WO2023086499A1 - Ionic liquid compositions - Google Patents

Ionic liquid compositions Download PDF

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Publication number
WO2023086499A1
WO2023086499A1 PCT/US2022/049585 US2022049585W WO2023086499A1 WO 2023086499 A1 WO2023086499 A1 WO 2023086499A1 US 2022049585 W US2022049585 W US 2022049585W WO 2023086499 A1 WO2023086499 A1 WO 2023086499A1
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WO
WIPO (PCT)
Prior art keywords
acid
sequence
seq
compound
therapeutic agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2022/049585
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English (en)
French (fr)
Inventor
Tyler Brown
Kelly IBSEN
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I2O Therapeutics Inc
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I2O Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2024527534A priority Critical patent/JP2024544920A/ja
Priority to MX2024005705A priority patent/MX2024005705A/es
Priority to EP22893624.1A priority patent/EP4429704A4/en
Priority to IL312672A priority patent/IL312672A/en
Priority to CN202280088496.5A priority patent/CN118541170A/zh
Priority to AU2022386166A priority patent/AU2022386166A1/en
Priority to CA3237751A priority patent/CA3237751A1/en
Priority to KR1020247019163A priority patent/KR20240126450A/ko
Application filed by I2O Therapeutics Inc filed Critical I2O Therapeutics Inc
Publication of WO2023086499A1 publication Critical patent/WO2023086499A1/en
Priority to US18/444,471 priority patent/US12233112B2/en
Priority to US18/444,501 priority patent/US12350320B2/en
Priority to US18/444,463 priority patent/US12233111B2/en
Priority to US18/444,443 priority patent/US12233110B2/en
Priority to US18/444,485 priority patent/US12337029B2/en
Anticipated expiration legal-status Critical
Priority to US18/946,213 priority patent/US20250144180A1/en
Priority to US18/960,864 priority patent/US20250161415A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
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    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
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    • A—HUMAN NECESSITIES
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6845—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
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    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • compositions of matter and methods of use for the treatment of diseases or disorders are provided herein.
  • the inventors have found that certain modifications to proteins surprisingly improve their use with ionic liquid compositions for formulation and delivery. These formulations can be delivered orally to a patient for the purpose of treating the patient.
  • ionic liquid compositions for formulation and delivery. These formulations can be delivered orally to a patient for the purpose of treating the patient.
  • described herein is a composition wherein a protein or a peptide is non- covalently attached to one or more ions wherein such ions are also present in the said ionic liquid that is present in the formulation.
  • a composition wherein a protein or a peptide is covalently attached to one or more ions wherein such ions are also present in the said ionic liquid that is present in the formulation.
  • a compound according to Formula I is a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; R 5 is a therapeutic agent.
  • R 1 , R 2 , and R 3 are methyl.
  • R 1 , R 2 , and R 3 are ethyl. [0010] In some embodiments, R 1 , R 2 , and R 3 are propyl. [0011] In some embodiments, R 1 and R 2 are methyl, and R 3 is ethyl. [0012] In some embodiments, R 1 and R 3 are methyl, and R 2 is ethyl. [0013] In some embodiments, R 1 and R 2 are ethyl, and R 3 is methyl. [0014] In some embodiments, R 1 and R 3 are ethyl, and R 2 is methyl. [0015] In some embodiments, R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • R 4 is [0019] In some embodiments, the compound is according to Formula Ia: Formula Ia. [0020] In some embodiments, the compound is according to Formula Ib: Formula Ib. [0021] In some embodiments, the compound is according to Formula Ic: Formula Ic.
  • the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound comprises the structure as shown in FIG.16. [0025] In some embodiments, the compound comprises a molar ratio of from about 1:1 to about 1:60. [0026] In some embodiments, the compound comprises a molar ratio of from about 1:1 to about 1:30.
  • the compound comprises a molar ratio of about 1:1. [0028] In some embodiments, the compound comprises a molar ratio of about 1:3. [0029] In some embodiments, the compound comprises a molar ratio of about 1:4. [0030] In some embodiments, the compound comprises a molar ratio of about 1:7. [0031] In some embodiments, the compound comprises a molar ratio of about 1:12. [0032] In some embodiments, the compound comprises a molar ratio of about 1:14. [0033] In some embodiments, the compound comprises a molar ratio of about 1:28. [0034] In some embodiments, the compound comprises a molar ratio of about 1:56.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the compound comprises a molar ratio of from about 1:1 to about 1:30.
  • the compound comprises a molar ratio of about 1:1.
  • the compound comprises a molar ratio of about 1:3.
  • the compound comprises a molar ratio of about 1:7. [0045] In some embodiments, the compound comprises a molar ratio of about 1:12. [0046] In some embodiments, the compound comprises a molar ratio of about 1:28. [0047] In some embodiments, the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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
  • 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the compound comprises a molar ratio of from about 1:1 to about 1:164.
  • the compound comprises a molar ratio of about 1:1.
  • the compound comprises a molar ratio of about 1:33.
  • the compound comprises a molar ratio of about 1:41.
  • the compound comprises a molar ratio of about 1:66.
  • the compound comprises a molar ratio of about 1:82. [0060] In some embodiments, the compound comprises a molar ratio of about 1:132. [0061] In some embodiments, the compound comprises a molar ratio of 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 SEQ ID NO: 7. [0064] In some embodiments, the compound comprises a molar ratio of from about 1:1 to about 1:144.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9.
  • the compound comprises molar ratio of from about 1:1 to about 1:140.
  • the therapeutic agent is golimumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11.
  • the compound comprises a molar ratio of from about 1:1 to about 1:80.
  • the therapeutic agent is natalizumab or an antibody fragment thereof.
  • 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. [0073] In some embodiments, the compound comprises molar ratio of from 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. [0076] In some embodiments, the compound comprises molar ratio of from about 1:1 to about 1:256. [0077] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19. [0079] In some embodiments, the compound comprises molar ratio of from about 1:1 to about 1:70. [0080] In some embodiments, the therapeutic agent is an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide salt formed on the C-terminus of a light chain, the C-terminus of a heavy chain or a combination thereof. [0081] In some embodiments, the therapeutic agent is a dual GIP/GLP-1 receptor agonist or 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.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25. [0084] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [0085] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25. [0086] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises molar ratio of from about 1:1 to about 1:20. [0088] In some embodiments, the compound comprises a molar ratio of about 1:1. [0089] In some embodiments, the compound comprises molar ratio of about 1:2. [0090] In some embodiments, the compound comprises molar ratio of about 1:3. [0091] In some embodiments, the compound comprises molar ratio of about 1:4. [0092] In some embodiments, the compound comprises molar ratio of about 1:5. [0093] In some embodiments, the compound comprises molar ratio of about 1:10. [0094] In some embodiments, the compound comprises molar ratio of about 1:20.
  • the compound comprises the therapeutic agent having a modified structure.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified structure.
  • the compound comprises the therapeutic agent having a cation moiety comprising choline or choline derivative.
  • the compound comprises the therapeutic agent having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises the therapeutic agent comprising one or more choline or choline derivative-peptide derivative formed on a Glu residue, an Asp residue, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide salt that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a diacid consisting of 10, 12, 14, 16, 18, or 20 carbons in length.
  • the diacid comprises a C10, C12, C14, C16, C18, or C20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 6 is a therapeutic agent.
  • R 7 , R 8 , and R 9 are independently C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl.
  • R 7 , R 8 , and R 9 are ethyl.
  • R 7 , R 8 , and R 9 are propyl.
  • R 7 and R 8 are methyl, and R 9 is ethyl.
  • R 7 and R 9 are methyl, and R 8 is ethyl.
  • R 7 and R 8 are ethyl, and R 9 is methyl.
  • R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound comprises the structure as shown in FIG.17B.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof. [00125] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof. [00126] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide. [00127] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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
  • 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is adalimumab or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9. [00141] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof. [00142] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11. [00143] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof. [00144] 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. [00145] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17. [00147] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof. [00148] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19. [00149] In some embodiments, the therapeutic agent is an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide ester formed on the C- terminus of a light chain, the C-terminus of a heavy chain or a combination thereof.
  • the therapeutic agent is an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-antibody ratio of 2-4, or a combination thereof.
  • the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00154] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 25. [00155] In some embodiments, the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00156] In some embodiments, the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified structure.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified salt structure.
  • the compound comprises the therapeutic agent having a cation moiety comprising choline or choline derivative.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified ester structure.
  • the compound comprises the therapeutic agent having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises the therapeutic agent comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-the therapeutic agent ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-the therapeutic agent ratio of 2-4, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide salt that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a diacid consisting of 10, 12, 14, 16, 18, or 20 carbons in length.
  • the diacid comprises a C 10 , C 12 , C 14 , C 16 , C 18 , or C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • a compound according to Formula III is a therapeutic agent; R 11 is substituted or unsubstituted C 5 -C 10 ; L 1 is a covalent bond or a linker.
  • L 1 is a non-cleavable linker.
  • L 1 comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • L 1 comprises [00176] In some embodiments, L 1 is a chemically cleavable linker.
  • L 1 comprises a hydrazone linker or a disulfide linker. [00178] In some embodiments, L 1 comprises . [00179] In some embodiments, R 11 is substituted or unsubstituted C 10 . [00180] In some embodiments, the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin. [00181] In some embodiments, the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof. [00183] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof. [00184] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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
  • 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is adalimumab or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9. [00198] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof. [00199] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11. [00200] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof. [00201] 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. [00202] In some embodiments, the therapeutic agent is vedolizumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17. [00204] In some embodiments, the therapeutic agent is certolizumab pegol or an antibody fragment thereof. [00205] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19. [00206] In some embodiments, the therapeutic agent is an antibody or an antibody fragment thereof comprising one or more R 11 linked to the C-terminus of a light chain, the C-terminus of a heavy chain or a combination thereof. [00207] In some embodiments, the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00209] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 25. [00210] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00211] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified structure.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified salt structure.
  • the compound comprises the therapeutic agent having a cation moiety comprising choline or choline derivative.
  • the compound comprises the therapeutic agent having a choline or choline derivative-modified ester structure.
  • the compound comprises the therapeutic agent having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises the therapeutic agent comprising one or more R 11 linked to a Lys residue, a Cys residue, or any combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-the therapeutic agent ratio of 2-4, R 11 is linked to the Cys residue with a linker-to-the therapeutic agent ratio of 2-8 or with a linker-to-the therapeutic agent ratio of 4, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a dual conjugation.
  • the dual conjugation comprises a linker-to-the therapeutic agent ratio of 1-2.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises the therapeutic agent comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide salt that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises the therapeutic agent comprising a diacid consisting of 10, 12, 14, 16, 18, or 20 carbons in length.
  • the diacid comprises a C 10 , C 12 , C 14 , C 16 , C 18 , or C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • a composition comprising the compound as provided herein, and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloct
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the composition as provided herein further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • the composition as provided herein further comprises at least one pharmaceutically acceptable excipient.
  • composition comprising a therapeutic agent, and one or more ionic liquid, wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) wherein the therapeutic agent is an antibody or an antibody fragment thereof; or (iv) a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the solubility of the therapeutic agent is increased relative to a therapeutic agent in a composition without a ionic liquid.
  • the delivery efficiency of the therapeutic agent in a subject in need thereof is enhanced or improved when administered to the subject, relative to a therapeutic agent in a composition without a ionic liquid.
  • the composition as provided herein further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • a pharmaceutical composition comprising the compound as provided herein or the composition as provided herein, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition as provided herein further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound as provided herein, the composition as provided herein, or the pharmaceutical composition as provided herein, wherein the administering is effective to treat the disease or disorder in the subject.
  • the disease or disorder is a metabolic disease or disorder.
  • the disease or disorder is diabetes mellitus.
  • the disease or disorder is type 1 diabetes mellitus (T1DM).
  • the disease or disorder is type 2 diabetes mellitus (T2DM).
  • the disease or disorder is non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the disease or disorder is obesity or overweight.
  • the administration activates GIP receptor signaling, GLP-1 receptor signaling, or a combination thereof.
  • the administration increases or improves glucose-dependent insulin secretion, improves glucose tolerance, or a combination thereof.
  • the administration increases or improves blood sugar control.
  • the administration decreases or reduces fasting serum glucose.
  • the administration decreases or reduces body weight, decreases or reduces food intake, or a combination thereof.
  • the administration delivers improvement in glycaemic control, body weight, or a combination thereof.
  • the disease or disorder is an autoimmune or immunological disease or disorder.
  • the disease or disorder is Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Behçet's disease, plaque psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis, plaque psoriasis, multiple sclerosis, or eosinophilic esophagitis.
  • a method of treating obesity, preventing weight gain, or reducing weight in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound as provided herein, the composition as provided herein, or the pharmaceutical composition as provided herein, wherein the administering is effective to treat the disease or disorder in the subject.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the composition, the compound, or the pharmaceutical composition is administered orally.
  • the composition, the compound, or the pharmaceutical composition is administered as a liquid-filled capsule.
  • the composition, the compound, or the pharmaceutical composition is administered in multiple doses. [00280] In some embodiments, the composition, the compound, or the pharmaceutical composition is administered in a single dose. [00281] In some embodiments, the composition, the compound, or the pharmaceutical composition is administered to a mucus membrane. [00282] In some embodiments, the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration. [00283] In some embodiments, the concentration of the compound as provided herein is at least 0.1% weight per volume. [00284] In some embodiments, the concentration of the compound as provided herein is at least 0.05M. [00285] In some embodiments, the composition further comprises one or more additional agents.
  • the one or more additional agent is selected from the group consisting of a nucleic acid, a small molecule, and a polypeptide.
  • the one or more additional agent is a nucleic acid.
  • the one or more additional agent is a small molecule.
  • the one or more additional agent is a polypeptide.
  • the one or more additional agent is a polypeptide.
  • the one or more additional agents is a therapeutic that treats a metabolic disease or disorder.
  • the one or more additional agents is a therapeutic that treats diabetes mellitus.
  • the one or more additional agents is a therapeutic that treats type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • the one or more additional agents is a therapeutic that treats obesity or overweight.
  • a method of increasing the solubility of a therapeutic agent comprising: preparing a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; and R 5 is the therapeutic agent; wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) wherein the therapeutic agent is an antibody or an antibody fragment thereof;
  • a method of enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof comprising preparing a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; and R 5 is the therapeutic agent; wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) wherein the therapeutic agent is:
  • R 1 , R 2 , and R 3 are methyl. [00298] In some embodiments, R 1 , R 2 , and R 3 are ethyl. [00299] In some embodiments, R 1 , R 2 , and R 3 are propyl. [00300] In some embodiments, R 1 and R 2 are methyl, and R 3 is ethyl. [00301] In some embodiments, R 1 and R 3 are methyl, and R 2 is ethyl. [00302] In some embodiments, R 1 and R 2 are ethyl, and R 3 is methyl. [00303] In some embodiments, R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • R 4 is [00308]
  • the compound is according to Formula Ia: Formula Ia.
  • in the compound is according to Formula Ib: Formula Ib.
  • the compound is according to Formula Ic: Formula Ic.
  • the therapeutic agent is the GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • the therapeutic agent is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound comprises the structure as shown in FIG.16. [00314] In some embodiments, the compound comprises a molar ratio of from about 1:1 to about 1:60. [00315] In some embodiments, the compound comprises a molar ratio of from about 1:1 to about 1:30.
  • the compound comprises a molar ratio of about 1:1. [00317] In some embodiments, the compound comprises a molar ratio of about 1:3. [00318] In some embodiments, the compound comprises a molar ratio of about 1:4. [00319] In some embodiments, the compound comprises a molar ratio of about 1:7. [00320] In some embodiments, the compound comprises a molar ratio of about 1:12. [00321] In some embodiments, the compound comprises a molar ratio of about 1:14. [00322] In some embodiments, the compound comprises a molar ratio of about 1:28. [00323] In some embodiments, the compound comprises a molar ratio of about 1:56.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof. [00325] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof. [00326] In some embodiments, the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the compound comprises a molar ratio of from about 1:1 to about 1:30.
  • the compound comprises a molar ratio of about 1:1. [00332] In some embodiments, the compound comprises a molar ratio of about 1:3. [00333] In some embodiments, the compound comprises a molar ratio of about 1:7. [00334] In some embodiments, the compound comprises a molar ratio of about 1:12. [00335] In some embodiments, the compound comprises a molar ratio of about 1:28. [00336] In some embodiments, the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the compound comprises a molar ratio of from about 1:1 to about 1:164.
  • the compound comprises a molar ratio of about 1:1.
  • the compound comprises a molar ratio of about 1:33.
  • the compound comprises a molar ratio of about 1:41.
  • the compound comprises molar ratio of about 1:66.
  • the compound comprises molar ratio of about 1:82. [00349] In some embodiments, the compound comprises molar ratio of about 1:132. [00350] In some embodiments, the compound comprises molar ratio of about 1:164. [00351] In some embodiments, the therapeutic agent is adalimumab or an antibody fragment thereof. [00352] 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 SEQ ID NO: 7. [00353] In some embodiments, the compound comprises molar ratio of from about 1:1 to about 1:144.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9.
  • the compound comprises molar ratio of from about 1:1 to about 1:140.
  • the therapeutic agent is golimumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11.
  • the compound comprises a molar ratio of from about 1:1 to about 1:80.
  • the therapeutic agent is natalizumab or an antibody fragment thereof.
  • 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.
  • the compound comprises molar ratio of from about 1:1 to about 1:156.
  • the therapeutic agent is vedolizumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17.
  • the compound comprises molar ratio of from about 1:1 to about 1:256.
  • the therapeutic agent is certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19.
  • the compound comprises molar ratio of from about 1:1 to about 1:70.
  • the therapeutic agent is the dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • R 5 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 5 comprises the sequence of SEQ ID NO: 25.
  • R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00373] In some embodiments, R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25. [00374] In some embodiments, R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25. [00375] In some embodiments, the compound comprises molar ratio of from about 1:1 to about 1:20.
  • the compound comprises molar ratio of about 1:1. [00377] In some embodiments, the compound comprises molar ratio of about 1:2. [00378] In some embodiments, the compound comprises molar ratio of about 1:3. [00379] In some embodiments, the compound comprises molar ratio of about 1:4. [00380] In some embodiments, the compound comprises molar ratio of about 1:5. [00381] In some embodiments, the compound comprises molar ratio of about 1:10. [00382] In some embodiments, the compound comprises molar ratio of about 1:20.
  • a method of increasing the solubility of a therapeutic agent comprising preparing a composition comprising a compound according to Formula II: Formula II, wherein: R 6 is the therapeutic agent, wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) an antibody or an antibody fragment thereof; or (iv) a dual GIP/GLP-1 receptor agonist or functional variant thereof; R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl. [00386] In some embodiments, R 7 , R 8 , and R 9 are ethyl. [00387] In some embodiments, R 7 , R 8 , and R 9 are propyl. [00388] In some embodiments, R 7 and R 8 are methyl, and R 9 is ethyl. [00389] In some embodiments, R 7 and R 9 are methyl, and R 8 is ethyl. [00390] In some embodiments, R 7 and R 8 are ethyl, and R 9 is methyl.
