herein further comprise at least one penetration enhancer. In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0293]

[0255] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0294]

[0256] In another aspect of the present specification, there is provided a pharmaceutical composition comprising a compound presented herein or a composition presented herein and at least one pharmaceutically acceptable excipient.

[0295]

[0257] In some embodiments, the pharmaceutical compositions presented herein further comprise at least one penetration enhancer. In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0296]

[0259] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0297]

[0260] In another aspect herein, provided is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound presented herein, a composition presented herein, or a pharmaceutical composition presented herein, wherein the administering is effective to treat the disease or disorder in the subject.

[0298] In some embodiments, the disease or disorder is a metabolic disease or disorder.

[0262] In some embodiments, the disease or disorder is diabetes.

[0299] In some embodiments, the disease or disorder is type 1 diabetes mellitus (T1DM). In some embodiments, the disease or disorder is type 2 diabetes mellitus (T2DM).

[0265] In some embodiments, the disease or disorder is non-alcoholic steatohepatitis (NASH).

[0300]

[0266] In some embodiments, the disease or disorder is obesity or overweight.

[0267] In some embodiments, the administration activates GIP receptor signaling, GLP-1 receptor signaling, or a combination thereof.

[0301]

[0268] In some embodiments, administration increases or improves glucose-dependent insulin secretion, improves glucose tolerance, or a combination thereof.

[0302]

[0269] In some embodiments, administration increases or improves glycemic control.

[0270] In some embodiments, administration decreases or reduces fasting serum glucose.

[0303]

[0271] In some embodiments, administration results in or reduces body weight, reduces or reduces food intake, or a combination thereof.

[0304]

[0272] In some embodiments, administration effects improvement in glycemic control, body weight, or a combination thereof. In some embodiments, the disease or disorder is an autoimmune disease or disorder, or an immune disease or disorder.

[0305]

[0274] In some embodiments, the disease or disorder is Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Behcet's disease, plaque psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis, plaque psoriasis, multiple sclerosis, or eosinophilic esophagitis.

[0306]

[0275] In another aspect herein, provided is a method for treating obesity, preventing weight gain, or reducing weight in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound presented herein, a composition presented herein, or a pharmaceutical composition presented herein, wherein the administering step is effective to treat a disease or disorder in the subject.

[0307]

[0276] In some embodiments, the composition, compound, or pharmaceutical composition is administered via subcutaneous administration, intravenous administration, or oral administration. In some embodiments, the composition, compound, or pharmaceutical composition is administered orally.

[0308]

[0278] In some embodiments, the composition, compound, or pharmaceutical composition is administered as a liquid-filled capsule. In some embodiments, the composition, compound, or pharmaceutical composition is administered in multiple doses.

[0309]

[0280] In some embodiments, the composition, compound, or pharmaceutical composition is administered in a single dose.

[0281] In some embodiments, the composition, compound, or pharmaceutical composition is administered to a mucosa.

[0310]

[0282] In some embodiments, the composition, compound, or pharmaceutical composition is administered via subcutaneous administration, intravenous administration, or oral administration.

[0283] In some embodiments, the concentration of a compound presented herein is at least 0.1% weight per volume.

[0311]

[0284] In some embodiments, the concentration of a compound presented herein is at least 0.05M.

[0285] In some embodiments, the composition further comprises one or more additional agents.

[0312]

[0286] In some embodiments, the one or more additional agents are selected from the group consisting of nucleic acids, small molecules, and polypeptides.

[0287] In some embodiments, the one or more additional agents is a nucleic acid.

[0313] In some embodiments, the one or more additional agents are small molecules.

[0289] In some embodiments, the one or more additional agents is a polypeptide.

[0314]

[0290] In some embodiments, the one or more additional agents is a polypeptide.

[0291] In some embodiments, the one or more additional agents are therapeutic agents that treat a metabolic disease or disorder.

[0315]

[0292] In some embodiments, the one or more additional agents is a therapeutic agent that treats diabetes.

[0293] In some embodiments, the one or more additional agents is a therapeutic agent that treats type 2 diabetes mellitus (T2DM).

[0316]

[0294] In some embodiments, the one or more additional agents is a therapeutic agent that treats obesity or overweight.

[0295] In another aspect herein, there is provided a method for increasing the solubility of a therapeutic agent, comprising:

[0317] [ka]

[0318] [In the formula, R 1 , R 2 , and R 3 are independently C1-C5 alkyl; R 4is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a therapeutic agent; The therapeutic agent is (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof is] A method is presented comprising preparing a composition comprising a compound according to

[0319]

[0296] In another aspect herein, there is provided a method for enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof, comprising administering to a subject a compound of Formula I:

[0320] [ka]

[0321] [In the formula, R 1 , R 2 , and R 3 are independently C1-C5 alkyl; R 4 is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a therapeutic agent; The therapeutic agent is (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof is] A method is presented comprising preparing a composition comprising a compound according to

[0322] In some embodiments, R 1 , R 2 , and R 3 is methyl. In some embodiments, R 1 , R 2 , and R 3 is ethyl. In some embodiments, R 1 , R 2 , and R 3 is propyl.

[0323] In some embodiments, R 1 and R 2 is methyl and R 3 is ethyl. In some embodiments, R 1 and R 3 is methyl and R 2 is ethyl.

[0324] In some embodiments, R 1 and R 2 is ethyl, and R 3 is methyl. In some embodiments, R 1and R 3 is ethyl, and R 2 is methyl.

[0325] In some embodiments, R 1 and R 2 is propyl, and R 3 is methyl. In some embodiments, R 1 and R 3 is propyl, and R 2 is methyl.

[0326] In some embodiments, R 4 is a C2-C5 alkyl substituted with hydroxyl. In some embodiments, R 4 teeth,

[0327] [ka]

[0328] is. In some embodiments, the compound has Formula Ia:

[0329] [ka]

[0330] It is a compound according to the following: In some embodiments, the compound has Formula Ib:

[0331] [ka]

[0332] It is a compound according to the following: In some embodiments, the compound has Formula Ic:

[0333] [ka]

[0334] It is a compound according to the following:

[0311] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0335]

[0312] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof. In some embodiments, the compound comprises the structure shown in FIG.

[0336] In some embodiments, the compound is

[0337] [ka]

[0338] of,

[0339] [ka]

[0340] The molar ratio to is about 1:1 to about 1:60. In some embodiments, the compound is

[0341] [ka]

[0342] of,

[0343] [ka]

[0344] The molar ratio of the compound to the compound is about 1:1 to about 1:30. In some embodiments, the compound is

[0345] [ka]

[0346] of,

[0347] [ka]

[0348] The molar ratio to is about 1:1. In some embodiments, the compound is

[0349] [ka]

[0350] of,

[0351] [ka]

[0352] The molar ratio to is about 1:3. In some embodiments, the compound is

[0353] [ka]

[0354] of,

[0355] [ka]

[0356] The molar ratio to is about 1:4. In some embodiments, the compound is

[0357] [ka]

[0358] The molar ratio of In some embodiments, the compound is

[0359] [ka]

[0360] The molar ratio of In some embodiments, the compound is

[0361] [ka]

[0362] The molar ratio of In some embodiments, the compound is

[0363] [ka]

[0364] The molar ratio of In some embodiments, the compound is

[0365] [ka]

[0366] The molar ratio of

[0324] In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0367]

[0325] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0368]

[0327] In some embodiments, the therapeutic agent is an amylin analog having a structure shown in Figure 2, Figure 3, or Figure 4, or a functional variant thereof, or a mimetic or analog thereof.

[0369]

[0328] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0370]

[0329] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising the N14E amino acid substitution. In some embodiments, the compound is

[0371] [ka]

[0372] of,

[0373] [ka]

[0374] The molar ratio of the compound to the compound is about 1:1 to about 1:30. In some embodiments, the compound is

[0375] [ka]

[0376] of,

[0377] [ka]

[0378] The molar ratio to is about 1:1. In some embodiments, the compound is

[0379] [ka]

[0380] of,

[0381] [ka]

[0382] The molar ratio to is about 1:3. In some embodiments, the compound is

[0383] [ka]

[0384] The molar ratio of In some embodiments, the compound is

[0385] [ka]

[0386] of,

[0387] [ka]

[0388] The molar ratio to is about 1:12. In some embodiments, the compound is

[0389] [ka]

[0390] The molar ratio of

[0336] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0337] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0391] In some embodiments, the therapeutic agent is: (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0392] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0393] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0394]

[0341] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0342] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0395] In some embodiments, the compound is

[0396] [ka]

[0397] of,

[0398] [ka]

[0399] The molar ratio to is about 1:1 to about 1:164. In some embodiments, the compound is

[0400] [ka]

[0401] of,

[0402] [ka]

[0403] The molar ratio to is about 1:1. In some embodiments, the compound is

[0404] [ka]

[0405] of,

[0406] [ka]

[0407] The molar ratio to is about 1:33. In some embodiments, the compound is

[0408] [ka]

[0409] of,

[0410] [ka]

[0411] The molar ratio to is about 1:41. In some embodiments, the compound is

[0412] [ka]

[0413] of,

[0414] [ka]

[0415] The molar ratio to is about 1:66. In some embodiments, the compound is

[0416] [ka]

[0417] of,

[0418] [ka]

[0419] The molar ratio to is about 1:82. In some embodiments, the compound is

[0420] [ka]

[0421] of,

[0422] [ka]

[0423] The molar ratio to is about 1:132. In some embodiments, the compound is

[0424] [ka]

[0425] of,

[0426] [ka]

[0427] The molar ratio to is about 1:164.

[0351] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0352] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:3 and the sequence of SEQ ID NO:6, the sequence of SEQ ID NO:4 and the sequence of SEQ ID NO:6, or the sequence of SEQ ID NO:5 and the sequence of SEQ ID NO:7.

[0428] In some embodiments, the compound is

[0429] [ka]

[0430] of,

[0431] [ka]

[0432] The molar ratio to is about 1:1 to about 1:144.

[0354] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0355] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0433] In some embodiments, the compound is

[0434] [ka]

[0435] of,

[0436] [ka]

[0437] The molar ratio to is about 1:1 to about 1:140.

[0357] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0358] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0438] In some embodiments, the compound is

[0439] [ka]

[0440] of,

[0441] [ka]

[0442] The molar ratio of the compound to the compound is about 1:1 to about 1:80.

[0360] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0361] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15.

[0443] In some embodiments, the compound is

[0444] [ka]

[0445] of,

[0446] [ka]

[0447] The molar ratio to is about 1:1 to about 1:156.

[0363] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0364] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0448] In some embodiments, the compound is

[0449] [ka]

[0450] of,

[0451] [ka]

[0452] The molar ratio to is about 1:1 to about 1:256.

[0366] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0453]

[0367] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19. In some embodiments, the compound is

[0454] [ka]

[0455] of,

[0456] [ka]

[0457] The molar ratio to is about 1:1 to about 1:70.

[0369] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0458] In some embodiments, R 5 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25. In some embodiments, R 5 comprises the sequence of SEQ ID NO:25.

[0459] In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0460] In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25. In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0461] In some embodiments, the compound is

[0462] [ka]

[0463] of,

[0464] [ka]

[0465] The molar ratio to is about 1:1 to about 1:20. In some embodiments, the compound is

[0466] [ka]

[0467] of,

[0468] [ka]

[0469] The molar ratio to is about 1:1. In some embodiments, the compound is

[0470] [ka]

[0471] of,

[0472] [ka]

[0473] The molar ratio to is about 1:2. In some embodiments, the compound is

[0474] [ka]

[0475] of,

[0476] [ka]

[0477] The molar ratio to is about 1:3. In some embodiments, the compound is

[0478] [ka]

[0479] of,

[0480] [ka]

[0481] The molar ratio to is about 1:4. In some embodiments, the compound is

[0482] [ka]

[0483] of,

[0484] [ka]

[0485] The molar ratio to is about 1:5. In some embodiments, the compound is

[0486] [ka]

[0487] of,

[0488] [ka]

[0489] The molar ratio to is about 1:10. In some embodiments, the compound is

[0490] [ka]

[0491] of,

[0492] [ka]

[0493] The molar ratio to is about 1:20.

[0383] In another aspect herein, there is provided a method for increasing the solubility of a therapeutic agent, comprising:

[0494] [ka]

[0495] [In the formula, R 6 is a therapeutic agent, and the therapeutic agent is (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof and; R 7 , R 8 , and R 9 are independently unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl; n is 1, 2, 3, 4, or 5] A method is presented comprising preparing a composition comprising a compound according to

[0496]

[0384] In another aspect herein, there is provided a method for enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof, comprising administering to a subject a compound of Formula II:

[0497] [ka]

[0498] [In the formula, R 6 is a therapeutic agent, and the therapeutic agent is (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof and; R 7 , R 8 , and R 9 are independently unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl; n is 1, 2, 3, 4, or 5] preparing a composition comprising a compound according to Administering the composition to a subject A method is presented that includes:

[0499] In some embodiments, R 7 , R 8 , and R 9 is methyl. In some embodiments, R 7 , R 8 , and R 9 is ethyl. In some embodiments, R 7 , R 8 , and R 9 is propyl.

[0500] In some embodiments, R 7 and R 8is methyl and R 9 is ethyl. In some embodiments, R 7 and R 9 is methyl and R 8 is ethyl.

[0501] In some embodiments, R 7 and R 8 is ethyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is ethyl, and R 8 is methyl.

[0502] In some embodiments, R 7 and R 8 is propyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is propyl, and R 8 is methyl.

[0503] In some embodiments, n is 1. In some embodiments, the compound has Formula IIa:

[0504] [ka]

[0505] It is a compound according to the following: In some embodiments, the compound has Formula IIb:

[0506] [ka]

[0507] It is a compound according to the following: In some embodiments, the compound has Formula IIc:

[0508] [ka]

[0509] It is a compound according to the following:

[0398] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0510]

[0400] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof.

[0400] In some embodiments, the compound comprises the structure shown in Figure 17B.

[0511]

[0401] In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0512]

[0402] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0513]

[0404] In some embodiments, the therapeutic agent is an amylin analog having a structure shown in Figure 2, Figure 3, or Figure 4, or a functional variant thereof, or a mimetic or analog thereof.

[0514]

[0405] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0515]

[0406] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising the N14E amino acid substitution.

[0407] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0516]

[0408] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0517] In some embodiments, the therapeutic agent is: (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0518] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0519] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0520]

[0412] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0413] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0521]

[0414] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0415] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:3 and the sequence of SEQ ID NO:6, the sequence of SEQ ID NO:4 and the sequence of SEQ ID NO:6, or the sequence of SEQ ID NO:5 and the sequence of SEQ ID NO:7.

[0522]

[0416] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0417] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0523]

[0418] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0419] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0524]

[0420] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0421] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15.

[0525]

[0422] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0423] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0526]

[0424] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0425] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19.

[0527]

[0426] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide. In some embodiments, R 6 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0528] In some embodiments, R 6 comprises the sequence of SEQ ID NO:25. In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0529] In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25. In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0530]

[0432] In some embodiments, the composition further comprises one or more ionic liquids.

[0433] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0531]

[0434] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0532]

[0436] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0533]

[0437] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0534]

[0438] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0535]

[0439] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0536]

[0440] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0537]

[0441] In another aspect herein, there is provided a method for increasing the solubility of a therapeutic agent, comprising preparing a composition comprising the therapeutic agent and one or more ionic liquids; The therapeutic agent, (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof A method is presented.

[0538]

[0442] Another aspect of the present specification provides a method of enhancing or improving delivery efficiency of a therapeutic agent in a subject in need thereof, the method comprising the steps of preparing a composition comprising the therapeutic agent and one or more ionic liquids; administering the composition to a subject; The therapeutic agent, (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof A method is presented.

[0539]

[0443] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0540]

[0444] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0541]

[0446] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0542]

[0447] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0543]

[0448] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0544]

[0449] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0545]

[0450] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0546]

[0451] In another aspect herein, there is provided a method for increasing the hydrophobicity of a therapeutic agent, comprising: 12 to a therapeutic agent, R 12 However, substitution C5~C 10 , or unsubstituted C5-C 10 and; The therapeutic agent, (i) GLP-1 analogs or functional variants thereof, or mimetics thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin; (ii) amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof; (iii) an antibody or antibody fragment thereof; or (iv) GIP / GLP-1 receptor dual agonist or a functional variant thereof A method is presented.

[0547] In some embodiments, R 12 is the therapeutic agent

[0548] [ka]

[0549] , -S-, or -NH-. In some embodiments, R 12 is linked to the therapeutic agent via a covalent bond or a linker.

[0550]

[0454] In some embodiments, the linker is a non-cleavable linker.

[0455] In some embodiments, the linker comprises a maleimidoalkane linker or a maleimidocyclohexane linker.

[0551] In some embodiments, the linker is:

[0552] [ka]

[0553] Includes.

[0457] In some embodiments, the linker is a chemically cleavable linker.

[0458] In some embodiments, the linker comprises a hydrazone linker or a disulfide linker.

[0554] In some embodiments, the linker is:

[0555] [ka]

[0556] Includes. In some embodiments, R 12 is a substitution C 10 or unsubstituted C 10 is.

[0461] In some embodiments, the therapeutic agent is a GLP-1 analog or functional variant thereof, or a mimetic thereof, liraglutide, exenatide, peptide YY (tyrosine tyrosine), glucagon, GIP (gastric inhibitory polypeptide), or amylin.

[0557]

[0462] In some embodiments, the therapeutic agent is a GLP-1 analog or a functional variant thereof, or a mimetic thereof.

[0463] In some embodiments, the therapeutic agent is amylin or a mimetic or analog thereof, or an amylin analog or functional variant thereof, or a mimetic or analog thereof.

[0558]

[0464] In some embodiments, the therapeutic agent is an amylin analog or a functional variant thereof, or a mimetic or analog thereof. In some embodiments, the therapeutic agent is: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide or a functional variant thereof, or a mimetic or analog thereof.

[0559]

[0466] In some embodiments, the therapeutic agent is an amylin analog having a structure shown in Figure 2, Figure 3, or Figure 4, or a functional variant thereof, or a mimetic or analog thereof.

[0560]

[0467] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.

[0561]

[0468] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof, or a mimetic or analog thereof, comprising the N14E amino acid substitution.

[0469] In some embodiments, the therapeutic agent is an antibody or antibody fragment thereof.

[0562]

[0470] In some embodiments, the therapeutic agent is any one selected from the group consisting of infliximab or its antibody fragment, adalimumab or its antibody fragment, ustekinumab or its antibody fragment, golimumab or its antibody fragment, natalizumab or its antibody fragment, vedolizumab or its antibody fragment, and certolizumab pegol or its antibody fragment.

[0563] In some embodiments, the therapeutic agent is: (i) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 2, or a combination thereof; (ii) a sequence with at least 75% sequence identity to SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, a sequence with at least 75% sequence identity to SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 8, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 9, or a combination thereof; (iv) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 10, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 16, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 18, a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof. Includes.

[0564] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, the sequence of SEQ ID NO: 2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6, or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO: 8, the sequence of SEQ ID NO: 9, or a combination thereof; (iv) the sequence of SEQ ID NO: 10, the sequence of SEQ ID NO: 11, or a combination thereof; (v) the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, the sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or any combination thereof; (vi) the sequence of SEQ ID NO: 16, the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) the sequence of SEQ ID NO: 18, the sequence of SEQ ID NO: 19, or a combination thereof Includes.

[0565] In some embodiments, the therapeutic agent is: (i) the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2; (ii) the sequences of SEQ ID NO: 3 and SEQ ID NO: 6, the sequences of SEQ ID NO: 4 and SEQ ID NO: 6, or the sequences of SEQ ID NO: 5 and SEQ ID NO: 7; (iii) the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9; (iv) the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11; (v) the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15; (vi) the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17; or (vii) the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19 Includes.

