Formulation of lipidated peptide inhibitors of the interleukin-23 receptor

Abstract

The present disclosure relates to oral pharmaceutical formulations comprising a lipidated peptide inhibitor of the interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer, and methods and / or uses thereof for increasing the bioavailability of the lipidated peptide and / or for treating autoimmune inflammation and related diseases and disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 480,068, filed January 16, 2023, which is incorporated herein by reference in its entirety.

[0002] (Incorporating sequence listing) The Sequence Listing in ST.26 XML format, entitled 739658_NTT-4253PC_SL.xml, created on January 12, 2024, containing 137,953 bytes, prepared in accordance with 37 CFR 1.822-1.824, and submitted contemporaneously with the filing of this application, is hereby incorporated by reference in its entirety.

[0003] FIELD OF THE INVENTION The present disclosure relates to oral pharmaceutical formulations comprising a lipidated peptide inhibitor of the Interleukin-23 Receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer, and methods and / or uses thereof for increasing the bioavailability of the lipidated peptide and / or for treating autoimmune inflammation and related diseases and disorders. [Background technology]

[0004] The interleukin-23 (IL-23) cytokine has been implicated as playing an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), e.g., ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a key role for the interleukin-23 receptor (IL-23R) and downstream effector cytokines in the pathogenesis of the disease.

[0005] Attempts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for use in treating IL-23-related diseases and disorders. More recently, polypeptide inhibitors that bind to IL-23R and inhibit IL-23 binding to IL-23R have been identified (see, e.g., U.S. Patent Application Publication No. 2013 / 0029907). Clinical trials of briakinumab (e.g., which also targets the common p40 subunit), as well as tildrakizumab, guselkumab, MEDI2070, and BI-655066 (e.g., which target the unique p19 subunit of IL-23) in Crohn's disease or psoriasis have revealed the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases. While these findings are promising, challenges remain regarding the successful targeted delivery of such drugs. Effective delivery could improve the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related disorders.

[0006] Lipidation of therapeutically useful polypeptides can provide advantageous physicochemical properties compared to the corresponding unmodified polypeptides: lipidated polypeptides may exhibit improved half-life, reduced immunogenicity, enhanced cellular uptake, and / or enhanced transepithelial delivery.

[0007] There remains a need in the art to develop effective pharmaceutical vehicles, such as pharmaceutical compositions, for delivering therapeutic agents to treat and prevent IL-23 and / or IL-23R-associated diseases, particularly diseases associated with autoimmune inflammation, such as in the intestinal tract, which may include, but are not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease (CD), psoriasis, or psoriatic arthritis.

[0008] The present disclosure is directed to overcoming these and other problems encountered in the art. Summary of the Invention [Means for solving the problem]

[0009] In general, the present disclosure relates to oral pharmaceutical compositions comprising lipidated peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts, solvates, and / or other forms thereof, and methods and / or uses thereof for increasing the bioavailability of lipidated peptides and / or for treating autoimmune inflammation and related diseases and disorders.

[0010] In some embodiments, the present disclosure relates to an oral pharmaceutical formulation comprising: (1) an absorption enhancer; and (2) a lipidated peptide comprising 9-20 amino acids, wherein the lipidated peptide is cyclized to form a ring, the ring comprising 4-14 amino acids, and the ratio of absorption enhancer to lipidated peptide is 50:1 (w / w) or less.

[0011] The present disclosure relates to oral pharmaceutical compositions described herein, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders, comprising a compound of Formula A, Formula B, Formula I, Formula Ia, Formula Ib, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, solvate, and / or other form thereof, and an absorption enhancer provided herein.

[0012] The present disclosure relates to oral pharmaceutical formulations comprising an absorption enhancer provided herein and a lipidated peptide provided herein.

[0013] The present disclosure provides:

[0014] [ka]

[0015] [ka] or a pharmaceutically acceptable salt or solvate form thereof, wherein the variables are as defined and provided herein.

[0016] The present disclosure relates to oral pharmaceutical formulations comprising an absorption enhancer and a compound or a pharmaceutically acceptable salt or solvate form thereof in a weight / weight ratio (w / w) of about 1 to about 200.