  • R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • the therapeutic agent is the GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • the therapeutic agent is the GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound comprises the structure as shown in FIG.17B.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is adalimumab or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9. [00418] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof. [00419] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11. [00420] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof. [00421] 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.
  • the therapeutic agent is vedolizumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17.
  • the therapeutic agent is certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19.
  • the therapeutic agent the GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide.
  • R 6 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 6 comprises the sequence of SEQ ID NO: 25.
  • R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the composition further comprises one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • a method of increasing the solubility of a therapeutic agent comprising preparing a composition comprising the therapeutic agent and one or more ionic liquid, wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) an antibody or an antibody fragment thereof; or (iv) a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amyl
  • a method of enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof comprising preparing a composition comprising the therapeutic agent and one or more ionic liquid, and administering the composition to the subject, wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) an antibody or an antibody fragment thereof; or (iv) a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glu
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • a method of enhancing the hydrophobicity of a therapeutic agent comprising linking R 12 to a therapeutic agent, wherein R 12 is substituted or unsubstituted C 5 -C 10 ; and wherein the therapeutic agent is: (i) an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin; (ii) an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof; (iii) an antibody or an antibody fragment thereof; or (iv) a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • GLP-l analog or functional variant thereof or mimetic thereof Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP
  • R 12 is linked to -S-, or -NH- of the therapeutic agent.
  • R 12 is linked to the therapeutic agent via a covalent bond or a linker.
  • the linker is a non-cleavable linker.
  • the linker comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • the linker comprises [00457] In some embodiments, the linker is a chemically cleavable linker.
  • the linker comprises a hydrazone linker or a disulfide linker. [00459] In some embodiments, the linker comprises [00460] In some embodiments, R 12 is substituted or unsubstituted C 10 . [00461] In some embodiments, the therapeutic agent is the GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin. [00462] In some embodiments, the therapeutic agent is the GLP-l analog or functional variant thereof or mimetic thereof.
  • the therapeutic agent is an amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the sequence of: [diacid]-[linker]-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic or analog thereof comprising an amino acid substitution of N14E.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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 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.
  • 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 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.
  • the therapeutic agent is infliximab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is adalimumab or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is ustekinumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9. [00480] In some embodiments, the therapeutic agent is golimumab or an antibody fragment thereof. [00481] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11. [00482] In some embodiments, the therapeutic agent is natalizumab or an antibody fragment thereof. [00483] 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.
  • the therapeutic agent is vedolizumab or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17.
  • the therapeutic agent is certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19.
  • the therapeutic agent is the dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the therapeutic agent is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • the therapeutic agent is linked to the one or more fatty acids or carboxylic acid-containing molecules via a dual conjugation.
  • the one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • the one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of the therapeutic agent.
  • the one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of the therapeutic agent. [00499] In some embodiments, the one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of the therapeutic agent. [00500] In some embodiments, the one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of the therapeutic agent.
  • the one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of the therapeutic agent.
  • the one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of the therapeutic agent.
  • provided herein is a method of enhancing or improving a delivery efficiency of a therapeutic agent in a subject in need thereof comprising adding at least one permeation enhancer to the compound as provided herein, the composition as provided herein, or the pharmaceutical composition as provided herein, and administering the composition, the compound, or the pharmaceutical composition to the subject.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • FIG.1 depicts the structure of an exemplary amylin analog or functional variant thereof or mimetic thereof.
  • FIG.2 depicts exemplary embodiments of an amylin analog or functional variant thereof or mimetic thereof with modified amylin analog or functional variant thereof or mimetic thereof structures.
  • FIG.3 depicts exemplary embodiments of an amylin analog or functional variant thereof or mimetic thereof with choline-modified amylin analog or functional variant thereof or mimetic thereof derivative structures.
  • FIG.4 depicts exemplary embodiments of an amylin analog or functional variant thereof or mimetic thereof with choline-modified amylin analog or functional variant thereof or mimetic thereof ester structures.
  • FIG.5 depicts an exemplary embodiment of an antibody or an antibody fragment thereof comprising a choline-peptide derivative that is formed on the C-terminal carboxylic acid of the heavy chain.
  • FIG.6A depicts an exemplary embodiment of an antibody or an antibody fragment thereof comprising a choline-peptide ester that is formed on the C-terminal carboxylic acid of the heavy chain.
  • FIG.6B depicts an exemplary chemical reaction to prepare a covalent choline derivative of an antibody or an antibody fragment thereof (e.g., choline-antibody covalent ester conjugation).
  • FIG.7 depicts an exemplary embodiment of an antibody or an antibody fragment thereof comprising a choline-peptide ester that is formed on a Cys residue or a Lys residue of the heavy chain of the antibody or an antibody fragment thereof.
  • the Linker to Antibody Ratio (LAR) for Cysteine conjugation is 2-8.
  • the Linker to Antibody Ratio is 2-4 for Lysine conjugation.
  • FIG.8A depicts an exemplary embodiment of an antibody or an antibody fragment thereof linked to fatty acids on the C-terminal carboxylic acid of the heavy chain. Fatty acid may include other lengths between C5 (hexanoic acid) to C10 (decanoic acid).
  • FIG.8B depicts an exemplary chemical reaction to prepare an antibody or an antibody fragment thereof linked to fatty acids.
  • FIG.8C depicts exemplary linkers that may be used to link an antibody or an antibody fragment thereof linked to fatty acids.
  • FIG.8D depicts an exemplary fatty acid that may be linked to an antibody or an antibody fragment thereof.
  • FIG.9A depicts an exemplary embodiment of an antibody or an antibody fragment thereof linked to fatty acids on a Lys residue or a Cys residue or of the heavy chain of the antibody or an antibody fragment thereof, or an antibody or an antibody fragment thereof linked to fatty acids via a dual conjugation.
  • the Linker to Antibody Ratio (LAR) is 2-4 for Lysine conjugation is 2-4.
  • the Linker to Antibody Ratio (LAR) for Cysteine conjugation is 2-8.
  • the Linker to Antibody Ratio (LAR) for Cysteine conjugation is 4.
  • the Linker to Antibody Ratio (LAR) for an antibody or an antibody fragment thereof linked to fatty acids via a dual conjugation is 1-2.
  • FIG.9B depicts an exemplary chemical reaction to prepare an antibody or an antibody fragment thereof linked to fatty acids via a dual conjugation.
  • FIG.10 depicts exemplary choline and choline derivatives.
  • FIG.11 depicts the structure of an exemplary dual GIP/GLP-1 receptor agonist.
  • FIG.12 depicts the structure schematic of an exemplary dual GIP/GLP-1 receptor agonist.
  • FIG.13 depicts an exemplary embodiment of a choline-modified dual GIP/GLP-1 receptor agonist ionic derivative structure using an exemplary dual GIP/GLP-1 receptor agonist backbone.
  • the circles indicate the exemplary sites of ionizable amino acid side-chains or carboxylic groups.
  • FIG.14 depicts an exemplary embodiment of a choline-modified a dual GIP/GLP-1 receptor agonist ester structure using an exemplary dual GIP/GLP-1 receptor agonist backbone.
  • the circles indicate the exemplary sites of potential esterification.
  • FIG.15A depicts the sequence of an exemplary GLP-l analog or functional variant thereof or mimetic thereof.
  • FIG.15B depicts the sequence of another exemplary GLP-l analog or functional variant thereof or mimetic thereof.
  • FIG.16 depicts an exemplary embodiment of the compound according to Formula I.
  • FIG.17A depicts an exemplary form of covalent attachment.
  • FIG.17B depicts an exemplary embodiment of the compound according to Formula II.
  • FIG.18 depicts the chemical structure of an exemplary form of the cinnamic acid derivative.
  • FIG.19 depicts an exemplary process by which the ionic liquid is prepared by mixing an acid with choline or choline derivative bicarbonate.
  • FIGs.20A-20D depict exemplary chemical structural variations of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof.
  • FIG.20A depicts a chemical structure of an exemplary GLP-l analog or functional variant thereof or mimetic thereof.
  • FIG.20B depicts an exemplary structure of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the 1:1 ratio. In some embodiments, choline ionization could occur at any of the –COOH sites.
  • FIG.20C depicts an exemplary structure of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the 7:1 ratio.
  • FIG.20D depicts an exemplary structure of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the 28:1 ratio. In some embodiments, excess bicarbonate is also present in the 28:1 ratio.
  • FIG.21 depicts Table 3 showing an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) mass normalization calculation.
  • FIG.22 shows exemplary analytical characterization of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • FIGs.23A-23D show exemplary analytical characterization of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH.
  • FIG.23A depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water. The results are not normalized to an exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.23B depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water.
  • FIG.23C depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water, wherein the exemplary reaction using choline bicarbonate as shown above the graph was used.
  • GLP-l analog an exemplary GLP-l analog or functional variant thereof or mimetic thereof
  • FIG.23D depicts exemplary analytical characterization results of the negative control of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water, wherein the exemplary reaction using choline chloride as shown above the graph was used.
  • the results of the choline-Cl-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIGs.24A-24D show exemplary analytical characterization of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity.
  • FIG.24A depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water. The results are not normalized to an exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.24B depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water. The results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.24C depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water, wherein the exemplary reaction using choline bicarbonate as shown above the graph was used.
  • the results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.24D depicts exemplary analytical characterization results of the negative control of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water, wherein the exemplary reaction using choline chloride as shown above the graph was used.
  • the results of the choline-Cl-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIGs.25A and 25B show exemplary analytical characterization based on NMR of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) ratios.
  • FIG.25A depicts exemplary analytical characterization results based on NMR of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) ratios.
  • FIG.25B depicts exemplary analytical characterization results based on NMR of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) ratios in a larger view.
  • FIG.26 shows exemplary analytical characterization based on Fourier-transform infrared spectroscopy (FTIR).
  • FIG.27 depicts an exemplary embodiment of a cinnamic acid-glucagon-like peptide (GLP-1) analog or functional variant thereof or mimetic thereof.
  • FTIR Fourier-transform infrared spectroscopy
  • the invention describes modification of drugs with ions to improve their formulation with ionic liquids for treating patients by oral administration.
  • Oral administration can be achieved in any one of the dosing forms including pills, caplets, capsules, aerosol sprays, or liquids.
  • the ionic liquid or the drug to be delivered with the ionic liquid can be encapsulated in a capsule.
  • the ionic liquid with the dosing form may be present in any of the physical forms including a clear neat ionic liquid, a homogenous mixture of an ionic liquid with a pharmaceutically acceptable diluent, an emulsion, or a suspension.
  • the oral dose can also be given as a syrup or a spray or an aerosol.
  • composition of any oral dose disclosed herein may contain a predetermined amount of ionic liquid and optionally one drug, and may be prepared by methods of pharmacy well known to those skilled in the art.
  • described herein is a method of treatment of patients comprising orally administering an oral formulation of insulin in combination with an ionic liquid.
  • described herein is a method of treatment of diabetes comprising orally administering an oral formulation of an amylin analog or functional variant thereof or mimetic thereof or a GLP-l polypeptide or mimetic or analog thereof in combination with ionic liquid.
  • ionic liquid is able to safely carry active compounds across the mucus membranes encountered during oral administration.
  • ionic liquids provide solubilization of the drug and enhanced delivery into systemic circulation. Accordingly, they are particularly suitable as a delivery vehicle to/across mucus membranes.
  • the ionic liquid can be combined with another solvent to enhance solubility and/or delivery.
  • the solvent may be aqueous or non-aqueous.
  • the purpose of the solvent is to control the dose of the ionic liquid experienced by the mucus membrane or the gastrointestinal tract. Dilution of the ionic liquid by the solvent can serve the purpose of delivering a safe dose to the subject.
  • the purpose of the solvent is to improve solubility of the drug.
  • Such improvement may come from the ability of the solvent to control the physicochemical environment of the ionic liquid to match the chemical properties of the drug.
  • the solvent may serve the purpose of improving the delivery across the mucosal membrane.
  • the solvents used in any of the embodiments include without limitation: sterile water, saline solution, glycerin, propylene glycol, ethanol, oils, ethyl oleate, isopropyl myristate, benzyl benzoate, or surfactants.
  • the solvent is chosen so as to not adversely impact the compatibility of the ionic liquid with the capsule.
  • ionic liquids refers to organic salts or mixtures of organic salts which are in liquid state at room temperature. Ionic liquids have been shown to be useful in a variety of fields, including in industrial processing, catalysis, pharmaceuticals, and electrochemistry.
  • the ionic liquids contain at least one anionic and at least one cationic component.
  • Ionic liquids can comprise an additional hydrogen bond donor (i.e. any molecule that can provide an -OH or an - NH group), examples include but are not limited to alcohols, fatty acids, and amines.
  • the anionic and the cationic component may be present in any molar ratio.
  • Exemplary molar ratios include but are not limited to 1:1, 1:2, 2:1, and ranges between these ratios.
  • the ionic liquid or solvent exists as a liquid below 100 °C.
  • the ionic liquid or solvent exists as a liquid at room temperature.
  • the ionic liquids comprise more than one anionic components and one cationic component.
  • the ionic liquid comprises choline or choline derivative, and cinnamic acid and mandelic acid.
  • the ionic liquid is dominated by the ionic interactions between the anion and the cation.
  • the ionic liquid is dominated by the hydrogen bonding interactions between the anion and cation.
  • the relative dominance of ionic and hydrogen bonding interactions may vary depending on the nature of the ions.
  • “in combination with” refers to two or more substances being present in the same dose administered to a subject in any form.
  • the drug(s) may form micelles or other self-assembled structures. In some embodiments, such structure may occur only in the presence of ionic liquids.
  • the terms “therapeutic agent” and “drug” are interchangeably used.
  • a therapeutic agent or a drug is any agent which will exert an effect on a target cell or organism.
  • a drug can be selected from a group comprising: chemicals; small organic or inorganic molecules; peptide; protein; or nucleic acid.
  • active compounds contemplated for use in the methods described herein include small molecules, polypeptides, nucleic acids, antibodies, vaccines, an antibody or an antibody fragment thereof, a GLP-l polypeptide or mimetic or analog thereof, amylin, an amylin analog or functional variant thereof or mimetic thereof, PYY, pramlintide, and insulin.
  • the terms “mimetic,” “functional variant,” “functional analog,” or “functional homolog thereof” may be used interchangeably.
  • a dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 (Glucagon-like peptide-1) receptor agonist or functional variant thereof is Tirzepatide or functional variant thereof or mimetic or functional analog thereof or functional homolog thereof.
  • Tirzepatide also known as LY3298176 and GIP/GLP-1 RA, refers to a fatty acid modified peptide with dual glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) receptor agonist activity.
  • Tirzepatide is a dual GIP and GLP-1 receptor agonist.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is a GIP-based dual Incretin receptor agonist.
  • GIP and GLP-1 are hormones involved in blood sugar control.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof activates both the GLP-1 and GIP receptors.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof activates both GIP and GLP-1 receptor signaling.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof shows glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof leads to improved blood sugar control.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof decreases body weight and food intake.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof shows that the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof reduces fasting serum glucose.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof results in reductions in body weight.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to treat diabetes mellitus.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to treat type 2 diabetes mellitus.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to treat T2DM patients.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to deliver clinically meaningful improvement in glycaemic control and body weight.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to deliver clinically meaningful improvement in glycaemic control. In some embodiments, a dual GIP/GLP-1 receptor agonist or functional variant thereof is used to deliver clinically meaningful improvement in body weight. In some embodiments, a dual GIP/GLP-1 receptor agonist or functional variant thereof is used for the treatment of T2DM and obesity. In some embodiments, a dual GIP/GLP-1 receptor agonist or functional variant thereof is used for the treatment of obesity. In some embodiments, a dual GIP/GLP-1 receptor agonist or functional variant thereof is designed for once-weekly subcutaneous administration. In some embodiments, a dual GIP/GLP-1 receptor agonist or functional variant thereof is designed for oral administration.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is designed for chronic administration.
  • a dual GIP/GLP-1 receptor 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.
  • GIP Glucose-dependent insulinotropic polypeptide
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is the compound as show in FIG.11 or FIG.12, [00552]
  • a dual GIP/GLP-1 receptor 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 of sequence identity to the sequence of: YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS, wherein Aib refers to ⁇ -amino isobutyric acid (SEQ ID NO: 25).
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises the sequence of: YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS, wherein Aib refers to ⁇ -amino isobutyric acid (SEQ ID NO: 25).
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached 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.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached 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.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached to a Lys residue of the sequence of SEQ ID NO: 25.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the 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.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached to the Lys residue at the position 20 (from the N-terminus) of the sequence of SEQ ID NO: 25.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached to the residue at the 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.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof comprises C20 diacid- ⁇ -Glu-(AEEA) 2 attached to the residue at the position 20 (from the N-terminus) of the sequence of SEQ ID NO: 25.
  • glucose-dependent insulinotropic polypeptide also known as gastric inhibitory polypeptide, GIP, or gastric inhibitory peptide, refers to an inhibiting hormone of the secretin family of hormones.
  • glucose-dependent insulinotropic polypeptide is a weak inhibitor of gastric acid secretion.
  • the main role of glucose- dependent insulinotropic polypeptide is to stimulate insulin secretion.
  • Glucose-dependent insulinotropic polypeptide includes any of the recombinant or naturally-occurring forms of glucose-dependent insulinotropic polypeptide or variants or homologs thereof that have or maintain glucose-dependent insulinotropic polypeptide activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring glucose-dependent insulinotropic polypeptide.
  • glucose-like peptide-1 also known as GLP-1, refers to a 30- or 31- amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide.
  • glucagon-like peptide-1 is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption.
  • Glucagon-like peptide-1 includes any of the 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).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring glucagon-like peptide-1.
  • ionizable groups present on a dual GIP/GLP-1 receptor agonist or functional variant thereof with a cation (e.g., FIG.13).
  • the choline:a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of the choline-a dual GIP/GLP-1 receptor agonist or functional variant thereof ionic derivatives is 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,
  • choline-a dual GIP/GLP-1 receptor agonist or functional variant thereof ester derivatives can 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 sites on the a dual GIP/GLP-1 receptor agonist or functional variant thereof structure.
  • the composition comprises a molar ratio of from about 1:1 to about 1:20.