[0566]

[0474] In some embodiments, the therapeutic agent is infliximab or an antibody fragment thereof.

[0475] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:1 or SEQ ID NO:24 and the sequence of SEQ ID NO:2.

[0567]

[0476] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof.

[0477] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:3 and the sequence of SEQ ID NO:6, the sequence of SEQ ID NO:4 and the sequence of SEQ ID NO:6, or the sequence of SEQ ID NO:5 and the sequence of SEQ ID NO:7.

[0568]

[0478] In some embodiments, the therapeutic agent is ustekinumab or an antibody fragment thereof.

[0479] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9.

[0569]

[0480] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof.

[0481] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11.

[0570]

[0482] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof.

[0483] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 14, or the sequence of SEQ ID NO: 13 and the sequence of SEQ ID NO: 15.

[0571]

[0484] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.

[0485] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17.

[0572]

[0486] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.

[0487] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19.

[0573]

[0488] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0489] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0574]

[0490] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0491] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.

[0575]

[0492] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0493] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0576]

[0494] In some embodiments, the therapeutic agent is linked to one or more fatty acids or carboxylic acid-containing molecules.

[0495] In some embodiments, the therapeutic agent is linked to one or more fatty acids or carboxylic acid-containing molecules via dual conjugation.

[0577]

[0496] In some embodiments, the one or more fatty acid or carboxylic acid-containing molecules include cinnamic acid.

[0497] In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of the therapeutic agent.

[0578]

[0500] In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine within the peptide backbone of the therapeutic agent.

[0499] In some embodiments, one or more fatty acid or carboxylic acid-containing molecules are non-covalently associated with an amine group of a Gln residue, an amine group of an Asn residue, an amine group of an Arg residue, an amine group of a Lys residue, an amine group of a His residue, or a combination thereof, of a therapeutic agent.

[0579]

[0500] In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of the therapeutic agent.

[0501] In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine within the peptide backbone of the therapeutic agent.

[0580]

[0502] In some embodiments, one or more fatty acid or carboxylic acid-containing molecules are covalently conjugated to an amine group of a Gln residue, an amine group of an Asn residue, an amine group of an Arg residue, an amine group of a Lys residue, an amine group of a His residue, or a combination thereof, of a therapeutic agent.

[0581]

[0503] In another aspect, the present specification provides a method for enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof, the method comprising adding at least one penetration enhancer to a compound presented herein, a composition presented herein, or a pharmaceutical composition presented herein, and administering the composition, compound, or pharmaceutical composition to the subject.

[0582]

[0504] In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0583]

[0505] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof. [Brief explanation of the drawings]

[0584] [Figure 1]

[0506] Figure depicting the structure of exemplary amylin analogs or functional variants thereof, or mimetics thereof. [Figure 2]

[0507] A diagram depicting an exemplary embodiment of an amylin analog or a functional variant thereof, or a mimic thereof, with a modified structure of the amylin analog or a functional variant thereof, or a mimic thereof. [Figure 3]

[0508] A figure depicting an exemplary embodiment of an amylin analog or a functional variant thereof, or a mimic thereof, with a derivative structure of the amylin analog or a functional variant thereof, or a mimic thereof, modified by choline. [Figure 4]

[0509] A figure depicting an exemplary embodiment of an amylin analog or a functional variant thereof, or a mimic thereof, with the ester structure of the amylin analog or a functional variant thereof, or a mimic thereof, modified by choline. [Figure 5]

[0510] Figure 1 depicts an exemplary embodiment of an antibody or antibody fragment thereof comprising a choline-peptide derivative formed at the C-terminal carboxylic acid of the heavy chain. [Figure 6A]

[0511] Figure 6A depicts an exemplary embodiment of an antibody or antibody fragment thereof comprising a choline-peptide ester formed at the C-terminal carboxylic acid of the heavy chain. Figure 6B depicts an exemplary chemical reaction for preparing a covalent choline derivative of an antibody or antibody fragment thereof (e.g., choline-antibody conjugation via a covalent ester). [Figure 6B]

[0511] Figure 6A depicts an exemplary embodiment of an antibody or antibody fragment thereof comprising a choline-peptide ester formed at the C-terminal carboxylic acid of the heavy chain. Figure 6B depicts an exemplary chemical reaction for preparing a covalent choline derivative of an antibody or antibody fragment thereof (e.g., choline-antibody conjugation via a covalent ester). [Figure 7]

[0512] Figure 1 depicts exemplary embodiments of an antibody or antibody fragment thereof comprising a choline-peptide ester formed at a Cys or Lys residue of the heavy chain of the antibody or antibody fragment thereof. In some embodiments, the linker-to-antibody ratio (LAR) for cysteine ​​conjugation is 2 to 8. In some embodiments, the linker-to-antibody ratio (LAR) for lysine conjugation is 2 to 4. [Figure 8A]

[0513] Figure 1 depicts an exemplary embodiment of an antibody or antibody fragment thereof linked to a fatty acid on the C-terminal carboxylic acid of the heavy chain. The fatty acid can include other lengths between C5 (hexanoic acid) and C10 (decanoic acid). [Figure 8B] FIG. 1 depicts an exemplary chemical reaction for preparing an antibody or antibody fragment thereof linked to a fatty acid. [Figure 8C] FIG. 1 depicts exemplary linkers that can be used to link an antibody or antibody fragment thereof linked to a fatty acid. [Figure 8D] FIG. 1 depicts exemplary fatty acids that can be linked to an antibody or antibody fragment thereof. [Figure 9A]

[0514] Figure 1 depicts exemplary embodiments of an antibody or antibody fragment thereof linked to a fatty acid via dual conjugation, or a fatty acid at a Lys or Cys residue of an antibody or antibody fragment thereof, or a fatty acid of the heavy chain. In some embodiments, the linker-to-antibody ratio (LAR) is 2 to 4 for lysine conjugation. In some embodiments, the linker-to-antibody ratio (LAR) is 2 to 8 for cysteine ​​conjugation. In some embodiments, the linker-to-antibody ratio (LAR) is 4 for cysteine ​​conjugation. In some embodiments, the linker-to-antibody ratio (LAR) is 1 to 2 for an antibody or antibody fragment thereof linked to a fatty acid via dual conjugation. [Figure 9B]FIG. 1 depicts an exemplary chemical reaction for preparing an antibody or antibody fragment thereof linked to a fatty acid via dual conjugation. [Figure 10]

[0515] Figure 1 depicts exemplary choline and choline derivatives. [Figure 11]

[0516] Figure 1 depicts the structure of an exemplary GIP / GLP-1 receptor dual agonist. [Figure 12]

[0517] Figure 1 depicts structural schematics for exemplary GIP / GLP-1 receptor dual agonists. [Figure 13]

[0518] Figure 1 depicts exemplary embodiments of ionic derivative structures of choline-modified GIP / GLP-1 receptor dual agonists using an exemplary GIP / GLP-1 receptor dual agonist scaffold. Circles indicate exemplary sites of ionizable amino acid side chains or carboxyl groups. [Figure 14]

[0519] Figure 1 depicts exemplary embodiments of ester structures of choline-modified GIP / GLP-1 receptor dual agonists using an exemplary GIP / GLP-1 receptor dual agonist scaffold. Circles indicate exemplary sites of potential esterification. [Figure 15A]

[0520] Figure 1 depicts the sequences of exemplary GLP-1 analogs or functional variants thereof, or mimetics thereof. [Figure 15B]

[0521] Figure 1 depicts the sequence of another exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 16]

[0522] Figure 1 depicts an exemplary embodiment for a compound according to Formula I. [Figure 17A]

[0523] A diagram depicting an exemplary form of covalent bonding. [Figure 17B]

[0524] Figure 1 depicts an exemplary embodiment for a compound according to Formula II. [Figure 18]

[0525] Figure 1 depicts the chemical structures of exemplary forms of cinnamic acid derivatives. [Figure 19]

[0526] Figure 1 depicts an exemplary process in which an ionic liquid is prepared by mixing an acid with a bicarbonate salt of choline or a choline derivative. [Figure 20A]

[0527] Figures 20A-20D depict exemplary chemical structure variations of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof]. Figure 20A depicts the chemical structure of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 20B] Figures 20A-20D depict exemplary chemical structure variations of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof]. Figure 20B depicts an exemplary structure of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] in a 1:1 ratio. In some embodiments, ionization of choline could occur at either of the -COOH sites. [Figure 20C] Figures 20A-20D depict exemplary chemical structure variations of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof]. Figure 20C depicts an exemplary structure of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] at a ratio of 7:1. [Figure 20D] Figures 20A-20D depict exemplary chemical structure variations of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof]. Figure 20D depicts an exemplary structure of choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] in a ratio of 28:1. In some embodiments, an excess of bicarbonate ions is also present in a ratio of 28:1. [Figure 21]

[0528] Figure 3 depicts Table 3 showing mass normalization calculations for exemplary GLP-1 analogs or functional variants thereof, or mimetics thereof ("GLP-1 analogs"). [Figure 22]

[0529] Figure 1 shows exemplary analytical characterization of exemplary GLP-1 analogs or functional variants thereof, or mimetics thereof ("GLP-1 analogs") based on high performance liquid chromatography (HPLC). [Figure 23A]

[0530] Figures 23A-23D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH. Figure 23A depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH using a 2 mg / mL aqueous solution. The results are not normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 23B] Figures 23A-23D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH. Figure 23B depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH using a 2 mg / mL aqueous solution. The results for choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 23C]Figures 23A-23D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH. Figure 23C depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH using a 2 mg / mL aqueous solution in which the exemplary reaction using choline bicarbonate shown in the graph above was used. The results for choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 23D] Figures 23A-23D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH. Figure 23D depicts the results of an exemplary analytical characterization of a negative control of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on pH using a 2 mg / mL aqueous solution in which the exemplary reaction using choline chloride shown in the graph above was used. The results for choline-Cl- [exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 24A]

[0531] Figures 24A-24D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity. Figure 24A depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity using a 2 mg / mL aqueous solution. The results are not normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 24B]Figures 24A-24D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity. Figure 24B depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity using a 2 mg / mL aqueous solution. The results for choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 24C] Figures 24A-24D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity. Figure 24C depicts the results of an exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity using a 2 mg / mL aqueous solution in which the exemplary reaction using choline bicarbonate shown in the graph above was used. The results for choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 24D]Figures 24A-24D depict exemplary analytical characterization of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity. Figure 24D depicts the results of an exemplary analytical characterization of a negative control of an exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog") based on conductivity, using a 2 mg / mL aqueous solution of choline chloride, in which the exemplary reaction shown in the graph above was used. The results for choline-Cl- [exemplary GLP-1 analog or functional variant thereof, or mimic thereof] are normalized to the mass of the exemplary GLP-1 analog or functional variant thereof, or mimic thereof. [Figure 25A]

[0532] Figures 25A and 25B depict exemplary analytical characterizations of the NMR-based choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog")] ratio. Figure 25A depicts the results of an exemplary analytical characterization of the NMR-based choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog")] ratio. [Figure 25B] Figures 25A and 25B depict an exemplary analytical characterization of the NMR-based choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog")] ratio. Figure 25B depicts a zoomed-in result of an exemplary analytical characterization of the NMR-based choline-[exemplary GLP-1 analog or functional variant thereof, or mimic thereof ("GLP-1 analog")] ratio. [Figure 26]

[0533] Figure 1 shows an exemplary analytical characterization based on Fourier transform infrared spectroscopy (FTIR). [Figure 27]

[0534] Figure 1 depicts an exemplary embodiment of a cinnamic acid-[glucagon-like peptide (GLP-1) analog or functional variant thereof, or mimetic thereof]. DETAILED DESCRIPTION OF THE INVENTION

[0585] The present invention describes the modification of drugs with ions to improve their formulation with ionic liquids for oral administration to treat patients. Oral administration can be achieved through any one of the following dosage forms: pill, caplet, capsule, aerosol spray, or liquid. The ionic liquid or drug delivered with the ionic liquid can be encapsulated in a capsule. The ionic liquid-containing dosage form can be in any of the following physical forms: clear, pure ionic liquid, a homogeneous mixture of the ionic liquid with a pharmaceutically acceptable diluent, an emulsion, or a suspension. Oral administration can also be administered as a syrup, spray, or aerosol. Any of the oral administration compositions disclosed herein can contain a predetermined amount of ionic liquid and, optionally, a drug, and can be prepared by methods well known to those skilled in the art.

[0586]

[0536] In one embodiment, described herein is a method of treating a patient comprising orally administering an oral formulation of insulin in combination with an ionic liquid.

[0537] In one embodiment, the present specification describes a method for treating diabetes, comprising orally administering an oral formulation of an amylin analog or functional variant thereof, or a mimetic thereof, or a GLP-1 polypeptide, or a mimetic or analog thereof, in combination with an ionic liquid.

[0587]

[0538] As described elsewhere herein, ionic liquids are capable of safely transporting active compounds across mucous membranes with which they are contacted upon oral administration. As described in the Examples herein, ionic liquids enhance drug solubilization and delivery to the systemic circulation, making them particularly suitable as delivery vehicles to / through mucosal membranes.

[0588] In one embodiment, an ionic liquid may be combined with another solvent to enhance solubility and / or delivery. The solvent may be aqueous or non-aqueous. In one embodiment, the purpose of the solvent is to control the dose of ionic liquid that contacts the mucosa or gastrointestinal tract. Dilution of the ionic liquid with a solvent is used to deliver a safe dose to the subject. In another embodiment, the purpose of the solvent is to improve the solubility of the drug. Such improvement may result from the solvent's ability to control the physicochemical environment of the ionic liquid to match the chemical properties of the drug. In one embodiment, a solvent may be used to improve delivery across mucosa.

[0589]

[0541] Solvents used in any of the embodiments include, but are not limited to, sterile water, saline solution, glycerin, propylene glycol, ethanol, oil, ethyl oleate, isopropyl myristate, benzyl benzoate, or surfactants.

[0590]

[0542] In one embodiment, the solvent is selected so as not to adversely affect the compatibility of the ionic liquid with the capsule. As used herein, the term "ionic liquid" refers to an organic salt or mixture of organic salts that is in a liquid state at room temperature. Ionic liquids have been shown to be useful in a variety of fields, including industrial processing, catalysis, medicine, and electrochemistry. Ionic liquids contain at least one anionic component and at least one cationic component. Ionic liquids can include additional hydrogen bond donors (i.e., any molecule that can provide an -OH or -NH group); examples include, but are not limited to, alcohols, fatty acids, and amines. The anionic and cationic components can be present in any molar ratio. Exemplary molar ratios (cation:anion ratio) include, but are not limited to, 1:1, 1:2, 2:1, and ranges between these ratios. In some embodiments, the ionic liquid or solvent exists as a liquid below 100°C. In some embodiments, the ionic liquid or solvent exists as a liquid at room temperature. In some embodiments, the ionic liquid includes more than one anionic component and one cationic component. In some embodiments, the ionic liquid comprises choline or a choline derivative, cinnamic acid, and mandelic acid.

[0591] In some embodiments, ionic liquids are dominated by ionic interactions between anions and cations. In some embodiments, ionic liquids are dominated by hydrogen bonding interactions between anions and cations. The relative dominance of ionic and hydrogen bonding interactions can vary depending on the nature of the ions.

[0592]

[0545] As used herein, "in combination with" refers to two or more substances present in the same dosage form, in any form, administered to a subject. In some embodiments, the drug(s) may form micelles or other self-assembled structures, which may occur only in the presence of an ionic liquid.

[0593] As used herein, the terms "therapeutic agent" and "drug" are used interchangeably. A therapeutic agent or drug is any agent that has an effect on a target cell or target organism. The drug may be selected from the group including: a chemical; a small organic or inorganic molecule; a peptide; a protein; or a nucleic acid. Non-limiting examples of active compounds contemplated for use in the methods described herein include small molecules, polypeptides, nucleic acids, antibodies, vaccines, antibodies or antibody fragments thereof, GLP-1 polypeptides or mimetics or analogs thereof, amylin, amylin analogs or functional variants thereof or mimetics thereof, PYY, pramlintide, and insulin.

[0594]

[0548] In some embodiments, the terms "mimetic," "functional variant," "functional analog," or "functional homolog" may be used interchangeably. GIP / GLP-1 receptor dual agonist or functional variant thereof, or mimic or functional analogue thereof, or functional homologue thereof In some embodiments, the GIP (glucose-dependent insulinotropic polypeptide) / GLP-1 (glucagon-like peptide-1) receptor dual agonist or functional variant thereof is tirzepatide or a functional variant thereof, or a mimetic or functional analog thereof, or a functional homolog thereof. As used herein, "tirzepatide," also known as LY3298176 and GIP / GLP-1 RA, refers to a fatty acid-modified peptide with glucose-dependent insulinotropic polypeptide (GIP) / glucagon-like peptide-1 (GLP-1) receptor dual agonist activity. In some embodiments, tirzepatide is a GIP / GLP-1 receptor dual agonist.

[0595] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is a GIP-based dual incretin receptor dual agonist. In some embodiments, GIP and GLP-1 are hormones involved in glycemic control. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof activates both the GLP-1 receptor and the GIP receptor. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof activates signaling through both the GIP receptor and the GLP-1 receptor. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof improves glucose-dependent insulin secretion and glucose tolerance by acting on both the GIP receptor and the GLP-1 receptor. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof improves glycemic control. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof reduces body weight and food intake. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof exhibits metabolic effects of GIP that augment the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof reduces fasting serum glucose. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof results in weight loss. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to treat diabetes. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to treat type 2 diabetes. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to treat T2DM patients. In some embodiments, dual GIP / GLP-1 receptor agonists or functional variants thereof are used to effect clinically meaningful improvements in glycemic control and body weight.In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to achieve a clinically meaningful improvement in glycemic control. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to achieve a clinically meaningful improvement in body weight. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to treat T2DM and obesity. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is used to treat obesity. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is designed for once-weekly subcutaneous administration. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is designed for oral administration. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is designed for chronic administration.

[0596] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is an analog of glucose-dependent insulinotropic polypeptide (GIP), a human hormone that stimulates the release of insulin from the pancreas. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is a 39-amino acid linear polypeptide that has been chemically modified by lipidation. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is a 39-amino acid linear polypeptide that has been chemically modified by lipidation to improve its uptake into cells and its stability against metabolism. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof is a compound depicted in FIG. 11 or FIG. 12.

[0597]

[0552] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS [wherein Aib refers to alpha-aminoisobutyric acid (SEQ ID NO: 25)].

[0598]

[0553] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises the sequence YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS [wherein Aib refers to alpha-aminoisobutyric acid (SEQ ID NO: 25)].

[0599] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. ...

[0600] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue of a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue of the sequence of SEQ ID NO: 25.

[0601] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 (from the N-terminus) of a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 (from the N-terminus) of the sequence of SEQ ID NO: 25.

[0602] In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue at position 20 (from the N-terminus) of a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, the GIP / GLP-1 receptor dual agonist or functional variant thereof comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue at position 20 (from the N-terminus) of the sequence of SEQ ID NO: 25.

[0603] As used herein, "glucose-dependent insulinotropic polypeptide," also known as gastric inhibitory polypeptide, GIP, or gastric inhibitory peptide, refers to an inhibitory hormone of the secretin family of hormones. In some embodiments, glucose-dependent insulinotropic polypeptide is a weak inhibitor of gastric acid secretion. In some embodiments, the primary role of glucose-dependent insulinotropic polypeptide is to stimulate insulin secretion. As used herein, glucose-dependent insulinotropic polypeptide includes any recombinant or naturally occurring form of glucose-dependent insulinotropic polypeptide or a variant or homolog thereof that has or maintains glucose-dependent insulinotropic polypeptide activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some embodiments, a variant or homologue has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring glucose-dependent insulinotropic polypeptide.