[0017] The present disclosure relates to a method for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), comprising administering an effective amount of an oral pharmaceutical formulation provided herein.

[0018] The present disclosure relates to a method for increasing the bioavailability of a compound in an oral pharmaceutical formulation provided herein in a subject, the method comprising orally administering the compound, or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0019] I. Overview In general, the present disclosure relates to oral pharmaceutical formulations comprising a lipidated peptide inhibitor of interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer, and methods and / or uses thereof for increasing the bioavailability of the lipidated peptide and / or for treating autoimmune inflammation and related diseases and disorders.

[0020] II. Definition The present disclosure relates to oral pharmaceutical formulations comprising a lipidated peptide inhibitor of the interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer.

[0021] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those skilled in the art.

[0022] When referring to a value, "about" includes the stated value + / - 10% of the stated value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to the stated value + / - 10% of each of the upper and lower limits of the stated range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3.

[0023] "Absorption enhancer" (AE) refers to a component that improves or facilitates mucosal absorption of a drug in the gastrointestinal tract, such as, but not limited to, a permeation enhancer (PE) or intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer is an agent intended to improve oral delivery of a therapeutic agent and help increase bioavailability. PEs can increase paracellular and / or transcellular passage of a drug. Pharmaceutical excipients that can increase permeation are referred to as "absorption modifying excipients" (AMEs). AMEs can be used in oral compositions, for example, as humectants (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogolglycerides), and can be included in compositions specifically as PEs to improve bioavailability. PEs can be classified according to how they alter barrier integrity via the paracellular or transcellular pathway. In this disclosure, the term "absorption enhancer" or AE is considered synonymous with the term "permeation enhancer" or PE.

[0024] "Administering" refers to administration of a composition of the present disclosure to a subject.

[0025] As used herein, "composition" is intended to encompass a product that includes a specific active product ingredient (API), as described herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in specific amounts, as defined, for example, throughout the originally filed disclosure, resulting from the combination of specific components, such as the specific ingredients in the specific amounts, as described herein.

[0026] "Intestinal permeation enhancer (IPE)" refers to a component that improves the bioavailability of a component that has poor bioavailability. Representative IPEs suitable for use in the present disclosure include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroid detergents, acylcarnitines and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, an IPE suitable for use in the present disclosure may be sodium caprate.

[0027] "Joint" or "joints" refers to the tissues that connect one bone to another in the human body. Examples of tissues encompassed by the term "joint" or "joints" include, but are not limited to, tendons, cartilage, ligaments, and synovial membranes. Synovial fluid adjacent to any of the above tissues is considered herein to be part of a "joint."

[0028] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds that function as lubricants can also have glidant properties. Examples of lubricants can include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0029] "Patient" or "subject" refers to a living organism, including, but not limited to, a human subject suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples can include, but are not limited to, humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, bovines, deer, horses, and other mammals. In some aspects, the patient is a human.

[0030] By "pharmaceutically acceptable" is meant that the carrier, diluent, or excipient must be compatible with the other components or ingredients of the compositions of the present disclosure, i.e., useful, safe, non-toxic, and acceptable for pharmaceutical use. According to the present disclosure, pharmaceutically acceptable means approved or approvable for use in animals, and more particularly in humans, as set forth in the L.S. Pharmacopoeia or other generally recognized pharmacopoeias.

[0031] The compositions or pharmaceutical compositions of the present disclosure may be in different pharmaceutically acceptable forms, including but not limited to liquid compositions, tablet or matrix compositions, capsule compositions, etc.

[0032] "Sodium caprate" or "NaC10" has the molecular formula C 10 H 19 It refers to NaO2 and the IUPAC compound sodium decanoate, which has the following structural formula:

[0033] [ka]

[0034] As used herein, "solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. This physical association involves varying degrees of bonding, including hydrogen bonding. In certain cases, the solvate will be isolable. The term "solvate" is intended to encompass both solution-phase solvates and isolable solvates. Non-limiting examples of suitable solvates include hydrates.