  • the composition comprises a to molar ratio of from about 1:1 to about 1:200, from about 1:1 to about 1:199, from about 1:1 to about 1:198, from about 1:1 to about 1:197, from about 1:1 to about 1:196, from about 1:1 to about 1:195, from about 1:1 to about 1:194, from about 1:1 to about 1:193, from about 1:1 to about 1:192, from about 1:1 to about 1:191, from about 1:1 to about 1:190, from about 1:1 to about 1:189, from about 1:1 to about 1:188, from about 1:1 to about 1:187, from about 1:1 to about 1:186, from about 1:1 to about 1:185, from about 1:1 to about 1:184, from about 1:1 to about 1:183, from about 1:1 to about 1:182, from about 1:1 to about 1:181, from about 1:1 to about 1:180, from about 1:1 to about 1:179, from about 1:1 to about 1:178, from about 1:1 to about 1:177, from about 1:1 to about 1:176, from about 1:1 to about 1:175, from about 1:1 to about 1:174, from about 1:1 to about 1:173, from about 1:1 to about 1:172, from about 1:1 to about 1:1
  • the composition comprises a molar ratio of about 1:200, about 1:199, about 1:198, about 1:197, about 1:196, about 1:195, about 1:194, about 1:193, about 1:192, about 1:191, about 1:190, about 1:189, about 1:188, about 1:187, about 1:186, about 1:185, about 1:184, about 1:183, about 1:182, about 1:181, about 1:180, about 1:179, about 1:178, about 1:177, about 1:176, about 1:175, about 1:174, about 1:173, about 1:172, about 1:171, about 1:170, about 1:169, about 1:168, about 1:167, about 1:166, about 1:165, about 1:164, about 1:163, about 1:162, about 1:161, about 1:160, about 1:159, about 1:158, about 1:157, about 1:156, about 1:155, about 1:154, about 1:153, about 1:152, about 1:151, about 1:150, about 1:149, about 1:148, about 1:147, about 1:146, about 1:145, about 1:144, about 1:143, about 1:1
  • R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl. In some embodiments, R 1 is C 1 -C 5 alkyl. In some embodiments, R 2 is C 1 -C 5 alkyl. In some embodiments, R 3 is C 1 -C 5 alkyl. [00566] In some embodiments, R 1 , R 2 , and R 3 are independently C 1 -C 20 alkyl. In some embodiments, R 1 is C 1 -C 20 alkyl. In some embodiments, R 1 is C 1 -C 19 alkyl.
  • R 1 is C 1 -C 18 alkyl. In some embodiments, R 1 is C 1 -C 17 alkyl. In some embodiments, R 1 is C 1 -C 16 alkyl. In some embodiments, R 1 is C 1 -C 15 alkyl. In some embodiments, R 1 is C 1 -C 14 alkyl. In some embodiments, R 1 is C 1 -C 13 alkyl. In some embodiments, R 1 is C 1 -C 12 alkyl. In some embodiments, R 1 is C 1 -C 11 alkyl. In some embodiments, R 1 is C 1 -C 10 alkyl. In some embodiments, R 1 is C 1 -C 9 alkyl.
  • R 1 is C 1 -C 8 alkyl. In some embodiments, R 1 is C 1 -C 7 alkyl. In some embodiments, R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is C 1 -C 5 alkyl. In some embodiments, R 1 is C 1 -C 4 alkyl. In some embodiments, R 1 is C 1 -C 3 alkyl. In some embodiments, R 1 is C 1 -C 2 alkyl. In some embodiments, R 2 is C 1 -C 20 alkyl. In some embodiments, R 2 is C 1 -C 19 alkyl. In some embodiments, R 2 is C 1 -C 18 alkyl.
  • R 2 is C 1 -C 17 alkyl. In some embodiments, R 2 is C 1 -C 16 alkyl. In some embodiments, R 2 is C 1 -C 15 alkyl. In some embodiments, R 2 is C 1 -C 14 alkyl. In some embodiments, R 2 is C 1 -C 13 alkyl. In some embodiments, R 2 is C 1 -C 12 alkyl. In some embodiments, R 2 is C 1 -C 11 alkyl. In some embodiments, R 2 is C 1 -C 10 alkyl. In some embodiments, R 2 is C 1 -C 9 alkyl. In some embodiments, R 2 is C 1 -C 8 alkyl.
  • R 2 is C 1 -C 7 alkyl. In some embodiments, R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 5 alkyl. In some embodiments, R 2 is C 1 -C 4 alkyl. In some embodiments, R 2 is C 1 -C 3 alkyl. In some embodiments, R 2 is C 1 -C 2 alkyl. In some embodiments, R 3 is C 1 -C 20 alkyl. In some embodiments, R 3 is C 1 -C 19 alkyl. In some embodiments, R 3 is C 1 -C 18 alkyl. In some embodiments, R 3 is C 1 -C 17 alkyl.
  • R 3 is C 1 -C 16 alkyl. In some embodiments, R 3 is C 1 -C 15 alkyl. In some embodiments, R 3 is C 1 -C 14 alkyl. In some embodiments, R 3 is C 1 -C 13 alkyl. In some embodiments, R 3 is C 1 -C 12 alkyl. In some embodiments, R 3 is C 1 -C 11 alkyl. In some embodiments, R 3 is C 1 -C 10 alkyl. In some embodiments, R 3 is C 1 -C 9 alkyl. In some embodiments, R 3 is C 1 -C 8 alkyl. In some embodiments, R 3 is C 1 -C 7 alkyl.
  • R 3 is C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 5 alkyl. In some embodiments, R 3 is C 1 -C 4 alkyl. In some embodiments, R 3 is C 1 -C 3 alkyl. In some embodiments, R 3 is C 1 -C 2 alkyl. [00567] In some embodiments, R 1 is C 1 alkyl. In some embodiments, R 1 is C 2 alkyl. In some embodiments, R 1 is C 3 alkyl. In some embodiments, R 1 is C 4 alkyl. In some embodiments, R 1 is C 5 alkyl. In some embodiments, R 1 is C 6 alkyl.
  • R 1 is C 7 alkyl. In some embodiments, R 1 is C 8 alkyl. In some embodiments, R 1 is C 9 alkyl. In some embodiments, R 1 is C 10 alkyl. In some embodiments, R 1 is C 11 alkyl. In some embodiments, R 1 is C 12 alkyl. In some embodiments, R 1 is C 13 alkyl. In some embodiments, R 1 is C 14 alkyl. In some embodiments, R 1 is C 15 alkyl. In some embodiments, R 1 is C 16 alkyl. In some embodiments, R 1 is C 17 alkyl. In some embodiments, R 1 is C 18 alkyl. In some embodiments, R 1 is C 19 alkyl.
  • R 1 is C 20 alkyl.
  • R 2 is C 1 alkyl. In some embodiments, R 2 is C 2 alkyl. In some embodiments, R 2 is C 3 alkyl. In some embodiments, R 2 is C 4 alkyl. In some embodiments, R 2 is C 5 alkyl. In some embodiments, R 2 is C 6 alkyl. In some embodiments, R 2 is C 7 alkyl. In some embodiments, R 2 is C 8 alkyl. In some embodiments, R 2 is C 9 alkyl. In some embodiments, R 2 is C 10 alkyl. In some embodiments, R 2 is C 11 alkyl. In some embodiments, R 2 is C 12 alkyl.
  • R 2 is C 13 alkyl. In some embodiments, R 2 is C 14 alkyl. In some embodiments, R 2 is C 15 alkyl. In some embodiments, R 2 is C 16 alkyl. In some embodiments, R 2 is C 17 alkyl. In some embodiments, R 2 is C 18 alkyl. In some embodiments, R 2 is C 19 alkyl. In some embodiments, R 2 is C 20 alkyl. In some embodiments, R 3 is C 1 alkyl. In some embodiments, R 3 is C 2 alkyl. In some embodiments, R 3 is C 3 alkyl. In some embodiments, R 3 is C 4 alkyl. In some embodiments, R 3 is C 5 alkyl.
  • R 3 is C 6 alkyl. In some embodiments, R 3 is C 7 alkyl. In some embodiments, R 3 is C 8 alkyl. In some embodiments, R 3 is C 9 alkyl. In some embodiments, R 3 is C 10 alkyl. In some embodiments, R 3 is C 11 alkyl. In some embodiments, R 3 is C 12 alkyl. In some embodiments, R 3 is C 13 alkyl. In some embodiments, R 3 is C 14 alkyl. In some embodiments, R 3 is C 15 alkyl. In some embodiments, R 3 is C 16 alkyl. In some embodiments, R 3 is C 17 alkyl. In some embodiments, R 3 is C 18 alkyl.
  • R 3 is C 19 alkyl. In some embodiments, R 3 is C 20 alkyl. [00568] In some embodiments, R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 20 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 19 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 18 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 17 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 16 alkyl, wherein the C 2 - C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 - C 15 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 14 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 13 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 12 alkyl, wherein the C 2 - C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 - C 11 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 10 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 9 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 8 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 7 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 6 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 4 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 3 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19, or C 20 alkyl, wherein the C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 5 is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • R 5 is a therapeutic agent that 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.
  • R 5 is a therapeutic agent that comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached 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.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu- (AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting 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 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , 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 , 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 fatty diacid.
  • R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 5 alkyl. [00576] In some embodiments, R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 - C 20 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 19 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 17 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 14 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 12 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 10 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 7 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 3 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 2 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 19 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 17 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 14 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 12 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 10 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 7 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 5 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 3 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 2 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 19 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 17 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 14 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 12 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 10 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 7 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 3 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 2 alkyl.
  • R 7 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 2 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 6 alkyl.
  • R 7 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 10 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 14 alkyl.
  • R 7 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 18 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 20 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 2 alkyl.
  • R 8 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 6 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 10 alkyl.
  • R 8 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 14 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 18 alkyl.
  • R 8 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 20 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 2 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 6 alkyl.
  • R 9 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 10 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 14 alkyl.
  • R 9 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 18 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 20 alkyl. [00578] In some embodiments, n is 1, 2, 3, 4, or 5.
  • 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.
  • R 6 is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • R 6 is a therapeutic agent that 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.
  • R 6 is a therapeutic agent that comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached 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.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25. In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu- (AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25. [00582] In some embodiments, the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-4, or a combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 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, 22-28, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 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.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting 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 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises a C 1 , C 2 , C 3 , C 4 , C 5 , C6, C 7 , C8, C 9 , 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 , 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 fatty diacid.
  • a compound according to Formula III Formula III, wherein: R 10 is a therapeutic agent; R 11 is substituted or unsubstituted C 5 -C 10 ; X 1 is -S-, or -NH-; and L 1 is a covalent bond or a linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising one or more R 11 linked to a Lys residue, a Cys residue, or any combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-4, R 11 is linked to the Cys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-8 or with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 4, or a combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • R 11 is linked to the Lys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • R 11 is linked to the Lys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • R 11 is linked to the Lys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 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.
  • R 11 is linked to the Cys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • R 11 is linked to the Cys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • R 11 is linked to the Cys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • R 11 is linked to the Cys residue with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 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, 22-28, 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.
  • R 11 is linked to a dual GIP/GLP-1 receptor agonist or functional variant thereof with a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a dual conjugation.
  • the dual conjugation comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-2.
  • the dual conjugation comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof 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.
  • the dual conjugation comprises a linker- to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • the dual conjugation comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the dual conjugation comprises a linker-to-a dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-2, 2-3, 3-4, 4- 5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20, 20-21, 21-22, 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.
  • the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the 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.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached 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.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu- (AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the concentration of the compound as described herein is at least 0.1% weight per volume.
  • the concentration of the compound as 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.
  • the concentration of the compound as described herein is at least 0.05M.
  • the concentration of the compound as 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.
  • the one or more ionic liquid independently comprises a cation selected from the group of the cations listed in Table 2.
  • the one or more ionic liquid independently comprises an anion selected from the group of the anions listed in Table 1.
  • the one or more ionic liquid independently comprises an ionic liquid selected from the group of the ionic liquids listed in Table 2.
  • the composition or the pharmaceutical composition as provided herein comprises the composition as provided herein or the compound as provided herein, and the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4-Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2-Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4-Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4-Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4-Hydroxybenzen
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of (R)- ⁇ -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, arachidonic acid, caffeic acid, cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)-galactonic acid,
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion 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.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises a cation selected from the group of the cations listed in Table 2. In some embodiments, the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group of the anions listed in Table 1. In some embodiments, some embodiments, the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an ionic liquid selected from the group of the ionic liquids listed in Table 2.
  • a dual GIP/GLP-1 receptor agonist or functional variant thereof is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid-containing molecules are linked to a dual GIP/GLP-1 receptor agonist or functional variant thereof via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of a dual GIP/GLP-1 receptor agonist or functional variant thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of a dual GIP/GLP-1 receptor agonist or functional variant thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; R 5 is a therapeutic agent.
  • R 1 , R 2 , and R 3 are methyl.
  • R 1 , R 2 , and R 3 are ethyl.
  • R 1 , R 2 , and R 3 are propyl.
  • R 1 and R 2 are methyl, and R 3 is ethyl.
  • R 1 and R 3 are methyl, and R 2 is ethyl.
  • R 1 and R 2 are ethyl, and R 3 is methyl.
  • R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • R 4 is [00627]
  • the compound is according to Formula Ia: Formula Ia.
  • the compound is according to Formula Ib: Formula Ib.
  • the compound is according to Formula Ic: Formula Ic.
  • the therapeutic agent is a dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 (Glucagon-like peptide-1) receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises a molar ratio of from about 1:1 to about 1:20. [00637] In some embodiments, the compound comprises a molar ratio of about 1:1. [00638] In some embodiments, the compound comprises a molar ratio of about 1:2. [00639] In some embodiments, the compound comprises a molar ratio of about 1:3. [00640] In some embodiments, the compound comprises molar ratio of about 1:4.
  • the compound comprises molar ratio of about 1:5. [00642] In some embodiments, the compound comprises molar ratio of about 1:10. [00643] In some embodiments, the compound comprises molar ratio of about 1:20. [00644] In some embodiments, the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a modified structure. [00645] In some embodiments, the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a choline or choline derivative-modified structure.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising choline or choline derivative.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising one or more choline or choline derivative-peptide derivative formed on a Glu residue, an Asp residue, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 6 is a therapeutic agent.
  • R 7 , R 8 , and R 9 are independently C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl.
  • R 7 , R 8 , and R 9 are ethyl.
  • R 7 , R 8 , and R 9 are propyl.
  • R 7 and R 8 are methyl, and R 9 is ethyl.
  • R 9 is ethyl.
  • R 7 and R 9 are methyl, and R 8 is ethyl.
  • R 7 and R 8 are ethyl, and R 9 is methyl.
  • R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C 20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a choline or choline derivative-modified structure.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising choline or choline derivative.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a choline or choline derivative-modified ester structure.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-the dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-the dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-4, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 10 is a therapeutic agent; R 11 is substituted or unsubstituted C 5 -C 10 ; X 1 is -S-, or -NH-; and L 1 is a covalent bond or a linker.
  • L 1 is a non-cleavable linker.
  • L 1 comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • L 1 comprises [00692]
  • L 1 comprises [00693]
  • L 1 is a chemically cleavable linker.
  • L 1 comprises a hydrazone linker or a disulfide linker.
  • R 11 is substituted or unsubstituted C 10 .
  • the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • the therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a choline or choline derivative-modified structure.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising choline or choline derivative.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a choline or choline derivative-modified ester structure.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising one or more R 11 linked to a Lys residue, a Cys residue, or any combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-the dual GIP/GLP- 1 receptor agonist or functional variant thereof ratio of 2-4, R 11 is linked to the Cys residue with a linker-to-the dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 2-8 or with a linker-to-the dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 4, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a dual conjugation.
  • the dual conjugation comprises a linker-to-the dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of 1-2.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • a composition comprising the compound as described herein, and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the composition as described herein further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • the composition as described herein further comprises at least one pharmaceutically acceptable excipient.
  • a composition comprising a dual GIP/GLP-1 receptor agonist or functional variant thereof and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the solubility of a dual GIP/GLP-1 receptor agonist or functional variant thereof is increased relative to a dual GIP/GLP-1 receptor agonist or functional variant thereof in a composition without a ionic liquid.
  • the delivery efficiency of a dual GIP/GLP-1 receptor agonist or functional variant thereof in a subject in need thereof is enhanced or improved when administered to the subject, relative to a dual GIP/GLP-1 receptor agonist or functional variant thereof in a composition without a ionic liquid.
  • the composition further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • a pharmaceutical composition comprising the compound as described herein or the composition as described herein, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound as described herein, the composition as described herein, or the pharmaceutical composition as described herein, wherein the administering is effective to treat the disease or disorder in the subject.
  • the disease or disorder is a metabolic disease or disorder.
  • the disease or disorder is diabetes mellitus.
  • the disease or disorder is type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • the disease or disorder is obesity or overweight.
  • the administration activates GIP receptor signaling, GLP-1 receptor signaling, or a combination thereof.
  • the administration increases or improves glucose-dependent insulin secretion, improves glucose tolerance, or a combination thereof.
  • the administration increases or improves blood sugar control.
  • the administration decreases or reduces fasting serum glucose.
  • the administration decreases or reduces body weight, decreases or reduces food intake, or a combination thereof.
  • the administration delivers improvement in glycaemic control, body weight, or a combination thereof.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the composition, the compound, or the pharmaceutical composition is administered orally.
  • the composition, the compound, or the pharmaceutical composition is administered as a liquid-filled capsule.
  • the composition, the compound, or the pharmaceutical composition is administered in multiple doses.
  • the composition, the compound, or the pharmaceutical composition is administered in a single dose.
  • the composition, the compound, or the pharmaceutical composition is administered to a mucus membrane.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the concentration of the compound as described herein is at least 0.1% weight per volume.
  • the concentration of the compound as described herein is at least 0.05M.
  • the composition further comprises one or more additional agents.
  • the one or more additional agent is selected from the group consisting of a nucleic acid, a small molecule, and a polypeptide.
  • the one or more additional agent is a nucleic acid. [00772] In some embodiments, the one or more additional agent is a small molecule. [00773] In some embodiments, the one or more additional agent is a polypeptide. [00774] In some embodiments, the one or more additional agent is a polypeptide. [00775] In some embodiments, the one or more additional agents is a therapeutic that treats a metabolic disease or disorder. [00776] In some embodiments, the one or more additional agents is a therapeutic that treats diabetes mellitus. [00777] In some embodiments, the one or more additional agents is a therapeutic that treats type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • the one or more additional agents is a therapeutic that treats obesity or overweight.
  • a method of increasing the solubility of a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising preparing a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; and R 5 is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • a method of enhancing or improving the delivery efficiency of a dual GIP/GLP-1 receptor agonist or functional variant thereof in a subject in need thereof comprising preparing a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; and R 5 is a dual GIP/GLP-1 receptor agonist or functional variant thereof; and administering the composition to the subject.
  • R 1 , R 2 , and R 3 are methyl.
  • R 1 , R 2 , and R 3 are ethyl.
  • R 1 , R 2 , and R 3 are propyl.
  • R 1 and R 2 are methyl, and R 3 is ethyl.
  • R 1 and R 3 are methyl, and R 2 is ethyl.
  • R 1 and R 3 are methyl, and R 2 is ethyl.
  • R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • R 4 is [00791] In some embodiments, R 4 is [00792] In some embodiments, the compound is according to Formula Ia: Formula Ia. [00793] In some embodiments, the compound is according to Formula Ib: Formula Ib. [00794] In some embodiments, the compound is according to Formula Ic: Formula Ic.