[0604] As used herein, "glucagon-like peptide 1," also known as GLP-1, refers to a 30- or 31-amino acid-long peptide hormone derived from tissue-specific post-translational processing of the proglucagon peptide. In some embodiments, glucagon-like peptide 1 is produced and secreted by enteroendocrine L-cells and certain neurons in the nucleus of the solitary tract in the brainstem upon feeding. As used herein, glucagon-like peptide 1 includes either recombinant or naturally occurring forms of glucagon-like peptide 1 or variants or homologs thereof that have or maintain glucagon-like peptide 1 activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some embodiments, a variant or homologue has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring glucagon-like peptide 1.

[0605] In some embodiments, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 ionizable groups on the GIP / GLP-1 receptor dual agonist or functional variant thereof associated with a cation (e.g., Figure 13). In some embodiments, the ionic derivative of choline-[GIP / GLP-1 receptor dual agonist or functional variant thereof] has a choline:[GIP / GLP-1 receptor dual agonist or functional variant thereof] ratio of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12: 1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42: 1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72 :1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, or 100:1.

[0606] In some embodiments, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 potential esterification sites on the GIP / GLP-1 receptor dual agonist or functional variant thereof with a cation (e.g., Figure 14). In some embodiments, ester derivatives of choline-[GIP / GLP-1 receptor dual agonist or functional variant thereof] may be formed by conjugating a cation (e.g., choline) to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 positions on the structure of the GIP / GLP-1 receptor dual agonist or functional variant thereof.

[0607] In some embodiments, the composition comprises:

[0608] [ka]

[0609] of,

[0610] [ka]

[0611] In some embodiments, the composition has a molar ratio of from about 1:1 to about 1:20.

[0612] [ka]

[0613] of,

[0614]

change

[0615] the molar ratio to the compound is about 1:1 to about 1:200, about 1:1 to about 1:199, about 1:1 to about 1:198, about 1:1 to about 1:197, about 1:1 to about 1:196, about 1:1 to about 1:195, about 1:1 to about 1:194, about 1:1 to about 1:193, about 1:1 to about 1:192, about 1:1 to about 1:191, about 1:1 to about 1:190, about 1:1 to about 1:189, about 1:1 to about 1:188, about 1:1 to about 1:187, about 1:1 to about 1:186, about 1:1 to about 1:185, about 1:1 to about 1:184, about 1:1 to about 1:183, about 1:1 to about 1:182, about 1:1 to about 1:181, About 1:1 to about 1:180, about 1:1 to about 1:179, about 1:1 to about 1:178, about 1:1 to about 1:177, about 1:1 to about 1:176, about 1:1 to about 1:175, about 1:1 to about 1:174, about 1:1 to about 1:173, about 1:1 to about 1:172, about 1:1 to about 1:171, about 1:1 to about 1:170, about 1:1 to about 1:169, about 1:1 to about 1:168, about 1:1 to about 1:167, about 1:1 to about 1:166, about 1:1 to about 1:165, about 1:1 to about 1:164, about 1:1 to about 1:163, about 1:1 to about 1:162, about 1:1 to about 1:161, about 1:1 to about 1: 160, about 1:1 to about 1:159, about 1:1 to about 1:158, about 1:1 to about 1:157, about 1:1 to about 1:156, about 1:1 to about 1:155, about 1:1 to about 1:154, about 1:1 to about 1:153, about 1:1 to about 1:152, about 1:1 to about 1:151, about 1:1 to about 1:150, about 1:1 to about 1:149, about 1:1 to about 1:148, about 1:1 to about 1:147, about 1:1 to about 1:146, about 1:1 to about 1:145, about 1:1 to about 1:144, about 1:1 to about 1:143, about 1:1 to about 1:142, about 1:1 to about 1:141, about 1:1 to about 1:140, about 1:1 to about 1:139, about 1:1 to about 1:138, about 1:1 to about 1:137, about 1:1 to about 1:136, about 1:1 to about 1:135, about 1:1 to about 1:134, about 1:1 to about 1:133, about 1:1 to about 1:132, about 1:1 to about 1:131, about 1:1 to about 1:130, about 1:1 to about 1: 129, about 1:1 to about 1:128, about 1:1 to about 1:127, about 1:1 to about 1:126, about 1:1 to about 1:125, about 1:1 to about 1:124, about 1:1 to about 1:123, about 1:1 to about 1:122, about 1:1 to about 1:121, about 1:1 to about 1:120, about 1:1 to about 1:119,about 1:1 to about 1:118, about 1:1 to about 1:117, about 1:1 to about 1:116, about 1:1 to about 1:115, about 1:1 to about 1:114, about 1:1 to about 1:113, about 1:1 to about 1:112, about 1:1 to about 1:111, about 1:1 to about 1:110, about 1:1 to about 1:109, about 1:1 to about 1:108, about 1:1 to about 1:107, about 1:1 to about 1:106, about 1:1 to about 1:105, about 1:1 to about 1:104, about 1:1 to about 1:103, about 1:1 to about 1:102, about 1:1 to about 1:101, about 1:1 to about 1:100, about 1:1 to about 1:99, about 1:1 to about 1:98 , about 1:1 to about 1:97, about 1:1 to about 1:96, about 1:1 to about 1:95, about 1:1 to about 1:94, about 1:1 to about 1:93, about 1:1 to about 1:92, about 1:1 to about 1:91, about 1:1 to about 1:90, about 1:1 to about 1:89, about 1:1 to about 1:88, about 1:1 to about 1:87, about 1: 1 to about 1:86, about 1:1 to about 1:85, about 1:1 to about 1:84, about 1:1 to about 1:83, about 1:1 to about 1:82, about 1:1 to about 1:81, about 1:1 to about 1:80, about 1:1 to about 1:79, about 1:1 to about 1:78, about 1:1 to about 1:77, about 1:1 to about 1:76, about 1:1 to about 1 :75, about 1:1 to about 1:74, about 1:1 to about 1:73, about 1:1 to about 1:72, about 1:1 to about 1:71, about 1:1 to about 1:70, about 1:1 to about 1:69, about 1:1 to about 1:68, about 1:1 to about 1:67, about 1:1 to about 1:66, about 1:1 to about 1:65, about 1:1 to about 1:64 , about 1:1 to about 1:63, about 1:1 to about 1:62, about 1:1 to about 1:61, about 1:1 to about 1:60, about 1:1 to about 1:59, about 1:1 to about 1:58, about 1:1 to about 1:57, about 1:1 to about 1:56, about 1:1 to about 1:55, about 1:1 to about 1:54, about 1:1 to about 1:53, about 1: 1 to about 1:52, about 1:1 to about 1:51, about 1:1 to about 1:50, about 1:1 to about 1:49, about 1:1 to about 1:48, about 1:1 to about 1:47, about 1:1 to about 1:46, about 1:1 to about 1:45, about 1:1 to about 1:44, about 1:1 to about 1:43, about 1:1 to about 1:42, about 1:1 to about 1 :41, about 1:1 to about 1:40, about 1:1 to about 1:39, about 1:1 to about 1:38, about 1:1 to about 1:37, about 1:1 to about 1:36, about 1:1 to about 1:35, about 1:1 to about 1:34, about 1:1 to about 1:33, about 1:1 to about 1:32, about 1:1 to about 1:31, about 1:1 to about 1:30,about 1:1 to about 1:29, about 1:1 to about 1:28, about 1:1 to about 1:27, about 1:1 to about 1:26, about 1:1 to about 1:25, about 1:1 to about 1:24, about 1:1 to about 1:23, about 1:1 to about 1:22, about 1:1 to about 1:21, about 1:1 to about 1:20, about 1:1 to about 1:19, about 1:1 to about 1:18, about 1:1 to about 1:17, about 1:1 to about 1:16 , about 1:1 to about 1:15, about 1:1 to about 1:14, about 1:1 to about 1:13, about 1:1 to about 1:12, about 1:1 to about 1:11, about 1:1 to about 1:10, about 1:1 to about 1:9, about 1:1 to about 1:8, about 1:1 to about 1:7, about 1:1 to about 1:6, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, or about 1:1 to about 1:2.

[0616] In some embodiments, the composition comprises:

[0617] [ka]

[0618] of,

[0619] [ka]

[0620] The molar ratio of 84, approx. 1:183, approx. 1:182, approx. 1:181, approx. 1:180, approx. 1:179, approx. 1:178, approx. 1:177, approx. 1:176, approx. 1:175, approx. 1:174, approx. 1:173, approx. 1:172, approx. 1:171, approx. 1:170, approx. 1:169, approx. 1:168, approx. 1:167, approx. 1: 166, approx. 1:165, approx. 1:164, approx. 1:163, approx. 1:162, approx. 1:161, approx. 1:160, approx. 1:159, approx. 1:158, approx. 1:157, approx. 1:156, approx. 1:155, approx. 1:154, approx. 1:153, approx. 1:152, approx. 1:151, approx. 1:150, approx. 1:149, approx. 1:148, approximately 1:147, approximately 1:146, approximately 1:145, approximately 1:144, approximately 1:143, approximately 1:142, approximately 1:141, approximately 1:140, approximately 1:139, approximately 1:138, approximately 1:137, approximately 1:136, approximately 1:135, approximately 1:134, approximately 1:133, approximately 1:132, approximately 1:131, Approximately 1:130, approximately 1:129, approximately 1:128, approximately 1:127, approximately 1:126, approximately 1:125, approximately 1:124, approximately 1:123, approximately 1:122, approximately 1:121, approximately 1:120, approximately 1:119, approximately 1:118, approximately 1:117, approximately 1:116, approximately 1:115, approximately 1:114, approximately 1:11 3, approx. 1:112, approx. 1:111, approx. 1:110, approx. 1:109, approx. 1:108, approx. 1:107, approx. 1:106, approx. 1:105, approx. 1:104, approx. 1:103, approx. 1:102, approx. 1:101, approx. 1:100, approx. 1:99, approx. 1:98, approx. 1:97, approx. 1:96, approx. 1:95, approx. 1 :94, approx. 1:93, approx. 1:92, approx. 1:91, approx. 1:90, approx. 1:89, approx. 1:88, approx. 1:87, approx. 1:86, approx. 1:85, approx. 1:84, approx. 1:83, approx. 1:82, approx. 1:81, approx. 1:80, approx. 1:79, approx. 1:78, approx. 1:77, approx. 1:76, approx. 1:75, approx. 1:74, approx. 1:73, approximately 1:72, approximately 1:71, approximately 1:70, approximately 1:69, approximately 1:68, approximately 1:67, approximately 1:66, approximately 1:65, approximately 1:64, approximately 1:63, approximately 1:62, approximately 1:61, approximately 1:60, approximately 1:59, approximately 1:58, approximately 1:57, approximately 1:56, approximately 1:55, approximately 1:54, approximately 1:53,Approximately 1:52, approximately 1:51, approximately 1:50, approximately 1:49, approximately 1:48, approximately 1:47, approximately 1:46, approximately 1:45, approximately 1:44, approximately 1:43, approximately 1:42, approximately 1:41, approximately 1:40, approximately 1:39, approximately 1:38, approximately 1:37, approximately 1:36, approximately 1:35, approximately 1:34, approximately 1:33, approximately 1:32, approximately 1:31, approximately 1:30, approximately 1:29, approximately 1:28, approximately 1:2 about 1:7, about 1:26, about 1:25, about 1:24, about 1:23, about 1:22, about 1:21, about 1:20, about 1:19, about 1:18, about 1:17, about 1:16, about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1.

[0621]

[0564] In some aspects herein, inter alia, compounds of Formula I:

[0622] [ka]

[0623] Compounds according to the formula: In some embodiments, R 1 , R 2 , and R 3 is independently C1-C5 alkyl. In some embodiments, R 1 is C1-C5 alkyl. In some embodiments, R 2 is C1-C5 alkyl. In some embodiments, R 3 is a C1-C5 alkyl.

[0624] In some embodiments, R 1 , R 2 , and R 3 are independently C1 to C 20 In some embodiments, R 1 is C1~C 20 In some embodiments, R 1 is C1~C 19 In some embodiments, R 1 is C1~C18 In some embodiments, R 1 is C1~C 17 In some embodiments, R 1 is C1~C 16 In some embodiments, R 1 is C1~C 15 In some embodiments, R 1 is C1~C 14 In some embodiments, R 1 is C1~C 13 In some embodiments, R 1 is C1~C 12 In some embodiments, R 1 is C1~C 11 In some embodiments, R 1 is C1~C 10 In some embodiments, R 1 is C1-C9 alkyl. In some embodiments, R 1 is C1-C8 alkyl. In some embodiments, R 1 is C1-C7 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C5 alkyl. In some embodiments, R 1 is C1-C4 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is C1-C2 alkyl. In some embodiments, R 2 is C1~C 20 In some embodiments, R 2 is C1~C 19 In some embodiments, R 2 is C1~C 18 In some embodiments, R 2 is C1~C 17 In some embodiments, R 2 is C1~C 16In some embodiments, R 2 is C1~C 15 In some embodiments, R 2 is C1~C 14 In some embodiments, R 2 is C1~C 13 In some embodiments, R 2 is C1~C 12 In some embodiments, R 2 is C1~C 11 In some embodiments, R 2 is C1~C 10 In some embodiments, R 2 is C1-C9 alkyl. In some embodiments, R 2 is C1-C8 alkyl. In some embodiments, R 2 is C1-C7 alkyl. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C5 alkyl. In some embodiments, R 2 is C1-C4 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is C1-C2 alkyl. In some embodiments, R 3 is C1~C 20 In some embodiments, R 3 is C1~C 19 In some embodiments, R 3 is C1~C 18 In some embodiments, R 3 is C1~C 17 In some embodiments, R 3 is C1~C 16 In some embodiments, R 3 is C1~C 15 In some embodiments, R 3 is C1~C 14 In some embodiments, R3 is C1~C 13 In some embodiments, R 3 is C1~C 12 In some embodiments, R 3 is C1~C 11 In some embodiments, R 3 is C1~C 10 In some embodiments, R 3 is C1-C9 alkyl. In some embodiments, R 3 is C1-C8 alkyl. In some embodiments, R 3 is C1-C7 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C5 alkyl. In some embodiments, R 3 is C1-C4 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is a C1-C2 alkyl.

[0625] In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is C4 alkyl. In some embodiments, R 1 is a C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is a C alkyl. In some embodiments, R 1 is C alkyl. In some embodiments, R 1 is a C alkyl. In some embodiments, R 1 is C 10 In some embodiments, R 1 is C 11 In some embodiments, R 1 is C12 In some embodiments, R 1 is C 13 In some embodiments, R 1 is C 14 In some embodiments, R 1 is C 15 In some embodiments, R 1 is C 16 In some embodiments, R 1 is C 17 In some embodiments, R 1 is C 18 In some embodiments, R 1 is C 19 In some embodiments, R 1 is C 20 In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is C4 alkyl. In some embodiments, R 2 is a C alkyl. In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is a C alkyl. In some embodiments, R 2 is C alkyl. In some embodiments, R 2 is a C alkyl. In some embodiments, R 2 is C 10 In some embodiments, R 2 is C 11 In some embodiments, R 2 is C 12 In some embodiments, R 2 is C 13 In some embodiments, R 2 is C 14 In some embodiments, R 2 is C15 In some embodiments, R 2 is C 16 In some embodiments, R 2 is C 17 In some embodiments, R 2 is C 18 In some embodiments, R 2 is C 19 In some embodiments, R 2 is C 20 In some embodiments, R 3 is C alkyl. In some embodiments, R 3 is C alkyl. In some embodiments, R 3 is C alkyl. In some embodiments, R 3 is C4 alkyl. In some embodiments, R 3 is a C alkyl. In some embodiments, R 3 is C alkyl. In some embodiments, R 3 is a C alkyl. In some embodiments, R 3 is C alkyl. In some embodiments, R 3 is a C alkyl. In some embodiments, R 3 is C 10 In some embodiments, R 3 is C 11 In some embodiments, R 3 is C 12 In some embodiments, R 3 is C 13 In some embodiments, R 3 is C 14 In some embodiments, R 3 is C 15 In some embodiments, R 3 is C 16 In some embodiments, R 3 is C 17 In some embodiments, R 3 is C18 In some embodiments, R 3 is C 19 In some embodiments, R 3 is C 20 It is alkyl.

[0626] In some embodiments, R 4 is a C2-C5 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 20 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 19 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 18 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 17 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 16 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 15 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 14 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C13 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 12 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 11 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is C2~C 10 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C9 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C8 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C7 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C6 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C5 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 is a C2-C4 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4is a C2-C3 alkyl, where the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls. 4 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 In this case, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 The alkyl in is unsubstituted or substituted with one or more hydroxyl groups.

[0627] In some embodiments, R 5 is a GIP / GLP-1 receptor dual agonist or a functional variant thereof. In some embodiments, R 5 is a therapeutic agent comprising a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, R 5 is a therapeutic agent comprising the sequence of SEQ ID NO:25.

[0628] In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO: 25.

[0629] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a diacid 18 or 20 carbons in length. In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a diacid 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 carbons in length.

[0630] In some embodiments, the diacid is C 20 In some embodiments, the diacid comprises a fatty diacid of C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Contains fatty diacids.

[0631]

[0574] In some embodiments herein, a compound of Formula II:

[0632] [ka]

[0633] Compounds according to the formula: In some embodiments, R 7 , R 8 , and R 9 is independently unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. 7 is unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. In some embodiments, R 8 is unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. In some embodiments, R 9 is unsubstituted C1 to C5 alkyl or substituted C1 to C5 alkyl.