[0035] A "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or exhibiting a detectable therapeutic or inhibitory effect. A "therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of a particular drug, which refers to an amount sufficient to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the patient's general health, the patient's age, and the like. The exact amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 2000). th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0036] "Treat," "treating," and "treatment" are defined as the application or administration of a therapeutic agent, i.e., a compound or formulation of the present disclosure, to a patient having a disorder or disease described herein, a symptom thereof, or a likelihood of developing such a disorder or disease, or the application or administration of a therapeutic agent to isolated tissues or cell lines derived from a patient (e.g., for diagnostic or ex vivo applications), with the purpose of curing, curing, alleviating, mitigating, altering, curing, ameliorating, improving, or affecting the disorder or disease, a symptom thereof, or the likelihood of developing said disorder or disease. Such treatments may be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0037] As used herein, the term "prevent" or "prevention" means the complete absence of onset of a disorder or disease in cases where no onset of a disorder or disease has occurred, or the absence of further onset of a disorder or disease in cases where there has already been onset of a disorder or disease. The ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0038] As used in the specification and claims, the terms "comprise(s)", "comprising", "include(s)", "having", "has", "can", "contain(s)", and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of specified features, groups, components, or steps and do not preclude the presence of additional features, groups, components, or steps. For example, "the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -3Pya-X 16 -X 17The term "peptide of formula (A) containing (A)" refers to a peptide of formula (A) containing amino acids X3 to X 17 This means, but is not limited to, that the peptide may include, in addition to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N- or C-terminal capping groups, chemical or biological moieties conjugated to the peptide at any position (including, but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.). The terms "comprise(s)", "comprising", "include(s)", "having", "has", "can", or "contain(s)" can include embodiments encompassed by the terms "consisting essentially of" or "consisting of".

[0039] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and typically refer to molecules comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0040] Naturally occurring L-amino acids are represented by the conventional three-letter or single-letter uppercase amino acid symbols in Table 1. The corresponding D-amino acids are represented by the single-letter lowercase amino acid symbols or by preceding the three-letter or single-letter uppercase amino acid symbol in Table 1 with the letter "D" (e.g., r, dR, or D-Arg).

[0041] [Table 1]

[0042] As used herein, the term "L-amino acid" refers to the "L" isomeric form of an amino acid, and conversely, the term "D-amino acid" refers to the "D" isomeric form of an amino acid (e.g., (D)Asp or D-Asp, (D)Phe, or D-Phe). D-amino acids, when referred to using single-letter abbreviations, may conventionally be designated by a lowercase letter. For example, D-arginine may be designated as "arg" or "r". Alternatively, a lowercase "d" may be used in front of an amino acid to indicate its D isomeric form, for example, D-lysine may be designated as dK.

[0043] For less common or non-naturally occurring amino acids, when not referred to by their full name (e.g., sarcosine, ornithine, etc.), the frequently used three- or four-letter abbreviation for the residue is used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0044] The D-isomer form of an amino acid may be any of the positions in the IL-23R inhibitors described herein (e.g., X3 through X4 appearing in the molecule). 17 In some embodiments, the D-isomer form of an amino acid may be at any of X3, X5, X6, X8, X 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, X, and optionally one additional position. 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, and optionally one additional position. 13, and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally two or three additional positions. In other embodiments, the D-isomer form of an amino acid may be located only at positions X3 through X4 appearing in the IL-23R inhibitors described herein. 17 In other embodiments, the D-isomer form of an amino acid may be located at only one or two of positions X3 through X4 appearing in the IL-23R inhibitors described herein. 17 For example, positions X3 to X 15 The IL-23R inhibitors described herein may have the D-isomer form of the amino acid present at three or four of these positions. In other embodiments, the D-isomer form of the amino acid is present at positions X3 through X4 that appear in the IL-23R inhibitors described herein. 17 It can be located in only five or six of the

[0045] Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also contain additional groups that modify the amino acid chain, such as functional groups added by post-translational modifications. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation. The term "peptide" also includes peptides containing modifications of the amino and / or carboxy termini. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., lower alkyl is C1-C4 alkyl). The term "peptide" also includes modifications of amino acids between the amino and carboxy termini, such as, but not limited to, those described above.