  • R 5 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 5 comprises the sequence of SEQ ID NO: 25.
  • R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25.
  • R 5 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25.
  • the compound comprises a to molar ratio of from about 1:1 to about 1:20. [00801] In some embodiments, the compound comprises molar ratio of about 1:1. [00802] In some embodiments, the compound comprises molar ratio of about 1:2. [00803] In some embodiments, the compound comprises molar ratio of about 1:3. [00804] In some embodiments, the compound comprises molar ratio of about 1:4.
  • the compound comprises molar ratio of about 1:5. [00806] In some embodiments, the compound comprises molar ratio of about 1:10. [00807] In some embodiments, the compound comprises molar ratio of about 1:20. [00808] In another aspect, provided herein is a method of increasing the solubility of a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising preparing a composition comprising a compound according to Formula II: Formula II, wherein: R 6 is a dual GIP/GLP-1 receptor agonist or functional variant thereof; R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • a method of enhancing or improving the delivery efficiency a dual GIP/GLP-1 receptor agonist or functional variant thereof in a subject in need thereof comprising preparing a composition comprising compound according to Formula II: Formula II, wherein: R 6 is a dual GIP/GLP-1 receptor agonist or functional variant thereof; R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5, and administering the composition to the subject. [00810] In some embodiments, R 7 , R 8 , and R 9 are methyl. [00811] In some embodiments, R 7 , R 8 , and R 9 are ethyl.
  • R 7 , R 8 , and R 9 are propyl. [00813] In some embodiments, R 7 and R 8 are methyl, and R 9 is ethyl. [00814] In some embodiments, R 7 and R 9 are methyl, and R 8 is ethyl. [00815] In some embodiments, R 7 and R 8 are ethyl, and R 9 is methyl. [00816] In some embodiments, R 7 and R 9 are ethyl, and R 8 is methyl. [00817] In some embodiments, R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • R 6 comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • R 6 comprises the sequence of SEQ ID NO: 25.
  • R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00826] In some embodiments, R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25. [00827] In some embodiments, R 6 comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25. [00828] In some embodiments, the composition further comprises one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • a method of increasing the solubility of a dual GIP/GLP-1 receptor agonist or functional variant thereof comprising preparing a composition comprising a dual GIP/GLP-1 receptor agonist or functional variant thereof and one or more ionic liquid.
  • a method of enhancing or improving the delivery efficiency of a dual GIP/GLP-1 receptor agonist or functional variant thereof in a subject in need thereof comprising preparing a composition comprising a dual GIP/GLP-1 receptor agonist or functional variant thereof and one or more ionic liquid, and administering the composition to the subject.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • a method of enhancing the hydrophobicity of a therapeutic agent comprising linking R 12 to a therapeutic agent, wherein R 12 is substituted or unsubstituted C 5 -C 10 ; and wherein the therapeutic agent is a dual GIP/GLP-1 receptor agonist or functional variant thereof.
  • R 12 is linked to - , -S-, or -NH- of the therapeutic agent.
  • R 12 is linked to the therapeutic agent via a covalent bond or a linker.
  • the linker is a non-cleavable linker.
  • the linker comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • the linker comprises [00853] In some embodiments, the linker is a chemically cleavable linker.
  • the linker comprises a hydrazone linker or a disulfide linker. [00855] In some embodiments, the linker comprises . [00856] In some embodiments, R 12 is substituted or unsubstituted C 10 . [00857] In some embodiments, therapeutic agent comprises a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25. [00858] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 25. [00859] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of a sequence with at least 75% sequence identity to the sequence of SEQ ID NO: 25.
  • the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to a residue of the sequence of SEQ ID NO: 25. [00861] In some embodiments, the therapeutic agent comprises C20 diacid- ⁇ -Glu-(AEEA)2 attached to the Lys residue at the position 20 from the N-terminus of the sequence of SEQ ID NO: 25. [00862] In another aspect, provided herein is a method of enhancing or improving a delivery efficiency of a therapeutic agent in a subject in need thereof comprising adding at least one permeation enhancer to the compound as described herein, the composition as described herein, or the pharmaceutical composition as described herein, and administering the composition, the compound, or the pharmaceutical composition to the subject.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • Antibody or antibody fragment thereof refers to a protein or a polypeptide derived from an immunoglobulin molecule that specifically binds to an antigen.
  • an antibody is polyclonal or monoclonal.
  • an antibody comprises multiple chains or a single chain.
  • an antibody comprises an intact immunoglobulins.
  • an antibody is naturally driven.
  • an antibody is recombinantly driven.
  • an antibody is in the form of a single domain antibody, a maxibody, a minibody, a nanobody, an intrabody, a diabody, a triabody, a tetrabody, and a multispecific antibody.
  • antibody fragment refers to at least a portion of an intact antibody or recombinant variants thereof.
  • the antibody fragment is an antigen binding domain that recognizes and specifically binds to an antigen.
  • an antibody or an antibody fragment comprises, but are not limited to, an Fab, an Fab’, an F(ab’)2, an Fv fragment, a scFv antibody fragments, a single domain antibodies (sdAb), a camelid VhH domain, and a single domain shark variable domain (BNAR).
  • an antibody or an antibody fragment comprises an anti-tumor necrosis factor-alpha (TNF- ⁇ ) antibody or an anti-TNF- ⁇ antibody fragment.
  • an antibody or an antibody fragment comprises a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • an antibody or an antibody fragment comprises infliximab or an antibody fragment thereof.
  • infliximab refers to a chimeric monoclonal antibody that binds to tumor necrosis factor-alpha (TNF- ⁇ ).
  • a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof neutralizes TNF- ⁇ by preventing TNF- ⁇ from interacting with its receptors on the cell.
  • a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is used to treat autoimmune diseases, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease.
  • a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00871] In some embodiments, a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00872] In some embodiments, a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence identified as PDB: 4G3Y_H by Pubmed.
  • a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00874]
  • Asn 300 (asparagine at the position 300) of the heavy chain of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is a glycosylation site.
  • Asn 300 of the heavy chain of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is glycosylated.
  • a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence identified as PDB: 4G3Y_L by Pubmed.
  • an antibody or an antibody fragment comprises an anti-tumor necrosis factor-alpha (TNF- ⁇ ) antibody or an anti-TNF- ⁇ antibody fragment.
  • an antibody or an antibody fragment comprises a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • an antibody or an antibody fragment comprises adalimumab or an antibody fragment thereof.
  • adalimumab refers to a monoclonal antibody that binds to TNF- ⁇ .
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof works by inactivating TNF- ⁇ .
  • a monoclonal anti-TNF- ⁇ antibody or an 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.
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is a disease-modifying antirheumatic drug (DMARD).
  • DMARD disease-modifying antirheumatic drug
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00880]
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00881]
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00882]
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: identified as PDB: 3WD5_H by Pubmed.
  • a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00884] In some embodiments, a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00885] In some embodiments, a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence identified as PDB: 3WD5_L by Pubmed. [00886] In some embodiments, an antibody or an antibody fragment comprises an anti-human interleukin 12 (IL-12) and interleukin 23 (IL-23) subunit antibody or an antibody fragment thereof.
  • IL-12 interleukin 12
  • IL-23 interleukin 23 subunit antibody or an antibody fragment thereof.
  • an antibody or an antibody fragment comprises ustekinumab or an antibody fragment thereof.
  • the term “ustekinumab” refers to a monoclonal antibody that targets a subunit of human interleukin 12 (IL-12) and interleukin 23 (IL-23), which regulate the immune system and immune-mediated inflammatory disorders.
  • IL-12 interleukin 12
  • IL-23 interleukin 23
  • an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof is used to treat Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis.
  • an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00890] In some embodiments, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence identified as PDB: 3HMX_H by Pubmed. [00891] In some embodiments, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00892] In some embodiments, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof comprises the light chain comprising the sequence identified as PDB: 3HMX_L by Pubmed.
  • an antibody or an antibody fragment comprises a monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof. In some embodiments, an antibody or an antibody fragment comprises a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof. In some embodiments, an antibody or an antibody fragment comprises golimumab or an antibody fragment thereof. [00894] As used herein, the term “golimumab” refers to a human monoclonal antibody that targets TNF- ⁇ . [00895] In some embodiments, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof works as a TNF- ⁇ inhibitor.
  • a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof functions as an effective modulator of inflammatory markers and bone metabolism. In some embodiments, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is used as an immunosuppressive medication. [00896] In some embodiments, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00897] In some embodiments, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence identified as PDB: 5YOY_R by Pubmed.
  • a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: ) [00899] In some embodiments, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof comprises the light chain comprising the sequence identified as PDB: 5YOY_O by Pubmed. [00900] In some embodiments, an antibody or an antibody fragment comprises an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof. In some embodiments, an antibody or an antibody fragment comprises a monoclonal anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof. In some embodiments, an antibody or an antibody fragment comprises natalizumab or an antibody fragment thereof.
  • the term “natalizumab” refers to a monoclonal antibody that targets integrin ⁇ 4 ⁇ 1.
  • an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof targets integrin ⁇ 4 ⁇ 1 on white blood cells involved in inflammation.
  • an anti- integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof stops white blood cells from entering the brain and spinal cord tissue by attaching to integrin, thereby reducing inflammation and the resulting nerve damage.
  • an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof works by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood-brain barrier.
  • an anti- integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof is used to treat the symptoms of both diseases, preventing relapse, vision loss, cognitive decline. In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof is used to treat multiple sclerosis and Crohn's disease. In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof increases rates of remission and prevents relapse in multiple sclerosis.
  • an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00904] In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00905] In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence identified as PDB: 4IRZ_H by Pubmed.
  • an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00907] In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00908] In some embodiments, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof comprises the light chain comprising the sequence identified as PDB: 4IRZ_L by Pubmed. [00909] In some embodiments, an antibody or an antibody fragment comprises an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof. In some embodiments, an antibody or an antibody fragment comprises a monoclonal anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof.
  • an antibody or an antibody fragment comprises vedolizumab or an antibody fragment thereof.
  • vedolizumab refers to a monoclonal antibody that targets integrin ⁇ 4 ⁇ 7.
  • an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof blocks integrin ⁇ 4 ⁇ 7, resulting in gut-selective anti-inflammatory activity.
  • an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof is used to treat ulcerative colitis and Crohn's disease.
  • an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof comprises the heavy chain comprising the sequence of: [00913] In some embodiments, an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof comprises the light chain comprising the sequence of: [00914] In some embodiments, an antibody or an antibody fragment comprises a fragment of an anti-TNF- ⁇ antibody. In some embodiments, an antibody or an antibody fragment comprises a fragment of a monoclonal anti-TNF- ⁇ antibody. In some embodiments, an antibody or an antibody fragment comprises certolizumab pegol.
  • certolizumab pegol refers to a fragment of a monoclonal antibody specific to TNF- ⁇ .
  • a fragment of an anti-TNF- ⁇ antibody is used to treat Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
  • a fragment of an anti-TNF- ⁇ antibody comprises the heavy chain comprising the sequence of: [00918] In some embodiments, a fragment of an anti-TNF- ⁇ antibody comprises the light chain comprising the sequence of: [00919] In some embodiments, the therapeutic agent or an antibody or an antibody fragment comprises: (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, 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 S
  • 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.
  • 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 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.
  • TNF- ⁇ also known as tumor necrosis factor alpha, TNF, DIF, TNF- alpha, TNFA, TNFSF2, Tumour necrosis factor, tumor necrosis factor, TNLG1F, refers to a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
  • TNF- ⁇ as an adipokine, promotes insulin resistance, and is associated with obesity-induced type 2 diabetes.
  • TNF- ⁇ as a cytokine, is used by the immune system for cell signaling.
  • TNF- ⁇ includes any of the recombinant or naturally-occurring forms of TNF- ⁇ or variants or homologs thereof that have or maintain TNF- ⁇ activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring TNF- ⁇ .
  • TNF- ⁇ is substantially identical to the protein identified by the UniProt reference number P01375 or a variant or homolog having substantial identity thereto.
  • IL-12 also known as interleukin 12, refers to a heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and IL-12B (p40).
  • 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 comprises the heterodimeric cytokines including IL-12, IL-23, IL-27 and IL-35 “IL-12A,” as used herein, includes any of the recombinant or naturally-occurring forms of IL-12A or variants or homologs thereof that have or maintain IL-12A activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL-12A.
  • IL-12A is substantially identical to the protein identified by the UniProt reference number P29459 or a variant or homolog having substantial identity thereto.
  • IL-12B includes any of the recombinant or naturally-occurring forms of IL-12B or variants or homologs thereof that have or maintain IL-12B activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL- 12B.
  • IL-12B is substantially identical to the protein identified by the UniProt reference number P29460 or a variant or homolog having substantial identity thereto.
  • IL-23 also known as interleukin 23, refers to a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 belongs to the IL-12 family of cytokines. In some embodiments, IL-23 is an inflammatory cytokine that plays a key role for T helper type 17 cell (Th17 cell) maintenance and expansion.
  • IL-23A includes any of the recombinant or naturally-occurring forms of IL-23A or variants or homologs thereof that have or maintain IL-23A activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL- 23A.
  • IL-23A is substantially identical to the protein identified by the UniProt reference number Q9NPF7 or a variant or homolog having substantial identity thereto.
  • integratedin ⁇ 4 ⁇ 1 also known as very late antigen-4 refers to an integrin dimer composed of CD49d (alpha 4) and CD29 (beta 1).
  • integrin ⁇ 4 (integrin alpha-4) includes any of the recombinant or naturally-occurring forms of integrin ⁇ 4 or variants or homologs thereof that have or maintain integrin ⁇ 4 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring integrin ⁇ 4.
  • integrin ⁇ 4 is substantially identical to the protein identified by the UniProt reference number P13612 or a variant or homolog having substantial identity thereto.
  • integrin ⁇ 1 (integrin beta-1)
  • integrin beta-1 includes any of the recombinant or naturally-occurring forms of integrin ⁇ 1 or variants or homologs thereof that have or maintain integrin ⁇ 1 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring integrin ⁇ 1.
  • integrin ⁇ 1 is substantially identical to the protein identified by the UniProt reference number P05556 or a variant or homolog having substantial identity thereto.
  • integrin ⁇ 4 ⁇ 7 also known as 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.
  • integrin ⁇ 7 (integrin beta-7) includes any of the recombinant or naturally-occurring forms of integrin ⁇ 1 or variants or homologs thereof that have or maintain integrin ⁇ 7 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring integrin ⁇ 7.
  • integrin ⁇ 7 is substantially identical to the protein identified by the UniProt reference number P26010 or a variant or homolog having substantial identity thereto.
  • an antibody or an antibody fragment encompasses polypeptides having the sequences specified, or sequences substantially identical or similar thereto, for example, sequences 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% identical or higher to the sequence specified.
  • sequences 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% identical or higher to the sequence specified.
  • the percent identity between the 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.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity can be determined using the on-line homology algorithm “BLAST” program, publicly available at http)://www.ncbi.nlm.nih.gov/BLAST/.
  • a nucleic acid molecule can be a vector, an expression vector, an inhibitory nucleic acid, an aptamer, a template molecule or cassette (e.g., for gene editing), or a targeting molecule (e.g., for CRISPR-Cas technologies), or any other natural or synthetic nucleic acid molecule intended for delivery to an organism.
  • the term “unsubstituted,” as used herein, means that the specified group bears no substituents.
  • substituted as used herein, unless otherwise indicated, can refer to the replacement of one or more hydrogen radicals in a given structure individually and independently with the radical of a specified substituent.
  • the drug may be designed with the intent of treating a local tissue, for example, the mucosal membrane of the intestine, a distant tissue, e.g., the liver, or systemic circulation.
  • a composition as described herein e.g., a composition comprising ionic liquids and a drug
  • the composition can contain minor amounts of additional excipients such as emulsifying agents, surfactants, pH buffering agents and the like which enhance the effectiveness of the drug.
  • the composition comprising an ionic liquid may be further encapsulated in a dosage designed to facilitate delivery to an organism.
  • doses include capsules, tablets, or syrups.
  • formulation may require excipients sugars such as lactose; starches, such as corn starch; cellulose, cellulose derivatives, such as sodium carboxymethyl cellulose; gelatin; and other compatible substances considered commonly in pharmaceutical formulations.
  • effective amount refers to the amount of a composition needed to alleviate at least one or more symptom of the disease or disorder and relates to a sufficient amount of pharmacological composition to provide the desired effect.
  • the composition comprises a molar ratio of from about 1:1 to about 1:164. In some embodiments, the composition comprises a molar ratio of from about 1:1 to about 1:500, from about 1:1 to about 1:499, from about 1:1 to about 1:498, from about 1:1 to about 1:497, from about 1:1 to about 1:496, from about 1:1 to about 1:495, from about 1:1 to about 1:494, from about 1:1 to about 1:493, from about 1:1 to about 1:492, from about 1:1 to about 1:491, from about 1:1 to about 1:490, from about 1:1 to about 1:489, from about 1:1 to about 1:488, from about 1:1 to about 1:487, from about 1:1 to about 1:486, from about 1:1 to about 1:485, from about 1:1 to about 1:484, from about 1:1 to about 1:483, from about 1:1 to about 1:482, from about 1:1 to about 1:481, from about 1:1 to about 1:480, from about 1:1 to about 1:479, from about 1:1 to about 1:47
  • the composition comprises molar ratio of about 1:500, about 1:499, about 1:498, about 1:497, about 1:496, about 1:495, about 1:494, about 1:493, about 1:492, about 1:491, about 1:490, about 1:489, about 1:488, about 1:487, about 1:486, about 1:485, about 1:484, about 1:483, about 1:482, about 1:481, about 1:480, 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 1:466, about 1:465, about 1:464, about 1:463, about 1:462, about 1:461, about 1:460, about 1:459, about 1:458, about 1:457, about 1:456, about
  • the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide derivative formed on the C-terminus of a light chain. In some embodiments, the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide derivative formed on the C-terminus of a heavy chain. In some embodiments, the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide derivative formed on the C-terminus of a light chain and on the C- terminus of a heavy chain.
  • the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on the C-terminus of a light chain, the C- terminus of a heavy chain or a combination thereof. In some embodiments, the an antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on the C-terminus of a light chain. In some embodiments, the an antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on the C-terminus of a heavy chain.
  • the an antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on the C-terminus of a light chain and the C-terminus of a heavy chain. [00940] In some embodiments, the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on a Cys residue. In some embodiments, the antibody or an antibody fragment thereof comprises one or more choline or choline derivative- peptide ester formed on a Lys residue. In some embodiments, the antibody or an antibody fragment thereof comprises one or more choline or choline derivative-peptide ester formed on a Cys residue and a Lys residue.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody ratio of 1-30, 2-30, 3-30, 4-30, 5- 30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody ratio of 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody 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, or 30. In some embodiments, the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody ratio of 1-6, 2-8, 3-10, 4-12, 5-14, 6-16, 7-18, 8-20, 9-22, 10-24, 11-26, 12-28, or 14-30.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-antibody ratio of 1-30, 2-30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22- 30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to- antibody ratio of 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-antibody 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, or 30. In some embodiments, the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-antibody ratio of 1-2, 2-4, 3-6, 4-8, 5-10, 6-12, 7-14, 8-16, 9-18, 10-20, 11-22, 12-24, 13-26, 14-28, or 15-30.