[0634] In some embodiments, R 7 , R 8 , and R9 are independently unsubstituted C1 to C 20 Alkyl or substituted C1-C 20 In some embodiments, R 7 is unsubstituted C1 to C 20 Alkyl or substituted C1-C 20 In some embodiments, R 7 is unsubstituted C1 to C 19 Alkyl or substituted C1-C 19 In some embodiments, R 7 is unsubstituted C1 to C 18 Alkyl or substituted C1-C 18 In some embodiments, R 7 is unsubstituted C1 to C 17 Alkyl or substituted C1-C 17 In some embodiments, R 7 is unsubstituted C1 to C 16 Alkyl or substituted C1-C 16 In some embodiments, R 7 is unsubstituted C1 to C 15 Alkyl or substituted C1-C 15 In some embodiments, R 7 is unsubstituted C1 to C 14 Alkyl or substituted C1-C 14 In some embodiments, R 7 is unsubstituted C1 to C 13 Alkyl or substituted C1-C 13 In some embodiments, R 7 is unsubstituted C1 to C 12 Alkyl or substituted C1-C 12 In some embodiments, R 7 is unsubstituted C1 to C 11 Alkyl or substituted C1-C 11 In some embodiments, R 7 is unsubstituted C1 to C 10 Alkyl or substituted C1-C 10 In some embodiments, R 7is an unsubstituted C1-C9 alkyl or a substituted C1-C9 alkyl. 7 is unsubstituted C1-C8 alkyl or substituted C1-C8 alkyl. 7 is unsubstituted C1-C7 alkyl or substituted C1-C7 alkyl. In some embodiments, R 7 is unsubstituted C1-C6 alkyl or substituted C1-C6 alkyl. In some embodiments, R 7 is unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. In some embodiments, R 7 is unsubstituted C1-C4 alkyl or substituted C1-C4 alkyl. In some embodiments, R 7 is unsubstituted C1-C3 alkyl or substituted C1-C3 alkyl. In some embodiments, R 7 is unsubstituted C1-C2 alkyl or substituted C1-C2 alkyl. In some embodiments, R 8 is unsubstituted C1 to C 20 Alkyl or substituted C1-C 20 In some embodiments, R 8 is unsubstituted C1 to C 19 Alkyl or substituted C1-C 19 In some embodiments, R 8 is unsubstituted C1 to C 18 Alkyl or substituted C1-C 18 In some embodiments, R 8 is unsubstituted C1 to C 17 Alkyl or substituted C1-C 17 In some embodiments, R 8 is unsubstituted C1 to C 16 Alkyl or substituted C1-C 16 In some embodiments, R 8 is unsubstituted C1 to C 15 Alkyl or substituted C1-C 15 In some embodiments, R 8 is unsubstituted C1 to C 14 Alkyl or substituted C1-C 14In some embodiments, R 8 is unsubstituted C1 to C 13 Alkyl or substituted C1-C 13 In some embodiments, R 8 is unsubstituted C1 to C 12 Alkyl or substituted C1-C 12 In some embodiments, R 8 is unsubstituted C1 to C 11 Alkyl or substituted C1-C 11 In some embodiments, R 8 is unsubstituted C1 to C 10 Alkyl or substituted C1-C 10 In some embodiments, R 8 is an unsubstituted C1-C9 alkyl or a substituted C1-C9 alkyl. 8 is unsubstituted C1-C8 alkyl or substituted C1-C8 alkyl. 8 is unsubstituted C1-C7 alkyl or substituted C1-C7 alkyl. In some embodiments, R 8 is unsubstituted C1-C6 alkyl or substituted C1-C6 alkyl. In some embodiments, R 8 is unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. In some embodiments, R 8 is unsubstituted C1-C4 alkyl or substituted C1-C4 alkyl. In some embodiments, R 8 is unsubstituted C1-C3 alkyl or substituted C1-C3 alkyl. In some embodiments, R 8 is unsubstituted C1-C2 alkyl or substituted C1-C2 alkyl. In some embodiments, R 9 is unsubstituted C1 to C 20 Alkyl or substituted C1-C 20 In some embodiments, R 9 is unsubstituted C1 to C 19 Alkyl or substituted C1-C 19 In some embodiments, R 9 is unsubstituted C1 to C 18Alkyl or substituted C1-C 18 In some embodiments, R 9 is unsubstituted C1 to C 17 Alkyl or substituted C1-C 17 In some embodiments, R 9 is unsubstituted C1 to C 16 Alkyl or substituted C1-C 16 In some embodiments, R 9 is unsubstituted C1 to C 15 Alkyl or substituted C1-C 15 In some embodiments, R 9 is unsubstituted C1 to C 14 Alkyl or substituted C1-C 14 In some embodiments, R 9 is unsubstituted C1 to C 13 Alkyl or substituted C1-C 13 In some embodiments, R 9 is unsubstituted C1 to C 12 Alkyl or substituted C1-C 12 In some embodiments, R 9 is unsubstituted C1 to C 11 Alkyl or substituted C1-C 11 In some embodiments, R 9 is unsubstituted C1 to C 10 Alkyl or substituted C1-C 10 In some embodiments, R 9 is an unsubstituted C1-C9 alkyl or a substituted C1-C9 alkyl. 9 is unsubstituted C1-C8 alkyl or substituted C1-C8 alkyl. 9 is unsubstituted C1-C7 alkyl or substituted C1-C7 alkyl. In some embodiments, R 9 is unsubstituted C1-C6 alkyl or substituted C1-C6 alkyl. In some embodiments, R 9 is unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl. In some embodiments, R 9is unsubstituted C1-C4 alkyl or substituted C1-C4 alkyl. In some embodiments, R 9 is unsubstituted C1-C3 alkyl or substituted C1-C3 alkyl. In some embodiments, R 9 is unsubstituted C1-C2 alkyl or substituted C1-C2 alkyl.

[0635] In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is an unsubstituted C4 alkyl or a substituted C4 alkyl. In some embodiments, R 7 is an unsubstituted C5 alkyl or a substituted C5 alkyl. In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is an unsubstituted C7 alkyl or a substituted C7 alkyl. In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 7 is the unsubstituted C 10 Alkyl or substituted C 10 In some embodiments, R 7 is the unsubstituted C 11 Alkyl or substituted C 11 In some embodiments, R 7 is the unsubstituted C 12 Alkyl or substituted C 12 In some embodiments, R 7 is the unsubstituted C 13 Alkyl or substituted C 13 In some embodiments, R 7 is the unsubstituted C 14Alkyl or substituted C 14 In some embodiments, R 7 is the unsubstituted C 15 Alkyl or substituted C 15 In some embodiments, R 7 is the unsubstituted C 16 Alkyl or substituted C 16 In some embodiments, R 7 is the unsubstituted C 17 Alkyl or substituted C 17 In some embodiments, R 7 is the unsubstituted C 18 Alkyl or substituted C 18 In some embodiments, R 7 is the unsubstituted C 19 Alkyl or substituted C 19 In some embodiments, R 7 is the unsubstituted C 20 Alkyl or substituted C 20 In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is an unsubstituted C4 alkyl or a substituted C4 alkyl. In some embodiments, R 8 is an unsubstituted C5 alkyl or a substituted C5 alkyl. In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is an unsubstituted C7 alkyl or a substituted C7 alkyl. In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 8 is the unsubstituted C 10 Alkyl or substituted C10 In some embodiments, R 8 is the unsubstituted C 11 Alkyl or substituted C 11 In some embodiments, R 8 is the unsubstituted C 12 Alkyl or substituted C 12 In some embodiments, R 8 is the unsubstituted C 13 Alkyl or substituted C 13 In some embodiments, R 8 is the unsubstituted C 14 Alkyl or substituted C 14 In some embodiments, R 8 is the unsubstituted C 15 Alkyl or substituted C 15 In some embodiments, R 8 is the unsubstituted C 16 Alkyl or substituted C 16 In some embodiments, R 8 is the unsubstituted C 17 Alkyl or substituted C 17 In some embodiments, R 8 is the unsubstituted C 18 Alkyl or substituted C 18 In some embodiments, R 8 is the unsubstituted C 19 Alkyl or substituted C 19 In some embodiments, R 8 is the unsubstituted C 20 Alkyl or substituted C 20 In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is an unsubstituted C4 alkyl or a substituted C4 alkyl. In some embodiments, R 9is an unsubstituted C5 alkyl or a substituted C5 alkyl. In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is an unsubstituted C7 alkyl or a substituted C7 alkyl. In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is an unsubstituted C alkyl or a substituted C alkyl. In some embodiments, R 9 is the unsubstituted C 10 Alkyl or substituted C 10 In some embodiments, R 9 is the unsubstituted C 11 Alkyl or substituted C 11 In some embodiments, R 9 is the unsubstituted C 12 Alkyl or substituted C 12 In some embodiments, R 9 is the unsubstituted C 13 Alkyl or substituted C 13 In some embodiments, R 9 is the unsubstituted C 14 Alkyl or substituted C 14 In some embodiments, R 9 is the unsubstituted C 15 Alkyl or substituted C 15 In some embodiments, R 9 is the unsubstituted C 16 Alkyl or substituted C 16 In some embodiments, R 9 is the unsubstituted C 17 Alkyl or substituted C 17 In some embodiments, R 9 is the unsubstituted C 18 Alkyl or substituted C 18 In some embodiments, R 9 is the unsubstituted C 19 Alkyl or substituted C 19 In some embodiments, R9 is the unsubstituted C 20 Alkyl or substituted C 20 It is alkyl.

[0636] In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0637] In some embodiments, R 6 is a GIP / GLP-1 receptor dual agonist or a functional variant thereof. In some embodiments, R 6 is a therapeutic agent comprising a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, R 6 is a therapeutic agent comprising the sequence of SEQ ID NO:25.

[0638] In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO: 25.

[0639]

[0582] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety that comprises a choline or choline derivative-like residue.

[0640]

[0583] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [one or more choline or choline derivatives]-peptide ester formed at a Cys residue, a Lys residue, or any combination thereof.

[0641]

[0584] In some embodiments, the ratio of the [one or more choline or choline derivatives]-peptide ester formed at a Cys residue to the GIP / GLP-1 receptor dual agonist or functional variant thereof is 2 to 8, or the ratio of the [one or more choline or choline derivatives]-peptide ester formed at a Lys residue to the GIP / GLP-1 receptor dual agonist or functional variant thereof is 2 to 4, or a combination thereof.

[0642]

[0585] In some embodiments, the [one or more choline or choline derivatives]-peptide ester formed at the Cys residue has a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Cys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, having a ratio of 1 to 50, 1 to 49, 1 to 48, 1 to 47, 1 to 46, 1 to 45, 1 to 44, 1 to 43, 1 to 42, 1 to 41, 1 to 40, 1 to 39, 1 to 38, 1 to 37, 1 to 49, 1 to 50, 1 to 51, 1 to 52, 1 to 53, 1 to 54, 1 to 55, 1 to 56, 1 to 57, 1 to 58, 1 to 59, 1 to 60, 1 to 61, 1 to 62, 1 to 63, 1 to 64, 1 to 65, 1 to 66, 1 to 67, 1 to 68, 1 to 69, 1 to 70, 1 to 71, 1 to 72, 1 to 73, 1 to 74, 1 to 75, 1 to 76, 1 to 77, 1 to 78, 1 to 79, 1 to 80, 1 to 81, 1 to 82, 1 to 83, 1 to 84, 1 to 85, 1 to 86, 1 to 87, 1 to 88, 1 to 89, 1 to 90, 1 to 91, 1 to 92, 1 to 93, 1 to 94, 1 to 9 ~36, 1-35, 1-34, 1-33, 1-32, 1-31, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Cys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, wherein the linker is selected from the group consisting of a choline or choline derivatives, ... 0, 19-50, 20-50, 21-50, 22-50, 23-50, 24-50, 25-50, 26-50, 27-50, 28-50, 29-50, 30-50, 31-50, 32-50, 33-50, 34-50, 35-50, 36-50, 37-50, 38-50, 39-50, 40-50, 41-50, 42-50, 43-50, 44-50, 45-50, 46-50, 47-50, 48-50, or 49-50.In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Cys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, wherein the ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof is 1 to 7, 2 to 8, 3 to 9, 4 to 10, 5 to 11, 6 to 12, 7 to 13, 8 to 14, 9 to 15, 10 to 16, 11 to 17, 12 to 18, 13 to 19, 14 to 20, 15 to 21, 16-22, 17-23, 18-24, 19-25, 20-26, 21-27, 22-28, 23-29, 24-30, 25-31, 26-32, 27-33, 28-34, 29-35, 30-36, 31-37, 32-38, 33-39, 34-40, 35-41, 36-42, 37-43, 38-44, 39-45, 40-46, 41-47, 42-48, 43-49, or 44-50.

[0643]

[0586] In some embodiments, the [one or more choline or choline derivatives]-peptide ester formed at the Lys residue has a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Lys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, having a ratio of 1 to 50, 1 to 49, 1 to 48, 1 to 47, 1 to 46, 1 to 45, 1 to 44, 1 to 43, 1 to 42, 1 to 41, 1 to 40, 1 to 39, 1 to 38, 1 to 37, 1 to 49, 1 to 50, 1 to 51, 1 to 52, 1 to 53, 1 to 54, 1 to 55, 1 to 56, 1 to 57, 1 to 58, 1 to 59, 1 to 60, 1 to 61, 1 to 62, 1 to 63, 1 to 64, 1 to 65, 1 to 66, 1 to 67, 1 to 68, 1 to 69, 1 to 70, 1 to 71, 1 to 72, 1 to 73, 1 to 74, 1 to 75, 1 to 76, 1 to 77, 1 to 78, 1 to 79, 1 to 80, 1 to 81, 1 to 82, 1 to 83, 1 to 84, 1 to 85, 1 to 86, 1 to 87, 1 to 88, 1 to 89, 1 to 90, 1 to 91, 1 to 92, 1 to 93, 1 to 94, 1 to 9 ~36, 1-35, 1-34, 1-33, 1-32, 1-31, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Lys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, wherein the linker is 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 11 to 50, 12 to 50, 13 to 50, 14 to 50, 15 to 50, 16 to 50, 17 to 50, 18 to 50, 19 to 50, 20 to 50, 21 to 50, 22 to 50, 23 to 50, 24 to 50, 25 to 50, 26 to 50, 27 to 50, 28 to 50, 29 to 50, 30 to 50, 31 to 50, 32 to 50, 33 to 50, 34 to 50, 35 to 50, 36 to 50, 37 to 50, 38 to 50, 39 to 60, 40 to 41, 42 to 43, 43 to 44, 44 to 45, 45 to 46, 46 to 47, 47 to 48, 48 to 49, 50 to 51, 51 to 52, 52 to 53, 53 to 54, 54 to 55, 55 to 56, 56 to 57, 57 to 58, 0, 19-50, 20-50, 21-50, 22-50, 23-50, 24-50, 25-50, 26-50, 27-50, 28-50, 29-50, 30-50, 31-50, 32-50, 33-50, 34-50, 35-50, 36-50, 37-50, 38-50, 39-50, 40-50, 41-50, 42-50, 43-50, 44-50, 45-50, 46-50, 47-50, 48-50, or 49-50.In some embodiments, the [one or more choline or choline derivatives]-peptide esters formed at Lys residues are selected from the group consisting of a linker to GIP / GLP-1 receptor dual agonist or functional variant thereof, and a functional variant thereof. ~20, 19-21, 20-22, 21-23, 22-24, 23-25, 24-26, 25-27, 26-28, 27-29, 28-30, 29-31, 30-32, 31-33, 32-34, 33-35, 34-36, 35-37, 36-38, 37-39, 38-40, 39-41, 40-42, 41-43, 42-44, 43-45, 44-46, 45-47, 46-48, 47-49, or 48-50.

[0644] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a diacid 18 or 20 carbons in length. In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a diacid 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 carbons in length.

[0645] In some embodiments, the diacid is C 20 In some embodiments, the diacid comprises a fatty diacid of C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Contains fatty diacids.

[0646]

[0589] In some embodiments herein, a compound of formula III:

[0647] [ka]

[0648] [In the formula, R 10 is a therapeutic agent; R 11 is substituted C5~C 10 , or unsubstituted C5-C 10 and; X 1 teeth,

[0649] [ka]

[0650] , -S-, or -NH-; L 1 is a covalent bond or a linker] Compounds according to the formula:

[0651] In some embodiments, the compound comprises one or more R linked to a Lys residue, a Cys residue, or any combination thereof. 11 or a functional variant thereof.

[0652] In some embodiments, R 11 is linked to a Lys residue in a ratio of 2 to 4 of the linker to the GIP / GLP-1 receptor dual agonist or functional variant thereof, or R 11 is linked to a Cys residue at a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 2 to 8, or at a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 4, or a combination thereof.

[0653] In some embodiments, R 11 is linked to a Lys residue at a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. 11The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 1 to 50, 1 to 49, 1 to 48, 1 to 47, 1 to 46, 1 to 45, 1 to 44, 1 to 43, 1 to 42, 1 to 41, 1 to 40, 1 to 39, 1 to 38, 1 to 37, 1 to 36, 1 to 35, 1 to 34, 1 to 33, 1 to 32, 1 to 31, 1 to 30 , 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. 11 The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 11 to 50, 12 to 50, 13 to 50, 14 to 50, 15 to 50, 16 to 50, 17 to 50, 18 to 50, 19 to 50, 20 to 50, 21 to 50, 22 to 50, 23 to 50, 24 to 50, 25 to 50, 26 to 50, 27 to 50, 28 to 50, 29 to 50, 30 to 50, 31 to 50, 32 to 50, 33 to 50, 34 to 50, 35 to 50, 36 to 50, 37 to 50, 38 to 50, 39 to 50, 40 to 50, 41 to 50, 42 to 50, 43 to 50, 44 to 50, 45 to 50, 46 to 50, 47 to 50, 48 to 50, 49 to 60, 51 to 51, 52 to 52, 53 to 53, 54 to 54, 55 to 55, 56 to 50, 57 to 50, 58 to 50, 59 to 61, 62 to 50, 63 to 50, 64 to 50, 65 to 50, 66 to 5 In some embodiments, R is linked to a Lys residue as 40-50, 41-50, 42-50, 43-50, 44-50, 45-50, 46-50, 47-50, 48-50, or 49-50. 11The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, 18-20, 19-21, 20-22, 21-23, 22-24, 23-25, 24-26, 25-27, 26-28, 27-29, 28-30, 29-31, 30-32, 31-33, 32-34, 33-35, 34-36, 35-37, 36-38, 37-39, 38-40, 39-41, 40-42, 41-43, 42-44, 43-45, 44-46, 45-47, 46-48, 47-49, or 48-50, and linked to a Lys residue.

[0654] In some embodiments, R 11 is linked to a Cys residue at a ratio of linker to the GIP / GLP-1 receptor dual agonist or functional variant thereof of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. 11 The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 1 to 50, 1 to 49, 1 to 48, 1 to 47, 1 to 46, 1 to 45, 1 to 44, 1 to 43, 1 to 42, 1 to 41, 1 to 40, 1 to 39, 1 to 38, 1 to 37, 1 to 36, 1 to 35, 1 to 34, 1 to 33, 1 to 32, 1 to 31, 1 to 30 , 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. 11The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 11 to 50, 12 to 50, 13 to 50, 14 to 50, 15 to 50, 16 to 50, 17 to 50, 18 to 50, 19 to 50, 20 to 50, 21 to 50, 22 to 50, 23 to 50, 24 to 50, 25 to 50, 26 to 50, 27 to 50, 28 to 50, 29 to 50, 30 to 50, 31 to 50, 32 to 50, 33 to 50, 34 to 50, 35 to 50, 36 to 50, 37 to 50, 38 to 50, 39 to 50, 40 to 50, 41 to 50, 42 to 50, 43 to 50, 44 to 50, 45 to 50, 46 to 50, 47 to 50, 48 to 50, 49 to 60, 51 to 51, 52 to 52, 53 to 53, 54 to 54, 55 to 55, 56 to 50, 57 to 50, 58 to 50, 59 to 61, 62 to 50, 63 to 50, 64 to 50, 65 to 50, 66 to 5 In some embodiments, R is linked to a Cys residue as 2-50, 25-50, 26-50, 27-50, 28-50, 29-50, 30-50, 31-50, 32-50, 33-50, 34-50, 35-50, 36-50, 37-50, 38-50, 39-50, 40-50, 41-50, 42-50, 43-50, 44-50, 45-50, 46-50, 47-50, 48-50, or 49-50. 11 The ratio of the linker to the GIP / GLP-1 receptor dual agonist or its functional variant is 1-7, 2-8, 3-9, 4-10, 5-11, 6-12, 7-13, 8-14, 9-15, 10-16, 11-17, 12-18, 13-19, 14-20, 15-21, 16-22, 17-23, 18-24, 19-25, 20-26, 21-27, 22-29, 23-30, 24-31, 25-32, 26-33, 27-34, 28-35, 29-40, 30-36, 31-37, 32-38, 33-39, 34-41, 35-42, 36-43, 37-44, 38-45, 39-50, 40-46, 41-47, 42-48, 43-49, 44-51, 45-52, 46-53, 47-54, 48-55, 49-60, 50-61, 51-62, 52-53, 53-54, 54-55, 55-56, 56-57, 57-58, 58-59, 59-60, 61-62, 63-64, 64-65, 65-66, 66-67, 67-68, 68-69, 69-70, 71-71, 72-73, 74-75, 75-76, 7, 22-28, 23-29, 24-30, 25-31, 26-32, 27-33, 28-34, 29-35, 30-36, 31-37, 32-38, 33-39, 34-40, 35-41, 36-42, 37-43, 38-44, 39-45, 40-46, 41-47, 42-48, 43-49, or 44-50, and linked to a Cys residue.

[0655] In some embodiments, R 11 is linked to the GIP / GLP-1 receptor dual agonist or functional variant thereof at a ratio of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 of linker to the GIP / GLP-1 receptor dual agonist or functional variant thereof.

[0656] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a dual conjugation, in which the ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof is 1 to 2.