[0046] As will be apparent to one of skill in the art, peptide sequences disclosed herein are presented from left to right, with the left-hand end of the sequence being the N-terminus of the peptide and the right-hand end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate either an "-OH" or an "-NH" moiety at the carboxy-terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "-OH" or "-NH" moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, respectively, corresponding to the presence of a carboxylic acid (COOH) or amide (CONH) group at the C-terminus. In each sequence of the present disclosure, the C-terminal "-NH" moiety may be substituted for a C-terminal "-OH" moiety, or vice versa.

[0047] As used herein, the phrases "amino acid," "amino acid residue," or "residue" refer to an amino acid, modified amino acid, amino acid analog, or amino acid mimetic that is incorporated into a peptide by an amide bond or amide bond mimetic.

[0048] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)," Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims deviate from these proposals, they will be made clear to the reader. In the amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-" or parentheses, e.g., lysine is designated as [K].

[0049] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when attached to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain; for example, one or more hydrogens may be removed or replaced upon attachment.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts, dashes at the beginning or end of chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in structures indicate the point of attachment of the group. Dashed lines indicate optional bonds. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or the point at which a chemical group is attached to the remainder of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, "arylalkyl" groups, for example, can be attached to the remainder of the molecule at either the aryl or alkyl portion of the group. "C u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

[0051] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon. For example, an alkyl group can be any group containing 1 to 10 carbon atoms (i.e., C1-C 10) alkyl), 1 to 5 carbon atoms (i.e., (C1-C5) alkyl), 1 to 4 carbon atoms (i.e., (C1-C4) alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3) alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2 CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10 CH3), and dodecyl (-(CH2) 11 In one embodiment, alkyl includes, but is not limited to, C (1~6) In another embodiment, alkyl refers to C (1~4) In another embodiment, alkyl refers to C (1~3) refers to alkyl.

[0052] The term "alkylene" refers to a divalent alkyl group. For example, an alkylene group can be an alkylene group having 1 to 10 carbon atoms (i.e., C1 to C6). 10(C1-C5) alkylene), 1 to 5 carbon atoms (i.e., (C1-C5) alkylene), 1 to 2 carbon atoms (i.e., (C1-C2) alkylene), or 1 carbon atom (i.e., (C1) alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), and the like.

[0053] Furthermore, within the scope of the present invention, particularly when referring to the peptides of the present disclosure or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, whether occurring in nature or synthetically produced, in either natural abundance or isotopically enriched form. For example, a reference to hydrogen includes within its scope: 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6) A group represented by alkyl includes not only -CH but also CD, not only CHCH but also CDCD, etc. Similarly, references to carbon and oxygen include, within their scope, respectively: 12 C. 13 C, and 14 C, and 15 O, and 16 O, and 17 O, and 18 These isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the present disclosure include: 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82The radioisotope may comprise a radioisotope selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 It is selected from the group F.

[0054] As used herein, the terms "lipophilic substituent," "lipid chain," and "lipid moiety" refer to a substituent containing 4 to 40 carbon atoms, 8 to 25 carbon atoms, or 12 to 22 carbon atoms. The lipophilic substituent may be attached to an amino group of a peptide (e.g., the ε-amino group of a lysine residue) through a carboxyl group of the lipophilic substituent. The lipophilic substituent may optionally include one or more spacers (e.g., a polyethylene glycol chain having two or more repeating —CHCHO— units or gamma-glutamic acid). In some embodiments, the lipophilic substituent comprises a straight-chain or branched-chain alkyl or alkylene group. In some embodiments, the lipophilic substituent is an acyl group of a straight-chain or branched-chain fatty acid.

[0055] As used herein, the term "lipidated peptide" refers to a peptide that includes one or more lipophilic substituents, as described herein. The lipophilic substituents of a lipidated peptide can be conjugated, for example, to the N-terminus, C-terminus, or side chain of an amino acid.

[0056] The abbreviation "(w / w)" refers to the phrase "weight for weight" or "weight by weight," i.e., the proportion of a particular substance in a mixture as measured by the weight or mass or amount of weight of a component of the composition relative to the amount of total weight of the compositions disclosed herein. Thus, the amount is unit-less or unitless and represents the weight percentage amount of the component relative to the total weight of the composition. For example, a 2% (w / w) solution means that 2 grams of solute are dissolved in 100 grams of solution.