  • the an antibody or an antibody fragment comprises a diacid consisting 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, or 40 carbons in length.
  • the antibody or an antibody fragment thereof comprising one or more fatty acid linked to the C-terminus of a light chain.
  • the antibody or an antibody fragment thereof comprising one or more fatty acid linked to the C-terminus of a heavy chain.
  • the antibody or an antibody fragment thereof comprising one or more fatty acid linked to the C-terminus of a light chain and the C-terminus of a heavy chain.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Cys residue.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue and a Cys residue.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue with a linker-to-antibody ratio of 1-30, 2- 30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17- 30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • a linker-to-antibody ratio of 1-30, 2- 30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17- 30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue with a linker-to-antibody ratio of 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.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue with a linker-to-antibody 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, or 30.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Lys residue with a linker-to-antibody ratio of 1-2, 2-4, 3-6, 4-8, 5-10, 6-12, 7-14, 8-16, 9-18, 10-20, 11- 22, 12-24, 13-26, 14-28, or 15-30.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Cys residue with a linker-to-antibody ratio of 1-30, 2-30, 3-30, 4-30, 5- 30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Cys residue with a linker-to-antibody ratio of 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.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Cys residue with a linker-to-antibody 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, or 30.
  • the antibody or an antibody fragment thereof comprises one or more fatty acid linked to a Cys residue with a linker-to- antibody ratio of 1-6, 2-8, 3-10, 4-12, 5-14, 6-16, 7-18, 8-20, 9-22, 10-24, 11-26, 12-28, or 14-30.
  • an antibody or an antibody fragment thereof is linked to fatty acids via a dual conjugation.
  • the dual conjugation comprises a linker-to-antibody ratio of 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.
  • the dual conjugation comprises a linker-to-antibody ratio of 1-30, 2-30, 3-30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30.
  • the dual conjugation comprises a linker-to-antibody 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, or 30.
  • the dual conjugation comprises a linker-to-antibody ratio of 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 19-20, 20-21, 21-22, 22-23, 23-24, 25-26, 27-28, 28-29, or 29-30.
  • the fatty acid is a substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or C30 fatty acid.
  • the fatty acid is a substituted or unsubstituted C1-C30, C1-C29, C1-C28, C1-C27, C1-C26, C1-C25, C1-C24, C1-C23, C1-C22, C1-C21, C1-C20, C1-C19, C1-C18, C1-C17, C1-C16, C1-C15, C1-C14, C1-C13, C1-C12, C1- C11, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 fatty acid.
  • the fatty acid is a substituted or unsubstituted C2-C30, C3-C30, C4-C30, C5-C30, C6-C30, C7-C30, C8-C30, C9-C30, C10-C30, C11-C30, C12-C30, C13-C30, C14-C30, C15-C30, C16-C30, C17-C30, C18-C30, C19-C30, C20-C30, C21-C30, C22-C30, C23-C30, C24-C30, C25- C30, C26-C30, C27-C30, C28-C30, or C29-C30 fatty acid.
  • the fatty acid is a substituted or unsubstituted C2-C25, C3-C20, C4-C15 or C5-C10 fatty acid.
  • a pharmaceutical composition comprising the composition as provided herein or the compound as provided herein, and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -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, arachidonic acid, caffeic acid, cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)-galactonic acid,
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, and mesaconic acid.
  • the one or more ionic liquid independently comprises choline or choline derivative-cinnamic acid, choline or choline derivative-mandelic acid, or choline or choline derivative-citric acid.
  • the pharmaceutical composition comprises the composition as provided herein or the compound as provided herein, and the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises choline or choline derivative.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of (R)- ⁇ -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,
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, and mesaconic acid.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises choline or choline derivative-cinnamic acid, choline or choline derivative-mandelic acid, or choline or choline derivative-citric acid.
  • a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; R 5 is a therapeutic agent.
  • R 1 , R 2 , and R 3 are methyl.
  • R 1 , R 2 , and R 3 are ethyl.
  • R 1 , R 2 , and R 3 are propyl.
  • R 1 and R 2 are methyl, and R 3 is ethyl.
  • R 1 and R 3 are methyl, and R 2 is ethyl.
  • R 1 and R 2 are ethyl, and R 3 is methyl.
  • R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • R 4 is [00972]
  • the compound is according to Formula Ia: Formula Ia.
  • the compound is according to Formula Ib: Formula Ib.
  • the compound is according to Formula Ic: Formula Ic.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, a monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof, and a fragment of an anti-TNF- ⁇ antibody.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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
  • 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.
  • 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 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.
  • the therapeutic agent is a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the composition comprises molar ratio of from about 1:1 to about 1:164.
  • the composition comprises molar ratio of about 1:1.
  • the composition comprises molar ratio of about 1:33.
  • the composition comprises molar ratio of about 1:41.
  • the composition comprises molar ratio of about 1:66.
  • the composition comprises molar ratio of about 1:82. [00989] In some embodiments, the composition comprises molar ratio of about 1:132. [00990] In some embodiments, the composition comprises molar ratio of about 1:164. [00991] In some embodiments, the therapeutic agent is a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof. [00992] 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 SEQ ID NO: 7.
  • the composition comprises molar ratio of from about 1:1 to about 1:144.
  • the therapeutic agent is an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9.
  • the composition comprises molar ratio of from about 1:1 to about 1:140.
  • the therapeutic agent is a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11.
  • the composition comprises a molar ratio of from about 1:1 to about 1:80.
  • the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof.
  • 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.
  • the composition comprises molar ratio of from about 1:1 to about 1:156.
  • the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17. [001005] In some embodiments, the composition comprises molar ratio of from about 1:1 to about 1:256. [001006] In some embodiments, the therapeutic agent is a fragment of an anti-TNF- ⁇ antibody. [001007] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19. [001008] In some embodiments, the composition comprises molar ratio of from about 1:1 to about 1:70. [001009] In some embodiments, the composition comprises molar ratio of from about 1:1 to about 1:20.
  • the composition comprises a molar ratio of from about 1:1 to about 1:260, from about 1:1 to about 1:259, from about 1:1 to about 1:258, from about 1:1 to about 1:257, from about 1:1 to about 1:256, from about 1:1 to about 1:255, from about 1:1 to about 1:254, from about 1:1 to about 1:253, from about 1:1 to about 1:252, from about 1:1 to about 1:251, from about 1:1 to about 1:250, from about 1:1 to about 1:249, from about 1:1 to about 1:248, from about 1:1 to about 1:247, from about 1:1 to about 1:246, from about 1:1 to about 1:245, from about 1:1 to about 1:244, from about 1:1 to about 1:243, from about 1:1 to about 1:242, from about 1:1 to about 1:241, from about 1:1 to about 1:240, from about 1:1 to about 1:239, from about 1:1 to about 1:238, from about 1:1 to about 1:237, from about 1:1 to about 1:236, from about 1:1 to about 1:235, from about 1:1 to about 1:234, from about 1:1 to about 1:233, from about 1:1 to about 1:232, from about 1:1 to about 1:231,
  • the composition comprises molar ratio of about 1:260, about 1:259, about 1:258, about 1:257, about 1:256, about 1:255, about 1:254, about 1:253, about 1:252, about 1:251, about 1:250, about 1:249, about 1:248, about 1:247, about 1:246, about 1:245, about 1:244, about 1:243, about 1:242, about 1:241, about 1:240, about 1:239, about 1:238, about 1:237, about 1:236, about 1:235, about 1:234, about 1:233, about 1:232, about 1:231, about 1:230, about 1:229, about 1:228, about 1:227, about 1:226, about 1:225, about 1:224, about 1:223, about 1:222, about 1:221, about 1:220, about 1:219, about 1:218, about 1:217, about 1:216, about 1:215, about 1:214, about 1:213, about 1:212, about 1:211, about 1:210, about 1:209, about 1:208, about 1:207, about 1:206, about 1:205, about 1:204, about 1:203, about 1:202, about
  • the composition comprises an antibody or an antibody fragment thereof having a modified antibody structure.
  • the composition comprises an antibody or an antibody fragment thereof having a choline or choline derivative-modified antibody structure.
  • the composition comprises an antibody or an antibody fragment thereof having a cation moiety comprising choline or choline derivative.
  • the composition comprises an antibody or an antibody fragment thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the composition comprises an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide derivative formed on the C- terminus of a light chain, the C-terminus of a heavy chain or a combination thereof.
  • the composition comprises an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide derivative formed on a Glu residue, a Asp residue, or a combination thereof.
  • the composition comprises an antibody or an antibody fragment thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the composition comprises an antibody or an antibody fragment thereof comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the composition comprises an antibody or an antibody fragment comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker
  • the composition comprises an antibody or an antibody fragment thereof comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the composition comprises an antibody or an antibody fragment thereof comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 6 is a therapeutic agent.
  • R 7 , R 8 , and R 9 are independently C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl.
  • R 7 , R 8 , and R 9 are ethyl.
  • R 7 , R 8 , and R 9 are propyl.
  • R 7 and R 8 are methyl, and R 9 is ethyl.
  • R 7 and R 9 are methyl, and R 8 is ethyl.
  • R 7 and R 8 are ethyl, and R 9 is methyl.
  • R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, a monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof, and a fragment of an anti-TNF- ⁇ antibody.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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 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.
  • 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 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.
  • the therapeutic agent is a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9.
  • the therapeutic agent is a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11.
  • the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof.
  • 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. [001054] In some embodiments, the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof. [001055] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17. [001056] In some embodiments, the therapeutic agent is a fragment of an anti-TNF- ⁇ antibody. [001057] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19.
  • the compound comprises an antibody or an antibody fragment thereof having a modified antibody structure.
  • the compound comprises an antibody or an antibody fragment thereof having a choline or choline derivative-modified antibody structure.
  • the compound comprises an antibody or an antibody fragment thereof having a cation moiety comprising choline or choline derivative.
  • the compound comprises an antibody or an antibody fragment thereof having a choline or choline derivative-modified ester structure.
  • the compound comprises an antibody or an antibody fragment thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide ester formed on the C- terminus of a light chain, the C-terminus of a heavy chain or a combination thereof.
  • the compound comprises an antibody or an antibody fragment thereof comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-antibody ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-antibody ratio of 2-4, or a combination thereof.
  • the compound comprises an antibody or an antibody fragment comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8- amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises an antibody or an antibody fragment comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises an antibody or an antibody fragment comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises an antibody or an antibody fragment comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises an antibody or an antibody fragment comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 10 is a therapeutic agent
  • R 11 is substituted or unsubstituted C 5 -C 10
  • X 1 is -S-, or -NH-
  • L 1 is a covalent bond or a linker.
  • L 1 is a non-cleavable linker.
  • L 1 comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • L 1 comprises [001077]
  • L 1 is a chemically cleavable linker.
  • L 1 comprises a hydrazone linker or a disulfide linker.
  • L 1 comprises .
  • R 11 is substituted or unsubstituted C 10 .
  • the therapeutic agent is an antibody or an antibody fragment thereof.
  • the therapeutic agent is any one selected from the group consisting of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, a monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof, and a fragment of an anti-TNF- ⁇ antibody.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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 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.
  • 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 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.
  • the therapeutic agent is a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 1 or SEQ ID NO: 24, and the sequence of SEQ ID NO: 2.
  • the therapeutic agent is a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • 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 SEQ ID NO: 7.
  • the therapeutic agent is an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO: 9.
  • the therapeutic agent is a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • the therapeutic agent comprises the sequence of SEQ ID NO: 10 and the sequence of SEQ ID NO: 11.
  • the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof.
  • 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. [001097] In some embodiments, the therapeutic agent is an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof. [001098] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17. [001099] In some embodiments, the therapeutic agent is a fragment of an anti-TNF- ⁇ antibody. [001100] In some embodiments, the therapeutic agent comprises the sequence of SEQ ID NO: 18 and the sequence of SEQ ID NO: 19.
  • the compound comprises an antibody or an antibody fragment thereof having a modified antibody structure.
  • the compound comprises an antibody or an antibody fragment thereof having a choline or choline derivative-modified antibody structure.
  • the compound comprises an antibody or an antibody fragment thereof having a cation moiety comprising choline or choline derivative.
  • the compound comprises an antibody or an antibody fragment thereof having a choline or choline derivative-modified ester structure.
  • the compound comprises an antibody or an antibody fragment thereof having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises an antibody or an antibody fragment thereof comprising one or more R 11 linked to the C-terminus of a light chain, the C-terminus of a heavy chain or a combination thereof.
  • the compound comprises an antibody or an antibody fragment thereof comprising one or more R 11 linked to a Lys residue, a Cys residue, or any combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-antibody ratio of 2- 4, R 11 is linked to the Cys residue with a linker-to-antibody ratio of 2-8 or with a linker-to-antibody ratio of 4, or a combination thereof.
  • the compound comprises an antibody or an antibody fragment thereof comprising a dual conjugation.
  • the dual conjugation comprises a linker-to-antibody ratio of 1-2.
  • the compound comprises an antibody or an antibody fragment comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8- amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the compound comprises an antibody or an antibody fragment comprising a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • the compound comprises an antibody or an antibody fragment comprising a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises an antibody or an antibody fragment comprising a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the compound comprises an antibody or an antibody fragment comprising a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • a pharmaceutical composition comprising the composition as provided herein or the compound as provided herein, and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -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, arachidonic acid, caffeic acid, cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)-galactonic acid, decanoic acid, deoxycholic acid, eicosapentanoic acid, fumaric acid,
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of glycolic acid, tartaric acid, malic acid, hydrocinnamic acid, citric acid, cinnamic acid, mandelic acid, and mesaconic acid.
  • the one or more ionic liquid independently comprises choline or choline derivative-cinnamic acid, choline or choline derivative-mandelic acid, or choline or choline derivative-citric acid.
  • the pharmaceutical composition further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising the composition as provided herein or the compound as provided herein, and at least one pharmaceutically acceptable excipient.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition as provided herein, the compound as provided herein, or the pharmaceutical composition as provided herein.
  • the disease or disorder is an autoimmune or immunological disease or disorder.
  • the disease or disorder is Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Behçet's disease, plaque psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis, plaque psoriasis, multiple sclerosis, or eosinophilic esophagitis.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the composition, the compound, or the pharmaceutical composition is administered orally.
  • the composition, the compound, or the pharmaceutical composition is administered as a liquid-filled capsule.
  • the composition, the compound, or the pharmaceutical composition is administered in multiple doses.
  • the composition, the compound, or the pharmaceutical composition is administered in a single dose.
  • the composition, the compound, or the pharmaceutical composition is administered to a mucus membrane.
  • the concentration of the compound as provided herein is at least 0.1% weight per volume.
  • the concentration of the compound as provided herein is at least 0.05M.
  • the composition further comprises one or more additional agents.
  • the one or more additional agent is selected from the group consisting of a nucleic acid, a small molecule, and a polypeptide.
  • the one or more additional agent is a nucleic acid.
  • the one or more additional agent is a small molecule.
  • the one or more additional agent is a polypeptide.
  • a method of enhancing the hydrophobicity of a therapeutic agent comprising linking R 12 to a therapeutic agent, wherein R 12 is substituted or unsubstituted C 5 -C 10 ; and wherein the therapeutic agent is an antibody or an antibody fragment thereof.
  • R 12 is linked to -S-, or -NH- of the therapeutic agent.
  • R 12 is linked to the therapeutic agent via a covalent bond or a linker.
  • the linker is a non-cleavable linker.
  • the linker comprises a maleimide alkane linker or a maleimide cyclohexane linker.
  • the linker comprises [001151] In some embodiments, the linker is a chemically cleavable linker.
  • the linker comprises a hydrazone linker or a disulfide linker.
  • the linker comprises 1154] In some embodiments, R 1 [00 2 is substituted or unsubstituted C 10 .
  • the therapeutic agent is any one selected from the group consisting of a chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, a monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof, a human monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 1 antibody or an antibody fragment thereof, an anti-integrin ⁇ 4 ⁇ 7 antibody or an antibody fragment thereof, and a fragment of an anti-TNF- ⁇ antibody.
  • the therapeutic agent is any one selected from the group consisting of infliximab or an antibody fragment thereof, adalimumab or an antibody fragment thereof, ustekinumab or an antibody fragment thereof, golimumab or an antibody fragment thereof, natalizumab or an antibody fragment thereof, vedolizumab or an antibody fragment thereof, and certolizumab pegol or an antibody fragment thereof.
  • the therapeutic agent comprises: (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 the sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, a sequence with at least 75% sequence identity to the sequence of 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
  • 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.
  • 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 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.
  • a method of enhancing or improving a delivery efficiency of a therapeutic agent in a subject in need thereof comprising adding at least one permeation enhancer to the composition as provided herein, the compound as provided herein, or the pharmaceutical composition as provided herein; and administering the composition, the compound, or the pharmaceutical composition to the subject.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • an antibody or antibody fragment thereof is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid- containing molecules are linked to an antibody or antibody fragment thereof via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid- containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid. [001164] In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of an antibody or antibody fragment thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non- covalently associated with the N-terminal amine in the peptide backbone of an antibody or antibody fragment thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an antibody or antibody fragment thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of an antibody or antibody fragment thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of an antibody or antibody fragment thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an antibody or antibody fragment thereof.
  • Amylin analog or functional variant thereof or mimetic thereof or functional homolog thereof [001166]
  • described herein is a method of treatment of diabetes comprising orally administering an oral formulation of an amylin analog or functional variant thereof or mimetic thereof in combination with ionic liquid.
  • an amylin analog or functional variant thereof or mimetic or functional analog thereof or functional homolog thereof is pramlintide or functional variant thereof or mimetic or functional homolog thereof.
  • “Pramlintide,” also known as Symlin refers to an injectable amylin analog drug for diabetes (both type 1 and 2).
  • an amylin analog or functional variant thereof is an acetate derivative form.
  • an amylin analog or functional variant thereof in synergy with endogenous amylin, aids in the regulation of blood glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors, and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin.
  • an amylin analog or functional variant thereof has effects in raising the acute first-phase insulin response threshold following a meal.
  • an amylin analog or functional variant thereof comprises the following sequence: KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide (SEQ ID NO: 20).
  • an amylin analog or functional variant thereof comprises the structure as shown in FIG.1.
  • an amylin analog or functional variant thereof or mimetic thereof comprises the following sequence: [diacid]-[linker]-KCNTATCATQ RLANFLVHSS NNFGPILPPT NVGSNTY-amide (SEQ ID NO: 21).
  • an amylin analog or functional variant thereof or mimetic thereof comprises the structure as shown in FIG.2.