[0657]

[0596] In some embodiments, the dual conjugation has a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, the dual conjugation comprises a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1 to 50, 1 to 49, 1 to 48, 1 to 47, 1 to 46, 1 to 45, 1 to 44, 1 to 43, 1 to 42, 1 to 41, 1 to 40, 1 to 39, 1 to 38, 1 to 37, 1 to 36, 1 to 35, 1 to 34, 1 to 33, 1-32, 1-31, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. In some embodiments, the dual conjugation is characterized by a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 2 to 50, 3 to 50, 4 to 50, 5 to 50, 6 to 50, 7 to 50, 8 to 50, 9 to 50, 10 to 50, 11 to 50, 12 to 50, 13 to 50, 14 to 50, 15 to 50, 16 to 50, 17 to 50, 18 to 50, 19 to 50, 20 to 50, 21 to 50, 22 to 50, 23 to 50, 24 to 50, 25 to 50, 26 to 50, 27 to 50, 28 to 50, 29 to 50, 30 to 50, 31 to 50, 32 to 50, 33 to 50, 34 to 50, 35 to 50, 36 to 50, 37 to 50, 38 to 50, 39 to 50, 40 to 50, 41 to 50, 42 to 50, 43 to 50, 44 to 50, 45 to 50, 46 to 50, 47 to 50, 48 to 50, 49 to 50, 50 to 51, 52 to 52, 53 to 53, 54 to 54, 55 to 55, 56 to 50, 57 to 50, 58 to 50, 59 to 60, 61 to 62, 63 to 64, 64 to 65, 65 ~50, 22~50, 23~50, 24~50, 25~50, 26~50, 27~50, 28~50, 29~50, 30~50, 31~50, 32~50, 33~50, 34~50, 35~50, 36~50, 37~50, 38~50, 39~50, 40~50, 41~50, 42~50, 43~50, 44~50, 45~50, 46~50, 47~50, 48~50, or 49~50.In some embodiments, the dual conjugation is characterized in that the ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof is 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 17 to 18, 18 to 19, 19 to 20, 20 to 21, 21 to 22, 22 to 23, 23 to 24, 24 to 25, 25 to 26, 26 to 27, 27 to 28, 28 to 30, 30 to 31, 31 to 32, 32 to 33, 33 to 34, 34 to 35, 35 to 36, 36 to 37, 37 to 38, 38 to 39, 39 to 40, 41 to 42, 42 to 43, 43 to 44, 44 to 45, 45 to 46, 45 to 47, 46 to 48, 47 to 49, 48 to 50, 50 to 51, 51 to 52, 52 to 53, 53 to 54, 54 to 55, 55 to 56, 56 to 57, 57 to 58, 58 to 59, 59 to 60, 60 to 61, 61 to 62, 62 to 63, 63 to 64, 64 2, 22-23, 23-24, 24-25, 25-26, 26-27, 27-28, 28-29, 29-30, 30-31, 31-32, 32-33, 33-34, 34-35, 35-36, 36-37, 37-38, 38-39, 39-40, 40-41, 41-42, 42-43, 43-44, 44-45, 45-46, 46-47, 47-48, 48-49, or 49-50.

[0658]

[0600] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof. In some embodiments, a therapeutic agent comprises a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises the sequence of SEQ ID NO:25.

[0659] In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO: 25. In some embodiments, a therapeutic agent comprises a C20 diacid-γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO: 25.

[0660]

[0600] In some embodiments, the concentration of a compound described herein is at least 0.1% weight per volume.

[0601] In some embodiments, the concentration of a compound described herein is at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% weight per volume.

[0661] In some embodiments, the concentration of a compound described herein is at least 0.05 M. In some embodiments, the concentration of a compound described herein is at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 M.

[0662] In some embodiments, one or more ionic liquids comprise a cation independently selected from the group of cations listed in Table 2. In some embodiments, one or more ionic liquids comprise an anion independently selected from the group of anions listed in Table 1. In some embodiments, one or more ionic liquids comprise an ionic liquid independently selected from the group of ionic liquids listed in Table 2.

[0663]

[0604] In some embodiments, the compositions or pharmaceutical compositions provided herein comprise a composition provided herein or a compound provided herein and an ionic liquid of rank 1, 2, 3, 4, 5, 6, 8, 9, 10, or higher.

[0664] In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative. In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise a choline or a choline derivative, carnitine, or acetylcholine.

[0665] In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids are independently (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, , 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid (protocatechuic acid), 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, Citronellic acid, crotonic acid, D-(+)-galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-alanine Corbic acid, L-aspartic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0666] In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3,7-dimethyloctanoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, abietic acid, acetic acid, acetylcysteine, arabinose ... Chidonic acid, caffeic acid, cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)-galactonic acid, decanoic acid, deoxycholic acid, eicosapentanoic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, hexanoic acid, 3-phenylpropionic acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-glutathione (reduced form), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, maleic acid, malonic acid, mesaconic acid, mandelic acid, nonanoic acid, octanoic acid, oleic acid, p-toluenesulfonic acid, perillic acid, phosphoric acid, pimelic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, sorbic acid, syringic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-ferulic acid, undecanoic acid, vanillic acid, α-ketoglutaric acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid (protocatechuic acid), 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, aconitic acid The anion comprises an anion selected from the group consisting of caffeic acid, benzoic acid, chenodeoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tropic acid, eicosanedioic acid, ellagic acid, formic acid, heptanoic acid, isobutyric acid, DL-tartaric acid, lithocholic acid, malic acid, nicotinic acid, p-coumaric acid, palmitic acid, pivalic acid, salicylic acid (2-hydroxybenzoic acid), sinapinic acid (3,5-dimethoxy-4-hydroxycinnamic acid), succinic acid, tiglic acid, valeric acid, stearic acid, and 8-[(2-hydroxybenzoyl)amino]octanoic acid.In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid. In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0667]

[0608] In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0668]

[0609] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0669]

[0610] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0670] In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise a cation selected from the group of cations listed in Table 2. In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise anions selected from the group of anions listed in Table 1. In some embodiments, the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or higher ionic liquids independently comprise an ionic liquid selected from the group of ionic liquids listed in Table 2.

[0671] In some embodiments, to enhance the hydrophobicity of the GIP / GLP-1 receptor dual agonist or functional variant thereof, the GIP / GLP-1 receptor dual agonist or functional variant thereof is linked to one or more fatty acid or carboxylic acid-containing molecules. In some embodiments, the one or more fatty acid or carboxylic acid-containing molecules are linked to the GIP / GLP-1 receptor dual agonist or functional variant thereof via dual conjugation (or double covalent conjugation). In some embodiments, the one or more fatty acid or carboxylic acid-containing molecules comprise cinnamic acid. In some embodiments, the one or more fatty acid or carboxylic acid-containing molecules are cinnamic acid.

[0672] In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are non-covalently associated with a free amine of the GIP / GLP-1 receptor dual agonist, or functional variant thereof. In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are non-covalently associated with an N-terminal amine within the peptide backbone of the GIP / GLP-1 receptor dual agonist, or functional variant thereof. In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are non-covalently associated with an amine group of a Gln residue, an amine group of an Asn residue, an amine group of an Arg residue, an amine group of a Lys residue, an amine group of a His residue, or a combination thereof, of the GIP / GLP-1 receptor dual agonist, or functional variant thereof.

[0673] In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are covalently conjugated to a free amine of the GIP / GLP-1 receptor dual agonist, or functional variant thereof. In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine within the peptide backbone of the GIP / GLP-1 receptor dual agonist, or functional variant thereof. In some embodiments, one or more fatty acid- or carboxylic acid-containing molecules are covalently conjugated to an amine group of a Gln residue, an amine group of an Asn residue, an amine group of an Arg residue, an amine group of a Lys residue, an amine group of a His residue, or a combination thereof, of the GIP / GLP-1 receptor dual agonist, or functional variant thereof.

[0674]

[0615] In certain aspects herein, inter alia, compounds of Formula I:

[0675] [ka]

[0676] [In the formula, R 1 , R 2 , and R3 are independently C1-C5 alkyl; R 4 is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a therapeutic agent] Compounds according to the formula:

[0677] In some embodiments, R 1 , R 2 , and R 3 is methyl. In some embodiments, R 1 , R 2 , and R 3 is ethyl. In some embodiments, R 1 , R 2 , and R 3 is propyl.

[0678] In some embodiments, R 1 and R 2 is methyl and R 3 is ethyl. In some embodiments, R 1 and R 3 is methyl and R 2 is ethyl.

[0679] In some embodiments, R 1 and R 2 is ethyl, and R 3 is methyl. In some embodiments, R 1 and R 3 is ethyl, and R 2 is methyl.

[0680] In some embodiments, R 1 and R 2 is propyl, and R 3 is methyl. In some embodiments, R 1 and R 3 is propyl, and R 2 is methyl.

[0681] In some embodiments, R 4 is a C2-C5 alkyl substituted with hydroxyl. In some embodiments, R 4 teeth,

[0682] [ka]

[0683] is.

[0627] In some embodiments, the compound has Formula Ia:

[0684] [ka]

[0685] It is a compound according to the following:

[0628] In some embodiments, the compound has Formula Ib:

[0686] [ka]

[0687] It is a compound according to the following:

[0629] In some embodiments, the compound has Formula Ic:

[0688] [ka]

[0689] It is a compound according to the following:

[0630] In some embodiments, the therapeutic agent is a GIP (glucose-dependent insulinotropic polypeptide) / GLP-1 (glucagon-like peptide-1) receptor dual agonist or a functional variant thereof.

[0690]

[0631] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0632] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0691]

[0633] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.

[0692]

[0634] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0635] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0693] In some embodiments, the compound is

[0694] [ka]

[0695] of,

[0696] [ka]

[0697] The molar ratio to is about 1:1 to about 1:20. In some embodiments, the compound is

[0698] [ka]

[0699] of,

[0700] [ka]

[0701] The molar ratio to is about 1:1. In some embodiments, the compound is

[0702] [ka]

[0703] of,

[0704] [ka]

[0705] The molar ratio to is about 1:2. In some embodiments, the compound is

[0706] [ka]

[0707] of,

[0708] [ka]

[0709] The molar ratio to is about 1:3. In some embodiments, the compound is

[0710] [ka]

[0711] of,

[0712] [ka]

[0713] The molar ratio to is about 1:4. In some embodiments, the compound is

[0714] [ka]

[0715] of,

[0716] [ka]

[0717] The molar ratio to is about 1:5. In some embodiments, the compound is

[0718] [ka]

[0719] of,

[0720] [ka]

[0721] The molar ratio to is about 1:10. In some embodiments, the compound is

[0722] [ka]

[0723] of,

[0724] [ka]

[0725] The molar ratio to is about 1:20.

[0644] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having a modified structure.

[0726]

[0645] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having a modified structure with choline or a choline derivative.

[0646] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety comprising choline or a choline derivative.

[0727]

[0647] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety that comprises a choline or choline derivative-like residue.

[0728]

[0648] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [one or more choline or choline derivatives]-peptide derivative formed at a Glu residue, an Asp residue, or a combination thereof.

[0729]

[0649] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a linker comprising one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0730]

[0650] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, which comprises a linker comprising one or more gamma glutamic acid (γGlu) residues.

[0731]

[0651] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0732]

[0652] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide derivative formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0733]

[0653] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof that includes a diacid that is 18 or 20 carbons in length.

[0654] In some embodiments, the diacid is C 20 Contains fatty diacids.

[0734]

[0655] In some embodiments, the diacid comprises 1,20-icosane diacid.

[0656] In another aspect herein, a compound of formula II:

[0735] [ka]

[0736] [In the formula, R 6 is a therapeutic agent; R 7 , R 8 , and R 9 are independently C1-C5 alkyl; n is 1, 2, 3, 4, or 5] Compounds according to the formula:

[0737] In some embodiments, R 7 , R 8 , and R 9 is methyl. In some embodiments, R 7 , R 8 , and R 9 is ethyl. In some embodiments, R 7 , R 8 , and R 9 is propyl.

[0738] In some embodiments, R 7 and R 8 is methyl and R 9 is ethyl. In some embodiments, R 7 and R 9 is methyl and R 8 is ethyl.

[0739] In some embodiments, R 7 and R 8 is ethyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is ethyl, and R 8 is methyl.

[0740] In some embodiments, R 7 and R 8 is propyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is propyl, and R 8 is methyl.

[0741] In some embodiments, n is 1.

[0667] In some embodiments, the compound has Formula IIa:

[0742] [ka]

[0743] It is a compound according to the following:

[0668] In some embodiments, the compound has Formula IIb:

[0744] [ka]

[0745] It is a compound according to the following:

[0669] In some embodiments, the compound has Formula IIc:

[0746] [ka]

[0747] It is a compound according to the following:

[0670] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0748]

[0671] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0672] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0749] In some embodiments, the therapeutic agent is a C conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25. 20 Contains diacid-γ-Glu-(AEEA)2.

[0750] In some embodiments, the therapeutic agent is a C conjugated to a residue of the sequence of SEQ ID NO:25. 20 Contains diacid-γ-Glu-(AEEA)2. In some embodiments, the therapeutic agent is a C 1 -carboxylate conjugated to the Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25. 20 Contains diacid-γ-Glu-(AEEA)2.

[0751]

[0676] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having a modified structure with choline or a choline derivative.

[0677] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety comprising choline or a choline derivative.

[0752]

[0678] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having an ester structure modified with choline or a choline derivative.

[0753]

[0679] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof having a cationic moiety that comprises a choline or choline derivative-like residue.

[0754]

[0680] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [one or more choline or choline derivatives]-peptide ester formed at a Cys residue, a Lys residue, or any combination thereof.

[0755]

[0681] In some embodiments, the ratio of the [one or more choline or choline derivatives]-peptide ester formed at a Cys residue to the GIP / GLP-1 receptor dual agonist or functional variant thereof is 2 to 8, or the ratio of the [one or more choline or choline derivatives]-peptide ester formed at a Lys residue to the GIP / GLP-1 receptor dual agonist or functional variant thereof is 2 to 4, or a combination thereof.

[0756]

[0682] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a linker comprising one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0757]

[0683] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a linker comprising one or more gamma glutamic acid (γGlu) residues.

[0758]

[0684] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide derivative formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0759]

[0685] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0760]

[0686] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof that includes a diacid that is 18 or 20 carbons in length.

[0687] In some embodiments, the diacid is C 20 Contains fatty diacids.

[0761]

[0688] In some embodiments, the diacid comprises 1,20-icosane diacid.

[0689] In another aspect herein, compounds of formula III:

[0762] [ka]

[0763] [In the formula, R 10 is a therapeutic agent; R 11 is substituted C5~C 10 , or unsubstituted C5-C 10 and; X 1 teeth,

[0764] [ka]

[0765] , -S-, or -NH-; L 1 is a covalent bond or a linker] Compounds according to the formula:

[0766] In some embodiments, L 1 is a non-cleavable linker. In some embodiments, L 1 comprises a maleimidoalkane linker or a maleimidocyclohexane linker.

[0767] In some embodiments, L 1 teeth,

[0768] [ka]

[0769] Includes. In some embodiments, L 1 is a chemically cleavable linker. In some embodiments, L 1 comprises a hydrazone linker or a disulfide linker.

[0770] In some embodiments, L 1 teeth,

[0771] [ka]

[0772] Includes. In some embodiments, R 11 is a substitution C 10 or unsubstituted C 10 is.

[0697] In some embodiments, the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0773]

[0698] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0699] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0774]

[0700] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.

[0775]

[0701] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0702] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0776]

[0703] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having a modified structure with choline or a choline derivative.

[0704] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety comprising choline or a choline derivative.

[0777]

[0705] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or a functional variant thereof having an ester structure modified with choline or a choline derivative.

[0778]

[0706] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof having a cationic moiety that comprises a choline or choline derivative-like residue.

[0779] In some embodiments, the compound comprises one or more R linked to a Lys residue, a Cys residue, or any combination thereof. 11 or a functional variant thereof.

[0780] In some embodiments, R 11 is linked to a Lys residue in a ratio of 2 to 4 of the linker to the GIP / GLP-1 receptor dual agonist or functional variant thereof, or R 11 is linked to a Cys residue at a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 2 to 8, or at a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 4, or a combination thereof.

[0781]

[0709] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, including a dual conjugation.

[0710] In some embodiments, the dual conjugation has a ratio of linker to GIP / GLP-1 receptor dual agonist or functional variant thereof of 1-2.

[0782]

[0711] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a linker comprising one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.

[0783]

[0712] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof, comprising a linker comprising one or more gamma glutamic acid (γGlu) residues.

[0784]

[0713] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide derivative formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0785]

[0714] In some embodiments, the compound comprises a GIP / GLP-1 receptor dual agonist or functional variant thereof comprising a [choline or choline derivative]-peptide ester formed at the carboxylic acid of one or more gamma glutamic acid residues of the linker.

[0786]

[0715] In some embodiments, the compound comprises a dual GIP / GLP-1 receptor agonist or functional variant thereof that includes a diacid that is 18 or 20 carbons in length.

[0716] In some embodiments, the diacid is C 20 Contains fatty diacids.

[0787]

[0717] In some embodiments, the diacid comprises 1,20-icosane diacid.

[0718] In another aspect, the present specification provides compositions comprising a compound described herein and one or more ionic liquids.

[0788]

[0719] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0789]

[0720] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0790]

[0722] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0791]

[0723] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0792]

[0724] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0793]

[0725] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0794]

[0726] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0795]

[0727] In some embodiments, the compositions described herein further comprise at least one penetration enhancer.

[0728] In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0796]

[0729] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0797]

[0730] In some embodiments, the compositions described herein further comprise at least one pharmaceutically acceptable excipient.

[0731] In another aspect, the present specification provides a composition comprising a GIP / GLP-1 receptor dual agonist or a functional variant thereof and one or more ionic liquids.

[0798]

[0732] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0799]

[0733] ​​In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0800]

[0735] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0801]

[0736] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0802]

[0737] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0803]

[0738] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0804]

[0739] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0805]

[0740] In some embodiments, the solubility of the GIP / GLP-1 receptor dual agonist or functional variant thereof is increased compared to the GIP / GLP-1 receptor dual agonist or functional variant thereof in a composition without the ionic liquid.

[0806]

[0741] In some embodiments, the delivery efficiency of the GIP / GLP-1 receptor dual agonist or functional variant thereof in a subject in need thereof is enhanced or improved when administered to a subject compared to the GIP / GLP-1 receptor dual agonist or functional variant thereof in a composition without the ionic liquid.

[0807]

[0742] In some embodiments, the composition further comprises at least one penetration enhancer.

[0743] In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0808]

[0744] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0809]

[0745] Another aspect of the present specification provides a pharmaceutical composition comprising a compound described herein or a composition described herein and at least one pharmaceutically acceptable excipient.

[0810]

[0746] In some embodiments, the pharmaceutical composition further comprises at least one penetration enhancer.

[0747] In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0811]

[0748] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof.

[0812]

[0749] In another aspect herein, there is provided a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, a composition described herein, or a pharmaceutical composition described herein, wherein the administering step is effective to treat the disease or disorder in the subject.

[0813]

[0750] In some embodiments, the disease or disorder is a metabolic disease or disorder.

[0751] In some embodiments, the disease or disorder is diabetes.

[0814]

[0752] In some embodiments, the disease or disorder is type 2 diabetes mellitus (T2DM).

[0753] In some embodiments, the disease or disorder is obesity or overweight.

[0754] In some embodiments, the administration activates GIP receptor signaling, GLP-1 receptor signaling, or a combination thereof.

[0815]

[0755] In some embodiments, administration increases or improves glucose-dependent insulin secretion, improves glucose tolerance, or a combination thereof.

[0816]

[0756] In some embodiments, administration increases or improves glycemic control.

[0757] In some embodiments, administration decreases or reduces fasting serum glucose.

[0817]

[0758] In some embodiments, administration results in or reduces weight loss, reduces or reduces food intake, or a combination thereof.