[0057] A systemic route of administration, as conventionally understood in the medical or pharmaceutical arts, refers to or is defined as a route of administration in which a drug, pharmaceutical composition or formulation, or other substance enters the circulatory system, thereby exposing various body tissues and organs to the drug, formulation, or other substance. As conventionally understood in the art, administration can be oral (a drug or oral preparation is taken by mouth and absorbed via the gastrointestinal tract), enteral (drug absorption also occurs throughout the gastrointestinal tract), or parenteral (generally, by injection, infusion, or implantation, etc.).

[0058] "Systemically active" peptide drug therapy, in the context of this disclosure, generally refers to treatment with a pharmaceutical composition comprising a peptide active ingredient, where the peptide resists immediate metabolism and / or excretion, resulting in exposure of the peptide in various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous, or immune systems.

[0059] Systemic drug activity in this disclosure also refers to treatments using substances that travel throughout the bloodstream to reach and affect cells in various body tissues and organs. Systemically active drugs are transported to their site of action and act throughout the body to attack the physiological processes that cause inflammatory disease.

[0060] Bioavailability refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby accesses its site of action. The bioavailability of a drug is affected by the properties of the dosage form, which in turn depend in part on the design and manufacture of the dosage form.

[0061] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)," Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from these proposals, they will be made clear to the reader. In the amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by hyphens "-".

[0062] III.Compound The present disclosure relates to oral pharmaceutical formulations comprising one or more lipidated cyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) provided herein, or pharmaceutically acceptable salts thereof, and one or more enhancers provided herein.

[0063] Some embodiments relate to oral pharmaceutical formulations comprising an absorption enhancer and a lipidated peptide.

[0064] In some embodiments, the disclosure provides an oral pharmaceutical formulation comprising: (1) an absorption enhancer; and (2) a lipidated peptide comprising 9-20 amino acids, wherein the lipidated peptide is cyclized to form a ring, the ring comprising 4-14 amino acids, and the ratio of absorption enhancer to lipidated peptide is 50:1 (w / w) or less.

[0065] In some embodiments, the lipidated peptide comprises 12-16 amino acids. In some embodiments, the lipidated peptide comprises 13, 14, or 15 amino acids. In some embodiments, the lipidated peptide comprises 9 amino acids. In some embodiments, the lipidated peptide comprises 10 amino acids. In some embodiments, the lipidated peptide comprises 11 amino acids. In some embodiments, the lipidated peptide comprises 12 amino acids. In some embodiments, the lipidated peptide comprises 13 amino acids. In some embodiments, the lipidated peptide comprises 14 amino acids. In some embodiments, the lipidated peptide comprises 15 amino acids. In some embodiments, the lipidated peptide comprises 16 amino acids. In some embodiments, the lipidated peptide comprises 17 amino acids. In some embodiments, the lipidated peptide comprises 18 amino acids. In some embodiments, the lipidated peptide comprises 19 amino acids. In some embodiments, the lipidated peptide comprises 20 amino acids.

[0066] In some embodiments, the lipidated peptide is an inhibitor of the interleukin-23 receptor.

[0067] In some embodiments, the lipidated peptide comprises a helical structure.

[0068] In some embodiments, the lipidated peptide is cyclized to form a ring, and the ring contains 4 to 11 or 14 amino acids. In some embodiments, the ring contains 4 to 9 or 11 amino acids. In some embodiments, the ring contains 4, 6, or 10 amino acids. In some embodiments, the ring contains 4 amino acids. In some embodiments, the ring contains 6 amino acids. In some embodiments, the ring contains 10 amino acids.