  • an amylin analog or functional variant thereof or mimetic thereof comprises one or more of the following amino acid substitutions: N14E, V17R, Y37P, F15E, L16E, and V17E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17R.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of Y37P.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of F15E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of L16E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the linker comprises one or more gamma glutamate ( ⁇ Glu) residues and/or one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues.
  • the linker comprises one or more gamma glutamate ( ⁇ Glu) residues. In some embodiments, the linker comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues. In some embodiments, the linker comprises gamma glutamate ( ⁇ Glu).
  • the diacid comprises diacids consisting of 18 or 20 carbons in length. In some embodiments, the diacid comprises a C20 fatty diacid. In some embodiments, the diacid comprises 1,20-icosanedioic acid.
  • an amylin analog or functional variant thereof or mimetic thereof comprises the structure as shown in FIG.3.
  • the cation moiety comprises choline or choline derivative.
  • an amylin analog or functional variant thereof or mimetic thereof comprises one or more of the following amino acid substitutions: N14E, V17R, Y37P, F15E, L16E, and V17E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17R.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of Y37P.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of F15E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of L16E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the linker comprises one or more gamma glutamate ( ⁇ Glu) residues and/or one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues. In some embodiments, the linker comprises one or more gamma glutamate ( ⁇ Glu) residues. In some embodiments, the linker comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues. In some embodiments, the linker comprises gamma glutamate ( ⁇ Glu). [001181] In some embodiments, the diacid comprises diacids consisting of 18 or 20 carbons in length.
  • the diacid comprises a C20 fatty diacid. In some embodiments, the diacid comprises 1,20-icosanedioic acid.
  • an exemplary amylin analog or functional variant thereof or mimetic thereof comprises the structure as shown in FIG.4. [001183] In some embodiments, the cation moiety comprises a choline or choline derivative-like residue. [001184] In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises one or more of the following amino acid substitutions: N14E, V17R, Y37P, F15E, L16E, and V17E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17R. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of Y37P. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of F15E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of L16E. In some embodiments, an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of V17E.
  • an amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the linker comprises one or more gamma glutamate ( ⁇ Glu) residues and/or one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues.
  • the linker comprises one or more gamma glutamate ( ⁇ Glu) residues.
  • the linker comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG) residues.
  • the linker comprises gamma glutamate ( ⁇ Glu).
  • the diacid comprises diacids consisting of 18 or 20 carbons in length. In some embodiments, the diacid comprises a C20 fatty diacid. In some embodiments, the diacid comprises 1,20-icosanedioic acid.
  • Amylin also known as islet amyloid polypeptide, IAPP, DAP, IAP, islet amyloid polypeptide, as used herein, refers to a 37-residue small peptide hormone that is released into the bloodstream by the ⁇ cells of the pancreas along with insulin after a meal.
  • amylin is co-secreted with insulin from the pancreatic ⁇ -cells in the ratio of approximately 100:1 (insulin:amylin).
  • amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
  • amylin is completely absent in individuals with Type I diabetes.
  • amylin includes any of the recombinant or naturally-occurring forms of amylin or variants or homologs thereof that have or maintain amylin activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity).
  • the 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 across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring amylin.
  • amylin is substantially identical to the protein identified by the UniProt reference number P10997 or a variant or homolog having substantial identity thereto.
  • UniProt reference number P10997 provides exemplary human amylin amino acid sequences.
  • amylin molecule is a naturally-existing amylin or a functional variant or fragment thereof.
  • a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; R 5 is amylin or mimetic or analog thereof, or an amylin analog or functional variant thereof or mimetic or analog thereof.
  • R 1 , R 2 , and R 3 are methyl.
  • R 1 , R 2 , and R 3 are ethyl.
  • R 1 , R 2 , and R 3 are propyl.
  • R 1 and R 2 are methyl, and R 3 is ethyl.
  • R 1 and R 3 are methyl, and R 2 is ethyl.
  • R 1 and R 2 are ethyl, and R 3 is methyl.
  • R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • the composition comprises molar ratio of from about 1:1 to about 1:30.
  • the composition comprises a molar ratio of about 1:1.
  • the composition comprises a molar ratio of about 1:3.
  • the composition comprises a molar ratio of about 1:7.
  • the composition comprises a molar ratio of about 1:12. [001204] In some embodiments, the composition comprises a molar ratio of about 1:28. [001205] In some embodiments, R 4 is [001206] In some embodiments, the compound is according to Formula Ia: [001207] In some embodiments, the compound is according to Formula Ib: [001208] In some embodiments, the compound is according to Formula Ic: Formula Ic. [001209] In some embodiments, R 5 is amylin or mimetic thereof, or an amylin analog or functional variant thereof or mimetic thereof. [001210] In some embodiments, R 5 is an amylin analog or functional variant thereof or mimetic thereof.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the sequence of: [diacid]-[linker]-KCNTATCATQ RLANFLVHSS NNFGPILPPT NVGSNTY-amide (SEQ ID NO: 21). [001212] In some embodiments, R 5 is an amylin analog or functional variant thereof or mimetic thereof having the structure as shown in FIG.2, FIG.3, or FIG.4. [001213] In some embodiments, R 5 is an amylin analog or functional variant thereof or mimetic thereof having a modified amylin analog or functional variant thereof or mimetic thereof structure.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having a choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof derivative structure.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a cation moiety comprising choline or choline derivative.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having a choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof ester structure.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a cation moiety comprising a choline or choline derivative-like residue.
  • the amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8- amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof derivative structure, and wherein the amylin analog or functional variant thereof or mimetic thereof comprises a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof ester structure, and wherein the amylin analog or functional variant thereof or mimetic thereof comprises a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the amylin analog or functional variant thereof or mimetic thereof comprises the amino acid substitution of N14E.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • R 6 is amylin or mimetic thereof, or an amylin analog or functional variant thereof or mimetic thereof ;
  • R 7 , R 8 , and R 9 are independently C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl. [001229] In some embodiments, R 7 , R 8 , and R 9 are ethyl. [001230] In some embodiments, R 7 , R 8 , and R 9 are propyl. [001231] In some embodiments, R 7 and R 8 are methyl, and R 9 is ethyl. [001232] In some embodiments, R 7 and R 9 are methyl, and R 8 is ethyl. [001233] In some embodiments, R 7 and R 8 are ethyl, and R 9 is methyl. [001234] In some embodiments, R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • R 6 is amylin or mimetic thereof, or an amylin analog or functional variant thereof or mimetic thereof.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the sequence of: [diacid]-[linker]-KCNTATCATQ RLANFLVHSS NNFGPILPPT NVGSNTY-amide (SEQ ID NO: 21).
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the structure as shown in FIG.2, FIG.3, or FIG.4.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having a modified amylin analog or functional variant thereof or mimetic thereof structure.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having a choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof derivative structure.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a cation moiety comprising choline or choline derivative.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having a choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof ester structure.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a cation moiety comprising a choline or choline derivative-like residue.
  • the amylin analog or functional variant thereof or mimetic thereof comprises an amino acid substitution of N14E, V17R, Y37P, F15E, L16E, V17E, or any combination thereof.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a linker comprising one or more gamma glutamate ( ⁇ Glu) residues, one or more 8- amino-3,6-dioxaoctanoic acid (OEG) residues, or a combination thereof.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a linker comprising one or more gamma glutamate ( ⁇ Glu) residues.
  • R 5 is the amylin analog or functional variant thereof or mimetic thereof having the choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof derivative structure, and wherein the amylin analog or functional variant thereof or mimetic thereof comprises a choline or choline derivative-peptide derivative that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • R 5 is an amylin analog or functional variant thereof or mimetic thereof having the choline or choline derivative-modified amylin analog or functional variant thereof or mimetic thereof ester structure, and wherein the amylin analog or functional variant thereof or mimetic thereof comprises a choline or choline derivative-peptide ester that is formed on the carboxylic acid of the one or more gamma glutamate residues of the linker.
  • the amylin analog or functional variant thereof or mimetic thereof comprises the amino acid substitution of N14E.
  • the amylin analog or functional variant thereof or mimetic thereof comprises a diacid consisting of 18 or 20 carbons in length.
  • the diacid comprises a C20 fatty diacid.
  • the diacid comprises 1,20-icosanedioic acid.
  • a pharmaceutical composition comprising the composition as described herein or the compound as described herein, and at least one pharmaceutically acceptable excipient.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition as described herein, the compound as described herein, or the pharmaceutical composition as described herein.
  • the disease or disorder is diabetes.
  • the disease or disorder is Type 1 diabetes.
  • the disease or disorder is Type 2 diabetes.
  • the disease or disorder is non-alcoholic steatohepatitis (NASH).
  • a method of treating obesity, preventing weight gain, or reducing weight in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition as described herein, the compound as described herein, or the pharmaceutical composition as described herein.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the composition, the compound, or the pharmaceutical composition is administered orally.
  • the composition, the compound, or the pharmaceutical composition is administered as a liquid-filled capsule.
  • the composition, the compound, or the pharmaceutical composition is administered in multiple doses.
  • the composition, the compound, or the pharmaceutical composition is administered in a single dose.
  • the composition, the compound, or the pharmaceutical composition is administered to a mucus membrane.
  • the concentration of the compound as described herein is at least 0.1% weight per volume.
  • the concentration of the compound as described herein is at least 0.05M.
  • the composition further comprises one or more additional agents.
  • the one or more additional agent is selected from the group consisting of a nucleic acid, a small molecule, and a polypeptide.
  • the one or more additional agent is a nucleic acid.
  • the one or more additional agent is a small molecule.
  • the one or more additional agent is a polypeptide.
  • diabetes mellitus a metabolic disease characterized by a deficiency or absence of insulin secretion by the pancreas.
  • diabetes includes all types including Type 1 and Type 2 diabetes mellitus unless otherwise specified herein. The two most common forms of diabetes are due to either a diminished production of insulin (in Type 1), or diminished response by the body to insulin (in Type 2).
  • Type 1 diabetes the function of the pancreas is progressively lost, thus eventually making the patient entirely dependent on the exogenously delivered insulin for the management of diabetes.
  • Type 2 the patient maintains some functioning of the pancreas, but the sensitivity of the body to insulin is reduced, thus reducing the extent of glycemia maintained by the patient.
  • Type 2 patients are treated by a variety of drugs including oral medications that increase glucose sensitivity, pramlintide, pramlintide mimetics/analogs, GLP-1, GLP-1 mimetics/analogs, or insulin.
  • a subject can be pre-diabetic, which can be characterized, for example, as having elevated fasting blood sugar or elevated post-prandial blood sugar such that the glucose levels do not fit the current medical definitions of diabetes.
  • a subject can be newly diagnosed which means Type 1 diabetic patients that are within 1-3 years of their diagnosis.
  • composition comprising the amylin analog or functional variant thereof or mimetic thereof and an ionic liquid of a cholinium cation and an anion selected from cinnamic acid, hydrocinnamic acid, malonic acid, citronellic acid, glutaric acid, mandelic acid, oleic acid, linoleic acid, and ricinoleic acid.
  • the therapeutic agent is an amylin analog or functional variant thereof or mimetic thereof.
  • the amylin analog or functional variant thereof or mimetic thereof is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid-containing molecules are linked to the amylin analog or functional variant thereof or mimetic thereof via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of an amylin analog or functional variant thereof or mimetic thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of an amylin analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an amylin analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of an amylin analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of an amylin analog or functional variant thereof or mimetic thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an amylin analog or functional variant thereof or mimetic thereof.
  • GLP-l or mimetic or functional variant, functional analog, or functional homolog thereof in one embodiment, described herein is a method of treatment of diabetes comprising orally administering an oral formulation of a GLP-l polypeptide or mimetic or analog thereof in combination with ionic liquid.
  • Glucagon-Like Peptide- l (GLP-l) is known to reduce food intake and hunger feelings in humans and is an incretin derived from the transcription product of the proglucagon gene that contributes to glucose homeostasis.
  • Natural GLP-1 has an extremely short half-life which makes its use as a therapeutic challenging. Modified versions of GLP-1 exist to overcome the stability challenge.
  • Such modifications can be done either in the sequence of the peptide or by conjugating another entity to the peptide.
  • a common modification includes attachment of a lipid tail.
  • GLP-l mimetics are currently being used in the treatment of Type 2 diabetes. Recent clinical trials have shown that these treatments improve glucose homeostasis. They also help in achieving weight loss.
  • GLP-1 Sequence is as follows: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp- Val-Ser-Ser-Tyr-Leu-Glu-Gly-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly- OH (SEQ ID NO: 22).
  • GLP-l mimetics are known in the art and used in the treatment of diabetes. GLP-l mimetics (or analogs) can include exenatide.
  • GLP-l analog or functional variant thereof or mimetic thereof sequence is as follows: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Ala-Val-Arg- Leu-Phe-Ile-Glu-Trp-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-NH2 (SEQ ID NO: 23).
  • GLP-l analog or functional variant thereof or mimetic thereof include derivatives for reducing enzymatic degradation, e.g., lixisenatide, dulaglutide, semaglutide, albiglutide, liraglutide, and taspoglutide.
  • exemplary GLP-l analog or functional variant thereof or mimetic thereof is shown in FIG.15A and another exemplary GLP-l analog or functional variant thereof or mimetic thereof is shown in FIG.15B.
  • the term "obesity" refers to excess fat in the body. Obesity can be determined by any measure accepted and utilized by those of skill in the art.
  • modification of the peptide can take on the following formula comprising non-covalent attachment.
  • R is a peptide including but not limited to an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide YY, Glucagon, GIP, Amylin.
  • a representative example comprising the compound according to Formula I is shown in FIG.16.
  • the modification can take an exemplary form of covalent attachment as shown in FIG.17.
  • the subject is administered a composition comprising an ionic liquid to treat a metabolic disorder or metabolic syndrome.
  • Metabolic disorders include but are not limited to obesity, diabetes, fatty liver disease, or non-alcoholic fatty liver disease.
  • a composition comprising a compound according to Formula I: Formula I, wherein: R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl; R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl; R 5 is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • R 1 , R 2 , and R 3 are methyl. [001301] In some embodiments, R 1 , R 2 , and R 3 are ethyl. [001302] In some embodiments, R 1 , R 2 , and R 3 are propyl. [001303] In some embodiments, R 1 and R 2 are methyl, and R 3 is ethyl. [001304] In some embodiments, R 1 and R 3 are methyl, and R 2 is ethyl. [001305] In some embodiments, R 1 and R 2 are ethyl, and R 3 is methyl. [001306] In some embodiments, R 1 and R 3 are ethyl, and R 2 is methyl.
  • R 1 and R 2 are propyl, and R 3 is methyl.
  • R 1 and R 3 are propyl, and R 2 is methyl.
  • R 4 is C 2 -C 5 alkyl substituted with a hydroxyl.
  • the composition comprises a molar ratio of from about 1:1 to about 1:60.
  • the composition comprises a molar ratio of from about 1:1 to about 1:30.
  • the composition comprises a molar ratio of about 1:1.
  • the composition comprises a molar ratio of about 1:3.
  • the composition comprises a molar ratio of about 1:4. [001315] In some embodiments, the composition comprises a molar ratio of about 1:7. [001316] In some embodiments, the composition comprises a molar ratio of about 1:12. [001317] In some embodiments, the composition comprises a molar ratio of about 1:14. [001318] In some embodiments, the composition comprises a molar ratio of about 1:28. [001319] In some embodiments, the composition comprises a molar ratio of about 1:56.
  • the composition comprises a molar ratio of from about 1:1 to about 1:200, from about 1:1 to about 1:199, from about 1:1 to about 1:198, from about 1:1 to about 1:197, from about 1:1 to about 1:196, from about 1:1 to about 1:195, from about 1:1 to about 1:194, from about 1:1 to about 1:193, from about 1:1 to about 1:192, from about 1:1 to about 1:191, from about 1:1 to about 1:190, from about 1:1 to about 1:189, from about 1:1 to about 1:188, from about 1:1 to about 1:187, from about 1:1 to about 1:186, from about 1:1 to about 1:185, from about 1:1 to about 1:184, from about 1:1 to about 1:183, from about 1:1 to about 1:182, from about 1:1 to about 1:181, from about 1:1 to about 1:180, from about 1:1 to about 1:179, from about 1:1 to about 1:178, from about 1:1 to about 1:177, from about 1:1 to about 1:176, from about 1:1 to about 1:175, from about 1:1 to about 1:174, from about 1:1 to about 1:173, from about 1:1 to about 1:172, from about 1:1
  • the composition comprises a molar ratio of about 1:200, about 1:199, about 1:198, about 1:197, about 1:196, about 1:195, about 1:194, about 1:193, about 1:192, about 1:191, about 1:190, about 1:189, about 1:188, about 1:187, about 1:186, about 1:185, about 1:184, about 1:183, about 1:182, about 1:181, about 1:180, about 1:179, about 1:178, about 1:177, about 1:176, about 1:175, about 1:174, about 1:173, about 1:172, about 1:171, about 1:170, about 1:169, about 1:168, about 1:167, about 1:166, about 1:165, about 1:164, about 1:163, about 1:162, about 1:161, about 1:160, about 1:159, about 1:158, about 1:157, about 1:156, about 1:155, about 1:154, about 1:153, about 1:152, about 1:151, about 1:150, about 1:149, about 1:148, about 1:147, about 1:146, about 1:145, about 1:144, about 1:143, about 1:1
  • R 4 is [001323] In some embodiments, the compound is according to Formula Ia: Formula Ia. [001324] In some embodiments, the compound is according to Formula Ib: Formula Ib. [001325] In some embodiments, the compound is according to Formula Ic: Formula Ic. [001326] In some embodiments, R 5 is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin. [001327] In some embodiments, R 5 is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound is the compound as shown in FIG.16.
  • a compound according to Formula II Formula II, wherein: R 6 is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin
  • R 7 , R 8 , and R 9 are independently C 1 -C 5 alkyl; and n is 1, 2, 3, 4, or 5.
  • R 7 , R 8 , and R 9 are methyl.
  • R 7 , R 8 , and R 9 are ethyl.
  • R 7 , R 8 , and R 9 are propyl.
  • R 7 and R 8 are methyl, and R 9 is ethyl.
  • R 7 and R 9 are methyl, and R 8 is ethyl.
  • R 7 and R 8 are ethyl, and R 9 is methyl.
  • R 7 and R 9 are ethyl, and R 8 is methyl.
  • R 7 and R 8 are propyl, and R 9 is methyl.
  • R 7 and R 9 are propyl, and R 8 is methyl.
  • n is 1.
  • the compound is according to Formula IIa: Formula IIa.
  • the compound is according to Formula IIb: Formula IIb.
  • the compound is according to Formula IIc: Formula IIc.
  • R 6 is an GLP-l analog or functional variant thereof or mimetic thereof, Liraglutide, Exenatide, Peptide tyrosine tyrosine (YY), glucagon, gastric inhibitory polypeptide (GIP), or amylin.
  • R 5 is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the compound is the compound as shown in FIG.17B.