[0818]

[0759] In some embodiments, administration effects improvement in glycemic control, body weight, or a combination thereof.

[0760] In some embodiments, the composition, compound, or pharmaceutical composition is administered via subcutaneous administration, intravenous administration, or oral administration.

[0819]

[0761] In some embodiments, the composition, compound, or pharmaceutical composition is administered orally.

[0762] In some embodiments, the composition, compound, or pharmaceutical composition is administered as a liquid-filled capsule.

[0820]

[0763] In some embodiments, the composition, compound, or pharmaceutical composition is administered in multiple doses.

[0764] In some embodiments, the composition, compound, or pharmaceutical composition is administered in a single dose.

[0821]

[0765] In some embodiments, the composition, compound, or pharmaceutical composition is administered to a mucosa.

[0766] In some embodiments, the composition, compound, or pharmaceutical composition is administered via subcutaneous administration, intravenous administration, or oral administration.

[0822]

[0767] In some embodiments, the concentration of a compound described herein is at least 0.1% weight per volume.

[0768] In some embodiments, the concentration of a compound described herein is at least 0.05M.

[0823]

[0769] In some embodiments, the composition further comprises one or more additional agents.

[0770] In some embodiments, the one or more additional agents are selected from the group consisting of nucleic acids, small molecules, and polypeptides.

[0824]

[0771] In some embodiments, the one or more additional agents are nucleic acids.

[0772] In some embodiments, the one or more additional agents are small molecules.

[0773] In some embodiments, the one or more additional agents is a polypeptide.

[0825]

[0774] In some embodiments, the one or more additional agents is a polypeptide.

[0775] In some embodiments, the one or more additional agents are therapeutic agents that treat a metabolic disease or disorder.

[0826]

[0776] In some embodiments, the one or more additional agents is a therapeutic agent that treats diabetes.

[0777] In some embodiments, the one or more additional agents is a therapeutic agent treating type 2 diabetes mellitus (T2DM).

[0827]

[0778] In some embodiments, the one or more additional agents is a therapeutic agent that treats obesity or overweight.

[0779] In another aspect herein, there is provided a method for increasing the solubility of a GIP / GLP-1 receptor dual agonist or a functional variant thereof, comprising administering to a patient a compound of Formula I:

[0828] [ka]

[0829] [In the formula, R 1 , R 2 , and R 3 are independently C1-C5 alkyl; R 4 is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a GIP / GLP-1 receptor dual agonist or its functional variant] A method is presented comprising preparing a composition comprising a compound according to

[0830]

[0780] In another aspect herein, there is provided a method for enhancing or improving the delivery efficiency of a GIP / GLP-1 receptor dual agonist, or a functional variant thereof, in a subject in need thereof, comprising administering to said subject a compound of Formula I:

[0831] [ka]

[0832] [In the formula, R 1 , R 2 , and R 3 are independently C1-C5 alkyl; R 4 is a C2-C5 alkyl, wherein the C2-C5 alkyl is unsubstituted or substituted with one or more hydroxyls; R 5 is a GIP / GLP-1 receptor dual agonist or its functional variant] preparing a composition comprising a compound according to Administering the composition to a subject A method is presented that includes:

[0833] In some embodiments, R 1 , R 2 , and R 3 is methyl. In some embodiments, R 1 , R 2 , and R 3 is ethyl. In some embodiments, R 1 , R 2 , and R 3 is propyl.

[0834] In some embodiments, R 1 and R 2 is methyl and R 3 is ethyl. In some embodiments, R 1 and R 3 is methyl and R 2 is ethyl.

[0835] In some embodiments, R 1 and R 2 is ethyl, and R 3 is methyl. In some embodiments, R 1 and R 3 is ethyl, and R 2 is methyl.

[0836] In some embodiments, R 1 and R 2 is propyl, and R 3 is methyl. In some embodiments, R 1 and R 3 is propyl, and R 2 is methyl.

[0837] In some embodiments, R 4 is a C2-C5 alkyl substituted with hydroxyl. In some embodiments, R 4 teeth,

[0838] [ka]

[0839] is.

[0792] In some embodiments, the compound has Formula Ia:

[0840] [ka]

[0841] It is a compound according to the following:

[0793] In some embodiments, the compound has Formula Ib:

[0842] [ka]

[0843] It is a compound according to the following:

[0794] In some embodiments, the compound has Formula Ic:

[0844] [ka]

[0845] It is a compound according to the following: In some embodiments, R 5 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0846] In some embodiments, R 5 comprises the sequence of SEQ ID NO:25. In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0847] In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25. In some embodiments, R 5 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0848] In some embodiments, the compound is

[0849] [ka]

[0850] of,

[0851] [ka]

[0852] The molar ratio to is about 1:1 to about 1:20.

[0801] In some embodiments, the compound is

[0853] [ka]

[0854] of,

[0855] [ka]

[0856] The molar ratio to is about 1:1.

[0802] In some embodiments, the compound is

[0857] [ka]

[0858] of,

[0859] [ka]

[0860] The molar ratio to is about 1:2.

[0803] In some embodiments, the compound is

[0861] [ka]

[0862] of,

[0863] [ka]

[0864] The molar ratio to is about 1:3.

[0804] In some embodiments, the compound is

[0865] [ka]

[0866] of,

[0867] [ka]

[0868] The molar ratio to is about 1:4.

[0805] In some embodiments, the compound is

[0869] [ka]

[0870] of,

[0871] [ka]

[0872] The molar ratio to is about 1:5.

[0806] In some embodiments, the compound is

[0873] [ka]

[0874] of,

[0875] [ka]

[0876] The molar ratio to is about 1:10.

[0807] In some embodiments, the compound is

[0877] [ka]

[0878] of,

[0879] [ka]

[0880] The molar ratio to is about 1:20.

[0808] In another aspect herein, there is provided a method for increasing the solubility of a GIP / GLP-1 receptor dual agonist or a functional variant thereof, comprising:

[0881] [ka]

[0882] [In the formula, R 6 is a GIP / GLP-1 receptor dual agonist or a functional variant thereof; R 7 , R 8 , and R 9 are independently unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl; n is 1, 2, 3, 4, or 5] A method is presented comprising preparing a composition comprising a compound according to

[0883]

[0809] In another aspect herein, there is provided a method for enhancing or improving the delivery efficiency of a GIP / GLP-1 receptor dual agonist, or a functional variant thereof, in a subject in need thereof, comprising administering to said subject a compound of Formula II:

[0884] [ka]

[0885] [In the formula, R 6 is a GIP / GLP-1 receptor dual agonist or a functional variant thereof; R 7 , R 8 , and R 9 are independently unsubstituted C1-C5 alkyl or substituted C1-C5 alkyl; n is 1, 2, 3, 4, or 5] preparing a composition comprising a compound according to Administering the composition to a subject A method is presented that includes:

[0886] In some embodiments, R 7 , R 8 , and R 9 is methyl. In some embodiments, R 7 , R 8, and R 9 is ethyl. In some embodiments, R 7 , R 8 , and R 9 is propyl.

[0887] In some embodiments, R 7 and R 8 is methyl and R 9 is ethyl. In some embodiments, R 7 and R 9 is methyl and R 8 is ethyl.

[0888] In some embodiments, R 7 and R 8 is ethyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is ethyl, and R 8 is methyl.

[0889] In some embodiments, R 7 and R 8 is propyl, and R 9 is methyl. In some embodiments, R 7 and R 9 is propyl, and R 8 is methyl.

[0890] In some embodiments, n is 1.

[0820] In some embodiments, the compound has Formula IIa:

[0891] [ka]

[0892] It is a compound according to the following:

[0821] In some embodiments, the compound has Formula IIb:

[0893] [ka]

[0894] It is a compound according to the following:

[0822] In some embodiments, the compound has Formula IIc:

[0895] [ka]

[0896] It is a compound according to the following: In some embodiments, R 6 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0897] In some embodiments, R 6 comprises the sequence of SEQ ID NO:25. In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0898] In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25. In some embodiments, R 6 comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0899]

[0828] In some embodiments, the composition further comprises one or more ionic liquids.

[0829] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0900]

[0830] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0901]

[0832] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0902]

[0833] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0903]

[0834] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0904]

[0835] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0905]

[0836] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0906]

[0837] In another aspect, the present specification provides a method for increasing the solubility of a GIP / GLP-1 receptor dual agonist or a functional variant thereof, the method comprising the step of preparing a composition comprising a GIP / GLP-1 receptor dual agonist or a functional variant thereof and one or more ionic liquids.

[0907]

[0838] In another aspect, the present specification provides a method for enhancing or improving the delivery efficiency of a GIP / GLP-1 receptor dual agonist, or a functional variant thereof, in a subject in need thereof, the method comprising the steps of preparing a composition comprising a GIP / GLP-1 receptor dual agonist, or a functional variant thereof, and one or more ionic liquids, and administering the composition to the subject.

[0908]

[0839] In some embodiments, the one or more ionic liquids independently comprise a cation selected from the group consisting of aminoguanidine, choline or a choline derivative, carnitine, acetylcholine, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, and a guanidine derivative.

[0909]

[0840] In some embodiments, the one or more ionic liquids independently comprise choline or a choline derivative, carnitine, or acetylcholine. In some embodiments, the one or more ionic liquids are independently selected from the group consisting of (R)-α-lipoic acid, 12-hydroxystearic acid, 2-(4-isobutylphenyl)propionic acid, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic acid, 2-aminoethanesulfonic acid (tauric acid), 2-hexyldecanoic acid, 2-hydroxyhippuric acid, 3-(4-hydroxyphenyl)propionic acid, 3-methylcrotonic acid, 3,3-diphenylpropionic acid, 3,4-dihydroxybenzoic acid, and the like. Protocatechuic acid, 3,7-dimethyloctanoic acid, 4-hydroxybenzenesulfonic acid, 4-hydroxybenzoic acid, 4-methylhexanoic acid, 4-methyloctanoic acid, 4-methylvaleric acid, 5-norbornene-2-carboxylic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, abietic acid, acetic acid, acetylcysteine, aconitic acid, arachidonic acid, behenic acid, benzoic acid, caffeic acid, chenodeoxycholic acid, cis-cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)- Galactonic acid, decanoic acid, deoxycholic acid, dihydrocaffeic acid, DL-2-phenylpropionic (hydratropic) acid, DL-tartaric acid, DL-tropic acid, eicosandioic acid, eicosapentanoic acid (EPA), elaidic acid, ellagic acid, erucic acid, ethylenediaminetetraacetic acid (EDTA), formic acid, fumaric acid, geranic acid, glutaric acid, glycolic acid, heptanoic acid, hexanoic acid, hydrocinnamic acid (3-phenylpropionic acid), isobutyric acid, isovaleric acid, L-(+)-tartaric acid, L-ascorbic acid, L-ascorbic acid Partic acid, L-glutamic acid, L-glutathione (reduced), lactic acid, lauric acid, levulinic acid, linoleic acid, linolenic acid, lithocholic acid, maleic acid, malic acid, malonic acid, mandelic acid, mesaconic acid, nicotinic acid, nonanoic acid, octanoic acid, oleic acid, oxalic acid, p-coumaric acid, p-toluenesulfonic acid, palmitic acid, perillic acid, phosphoric acid, pimelic acid, pivalic acid, propionic acid, pyroglutamic acid, pyruvic acid, ricinoleic acid, salicylic acid (2-hydroxybenzoic acid), sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid), sorbic acid, stearic acid, succinic acid, syringic acid, tiglic acid, trans-2-decenoic acid, trans-2-hexenoic acid, trans-2-octenoic acid, trans-3-octenoic acid, trans-7-octenoic acid, trans-cinnamic acid, trans-ferulic acid, undecanoic acid, valeric acid, vanillic acid, and α-ketoglutaric acid.

[0910]

[0842] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, mesaconic acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0911]

[0843] In some embodiments, the one or more ionic liquids independently comprise anions selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.

[0912]

[0844] In some embodiments, the one or more ionic liquids independently comprise [choline or choline derivative]-cinnamic acid, [choline or choline derivative]-mandelic acid, [choline or choline derivative]-citric acid, [choline or choline derivative]-ricinoleic acid, [choline or choline derivative]-linoleic acid, or [choline or choline derivative]-tiglic acid.

[0913]

[0845] In some embodiments, the one or more ionic liquids independently comprise carnitine-cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine-linoleic acid, or carnitine-tiglic acid.

[0914]

[0846] In some embodiments, the one or more ionic liquids independently comprise acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine-ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.

[0915]

[0847] In another aspect herein, there is provided a method for increasing the hydrophobicity of a therapeutic agent, comprising: 12 to a therapeutic agent, 12 However, substitution C5~C 10 , or unsubstituted C5-C 10 and wherein the therapeutic agent is a GIP / GLP-1 receptor dual agonist or a functional variant thereof.

[0916] In some embodiments, R 12 is the therapeutic agent

[0917] [ka]

[0918] , -S-, or -NH-. In some embodiments, R 12 is linked to the therapeutic agent via a covalent bond or a linker.

[0919]

[0850] In some embodiments, the linker is a non-cleavable linker.

[0851] In some embodiments, the linker comprises a maleimidoalkane linker or a maleimidocyclohexane linker.

[0920]

[0852] In some embodiments, the linker is:

[0921] [ka]

[0922] Includes.

[0853] In some embodiments, the linker is a chemically cleavable linker.

[0854] In some embodiments, the linker comprises a hydrazone linker or a disulfide linker.

[0923]

[0855] In some embodiments, the linker is:

[0924] [ka]

[0925] Includes. In some embodiments, R 12 is a substitution C 10 or unsubstituted C 10 is.

[0857] In some embodiments, the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO:25.

[0926]

[0858] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO:25.

[0859] In some embodiments, the therapeutic agent comprises the C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.

[0927]

[0860] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a residue of the sequence of SEQ ID NO:25.

[0861] In some embodiments, the therapeutic agent comprises a C20 diacid -γ-Glu-(AEEA)2 conjugated to a Lys residue at position 20 from the N-terminus of the sequence of SEQ ID NO:25.

[0928]

[0862] In another aspect, the present specification provides a method for enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof, the method comprising adding at least one penetration enhancer to a compound described herein, a composition described herein, or a pharmaceutical composition described herein, and administering the composition, compound, or pharmaceutical composition to the subject.

[0929]

[0863] In some embodiments, the at least one penetration enhancer is selected from the group consisting of sulcaprozate sodium (SNAC), sodium caprylate, sodium caprate, bile salts, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 3-[N,N-dimethyl(3-palmitoylaminopropyl)-ammonio]-propanesulfonate (PPS), and any combination thereof.

[0930]

[0864] In some embodiments, the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and combinations thereof. Antibodies or antibody fragments thereof As used herein, the term "antibody" refers to a protein or polypeptide derived from an immunoglobulin molecule that specifically binds to an antigen. In some embodiments, an antibody is a polyclonal antibody or a monoclonal antibody. In some embodiments, an antibody comprises multiple chains or a single chain. In some embodiments, an antibody comprises an intact immunoglobulin. In some embodiments, an antibody is a naturally occurring antibody. In some embodiments, an antibody is a recombinant antibody. In some embodiments, an antibody is in the form of a single domain antibody, maxibody, minibody, nanobody, intrabody, diabody, triabody, tetrabody, and multispecific antibody.

[0931] As used herein, the term "antibody fragment" refers to at least a portion of an intact antibody, or a recombinant variant thereof. In some embodiments, an antibody fragment is an antigen-binding domain that recognizes and specifically binds to an antigen. Exemplary antibody fragments include, but are not limited to, Fab, Fab', F(ab'), Fv fragments, scFv antibody fragments, single domain antibodies (sdAbs), camelid VhH domains, and shark single domain variable domains (BNARs).

[0932] In some embodiments, the antibody or antibody fragment thereof comprises an anti-tumor necrosis factor alpha (TNF-α) antibody or anti-TNF-α antibody fragment. In some embodiments, the antibody or antibody fragment thereof comprises an anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises infliximab or an antibody fragment thereof.

[0933]

[0868] As used herein, the term "infliximab" refers to a chimeric monoclonal antibody that binds to tumor necrosis factor alpha (TNF-α). In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof neutralizes TNF-α by preventing TNF-α from interacting with its receptor on cells. In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is used to treat autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behcet's disease.

[0934] In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is EVKLEESGGGLVQPGGSMKLSCVASGFIFSNHWMNWVRQSPEKGLEWVAEIRSKSINSATHYAESVKGRFTISRDDSKSAVYLQMTDLRTEDTGVYYCSRNYYGSTYDYWGQGT TLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1) The heavy chain comprises a sequence of

[0935] In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is EVKLEESGGGLVQPGGSMKLSCVASGFIFSNHWMNWVRQSPEKGLEWVAEIRSKSINSATHYAESVKGRFTISRDDSKSAVYLQMTDLRTEDTGVYYCSRNYYGSTYDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 24) The heavy chain comprises a sequence of

[0936]

[0872] In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof comprises a heavy chain comprising the sequence identified by Pubmed as PDB:4G3Y_H.

[0937] In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is DILLTQSPAILSVSPGERVSFSCRASQFVGSSIHWYQQRTNGSPRLLIKYASESMSGIPSRFSGSGSGTDFTLSINTVESEDIADYYCQQSHSWPFTFGSGTNLEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2) and a light chain comprising the sequence:

[0938] In some embodiments, Asn300 (asparagine at position 300) of the heavy chain of an anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is a glycosylation site. In some embodiments, Asn300 of the heavy chain of an anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof is glycosylated.

[0939]

[0875] In some embodiments, the anti-TNF-α chimeric monoclonal antibody or antibody fragment thereof comprises a light chain comprising the sequence identified by Pubmed as PDB:4G3Y_L.

[0940] In some embodiments, the antibody or antibody fragment thereof comprises an anti-tumor necrosis factor alpha (TNF-α) antibody or anti-TNF-α antibody fragment. In some embodiments, the antibody or antibody fragment thereof comprises an anti-TNF-α monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises adalimumab or its antibody fragment.

[0941]

[0877] As used herein, the term "adalimumab" refers to a monoclonal antibody that binds to TNF-α. In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof acts by inactivating TNF-α. In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis. In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is a disease-modifying antirheumatic drug (DMARD).

[0942] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 3) The heavy chain comprises a sequence of

[0943] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLDMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKI (SEQ ID NO: 4) The heavy chain comprises a sequence of

[0944] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 5) The heavy chain comprises a sequence of

[0945]

[0882] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof comprises a heavy chain comprising the sequence identified by Pubmed as PDB:3WD5_H. In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 6) and a light chain comprising the sequence:

[0946] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof is DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNRAPYTFGQGTKVEIKRTVAAPTVKILQSSCDGGGHFPPTIQLLCLVSGYTPGTIQITWLEDGQVMDVDLSTASTTQEGELASTQSELTLSQKHWLSDRTYTCQVTYQGHTFEDSGKKCA (SEQ ID NO: 7) and a light chain comprising the sequence:

[0947]

[0885] In some embodiments, the anti-TNF-α monoclonal antibody or antibody fragment thereof comprises a light chain comprising the sequence identified by Pubmed as PDB:3WD5_L. In some embodiments, the antibody or antibody fragment thereof comprises an anti-human interleukin-12 (IL-12) / interleukin-23 (IL-23) subunit antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises ustekinumab or an antibody fragment thereof.

[0948]

[0887] As used herein, the term "ustekinumab" refers to a monoclonal antibody that targets subunits of human interleukin-12 (IL-12) and interleukin-23 (IL-23), which regulate the immune system and immune-mediated inflammatory disorders.

[0949]

[0888] In some embodiments, the anti-IL-12 / IL-23 subunit human antibody or antibody fragment thereof is used to treat Crohn's disease, ulcerative colitis, plaque psoriasis, and psoriatic arthritis.