[0069] In some embodiments, the lipidated peptide has the formula (A): R 1a -X3-X4-X5-X6-X7-X8-X9-X10 -X 11 -X 12 -X 13 -X 14 -3Pya-X 16 -X 17 -R 2a (A) the amino acid sequence of or a pharmaceutically acceptable salt thereof, wherein: R 1a is an N-terminal capping group (e.g., MeCO), Z peg , or Z 脂質 and X3 is any amino acid or is absent, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is any amino acid, X6 is any amino acid, X7 is 7MeW, W or absent; X8 is any amino acid, X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 AEF, TMAPF, AEF(d), TMAPF-Z 脂質 , APEG3F, or AEF-Z 脂質 and X 11 is any amino acid, X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 16 is any amino acid, X 17 is any amino acid or is absent, R 2a is a C-terminal capping group (e.g., CONH), CONH-Z peg , or CO-Z 脂質 and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The peptide comprises a bond between residues X4 and X9, The polypeptide is R1, X3, X5, X6, X8, X 10 , X 12 , X 13 , X 14 , X 16 , X 17 or R2.

[0070] In some embodiments, the lipidated peptide has the formula (A): R 1a -X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -3Pya-X 16 -X 17 -R 2a (A) the amino acid sequence of or a pharmaceutically acceptable salt thereof, wherein: R 1a MeCO, Z peg , Z 脂質 , succiniccarn, 5cpaCO, or AEEP-Z 脂質 and X3, R, KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is N, N(NMe2), K(d), KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X6, T, KZ 脂質 , NMeK-Z 脂質, or Dab-Z 脂質 and X7 is 7MeW, W or absent; X8 is K(Ac), K(d), K(NMeAc), Q, KZ 脂質 , K.Z. peg , NMeK-Z 脂質 , Dab-Z 脂質 , Dab(NMecarn), or Dab-Z peg and X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 AEF, TMAPF, AEF(d), TMAPF-Z 脂質 , APEG3F, or AEF-Z 脂質 and X 11 is a substituted or unsubstituted 2Nal or a substituted or unsubstituted 3Quin, X 12 THP, KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X 13 are E, K(Ac), K(d), KZ peg , K(NMeAc), Dab(NMecarn), E(OAll), KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X 14 , N, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X 16 are Sar, NMeK(d), and KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X 17 is KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R 2aare CONH2, CONMe2, and CONH-Z peg , or CO-Z 脂質 and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The peptide includes a bond between residues at X4 and X9.

[0071] In some embodiments, for Formula (A), X7 is a substituted or unsubstituted W. In some embodiments, X7 is 7(3NacPh)W, 7BrW, 7MeW, or W. In some embodiments, X7 is 7MeW.

[0072] In some embodiments, R 1a MeCO, Z peg , or Z 脂質 In some embodiments, X3 is r. In some embodiments, X4 is Pen. In some embodiments, X5 is N. In some embodiments, X6 is T. In some embodiments, X8 is K(Ac). In some embodiments, X9 is Pen. In some embodiments, X 10 is AEF. In some embodiments, X 10 is AEF-Z 脂質 In some embodiments, X 11 is a substituted or unsubstituted 2Nal, or a substituted or unsubstituted 3Quin. 11 is a substituted or unsubstituted 2Nal. In some embodiments, X 12 is THP. In some embodiments, X 12 is THP-Z 脂質 In some embodiments, X 13 is E. In some embodiments, X 13 is EZ 脂質 In some embodiments, X 14 is N. In some embodiments, X14 is NZ 脂質 In some embodiments, X 16 is Sar. In some embodiments, X 16 is NMeK(d). In some embodiments, X 16 is KZ 脂質 In some embodiments, X 16 Dab-Z 脂質 In some embodiments, X 16 is NMeK-Z 脂質 In some embodiments, X 17 is KZ 脂質 In some embodiments, X 17 Dab-Z 脂質 In some embodiments, X 17 is NMeK-Z 脂質 In some embodiments, X 17 is absent. In some embodiments, R 2a is CONH. In some embodiments, R 2a is CONMe. In some embodiments, R 2a is CONH-Z peg In some embodiments, R 2a CO-Z 脂質 is.