  • a pharmaceutical composition comprising the composition as described herein, and at least one pharmaceutically acceptable excipient, carrier, or diluent.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition as described herein, or the pharmaceutical composition as described herein.
  • the disease or disorder is diabetes.
  • the disease or disorder is Type 1 diabetes.
  • the disease or disorder is Type 2 diabetes.
  • the disease or disorder is non-alcoholic steatohepatitis (NASH).
  • provided herein is a method of treating obesity, preventing weight gain, or reducing weight in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 40.
  • a method of treating obesity, preventing weight gain, or reducing weight in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 23 to 39, or the pharmaceutical composition according to claim 41.
  • the composition, the compound, or the pharmaceutical composition is administered via subcutaneous, intravenous, or oral administration.
  • the composition, the compound, or the pharmaceutical composition is administered orally.
  • the composition, the compound, or the pharmaceutical composition is administered as a liquid-filled capsule.
  • the composition, the compound, or the pharmaceutical composition is administered in multiple doses.
  • the composition, the compound, or the pharmaceutical composition is administered in a single dose.
  • the composition, the compound, or the pharmaceutical composition is administered to a mucus membrane.
  • the concentration of the compound is at least 0.1% weight per volume.
  • the concentration of the compound is at least 0.05M.
  • the composition further comprises one or more additional agents.
  • the one or more additional agent is selected from a nucleic acid, a small molecule, and a polypeptide.
  • the one or more additional agent is a nucleic acid.
  • the one or more additional agent is a small molecule.
  • the one or more additional agent is a polypeptide.
  • the therapeutic agent is a GLP-l polypeptide or mimetic or analog thereof.
  • the GLP-l polypeptide or mimetic or analog thereof is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid-containing molecules are linked to the GLP-l polypeptide or mimetic or analog thereof via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of a GLP-l polypeptide or mimetic or analog thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of a GLP-l polypeptide or mimetic or analog thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a GLP-l polypeptide or mimetic or analog thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of a GLP-l polypeptide or mimetic or analog thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of a GLP-l polypeptide or mimetic or analog thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a GLP-l polypeptide or mimetic or analog thereof.
  • an GLP-l analog or functional variant thereof or mimetic thereof is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid-containing molecules are linked to an GLP-l analog or functional variant thereof or mimetic thereof via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of an GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of an GLP-l analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an GLP-l analog or functional variant thereof or mimetic thereof.
  • cinnamic acid is non-covalently associated with a free amine of an GLP-l analog or functional variant thereof or mimetic thereof.
  • cinnamic acid is non-covalently associated with the N-terminal amine in the peptide backbone of an GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, cinnamic acid is non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an GLP-l analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of an GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N-terminal amine in the peptide backbone of an GLP-l analog or functional variant thereof or mimetic thereof.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an GLP-l analog or functional variant thereof or mimetic thereof.
  • cinnamic acid is covalently conjugated to a free amine of an GLP-l analog or functional variant thereof or mimetic thereof.
  • cinnamic acid is covalently conjugated to the N-terminal amine in the peptide backbone of an GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, cinnamic acid is covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of an GLP-l analog or functional variant thereof or mimetic thereof.
  • the anion in the ionic liquid may be chosen from cinnamic acid, hydrocinnamic acid, hydroxycinnamic (3-phenylpropanoic or benzylacetic) acid, methoxycinnamic acid, ferulic acid, isoferulic acid, 2-phenylpropionic (hydratropic acid), coumaric acid, 3,3- diphenylpropionic acid, 3,5-dimethoxy-4-hydroxy-cinnamic acid (sinapinic acid).
  • Other structural analogs of cinnamic acid could be used.
  • the cation can be chosen from a variety of molecules including choline or choline derivatives, for example, choline or choline derivative chloride, derivates of choline, or any other biocompatible cation that is otherwise able to form an ionic liquid to with the anions described herein.
  • choline derivatives refers to a substance that is derived from choline.
  • the ionic liquid is prepared by mixing an acid with choline or choline derivative bicarbonate by the process shown in FIG.19. Choline or choline derivative bicarbonate reacts with carboxylic acid with a byproduct of water and carbon dioxide.
  • the resultant ionic liquid is represented by the following formula; [001382] Depending on the ratio of anion and cation in the reaction mixture, the resultant mixture may also contain either excess acid or excess choline or choline derivative bicarbonate.
  • the term ionic liquid used herein includes all stoichiometries including equimolar acid and choline or choline derivative carbonate, excess acid or excess choline or choline derivative bicarbonate.
  • the ionic liquid structures drawn with the with or without the proton are equivalent and interchangeable depending on the concentration and composition.
  • the composition as used herein or the pharmaceutical the composition as used herein comprises one or more ionic liquids as listed in Table 1. Table 1. Exemplary ionic liquids
  • the following cations are used in the products of an exemplary GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, the following cations are used in the products of an exemplary GLP-l analog or functional variant thereof or mimetic thereof as covalent attachment. In some embodiments, the following cations are used in the products of an exemplary GLP-l analog or functional variant thereof or mimetic thereof as non- covalent attachment. In some embodiments, the cations in Table 2 are used in the therapeutic products. In some embodiments, the cations in Table 2 are used in an antibody or an antibody fragment thereof.
  • the cations in Table 2 are used in the products of an exemplary GLP-l analog or functional variant thereof or mimetic thereof. In some embodiments, the cations in Table 2 are used in the products of an exemplary GLP-l analog or functional variant thereof or mimetic thereof as covalent attachment. In some embodiments, the cations in Table 2 are used in the products of an GLP-l analog or functional variant thereof or mimetic thereof as non- covalent attachment. Table 2. Exemplary cations used in therapeutic agents. [001386] In one aspect, provided herein is a method of treating a subject by oral administration of a composition comprising; a. a polypeptide with at least one associated ionic species, and b.
  • the association between the said polypeptide and the ionic species is non-covalent.
  • the association between the said polypeptide and the ionic species is covalent.
  • the oral administration is intended for treating diabetes.
  • a composition comprising an ionic liquid wherein the anion has the chemical form of [001390]
  • compositions comprising an ionic liquid described by the formula .
  • a composition comprising an ionic liquid of a cholinium cation and an anion selected from the group consisting of cinnamic acid, hydrocinnamic acid, malonic acid, citronellic acid, glutaric acid, mandelic acid, oleic acid, linoleic acid, and ricinoleic acid.
  • a capsule comprising a composition of embodiment 1, 3, or 6 with an additional pharmaceutically acceptable excipient.
  • the drug is an GLP-l analog or functional variant thereof or mimetic thereof.
  • the drug is a GLP-1 mimetic drug selected from liraglutide, exenatide, or semaglutide.
  • the drug is liraglutide, exenatide or semaglutide.
  • a method of delivery of at least one drug comprising administering the drug in combination with an ionic liquid to a mucus membrane.
  • ionic liquid is at a concentration of at least 0.1 %w/v.
  • the ionic liquid comprises a ratio of cation:anion ratio from 2:1 to about 1:2.
  • the active compound in combination with the ionic liquid is administered once.
  • the active compound in combination with ionic liquid is administered in multiple doses.
  • the active compound comprises a nucleic acid molecule.
  • the active compound comprises a small molecule.
  • the active compound comprises a polypeptide.
  • a method of treating obesity, preventing weight gain, or reducing a subject’s weight comprising orally administering to the subject a composition comprising; a. a polypeptide with at least one associated ionic species; b. and at least one ionic liquid such that the said ionic species is also an ion in the ionic liquid.
  • a method of treating diabetes by administering a composition comprising an ionic liquid wherein the administration induces at least some reduction of blood glucose levels.
  • a composition comprising; a. a chemical with the formula, and b.
  • a glucagon-like peptide-1 analog or functional variant thereof or mimetic thereof such that the said glucagon-like peptide-1 analog or functional variant thereof or mimetic thereof is associated with at least one ionic species.
  • a composition comprising; a. a chemical with the formula, and b. a glucagon-like peptide selected from liraglutide, exenatide or semaglutide such that the said glucagon-like peptide is associated with at least one ionic species.
  • ionic liquid compositions for formulation and delivery. These formulations can be delivered orally to a patient for the purpose of treating the patient.
  • described herein is a composition wherein a protein or a peptide is non-covalently attached to one more ions wherein such ions are also present in the said ionic liquid is present in the formulation.
  • described herein is a composition wherein a protein or a peptide is covalently attached to one more ions wherein such ions are also present in the said ionic liquid is present in the formulation.
  • the ion used for covalent or non-covalent modification of peptide is choline or choline derivative.
  • the ionic liquid is a composition comprising a cation of choline or choline derivative and is cinnamic acid.
  • the ionic liquid is at a concentration of at least 0.1%w/v.
  • the ionic liquid comprises a ratio of cation:anion from about 2:1 to about 1:2.
  • the peptide formulation is administered once. In some embodiments, the formulation is administered in multiple doses.
  • the ionic liquid is delivered as a liquid-filled capsule.
  • the peptide delivered with the ionic liquid is a glucagon-like peptide (GLP-1) or glucagon-like peptide derivative.
  • the protein delivered with the ionic liquid is an antibody or antibody fragment.
  • provided herein is a method of treating Type 1 diabetes, Type 2 diabetes, NASH, prediabetes, obesity, or other metabolic disorders.
  • the ionic liquid is mixed with a pharmaceutically acceptable diluent such that the ionic liquid is present at a concentration of at least 0.05M.
  • the ionic liquid dissolves after administration.
  • the ionic liquid is a pure or anhydrous liquid.
  • the ionic liquid is an aqueous solution.
  • the ionic liquid serves to solubilize and stabilize the peptide to be delivered.
  • a composition comprising a therapeutic agent and one or more ionic liquid.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the composition as described herein further comprises at least one permeation enhancer.
  • the at least one permeation enhancer is selected from the group consisting of salcaprozate sodium (SNAC), sodium caprylate, sodium caprate, a bile salt, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA), and 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate (PPS), and any combination thereof.
  • SNAC salcaprozate sodium
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'- tetraacetic acid
  • PPS 3-[N,N-Dimethyl(3-palmitoylaminopropyl)-ammonio]- propanesulfonate
  • the bile salt is selected from the group consisting of sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate, and a combination thereof.
  • a method of increasing the solubility of a therapeutic agent comprising preparing a composition comprising the therapeutic agent and one or more ionic liquid.
  • a method of enhancing or improving the delivery efficiency of a therapeutic agent in a subject in need thereof comprising preparing a composition comprising the therapeutic agent and one or more ionic liquid, and administering the composition to the subject.
  • the one or more ionic liquid independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the one or more ionic liquid independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4- Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2- Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4- Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4- Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4- Hydroxybenzenesulfonic Acid, 4-Hydroxybenzoic Acid, 4-Methylhexanoic Acid, 4- Methyloc
  • the one or more ionic liquid independently comprises an anion 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.
  • the one or more ionic liquid independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the one or more ionic liquid independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the one or more ionic liquid independently comprises a cation selected from the group of the cations listed in Table 2.
  • the one or more ionic liquid independently comprises an anion selected from the group of the anions listed in Table 1.
  • the one or more ionic liquid independently comprises an ionic liquid selected from the group of the ionic liquids listed in Table 2.
  • the composition or the pharmaceutical composition as provided herein comprises the composition as provided herein or the compound as provided herein, and the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises a cation selected from the group consisting of aminoguanidine, choline or choline derivative, carnitine, acetylcholine, ammonium, tetramethyl ammonium, tetraethyl ammonium, tetrabutyl ammonium, and guanidine derivatives.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises choline or choline derivative, carnitine, or acetylcholine.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of (R)- ⁇ -Lipoic Acid, 12-Hydroxystearic Acid, 2-(4-Isobutylphenyl)propionic Acid, 2-(4,4-Dimethyl-2-pentanyl)-5,7,7-trimethyloctanoic Acid, 2-Aminoethanesulfonic Acid (Taurine Acid), 2-Hexyldecanoic Acid, 2-Hydroxyhippuric Acid, 3-(4-Hydroxyphenyl)propionic Acid, 3-Methylcrotonic Acid, 3,3-Diphenylpropionic Acid, 3,4-Dihydroxbenzoic Acid (Protocatechuic Acid), 3,7-Dimethyloctanoic Acid, 4-Hydroxybenzen
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of (R)- ⁇ -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, arachidonic acid, caffeic acid, cinnamic acid, citric acid, citronellic acid, crotonic acid, D-(+)-galactonic acid,
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion 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.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group consisting of cinnamic acid, mandelic acid, citric acid, ricinoleic acid, linoleic acid, and tiglic acid.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises 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.
  • the one or more ionic liquid independently comprises carnitine- cinnamic acid, carnitine-mandelic acid, carnitine-citric acid, carnitine-ricinoleic acid, carnitine- linoleic acid, or carnitine-tiglic acid.
  • the one or more ionic liquid independently comprises acetylcholine-cinnamic acid, acetylcholine-mandelic acid, acetylcholine-citric acid, acetylcholine- ricinoleic acid, acetylcholine-linoleic acid, or acetylcholine-tiglic acid.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises a cation selected from the group of the cations listed in Table 2.
  • the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an anion selected from the group of the anions listed in Table 1. In some embodiments, some embodiments, the first, the second, the third, the fourth, the fifth, the sixth, the eighth, the ninth, the tenth, or more ionic liquids independently comprises an ionic liquid selected from the group of the ionic liquids listed in Table 2.
  • Therapeutic Agents [001457] In some aspects, provided herein, inter alia, is a compound according to Formula I: Formula I. [001458] In some embodiments, R 1 , R 2 , and R 3 are independently C 1 -C 5 alkyl.
  • R 1 is C 1 -C 5 alkyl. In some embodiments, R 2 is C 1 -C 5 alkyl. In some embodiments, R 3 is C 1 -C 5 alkyl. [001459] In some embodiments, R 1 , R 2 , and R 3 are independently C 1 -C 20 alkyl. In some embodiments, R 1 is C 1 -C 20 alkyl. In some embodiments, R 1 is C 1 -C 19 alkyl. In some embodiments, R 1 is C 1 -C 18 alkyl. In some embodiments, R 1 is C 1 -C 17 alkyl. In some embodiments, R 1 is C 1 -C 16 alkyl.
  • R 1 is C 1 -C 15 alkyl. In some embodiments, R 1 is C 1 -C 14 alkyl. In some embodiments, R 1 is C 1 -C 13 alkyl. In some embodiments, R 1 is C 1 -C 12 alkyl. In some embodiments, R 1 is C 1 -C 11 alkyl. In some embodiments, R 1 is C 1 -C 10 alkyl. In some embodiments, R 1 is C 1 -C 9 alkyl. In some embodiments, R 1 is C 1 -C 8 alkyl. In some embodiments, R 1 is C 1 -C 7 alkyl. In some embodiments, R 1 is C 1 -C 6 alkyl.
  • R 1 is C 1 -C 5 alkyl. In some embodiments, R 1 is C 1 -C 4 alkyl. In some embodiments, R 1 is C 1 -C 3 alkyl. In some embodiments, R 1 is C 1 -C 2 alkyl. In some embodiments, R 2 is C 1 -C 20 alkyl. In some embodiments, R 2 is C 1 -C 19 alkyl. In some embodiments, R 2 is C 1 -C 18 alkyl. In some embodiments, R 2 is C 1 -C 17 alkyl. In some embodiments, R 2 is C 1 -C 16 alkyl. In some embodiments, R 2 is C 1 -C 15 alkyl.
  • R 2 is C 1 -C 14 alkyl. In some embodiments, R 2 is C 1 -C 13 alkyl. In some embodiments, R 2 is C 1 -C 12 alkyl. In some embodiments, R 2 is C 1 -C 11 alkyl. In some embodiments, R 2 is C 1 -C 10 alkyl. In some embodiments, R 2 is C 1 -C 9 alkyl. In some embodiments, R 2 is C 1 -C 8 alkyl. In some embodiments, R 2 is C 1 -C 7 alkyl. In some embodiments, R 2 is C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 5 alkyl.
  • R 2 is C 1 -C 4 alkyl. In some embodiments, R 2 is C 1 -C 3 alkyl. In some embodiments, R 2 is C 1 -C 2 alkyl. In some embodiments, R 3 is C 1 -C 20 alkyl. In some embodiments, R 3 is C 1 -C 19 alkyl. In some embodiments, R 3 is C 1 -C 18 alkyl. In some embodiments, R 3 is C 1 -C 17 alkyl. In some embodiments, R 3 is C 1 -C 16 alkyl. In some embodiments, R 3 is C 1 -C 15 alkyl. In some embodiments, R 3 is C 1 -C 14 alkyl.
  • R 3 is C 1 -C 13 alkyl. In some embodiments, R 3 is C 1 -C 12 alkyl. In some embodiments, R 3 is C 1 -C 11 alkyl. In some embodiments, R 3 is C 1 -C 10 alkyl. In some embodiments, R 3 is C 1 -C 9 alkyl. In some embodiments, R 3 is C 1 -C 8 alkyl. In some embodiments, R 3 is C 1 -C 7 alkyl. In some embodiments, R 3 is C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 5 alkyl. In some embodiments, R 3 is C 1 -C 4 alkyl.
  • R 3 is C 1 -C 3 alkyl. In some embodiments, R 3 is C 1 -C 2 alkyl. [001460] In some embodiments, R 1 is C 1 alkyl. In some embodiments, R 1 is C 2 alkyl. In some embodiments, R 1 is C 3 alkyl. In some embodiments, R 1 is C 4 alkyl. In some embodiments, R 1 is C 5 alkyl. In some embodiments, R 1 is C 6 alkyl. In some embodiments, R 1 is C 7 alkyl. In some embodiments, R 1 is C 8 alkyl. In some embodiments, R 1 is C 9 alkyl. In some embodiments, R 1 is C 10 alkyl.
  • R 1 is C 11 alkyl. In some embodiments, R 1 is C 12 alkyl. In some embodiments, R 1 is C 13 alkyl. In some embodiments, R 1 is C 14 alkyl. In some embodiments, R 1 is C 15 alkyl. In some embodiments, R 1 is C 16 alkyl. In some embodiments, R 1 is C 17 alkyl. In some embodiments, R 1 is C 18 alkyl. In some embodiments, R 1 is C 19 alkyl. In some embodiments, R 1 is C 20 alkyl. In some embodiments, R 2 is C 1 alkyl. In some embodiments, R 2 is C 2 alkyl. In some embodiments, R 2 is C 3 alkyl.
  • R 2 is C 4 alkyl. In some embodiments, R 2 is C 5 alkyl. In some embodiments, R 2 is C 6 alkyl. In some embodiments, R 2 is C 7 alkyl. In some embodiments, R 2 is C 8 alkyl. In some embodiments, R 2 is C 9 alkyl. In some embodiments, R 2 is C 10 alkyl. In some embodiments, R 2 is C 11 alkyl. In some embodiments, R 2 is C 12 alkyl. In some embodiments, R 2 is C 13 alkyl. In some embodiments, R 2 is C 14 alkyl. In some embodiments, R 2 is C 15 alkyl. In some embodiments, R 2 is C 16 alkyl.