[0950] In some embodiments, the anti-IL-12 / IL-23 subunit human antibody or antibody fragment thereof is EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGIMSPVDSDIRYSPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRRPGQGYFDFWGQGTLVTVSSSSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 8) The heavy chain comprises a sequence of

[0951]

[0890] In some embodiments, the anti-IL-12 / IL-23 subunit human antibody or antibody fragment thereof comprises a heavy chain comprising the sequence identified by Pubmed as PDB:3HMX_H.

[0952] In some embodiments, the anti-IL-12 / IL-23 subunit human antibody or antibody fragment thereof is DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9) and a light chain comprising the sequence:

[0953]

[0892] In some embodiments, the anti-IL-12 / IL-23 subunit human antibody or antibody fragment thereof comprises a light chain comprising the sequence identified by Pubmed as PDB:3HMX_L.

[0954] In some embodiments, the antibody or antibody fragment thereof comprises an anti-TNF-α monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises an anti-TNF-α human monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises golimumab or an antibody fragment thereof.

[0955]

[0894] As used herein, the term "golimumab" refers to a human monoclonal antibody that targets TNF-α. In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof acts as a TNF-α inhibitor. In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof functions as an effective modulator of inflammatory markers and bone metabolism. In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof is used as an immunosuppressive pharmaceutical.

[0956] In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof is SKLQVQLVESGGGVVQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSS (SEQ ID NO: 10) The heavy chain comprises a sequence of

[0957]

[0897] In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof comprises a heavy chain comprising the sequence identified by Pubmed as PDB:5YOY_R.

[0958] In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof is AGSEIVLTQSPATLSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIKTSENLYFQ (SEQ ID NO: 11) and a light chain comprising the sequence:

[0959]

[0899] In some embodiments, the anti-TNF-α human monoclonal antibody or antibody fragment thereof comprises a light chain comprising the sequence identified by Pubmed as PDB:5YOY_O.

[0960] In some embodiments, the antibody or antibody fragment thereof comprises an anti-integrin α4β1 antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises an anti-integrin α4β1 monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises natalizumab or an antibody fragment thereof.

[0961]

[0901] As used herein, the term "natalizumab" refers to a monoclonal antibody that targets integrin α4β1. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof targets integrin α4β1 on leukocytes involved in inflammation. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof binds to the integrin, thereby stopping leukocyte invasion into brain and spinal cord tissues by reducing inflammation and resulting neuronal damage. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof works by reducing the ability of inflammatory immune cells to adhere to and cross the inner wall cell layers of the gut and blood-brain barrier. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is used to treat symptoms of both gut and blood-brain barrier disease, thereby preventing relapses, blindness, and cognitive decline. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is used to treat multiple sclerosis and Crohn's disease. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof increases the remission rate and prevents relapses in multiple sclerosis.

[0962] In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPANGYTKYDPKFQGRVTITADTSASTAYMELSSLRSEDEAVYYCAREGYYGNYGVYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE (SEQ ID NO: 12) The heavy chain comprises a sequence of

[0963] In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPANGYTKYDPKFQGRVTITADTSASTAYMELSSLRSEDEAVYYCAREGYYGNYGVYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPENLYFQ (SEQ ID NO: 13) The heavy chain comprises a sequence of

[0964]

[0905] In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof comprises a heavy chain comprising the sequence identified by Pubmed as PDB:4IRZ_H. In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHYTSALQPGIPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR (SEQ ID NO: 14) and a light chain comprising the sequence:

[0965] In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof is DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHYTSALQPGIPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG (SEQ ID NO: 15) and a light chain comprising the sequence:

[0966]

[0908] In some embodiments, the anti-integrin α4β1 antibody or antibody fragment thereof comprises a light chain comprising the sequence identified by Pubmed as PDB:4IRZ_L. In some embodiments, the antibody or antibody fragment thereof comprises an anti-integrin α4β7 antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises an anti-integrin α4β7 monoclonal antibody or antibody fragment thereof. In some embodiments, the antibody or antibody fragment thereof comprises vedolizumab or its antibody fragment.

[0967]

[0910] As used herein, the term "vedolizumab" refers to a monoclonal antibody that targets integrin α4β7. In some embodiments, the anti-integrin α4β7 antibody or antibody fragment thereof provides gut-selective anti-inflammatory activity as a result of blocking integrin α4β7. In some embodiments, the anti-integrin α4β7 antibody or antibody fragment thereof is used to treat ulcerative colitis and Crohn's disease.

[0968] In some embodiments, the anti-integrin α4β7 antibody or antibody fragment thereof is QVQLVQSGAEVKKPGASVKVSCKGSGYTFTSYWMHWVRQAPGQRLEWIGEIDPSESNTNYNQKFKGRVTLTVDISASTAYMELSSLRSEDTAVYYCARGGYDGWDYAIDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 16) The heavy chain comprises a sequence of

[0969] In some embodiments, the anti-integrin α4β7 antibody or antibody fragment thereof is DVVMTQSPLSLPVTPGEPASISCRSSQSLAKSYGNTYLSWYLQKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 17) and a light chain comprising the sequence:

[0970] In some embodiments, the antibody or antibody fragment thereof comprises a fragment of an anti-TNF-α antibody. In some embodiments, the antibody or antibody fragment thereof comprises a fragment of an anti-TNF-α monoclonal antibody. In some embodiments, the antibody or antibody fragment thereof comprises certolizumab pegol.

[0971]

[0915] As used herein, the term "certolizumab pegol" refers to a fragment of a monoclonal antibody specific for TNF-α.

[0916] In some embodiments, fragments of anti-TNF-α antibodies are used to treat Crohn's disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

[0972] In some embodiments, the fragment of an anti-TNF-α antibody is EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIYADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA (SEQ ID NO: 18) The heavy chain comprises a sequence of

[0973] In some embodiments, the fragment of an anti-TNF-α antibody is DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPYRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 19) and a light chain comprising the sequence:

[0974] In some embodiments, the therapeutic agent, or antibody or antibody fragment is (i) a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO:1 or SEQ ID NO:24, at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99.9% sequence identity to the sequence of SEQ ID NO:2, (ii) a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, or at least 60%, 65%, 70%, to the sequence of SEQ ID NO:6 or SEQ ID NO:7, (iii) a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 8, SEQ ID NO: 9 (iv) a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 10, or a combination thereof;9% sequence identity, at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 11, or a combination thereof; (v) at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the sequence of SEQ ID NO: 12 or SEQ ID NO: 13, (vi) a sequence with 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity, at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO:14 or SEQ ID NO:15, or any combination thereof; 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 17, a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 17, or a combination thereof; or (vii) a sequence with at least 60% to the sequence of SEQ ID NO: 18. , 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 19, a sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to the sequence of SEQ ID NO: 19, or a combination thereof.

[0975]

[0920] In some embodiments, the therapeutic agent comprises (i) the sequence of SEQ ID NO:1 or SEQ ID NO:24, the sequence of SEQ ID NO:2, or a combination thereof; (ii) the sequence of SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5, the sequence of SEQ ID NO:6 or SEQ ID NO:7, or any combination thereof; (iii) the sequence of SEQ ID NO:8, the sequence of SEQ ID NO:9, or a combination thereof; (iv) the sequence of SEQ ID NO:10, the sequence of SEQ ID NO:11, or a combination thereof; (v) the sequence of SEQ ID NO:12 or SEQ ID NO:13, the sequence of SEQ ID NO:14 or SEQ ID NO:15, or any combination thereof; (vi) the sequence of SEQ ID NO:16, the sequence of SEQ ID NO:17, or a combination thereof; or (vii) the sequence of SEQ ID NO:18, the sequence of SEQ ID NO:19, or a combination thereof.

[0976]

[0921] In some embodiments, the therapeutic agent comprises (i) the sequence of SEQ ID NO:1 or SEQ ID NO:24, and the sequence of SEQ ID NO:2; (ii) the sequence of SEQ ID NO:3 and the sequence of SEQ ID NO:6, the sequence of SEQ ID NO:4 and the sequence of SEQ ID NO:6, or the sequence of SEQ ID NO:5 and the sequence of SEQ ID NO:7; (iii) the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9; (iv) the sequence of SEQ ID NO:10 and the sequence of SEQ ID NO:11; (v) the sequence of SEQ ID NO:12 and the sequence of SEQ ID NO:14, or the sequence of SEQ ID NO:13 and the sequence of SEQ ID NO:15; (vi) the sequence of SEQ ID NO:16 and the sequence of SEQ ID NO:17; or (vii) the sequence of SEQ ID NO:18 and the sequence of SEQ ID NO:19.

[0977] As used herein, "TNF-α," also known as tumor necrosis factor alpha, TNF, DIF, TNF-alpha, TNFA, TNFSF2, tumor necrosis factor, and TNLG1F, refers to a member of the TNF superfamily, which consists of diverse transmembrane proteins with homologous TNF domains. In some embodiments, TNF-α as an adipokine promotes insulin resistance and is associated with obesity-induced type 2 diabetes. In some embodiments, TNF-α as a cytokine is used by the immune system for intracellular signaling. As used herein, TNF-α includes any recombinant or naturally occurring form of TNF-α or a variant or homolog thereof that has or maintains TNF-α activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some aspects, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring TNF-α. In some embodiments, the TNF-α is substantially identical to a protein identified by UniProt reference number P01375, or a variant or homolog having substantial identity thereto.

[0978] As used herein, "IL-12," also known as interleukin-12, refers to a heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and IL-12B (p40). In some embodiments, IL-12 is naturally produced by dendritic cells, macrophages, neutrophils, and human B lymphoblastoid cells in response to antigenic stimulation. IL-12 belongs to the IL-12 family, which includes heterodimeric cytokines including IL-12, IL-23, IL-27, and IL-35. As used herein, "IL-12A" includes any recombinant or naturally occurring form of IL-12A or a variant or homolog thereof that has or maintains IL-12A activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some embodiments, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring IL-12A. In some embodiments, the IL-12A is substantially identical to a protein identified by UniProt reference number P29459, or a variant or homolog having substantial identity thereto. As used herein, "IL-12B" includes any recombinant or naturally occurring form of IL-12B or a variant or homolog thereof that has or maintains IL-12B activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity).In some aspects, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring IL-12B. In some embodiments, the IL-12B is substantially identical to a protein identified by UniProt reference number P29460, or a variant or homolog having substantial identity thereto.

[0979] As used herein, "IL-23," also known as interleukin-23, refers to a heterodimeric cytokine composed of the IL-12B (IL-12p40) and IL-23A (IL-23p19) subunits. IL-23 belongs to the IL-12 family of cytokines. In some embodiments, IL-23 is a proinflammatory cytokine that plays a key role in the maintenance and expansion of type 17 helper T cells (Th17 cells). As used herein, "IL-23A" includes any recombinant or naturally occurring form of IL-23A or a variant or homolog thereof that has or maintains IL-23A activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some aspects, variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring IL-23A. In some embodiments, the IL-23A is substantially identical to a protein identified by UniProt reference number Q9NPF7, or a variant or homolog having substantial identity thereto.

[0980] As used herein, "integrin α4β1," also known as VLA-4 (very late antigen-4), refers to an integrin dimer composed of CD49d (alpha 4) and CD29 (beta 1). As used herein, "integrin α4" includes any recombinant or naturally occurring form of integrin α4 or a variant or homolog thereof that has or maintains integrin α4 activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some aspects, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring integrin alpha 4. In some embodiments, the integrin alpha 4 is substantially identical to a protein identified by UniProt reference number P13612, or a variant or homolog having substantial identity thereto. As used herein, "integrin β1" includes any recombinant or naturally occurring form of integrin β1 or a variant or homolog thereof that has or maintains integrin β1 activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some embodiments, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring integrin β1.In some embodiments, the integrin β1 is substantially identical to the protein identified by UniProt reference number P05556, or a variant or homologue having substantial identity thereto.

[0981] As used herein, "integrin α4β7," also known as LPAM-1, LPAM-1 (lymphocyte Peyer's patch adhesion molecule 1), a dimer of integrin alpha 4 and integrin beta 7, refers to an integrin dimer composed of CD49d (alpha 4) and beta 7. As used herein, "integrin β7" includes any recombinant or naturally occurring form of integrin β1 or a variant or homolog thereof that has or maintains integrin β7 activity (e.g., at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity). In some aspects, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to naturally occurring integrin β7. In some embodiments, the integrin β7 is substantially identical to a protein identified by UniProt reference number P26010, or a variant or homolog having substantial identity thereto.

[0982]

[0927] In some embodiments, the antibody or antibody fragment includes a polypeptide having a designated sequence or a sequence that is substantially identical or similar thereto, for example, a sequence that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or more identical to the designated sequence.

[0983] As used herein, the terms "homology" and "sequence identity" are used interchangeably and refer to the subunit sequence identity between two polypeptide molecules. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap. Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, percent identity between two amino acid sequences is determined using the algorithm by Needleman and Wunsch ((1970), J. Mol. Biol., 48:444-453), as incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using a Blosum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In some embodiments, percent identity between two amino acid or nucleotide sequences may be determined using the algorithm by E. Meyers and W. Miller ((1989), CABIOS, 4:11-17), as incorporated into the ALIGN program (version 2.0), using a PAM120 weighted residue table with a gap length penalty of 12 and a gap penalty of 4. In some embodiments, percent identity may be determined using the "BLAST" program, a publicly available online homology algorithm at http: / / www.ncbi.nlm.nih.gov / BLAST / .

[0984]

[0929] The nucleic acid molecules described herein may be vectors, expression vectors, inhibitory nucleic acids, aptamers, template molecules or cassettes (e.g., for gene editing), or targeting molecules (e.g., for CRISPR-Cas technology), or any other natural or synthetic nucleic acid molecule intended for delivery to an organism.

[0985] As used herein, the term "unsubstituted" means that a specified group does not bear any substituents. Unless otherwise indicated, as used herein, the term "substituted" may refer to the individual and independent replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.

[0986]

[0931] In any of the embodiments, the drug may be designed to treat a local tissue, e.g., the intestinal mucosa, or may be designed to treat a distant tissue, e.g., the liver, or may be designed to treat the systemic circulation.

[0987]

[0932] In some embodiments, compositions described herein, e.g., compositions comprising an ionic liquid and a drug, can further comprise a pharmaceutically acceptable excipient. Suitable excipients include, for example, water, saline, glycerol, ethanol, and the like, and combinations thereof. In addition, if desired, the composition can contain minor amounts of additional excipients, such as emulsifiers, surfactants, pH buffers, and the like, that enhance the effectiveness of the drug.

[0988]

[0933] In some embodiments, compositions comprising ionic liquids may be further encapsulated within dosage forms designed to facilitate delivery to an organism. Non-limiting examples of such dosage forms include capsules, tablets, or syrups.

[0989]

[0934] In some embodiments, the formulation may require excipients such as sugars, such as lactose; starches, such as corn starch; cellulose, cellulose derivatives, such as sodium carboxymethylcellulose; gelatin; and other compatible substances commonly considered in pharmaceutical formulations.

[0990]

[0935] As used herein, the term "effective amount" refers to the amount of a composition required to alleviate at least one or more symptoms of a disease or disorder, and relates to a sufficient amount of a pharmacological composition to produce the desired effect.

[0991]

[0936] In some embodiments, the composition comprises:

[0992] [ka]

[0993] of,

[0994] [ka]

[0995] In some embodiments, the composition has a molar ratio of from about 1:1 to about 1:164.

[0996] [ka]

[0997] of,

[0998] [ka]