[0073] In some embodiments, the lipidated peptide has the formula (B): R 1a -X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -3Pya-X 16 -X 17 -R 2a (B) the amino acid sequence of or a pharmaceutically acceptable salt thereof, wherein: R 1a is an N-terminal capping group (e.g., MeCO), Z peg , or Z 脂質 and X3 is any amino acid or is absent, X4 is any amino acid, X5 is any amino acid, X6 is any amino acid, X7 is 7MeW or W, X8 is any amino acid, X9 is any amino acid, X 10 AEF, TMAPF, AEF(d), TMAPF-Z peg , TMAPF-Z 脂質 , APEG3F, AEF-Z peg , or AEF-Z 脂質 and X 11 is any amino acid, X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 16 is any amino acid, X 17 is any amino acid or is absent, R 2a is a C-terminal capping group (e.g., CONH), CONH-Z peg , or CO-Z 脂質 and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The polypeptide is R 1a ,X3,X4,X5,X6,X8,X9,X 10 , X 11 , X 12 , X 13 , X 14 , X 16 , X 17 , or R 2a and at least one lipophilic substituent or polyethylene glycol chain at a position selected from The peptide is cyclized to form a first ring, the first ring containing 4 to 14 amino acids.

[0074] In some embodiments of the peptide of formula (B), R 1a is an N-terminal capping group (e.g., MeCO), Z peg , or Z 脂質 and X3 is r, k(d), kZ 脂質 , dab-Z 脂質 , NMek-Z 脂質 or not present, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is E, N, N(NMe2), K(d), KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X6, T, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X7 is 7MeW or W, X8 is K(Ac), K(d), K(NMeAc), Q, KZ 脂質 , K.Z. peg , NMeK-Z 脂質 , Dab-Z 脂質 , Dab(NMecarn), or Dab-Z peg and X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 AEF, TMAPF, AEF(d), TMAPF-Z peg , TMAPF-Z 脂質 , APEG3F, AEF-Z peg , or AEF-Z 脂質 and X 11 is 2Nal or 6OH2Nal, X 12THP, KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X 13 are E, K(Ac), K(d), KZ peg , K(NMeAc), Dab(NMecarn), E(OAll), KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 and X 14 , N, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X 16 are Sar, NMeK(d), and KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X 17 is KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R 2a is a C-terminal capping group (e.g., CONH), CONH-Z peg , or CO-Z 脂質 and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The peptide comprises a bond between residues X4 and X9, The polypeptide is R 1a , X3, X5, X6, X8, X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , or R 2a or R 1a , X8, X 10 , X 13 , or R 2aThe polyethylene glycol chain is contained at a position selected from

[0075] In some embodiments of the peptide of formula (B), R 1a MeCO, Z peg , Z 脂質 , or 5 cpaCO X3 is r, k(d), kZ 脂質 , dab-Z 脂質 , NMek-Z 脂質 or not present, X4 is a Pen, X5 is E, N, N(NMe2), KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X6 is T, X7 is 7 MeW, X8 is K(Ac), K(d), K(NMeAc), KZ 脂質 , K.Z. peg , NMeK-Z 脂質 , Dab-Z 脂質 , or Dab-Z peg and The X9 is a Pen, X 10 AEF, TMAPF, APEG3F, AEF-Z peg , or AEF-Z 脂質 and X 11 is 2Nal or 6OH2Nal, X 12 is THP, X 13 are E, K(Ac), KZ peg , K(NMeAc), KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X 14 is N, X 16 is Sar or NMeK-Z 脂質 and X 17 is KZ脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R 2a are CONH2, CONMe2, and CONH-Z peg , or CO-Z 脂質 and the peptide contains a disulfide bond between residues X4 and X9, The polypeptide is R 1a , X3, X5, X8, X 10 , X 13 , X 16 , X 17 , or R 2a or R 1a , X8, X 10 , X 13 , or R 2a The polyethylene glycol chain is contained at a position selected from

[0076] In some embodiments of the peptide of formula (B), R 1a MeCO, Z peg , Z 脂質 , or 5 cpaCO. In some embodiments, R 1a is an N-terminal capping group. In some embodiments, R 1a is MeCO. In some embodiments, R 1a is 5 cpaCO. In some embodiments, R 1a is Z peg In some embodiments, R 1a is Z 脂質 is.