  • R 2 is C 17 alkyl. In some embodiments, R 2 is C 18 alkyl. In some embodiments, R 2 is C 19 alkyl. In some embodiments, R 2 is C 20 alkyl. In some embodiments, R 3 is C 1 alkyl. In some embodiments, R 3 is C 2 alkyl. In some embodiments, R 3 is C 3 alkyl. In some embodiments, R 3 is C 4 alkyl. In some embodiments, R 3 is C 5 alkyl. In some embodiments, R 3 is C 6 alkyl. In some embodiments, R 3 is C 7 alkyl. In some embodiments, R 3 is C 8 alkyl. In some embodiments, R 3 is C 9 alkyl.
  • R 3 is C 10 alkyl. In some embodiments, R 3 is C 11 alkyl. In some embodiments, R 3 is C 12 alkyl. In some embodiments, R 3 is C 13 alkyl. In some embodiments, R 3 is C 14 alkyl. In some embodiments, R 3 is C 15 alkyl. In some embodiments, R 3 is C 16 alkyl. In some embodiments, R 3 is C 17 alkyl. In some embodiments, R 3 is C 18 alkyl. In some embodiments, R 3 is C 19 alkyl. In some embodiments, R 3 is C 20 alkyl.
  • R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 20 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 19 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 18 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 17 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 16 alkyl, wherein the C 2 - C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 - C 15 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 14 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 13 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 12 alkyl, wherein the C 2 - C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 - C 11 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 10 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 9 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 8 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 7 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 2 -C 6 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 5 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 4 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl. In some embodiments, R 4 is C 2 -C 3 alkyl, wherein the C 2 -C 5 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 4 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 alkyl, wherein the C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19, or C 20 alkyl is unsubstituted or substituted with 1 or more hydroxyl.
  • R 5 is a therapeutic agent.
  • the compound comprises a therapeutic agent comprising a diacid consisting of 18 or 20 carbons in length.
  • the compound comprises a therapeutic agent comprising a diacid consisting 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 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , 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 , 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 fatty diacid.
  • R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 5 alkyl. [001466] In some embodiments, R 7 , R 8 , and R 9 are independently unsubstituted or substituted C 1 - C 20 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 19 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 17 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 14 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 12 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 10 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 7 alkyl.
  • R 7 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 3 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 1 -C 2 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 19 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 17 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 14 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 12 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 10 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 7 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 5 alkyl.
  • R 8 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 3 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 -C 2 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 20 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 19 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 18 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 17 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 16 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 15 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 14 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 13 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 12 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 11 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 10 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 9 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 8 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 7 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 6 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 4 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 -C 3 alkyl.
  • R 9 is unsubstituted or substituted C 1 -C 2 alkyl.
  • R 7 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 2 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 6 alkyl.
  • R 7 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 10 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 14 alkyl.
  • R 7 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 18 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 7 is unsubstituted or substituted C 20 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 2 alkyl.
  • R 8 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 6 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 10 alkyl.
  • R 8 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 14 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 18 alkyl.
  • R 8 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 8 is unsubstituted or substituted C 20 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 1 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 2 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 3 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 4 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 5 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 6 alkyl.
  • R 9 is unsubstituted or substituted C 7 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 8 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 9 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 10 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 11 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 12 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 13 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 14 alkyl.
  • R 9 is unsubstituted or substituted C 15 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 16 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 17 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 18 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 19 alkyl. In some embodiments, R 9 is unsubstituted or substituted C 20 alkyl. [001468] In some embodiments, n is 1, 2, 3, 4, or 5.
  • 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.
  • R 6 is a therapeutic agent.
  • the compound comprises a therapeutic agent having a cation moiety comprising a choline or choline derivative-like residue.
  • the compound comprises a therapeutic agent comprising one or more choline or choline derivative-peptide ester formed on a Cys residue, a Lys residue, or any combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to- a therapeutic agent ratio of 2-8
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a therapeutic agent thereof ratio of 2-4, or a combination thereof.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a therapeutic agent 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a therapeutic agent ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1- 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a therapeutic agent ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Cys residue comprises a linker-to-a therapeutic agent ratio of 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, 22-28, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a therapeutic agent 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a therapeutic agent ratio of 1-50, 1-49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1- 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a therapeutic agent ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the one or more choline or choline derivative-peptide ester formed on the Lys residue comprises a linker-to-a therapeutic agent ratio of 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.
  • the compound comprises a therapeutic agent comprising a diacid consisting of 18 or 20 carbons in length.
  • the compound comprises a therapeutic agent comprising a diacid consisting 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 carbons in length.
  • the diacid comprises a C 20 fatty diacid.
  • the diacid comprises a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , 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 , 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 fatty diacid.
  • a compound according to Formula III Formula III, wherein: R 10 is a therapeutic agent; R 11 is substituted or unsubstituted C 5 -C 10 ; X 1 is -S-, or -NH-; and L 1 is a covalent bond or a linker.
  • the compound comprises a therapeutic agent comprising one or more R 11 linked to a Lys residue, a Cys residue, or any combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-a therapeutic agent ratio of 2-4, R 11 is linked to the Cys residue with a linker-to-a therapeutic agent ratio of 2-8 or with a linker-to-a therapeutic agent ratio of 4, or a combination thereof.
  • R 11 is linked to the Lys residue with a linker-to-a therapeutic agent 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.
  • R 11 is linked to the Lys residue with a linker-to-a therapeutic agent ratio of 1-50, 1- 49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • R 11 is linked to the Lys residue with a linker-to-a therapeutic agent ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • R 11 is linked to the Lys residue with a linker-to-a therapeutic agent ratio of 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.
  • R 11 is linked to the Cys residue with a linker-to-a therapeutic agent 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.
  • R 11 is linked to the Cys residue with a linker-to-a therapeutic agent ratio of 1-50, 1- 49, 1-48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • R 11 is linked to the Cys residue with a linker-to-a therapeutic agent ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • R 11 is linked to the Cys residue with a linker-to-a therapeutic agent ratio of 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, 22-28, 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.
  • a linker-to-a therapeutic agent ratio of 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
  • R 11 is linked to a therapeutic agent with a linker-to-a therapeutic agent 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.
  • the compound comprises a therapeutic agent comprising a dual conjugation.
  • the dual conjugation comprises a linker-to-a therapeutic agent ratio of 1-2.
  • the dual conjugation comprises a linker-to-a therapeutic agent 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.
  • the dual conjugation comprises a linker-to-a therapeutic agent ratio of 1-50, 1-49, 1- 48, 1-47, 1-46, 1-45, 1-44, 1-43, 1-42, 1-41, 1-40, 1-39, 1-38, 1-37, 1-36, 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.
  • the dual conjugation comprises a linker-to-a therapeutic agent ratio of 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8- 50, 9-50, 10-50, 11-50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 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.
  • the dual conjugation comprises a linker-to-a therapeutic agent ratio of 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18- 19, 19-20, 20-21, 21-22, 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.
  • the concentration of the compound as described herein is at least 0.1% weight per volume.
  • the concentration of the compound as 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.
  • the concentration of the compound as described herein is at least 0.05M.
  • the concentration of the compound as 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.
  • a therapeutic agent is linked to one or more fatty acids or carboxylic acid-containing molecules.
  • one or more fatty acids or carboxylic acid-containing molecules are linked to a therapeutic agent via a dual conjugation (or dual covalent conjugation).
  • one or more fatty acids or carboxylic acid-containing molecules comprise cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are cinnamic acid.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with a free amine of a therapeutic agent.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the N-terminal amine in the peptide backbone of a therapeutic agent.
  • one or more fatty acids or carboxylic acid-containing molecules are non-covalently associated with the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a therapeutic agent.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to a free amine of a therapeutic agent.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the N- terminal amine in the peptide backbone of a therapeutic agent.
  • one or more fatty acids or carboxylic acid-containing molecules are covalently conjugated to the amine group of a Gln residue, the amine group of an Asn residue, the amine group of an Arg residue, the amine group of a Lys residue, the amine group of a His residue, or a combination thereof of a therapeutic agent.
  • Example 1 Choline-an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof
  • a non-covalent choline derivative of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof was prepared at ratios form 1:1 (choline: an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof) to 164:1 (choline: an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof).
  • choline- an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof 164, 132, 82, 66, 41, 33, or 1 equivalents of choline bicarbonate (80 wt% solution) were added to 10 mg an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof in 100 uL of phosphate buffered saline in a 5 mL Protein LoBind® Eppendorf Tube. Water was removed by lyophilization.
  • the physical appearance of choline derivative of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is a solid white crystal.
  • the residues of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof able to react include: 44 E (Glutamic acid), 34 D (Aspartic acid) residues, 4 C-terminus regions (1 on each heavy and light chain), totaling 82 residues according to the sequences of SEQ ID NO: 24 and SEQ ID NO: 2.
  • the residues of the heavy chain of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof able to react include 10 E residues and 8 D on one heavy chain according to the sequence of SEQ ID NO: 24.
  • the residues of the light chain of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof able to react include 12 E and 9 D residues on each light chain according to the sequence of SEQ ID NO: 2.
  • the residues of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof able to react include 44 E residues and 34 D residues.
  • 4 C-terminus regions are ionizable.
  • an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof totally comprises 82 ionizable residues.
  • a covalent choline derivative of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof is prepared by an exemplary chemical reaction, as shown by FIG.6B, to link choline to an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof.
  • one or more choline is further linked to lysine residues, cystine residues or a combination thereof of an exemplary chimeric monoclonal anti- TNF- ⁇ antibody or an antibody fragment thereof (e.g., FIG.7)
  • Example 2 An exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof Lipidation [001494] To enhance the hydrophobicity of an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof linked to fatty acids (e.g., FIG.8A) is prepared by an exemplary chemical reaction as shown by FIG.8B.
  • fatty acids or carboxylic acid- containing molecules are linked to an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof via a dual conjugation (or dual covalent conjugation) (e.g., FIG.9A) according to the reaction procedure (e.g., FIG.9B) of which reaction conditions are generally described in, for example, Chaubet et al., Investigating Ugi/Passerini Multicomponent Reactions for the Site-Selective Conjugation of Native Trastuzumab, Chem. Eur. J.2020, 26, 13797 – 13805.
  • Example 3 Choline-other antibodies [001495] Using the similar procedure described in Example 1 and 2, choline derivatives forms of other antibodies and antibodies linked to fatty acids or carboxylic acid-containing molecules are prepared.
  • the exemplary antibodies include, but are not limited to, a monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof, an anti-human IL-12 and IL-23 subunit antibody or an antibody fragment thereof, a human monoclonal anti-TNF- ⁇ antibody, an anti-integrin ⁇ 4 ⁇ 1 antibody, an anti-integrin ⁇ 4 ⁇ 7 antibody, and a fragment of an anti-TNF- ⁇ antibody.
  • the exemplary antibodies include, but are not limited to, adalimumab, ustekinumab, golimumab, natalizumab, vedolizumab, and certolizumab pegol.
  • Example 4 Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof [001496] A non-covalent derivative of choline was prepared at ratios from 1:1 (choline:an exemplary GLP-l analog or functional variant thereof or mimetic thereof) to 28:1 (choline:an exemplary GLP-l analog or functional variant thereof or mimetic thereof).
  • choline derivative of an exemplary GLP-l analog or functional variant thereof or mimetic thereof is a solid white crystal.
  • Example 5 Covalent choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof
  • a covalent choline derivative of an exemplary GLP-l analog or functional variant thereof or mimetic thereof is prepared at ratios form 1:1 (choline:an exemplary GLP-l analog or functional variant thereof or mimetic thereof) to 28:1 (choline:an exemplary GLP-l analog or functional variant thereof or mimetic thereof).
  • choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof ester derivatives can be formed by conjugating a cation (e.g., choline) to at least 1 or up to 7 sites on the an exemplary GLP-l analog or functional variant thereof or mimetic thereof structure.
  • FIG.20A An exemplary chemical structure of an exemplary GLP-l analog or functional variant thereof or mimetic thereof is shown in FIG.20A and exemplary structures of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof are shown in at the various ratios are shown in FIG.20B (1:1 ratio), FIG.20C (7:1 ratio), and FIG.20D (28:1 ratio).
  • choline ionization could occur at any of the –COOH sites.
  • excess bicarbonate is also present in the 28:1 ratio.
  • Example 6 Exemplary analytical characterization of exemplary embodiments of choline- an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on HPLC [001500] Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on high- performance liquid chromatography (HPLC) is shown in FIG.22.
  • HPLC high- performance liquid chromatography
  • Retention Times was 22.039 min for an exemplary GLP-l analog or functional variant thereof or mimetic thereof; 22.031 min for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 1:1; 22.047 min for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 7:1; and 22.043 min for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 28:1.
  • the concentration for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 1:1 was 7.848 mg/mL
  • the concentration for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 7:1 was 6.573 mg/mL
  • the concentration for Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at the ratio of 28:1 was 3.868 mg/mL.
  • Example 7 Exemplary analytical characterization of exemplary embodiments of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on pH
  • FIGs.23A-23D Exemplary analytical characterization of exemplary embodiments of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on pH is shown in FIGs.23A-23D.
  • FIG.23A depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water. The results are not normalized to an exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.23B depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water.
  • the results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • Reference Data - pKa of choline was approximately 14, and pKa of bicarbonate was approximately 6.
  • Conclusions [001512] Very minor differences were observed when accounting for normalization of the exemplary GLP-l analog or functional variant thereof or mimetic thereof mass present in each of the ion ratios.
  • Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 7:1 has the most basic pH in water, compared with Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 1:1 and Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 28:1, which are slightly more acidic. [001514] Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 7:1 would have the least amount of bicarbonate present, as nearly 100% of bicarbonate would be consumed during the reaction, causing the solution to tend towards the choline pKa.
  • FIG.23C depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water, wherein the exemplary reaction using choline bicarbonate as shown above the graph was used.
  • the results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.23D depicts exemplary analytical characterization results of the negative control of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on pH using 2 mg/mL solutions in water, wherein the exemplary reaction using choline chloride as shown above the graph was used.
  • the results of the choline-Cl-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • Reference Data - pKa of choline was approximately 14, and pKa of bicarbonate was approximately 6.
  • Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 4:1 has the most basic pH in water when formed using choline bicarbonate, whereas Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 1:1, Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 7:1, Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 14:1, Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 28:1, and Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 56:1 show lower pH compared with Choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof 4:1.
  • choline bicarbonate can react with free carboxylic groups on the GLP-l analog or functional variant thereof or mimetic thereof to create the novel Choline-GLP-l analog or functional variant thereof or mimetic thereof.
  • choline chloride can be used as a negative control, as it will not react with the free carboxylic acid groups.
  • Non-reacted GLP-l analog or functional variant thereof or mimetic thereof were listed as Choline-Cl-GLP Analog in the figures. The included pH data as described above further support that the GLP-l analog or functional variant thereof or mimetic thereof is indeed ionized when choline bicarbonate is used.
  • Example 8 Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on conductivity
  • FIGs. 24A-24D Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on conductivity is shown in FIGs. 24A-24D.
  • FIG. 24A depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water. The results are not normalized to an exemplary GLP- l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.24B depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water.
  • the results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • Conclusion [001524] Conductivity of each of the choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof at various ratios in solution increases with increasing choline amount, even after normalizing to the exemplary GLP-l analog or functional variant thereof or mimetic thereof mass.
  • FIG.24C depicts exemplary analytical characterization results of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water, wherein the exemplary reaction using choline bicarbonate as shown above the graph was used.
  • the results of the choline-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • FIG.24D depicts exemplary analytical characterization results of the negative control of an exemplary GLP-l analog or functional variant thereof or mimetic thereof (“GLP-l analog”) based on conductivity using 2 mg/mL solutions in water, wherein the exemplary reaction using choline chloride as shown above the graph was used.
  • the results of the choline-Cl-the exemplary GLP-l analog or functional variant thereof or mimetic thereof are normalized to the exemplary GLP-l analog or functional variant thereof or mimetic thereof Mass.
  • choline bicarbonate can react with free carboxylic groups on the GLP-l analog or functional variant thereof or mimetic thereof to create the novel Choline-GLP-l analog or functional variant thereof or mimetic thereof.
  • choline chloride can be used as a negative control, as it will not react with the free carboxylic acid groups.
  • Non-reacted GLP-l analog or functional variant thereof or mimetic thereof were listed as Choline-Cl-GLP Analog in the figures.
  • the conductivity data as described above further support that the GLP-l analog or functional variant thereof or mimetic thereof is indeed ionized when choline bicarbonate is used.
  • Example 9 Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on NMR [001530] Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on NMR is shown in FIGs.25A and 25B.
  • FIG.25A depicts exemplary analytical characterization results based on NMR of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof ratios.
  • FIG.25B depicts exemplary analytical characterization results based on NMR of choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof ratios in a larger view.
  • Example 10 Exemplary analytical characterization of exemplary embodiments of Choline-an exemplary GLP-l analog or functional variant thereof or mimetic thereof based on Fourier- transform infrared spectroscopy (FTIR)
  • FTIR Fourier- transform infrared spectroscopy
  • esterification on an exemplary GLP-l analog or functional variant thereof or mimetic thereof with an anion there are 7 potential sites of esterification on an exemplary GLP-l analog or functional variant thereof or mimetic thereof with an anion (e.g., FIG.27).
  • cinnamic acid-an exemplary GLP-l analog or functional variant thereof or mimetic thereof ester derivatives can be formed by conjugating an anion (e.g., cinnamic acid) to at least 1 or up to 7 sites on the exemplary GLP-l analog or functional variant thereof or mimetic thereof structure.
  • Example 12 An exemplary Choline-Modified Dual GIP/GLP-1 Receptor Agonist Or Functional Variant Thereof Ionic Derivative Structure Using An Exemplary Dual GIP/GLP-1 Receptor Agonist Or Functional Variant Thereof Backbone [001538]
  • a non-covalent choline derivative of an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof or functional variant thereof is prepared at ratios form 1:1 (choline:an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof) to 20:1 (choline:an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof).
  • choline-an exemplary chimeric monoclonal anti-TNF- ⁇ antibody or an antibody fragment thereof 1, 2, 3, 4, 5, 10, or 20 equivalents of choline bicarbonate (80 wt% solution) are added to an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof in phosphate buffered saline in a 5 mL Protein LoBind® Eppendorf Tube. Water is removed by lyophilization.
  • the choline:an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof ratio of the choline-an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof ionic derivatives is 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, or 20:1.
  • Example 13 An Exemplary Choline-Modified Dual GIP/GLP-1 Receptor Agonist Or Functional Variant Thereof Ester Structure using an exemplary Dual GIP/GLP-1 Receptor Agonist Or Functional Variant Thereof Backbone [001540]
  • a covalent choline derivative of an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof is prepared at ratios form 1:1 (choline: an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof) to 20:1 (choline: an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof).
  • ester derivatives can be formed by conjugating a cation (e.g., choline) to at least 1 or up to 5 sites on the an exemplary dual GIP/GLP-1 receptor agonist or functional variant thereof structure.
  • a cation e.g., choline

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