[0999] the molar ratio to the compound is about 1:1 to about 1:500, about 1:1 to about 1:499, about 1:1 to about 1:498, about 1:1 to about 1:497, about 1:1 to about 1:496, about 1:1 to about 1:495, about 1:1 to about 1:494, about 1:1 to about 1:493, about 1:1 to about 1:492, about 1:1 to about 1:491, about 1:1 to about 1:490, about 1:1 to about 1:489, about 1:1 to about 1:488, about 1:1 to about 1:487, about 1:1 to about 1:486, about 1:1 to about 1:485, about 1:1 to about 1:484, about 1:1 to about 1:483, about 1:1 to about 1:482, about 1:1 to about 1:481, About 1:1 to about 1:480, about 1:1 to about 1:479, about 1:1 to about 1:478, about 1:1 to about 1:477, about 1:1 to about 1:476, about 1:1 to about 1:475, about 1:1 to about 1:474, about 1:1 to about 1:473, about 1:1 to about 1:472, about 1:1 to about 1:471, about 1:1 to about 1:470, about 1:1 to about 1:469, about 1:1 to about 1:468, about 1:1 to about 1:467, about 1:1 to about 1:466, about 1:1 to about 1:465, about 1:1 to about 1:464, about 1:1 to about 1:463, about 1:1 to about 1:462, about 1:1 to about 1:461, about 1:1 to about 1: 460, about 1:1 to about 1:459, about 1:1 to about 1:458, about 1:1 to about 1:457, about 1:1 to about 1:456, about 1:1 to about 1:455, about 1:1 to about 1:454, about 1:1 to about 1:453, about 1:1 to about 1:452, about 1:1 to about 1:451, about 1:1 to about 1:450, About 1:1 to about 1:449, about 1:1 to about 1:448, about 1:1 to about 1:447, about 1:1 to about 1:446, about 1:1 to about 1:445, about 1:1 to about 1:444, about 1:1 to about 1:443, about 1:1 to about 1:442, about 1:1 to about 1:441, about 1:1 to about 1:440, about 1:1 to about 1:439, about 1:1 to about 1:438, about 1:1 to about 1:437, about 1:1 to about 1:436, about 1:1 to about 1:435, about 1:1 to about 1:434, about 1:1 to about 1:433, about 1:1 to about 1:432, about 1:1 to about 1:431, about 1:1 to about 1:430, about 1:1 to about 1: 429, about 1:1 to about 1:428, about 1:1 to about 1:427, about 1:1 to about 1:426, about 1:1 to about 1:425, about 1:1 to about 1:424, about 1:1 to about 1:423, about 1:1 to about 1:422, about 1:1 to about 1:421, about 1:1 to about 1:420, about 1:1 to about 1:419,about 1:1 to about 1:418, about 1:1 to about 1:417, about 1:1 to about 1:416, about 1:1 to about 1:415, about 1:1 to about 1:414, about 1:1 to about 1:413, about 1:1 to about 1:412, about 1:1 to about 1:411, about 1:1 to about 1:410, about 1:1 to about 1:409, about 1:1 to about 1:408, about 1:1 to about 1:407, about 1:1 to about 1:406, about 1:1 to about 1:405, about 1:1 to about 1:404, about 1:1 to about 1:403, about 1:1 to about 1:402, about 1:1 to about 1:401, about 1:1 to about 1:400, about 1:1 to about 1:399, about 1:1 to about 1:398, about 1:1 to about 1:397, about 1:1 to about 1:396, about 1:1 to about 1:395, about 1:1 to about 1:394, about 1:1 to about 1:393, about 1:1 to about 1:392, about 1:1 to about 1:391, about 1:1 to about 1:390, about 1:1 to about 1:389, about 1:1 to about 1:388, about 1:1 to about 1:387, about 1:1 to about 1:386, about 1:1 to about 1:385, about 1:1 to about 1:384, about 1:1 to about 1:383, about 1:1 to about 1:382, about 1:1 to about 1:381, about 1:1 to about 1:380, about 1:1 to about 1:379, about 1:1 to about 1:378, about 1:1 to about 1:377, about 1:1 to about 1:376, about 1:1 to about 1:375, about 1:1 to about 1:374, about 1:1 to about 1:373, about 1:1 to about 1:372, about 1:1 to about 1:371, about 1:1 to about 1:370, about 1:1 to about 1:369, about 1:1 to about 1:368, about 1:1 to about 1:367, about 1:1 to about 1:366, about 1:1 to about 1:365, About 1:1 to about 1:364, about 1:1 to about 1:363, about 1:1 to about 1:362, about 1:1 to about 1:361, about 1:1 to about 1:360, about 1:1 to about 1:359, about 1:1 to about 1:358, about 1:1 to about 1:357, about 1:1 to about 1:356, about 1:1 to about 1:355, about 1:1 to about 1:354, about 1:1 to about 1:353, about 1:1 to about 1:352, about 1:1 to about 1:351, about 1:1 to about 1:350, about 1:1 to about 1:349, about 1:1 to about 1:348, about 1:1 to about 1:347, about 1:1 to about 1:346, about 1:1 to about 1:345, about 1:1 to about 1:3 44, about 1:1 to about 1:343, about 1:1 to about 1:342, about 1:1 to about 1:341, about 1:1 to about 1:340, about 1:1 to about 1:339, about 1:1 to about 1:338, about 1:1 to about 1:337, about 1:1 to about 1:336, about 1:1 to about 1:335, about 1:1 to about 1:334, about 1:1 to about 1:333, about 1:1 to about 1:332, about 1:1 to about 1:331, about 1:1 to about 1:330, about 1:1 to about 1:329, about 1:1 to about 1:328, about 1:1 to about 1:327, about 1:1 to about 1:326, about 1:1 to about 1:325, about 1:1 to about 1:324, about 1:1 to about 1:323, about 1:1 to about 1:322, about 1:1 to about 1:321, about 1:1 to about 1:320, about 1:1 to about 1:319, about 1:1 to about 1:318, about 1:1 to about 1:317, about 1:1 to about 1:316, about 1:1 to about 1:315, about 1:1 to about 1:314, about 1:1 to about 1:31 3, about 1:1 to about 1:312, about 1:1 to about 1:311, about 1:1 to about 1:310, about 1:1 to about 1:309, about 1:1 to about 1:308, about 1:1 to about 1:307, about 1:1 to about 1:306, about 1:1 to about 1:305, about 1:1 to about 1:304, about 1:1 to about 1:303, about 1: 1 to about 1:302, about 1:1 to about 1:301, about 1:1 to about 1:300, about 1:1 to about 1:299, about 1:1 to about 1:298, about 1:1 to about 1:297, about 1:1 to about 1:296, about 1:1 to about 1:295, about 1:1 to about 1:294, about 1:1 to about 1:293, about 1:1 to about 1 :292, about 1:1 to about 1:291, about 1:1 to about 1:290, about 1:1 to about 1:289, about 1:1 to about 1:288, about 1:1 to about 1:287, about 1:1 to about 1:286, about 1:1 to about 1:285, about 1:1 to about 1:284, about 1:1 to about 1:283, about 1:1 to about 1:282,about 1:1 to about 1:281, about 1:1 to about 1:280, about 1:1 to about 1:279, about 1:1 to about 1:278, about 1:1 to about 1:277, about 1:1 to about 1:276, about 1:1 to about 1:275, about 1:1 to about 1:274, about 1:1 to about 1:273, about 1:1 to about 1:272, about 1:1 to about 1:271, about 1:1 to about 1:270, about 1:1 to about 1:269, about 1:1 to about 1:268, about 1: 1 to about 1:267, about 1:1 to about 1:266, about 1:1 to about 1:265, about 1:1 to about 1:264, about 1:1 to about 1:263, about 1:1 to about 1:262, about 1:1 to about 1:261, about 1:1 to about 1:260, about 1:1 to about 1:259, about 1:1 to about 1:258, about 1:1 to about 1:257, about 1:1 to about 1:256, about 1:1 to about 1:255, about 1:1 to about 1:254, about 1:1 to about 1:253, about 1:1 to about 1:252, about 1:1 to about 1:251, about 1:1 to about 1:250, about 1:1 to about 1:249, about 1:1 to about 1:248, about 1:1 to about 1:247, about 1:1 to about 1:246, about 1:1 to about 1:245, about 1:1 to about 1:244, about 1:1 to about 1:243, about 1:1 to about 1:242, about 1:1 to about 1:241, about 1:1 to about 1:240, about 1:1 to about 1:2 39, about 1:1 to about 1:238, about 1:1 to about 1:237, about 1:1 to about 1:236, about 1:1 to about 1:235, about 1:1 to about 1:234, about 1:1 to about 1:233, about 1:1 to about 1:232, about 1:1 to about 1:231, about 1:1 to about 1:230, about 1:1 to about 1:229, about 1:1 to about 1:228, about 1:1 to about 1:227, about 1:1 to about 1:226, about 1:1 to about 1:225, About 1:1 to about 1:224, about 1:1 to about 1:223, about 1:1 to about 1:222, about 1:1 to about 1:221, about 1:1 to about 1:220, about 1:1 to about 1:219, about 1:1 to about 1:218, about 1:1 to about 1:217, about 1:1 to about 1:216, about 1:1 to about 1:215, about 1:1 to about 1:214, about 1:1 to about 1:213, about 1:1 to about 1:212, about 1:1 to about 1:211, about 1:1 to about 1:210, about 1:1 to about 1:209, about 1:1 to about 1:208, about 1:1 to about 1:207, about 1:1 to about 1:206, about 1:1 to about 1:205, about 1:1 to about 1:2 04, about 1:1 to about 1:203, about 1:1 to about 1:202, about 1:1 to about 1:201, about 1:1 to about 1:200, about 1:1 to about 1:199, about 1:1 to about 1:198, about 1:1 to about 1:197, about 1:1 to about 1:196, about 1:1 to about 1:195, about 1:1 to about 1:194, about 1:1 to about 1:193, about 1:1 to about 1:192, about 1:1 to about 1:191, about 1:1 to about 1:190, about 1:1 to about 1:189, about 1:1 to about 1:188, about 1:1 to about 1:187, about 1:1 to about 1:186, about 1:1 to about 1:185, about 1:1 to about 1:184, about 1:1 to about 1:183, about 1:1 to about 1:182, about 1:1 to about 1:181, about 1:1 to about 1:180, about 1:1 to about 1:179, about 1:1 to about 1:178, about 1:1 to about 1:177, about 1:1 to about 1:176, about 1:1 to about 1:175, about 1:1 to about 1:174, about 1:1 to about 1:17 3, about 1:1 to about 1:172, about 1:1 to about 1:171, about 1:1 to about 1:170, about 1:1 to about 1:169, about 1:1 to about 1:168, about 1:1 to about 1:167, about 1:1 to about 1:166, about 1:1 to about 1:165, about 1:1 to about 1:164, about 1:1 to about 1:163, about 1: 1 to about 1:162, about 1:1 to about 1:161, about 1:1 to about 1:160, about 1:1 to about 1:159, about 1:1 to about 1:158, about 1:1 to about 1:157, about 1:1 to about 1:156, about 1:1 to about 1:155, about 1:1 to about 1:154, about 1:1 to about 1:153, about 1:1 to about 1 :152, about 1:1 to about 1:151, about 1:1 to about 1:150, about 1:1 to about 1:149, about 1:1 to about 1:148, about 1:1 to about 1:147, about 1:1 to about 1:146, about 1:1 to about 1:145, about 1:1 to about 1:144, about 1:1 to about 1:143, about 1:1 to about 1:142,about 1:1 to about 1:141, about 1:1 to about 1:140, about 1:1 to about 1:139, about 1:1 to about 1:138, about 1:1 to about 1:137, about 1:1 to about 1:136, about 1:1 to about 1:135, about 1:1 to about 1:134, about 1:1 to about 1:133, about 1:1 to about 1:132, about 1:1 to about 1:131, about 1:1 to about 1:130, about 1:1 to about 1:129, about 1:1 to about 1:128, about 1:1 to about 1:127, about 1:1 to about 1:126, about 1:1 to about 1:125, about 1:1 to about 1:124, about 1:1 to about 1:123, about 1:1 to about 1:122, about 1:1 to about 1:1 21, about 1:1 to about 1:120, about 1:1 to about 1:119, about 1:1 to about 1:118, about 1:1 to about 1:117, about 1:1 to about 1:116, about 1:1 to about 1:115, about 1:1 to about 1:114, about 1:1 to about 1:113, about 1:1 to about 1:112, about 1:1 to about 1:111, about 1 :1 to about 1:110, about 1:1 to about 1:109, about 1:1 to about 1:108, about 1:1 to about 1:107, about 1:1 to about 1:106, about 1:1 to about 1:105, about 1:1 to about 1:104, about 1:1 to about 1:103, about 1:1 to about 1:102, about 1:1 to about 1:101, about 1:1 to about 1 :100, about 1:1 to about 1:99, about 1:1 to about 1:98, about 1:1 to about 1:97, about 1:1 to about 1:96, about 1:1 to about 1:95, about 1:1 to about 1:94, about 1:1 to about 1:93, about 1:1 to about 1:92, about 1:1 to about 1:91, about 1:1 to about 1:90, about 1:1 to about 1:89 , about 1:1 to about 1:88, about 1:1 to about 1:87, about 1:1 to about 1:86, about 1:1 to about 1:85, about 1:1 to about 1:84, about 1:1 to about 1:83, about 1:1 to about 1:82, about 1:1 to about 1:81, about 1:1 to about 1:80, about 1:1 to about 1:79, about 1:1 to about 1:78, about 1: 1 to about 1:77, about 1:1 to about 1:76, about 1:1 to about 1:75, about 1:1 to about 1:74, about 1:1 to about 1:73, about 1:1 to about 1:72, about 1:1 to about 1:71, about 1:1 to about 1:70, about 1:1 to about 1:69, about 1:1 to about 1:68, about 1:1 to about 1:67, about 1:1 to about 1 :66, about 1:1 to about 1:65, about 1:1 to about 1:64, about 1:1 to about 1:63, about 1:1 to about 1:62, about 1:1 to about 1:61, about 1:1 to about 1:60, about 1:1 to about 1:59, about 1:1 to about 1:58, about 1:1 to about 1:57, about 1:1 to about 1:56, about 1:1 to about 1:55,about 1:1 to about 1:54, about 1:1 to about 1:53, about 1:1 to about 1:52, about 1:1 to about 1:51, about 1:1 to about 1:50, about 1:1 to about 1:49, about 1:1 to about 1:48, about 1:1 to about 1:47, about 1:1 to about 1:46, about 1:1 to about 1:45, about 1:1 to about 1:44, about 1:1 to about 1:43, about 1:1 to about 1:42, about 1 1:1 to about 1:41, about 1:1 to about 1:40, about 1:1 to about 1:39, about 1:1 to about 1:38, about 1:1 to about 1:37, about 1:1 to about 1:36, about 1:1 to about 1:35, about 1:1 to about 1:34, about 1:1 to about 1:33, about 1:1 to about 1:32, about 1:1 to about 1:31, about 1:1 to about 1:30, about 1:1 to about 1:29, about 1:1 to about 1:28, about 1:1 to about 1:27, about 1:1 to about 1:26, about 1:1 to about 1:25, about 1:1 to about 1:24, about 1:1 to about 1:23, about 1:1 to about 1:22, about 1:1 to about 1:21, about 1:1 to about 1:20, about 1:1 to about 1:19, about 1:1 to about 1:18, about 1:1 to about 1:17, about 1:1 to about 1:16, about 1:1 to about 1:15, about 1:1 to about 1:14, about 1:1 to about 1:13, about 1:1 to about 1:12, about 1:1 to about 1:11, about 1:1 to about 1:10, about 1:1 to about 1:9, about 1:1 to about 1:8, about 1:1 to about 1:7, about 1:1 to about 1:6, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, or about 1:1 to about 1:2.

[1000]

[0937] In some embodiments, the composition comprises:

[1001] [ka]

[1002] of,

[1003] [ka]

[1004] about 1:479, about 1:478, about 1:477, about 1:476, about 1:475, about 1:474, about 1:473, about 1:472, about 1:471, about 1:470, about 1:469, about 1:468, about 1:467, about 1:474, about 1:475, about 1:476, about 1:478, about 1:479, about 1:478, about 1:477, about 1:476, about 1:475, about 1:474, about 1:475, about 1:476, about 1:478, about 1:479, about 1:478, about 1:479, about 1:478, about 1:479, about 1:476, about 1:475, about 1:474, about 1:475, about 1:476, about 1:478, about 1:479 ... :466, approximately 1:465, approximately 1:464, approximately 1:463, approximately 1:462, approximately 1:461, approximately 1:460, approximately 1:459, approximately 1:458, approximately 1:457, approximately 1:456, approximately 1:455, approximately 1:454, approximately 1:453, approximately 1:452, approximately 1:451, approximately 1:450, approximately 1:449, Approximately 1:448, approximately 1:447, approximately 1:446, approximately 1:445, approximately 1:444, approximately 1:443, approximately 1:442, approximately 1:441, approximately 1:440, approximately 1:439, approximately 1:438, approximately 1:437, approximately 1:436, approximately 1:435, approximately 1:434, approximately 1:433, approximately 1:432, approximately 1:431 , about 1:430, about 1:429, about 1:428, about 1:427, about 1:426, about 1:425, about 1:424, about 1:423, about 1:422, about 1:421, about 1:420, about 1:419, about 1:418, about 1:417, about 1:416, about 1:415, about 1:414, about 1:4 13, approx. 1:412, approx. 1:411, approx. 1:410, approx. 1:409, approx. 1:408, approx. 1:407, approx. 1:406, approx. 1:405, approx. 1:404, approx. 1:403, approx. 1:402, approx. 1:401, approx. 1:400, approx. 1:399, approx. 1:398, approx. 1:397, approx. 1:396, approx. 1: 395, approx. 1:394, approx. 1:393, approx. 1:392, approx. 1:391, approx. 1:390, approx. 1:389, approx. 1:388, approx. 1:387, approx. 1:386, approx. 1:385, approx. 1:384, approx. 1:383, approx. 1:382, approx. 1:381, approx. 1:380, approx. 1:379, approx....

Claims

1. Formula I: 【Chemistry 1】 A compound having the structure (i) 【Chemistry 2】 is a first therapeutic agent having the sequence of SEQ ID NO: 35; The compounds are mixed in a ratio of about 1:1 to about 1:

7. 【Transformation 3】 or having a molar ratio of (ii) 【Chemistry 4】 is a second therapeutic agent having the configuration [diacid]-[linker]-[amylin analog]; The amylin analog has an amino acid sequence of KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide (SEQ ID NO:20), wherein the amino acid sequence contains one or more of the following amino acid substitutions: N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof; The compounds are mixed in a ratio of about 1:1 to about 1:

3. 【Transformation 5】 having a molar ratio of The compound. 【Request Item 2】 【Chemistry 6】 is the first therapeutic agent, and the sequence of SEQ ID NO: 35 has the following structure: 【Transformation 7】 2. The compound of claim 1 having the formula: 【Request Item 3】 【Transformation 8】 is the first therapeutic agent and the compound is 【Chemistry 9】 having a molar ratio of 【Chemistry 10】 The compound of claim 1 consisting of: 【Request Item 4】 【Chemistry 11】 is the first therapeutic agent and the compound is in a ratio of about 1:2 【Chemistry 12】 having a molar ratio of 【Chemistry 13】 The compound of claim 1 consisting of: 【Request Item 5】 【Chemistry 14】 is the first therapeutic agent and the compound is in a ratio of about 1:3 【Chemistry 15】 having a molar ratio of 【Chemistry 16】 The compound of claim 1 consisting of: 【Request Item 6】 【Chemistry 17】 is the first therapeutic agent and the compound is in a ratio of about 1:4 [Chemistry 18] having a molar ratio of 【Chemistry 19】 The compound of claim 1 consisting of: 【Request Item 7】 【Chemistry 20】 is the first therapeutic agent and the compound is 【Chemistry 21】 having a molar ratio of 【Chemistry 22】 2. The compound of claim 1, consisting of: 【Request Item 8】 【Chemistry 23】 is the first therapeutic agent and the compound is 【Chemistry 24】 having a molar ratio of 【Chemistry 25】 2. The compound of claim 1, consisting of: 【Request Item 9】 【Chemistry 26】 is the first therapeutic agent and the compound is in a ratio of about 1:7 【Chemistry 27】 having a molar ratio of 【Chemistry 28】 2. The compound of claim 1, consisting of: 【Request Item 10】 【Chemistry 29】 is the first therapeutic agent, and the compound has the following structure: 【Transformation 30】 2. The compound of claim 1 having the formula: 【Request Item 11】 【Chemistry 31】 The compound of claim 1, wherein: is the second therapeutic agent; and Cys at position 2 and Cys at position 7 of the amino acid sequence of the amylin analog form a disulfide bond.

12. The sequence of rupture number 20 with the arrangement [diacid]-[linker]-[amylin analog] is: 【Chemistry 32】 12. The compound of claim 11 having the structure:

13. The compounds are mixed in a ratio of about 1:

1. 【Transformation 33】 having a molar ratio of 【Transformation 34】 13. The compound of claim 12, consisting of:

14. The compounds are mixed in a ratio of about 1:

2. 【Chemistry 35】 having a molar ratio of 【Transformation 36】 13. The compound of claim 12, consisting of:

15. The compounds are mixed in a ratio of about 1:

3. 【Chemistry 37】 having a molar ratio of 【Transformation 38】 13. The compound of claim 12, consisting of:

16. 13. The compound of claim 12, wherein the amino acid sequence has the following substitutions: N14E, V17R, and Y37P.

17. The compounds are mixed in a ratio of about 1:

1. 【Chemistry 39】 having a molar ratio of 【Chemistry 40】 17. The compound of claim 16, consisting of:

18. The compounds are mixed in a ratio of about 1:

2. 【Chemistry 41】 having a molar ratio of 【Chemistry 42】 17. The compound of claim 16, consisting of:

19. The compounds are mixed in a ratio of about 1:

3. 【Chemistry 43】 having a molar ratio of 【Chemistry 44】 17. The compound of claim 16, consisting of:

20. 12. The compound of claim 11, wherein the linker of the second therapeutic agent comprises one or more gamma glutamic acid (γGlu) residues, one or more 8-amino-3,6-dioxaoctanoic acid residues, or a combination thereof.

21. The second therapeutic agent is C １０ , C １２ , C １４ , C １６ , C １８ , or C ２０ 12. The compound of claim 11, comprising a fatty diacid of 【Request Item 22】 【Chemistry 45】 is the second therapeutic agent, and the compound has the following structure: 【Chemistry 46】 2. The compound of claim 1 , having the structure:

23. 23. The compound of claim 22, wherein the compound has the following substitutions: N14E, V17R, and Y37P.

24. 24. A composition comprising a compound according to any one of claims 1 to 23 for use in treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is a metabolic disease or disorder.

25. 25. A composition comprising the compound of claim 24, wherein the metabolic disease or disorder is type 1 diabetes, type 2 diabetes, obesity, overweight, or nonalcoholic steatohepatitis (NASH).

26. 25. The composition of claim 24, wherein the compound is formulated for oral, subcutaneous, or intravenous administration.

27. A composition comprising a compound according to any one of claims 1 to 23 for use in reducing weight in a subject in need thereof.

28. 25. The composition of claim 24, wherein the compound is formulated for oral, subcutaneous, or intravenous administration.

29. (i) a first compound, which is a compound according to any one of claims 1 to 10, 【Chemistry 47】 is the first therapeutic agent; and (ii) an additional therapeutic agent which is a second compound which is a compound according to any one of claims 1 and 11-23, 【Chemistry 48】 is the second therapeutic agent A composition comprising:

30. 30. The composition of claim 29, for use in treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is a metabolic disease or disorder.

31. 31. A composition comprising the compound of claim 30, wherein the metabolic disease or disorder is type 1 diabetes, type 2 diabetes, obesity, overweight, or nonalcoholic steatohepatitis (NASH).

32. 31. The composition of claim 30, wherein the compound is formulated for oral, subcutaneous, or intravenous administration.

33. 30. The composition of claim 29 for use in reducing weight in a subject in need thereof.

34. 34. The composition of claim 33, wherein the compound is formulated for oral, subcutaneous, or intravenous administration.

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