[0077] In some embodiments of the peptide of formula (B), X3 is r, k(d), kZ 脂質 , dab-Z 脂質 , NMek-Z 脂質 In some embodiments, X3 is r, k(d), or absent. In some embodiments, X3 is kZ 脂質 , dab-Z 脂質, or NMek-Z 脂質 In some embodiments, X3 is r. In some embodiments, X3 is k(d). In some embodiments, X3 is kZ 脂質 In some embodiments, X3 is dab-Z 脂質 In some embodiments, X3 is NMek-Z 脂質 In some embodiments, X3 is absent.

[0078] In some embodiments of a peptide of Formula (B), X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is C. In some embodiments, X4 is Dap. In some embodiments, X4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X4 is Pen(pXyl). In some embodiments, X4 is Pra.

[0079] In some embodiments of the peptide of formula (B), X5 is E, N, N(NMe2), K(d), KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X5 is E, N, N(NMe2), or K(d). In some embodiments, X5 is KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X5 is E. In some embodiments, X5 is N. In some embodiments, X5 is N(NMe2). In some embodiments, X5 is K(d). In some embodiments, X5 is KZ 脂質In some embodiments, X5 is Dab-Z 脂質 In some embodiments, X5 is NMeK-Z 脂質 is.

[0080] In some embodiments of the peptide of formula (B), X6 is T, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 In some embodiments, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 In some embodiments, X6 is T. In some embodiments, X6 is KZ. 脂質 In some embodiments, X6 is NMeK-Z 脂質 In some embodiments, X6 is Dab-Z 脂質 is.

[0081] In some embodiments of the peptide of Formula (B), X7 is 7MeW or W. In some embodiments, X7 is 7MeW. In some embodiments, X7 is W.

[0082] In some embodiments of the peptide of formula (B), X8 is selected from the group consisting of K(Ac), K(d), K(NMeAc), Q, KZ 脂質 , K.Z. peg , NMeK-Z 脂質 , Dab-Z 脂質 , Dab(NMecarn), or Dab-Z peg In some embodiments, X8 is K(Ac), K(d), K(NMeAc), Q, or Dab(NMecarn). In some embodiments, X8 is KZ peg , or Dab-Z peg In some embodiments, X8 is KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質In some embodiments, X8 is K(Ac). In some embodiments, X8 is K(d). In some embodiments, X8 is K(NMeAc). In some embodiments, X8 is Q. In some embodiments, X8 is KZ 脂質 In some embodiments, X8 is KZ peg In some embodiments, X8 is NMeK-Z 脂質 In some embodiments, X8 is Dab-Z 脂質 In some embodiments, X8 is Dab(NMecarn). In some embodiments, X8 is Dab-Z peg is.

[0083] In some embodiments of a peptide of Formula (B), X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3). In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is C. In some embodiments, X9 is D. In some embodiments, X9 is E. In some embodiments, X9 is hE. In some embodiments, X9 is Pen. In some embodiments, X9 is Dap. In some embodiments, X9 is Dap(N3).

[0084] In some embodiments of the peptide of formula (B), X 10 AEF, TMAPF, AEF(d), TMAPF-Z peg , TMAPF-Z 脂質 , APEG3F, AEF-Z peg , or AEF-Z 脂質 In some embodiments, X 10 is AEF, TMAPF, AEF(d), or APEG3F. In some embodiments, X 10 is TMAPF-Z peg , or AEF-Z peg In some embodiments, X 10 is TMAPF-Z 脂質 or AEF-Z脂質 In some embodiments, X 10 is AEF. In some embodiments, X 10 In some embodiments, X is TMAPF. 10 is AEF(d). In some embodiments, X 10 is TMAPF-Z peg In some embodiments, X 10 is TMAPF-Z 脂質 In some embodiments, X 10 In some embodiments, X is APEG3F. 10 is AEF-Z peg In some embodiments, X 10 is AEF-Z 脂質 is.

[0085] In some embodiments of the peptide of formula (B), X 11 is 2Nal or 6OH2Nal. In some embodiments, X 11 In some embodiments, X is 2Nal. 11 is 6OH2Nal.

[0086] In some embodiments of the peptide of formula (B), X 12 THP, KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X 12 is KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X 12 is THP. In some embodiments, X 12 is KZ 脂質 In some embodiments, X 12 Dab-Z 脂質 In some embodiments, X 12 is NMeK-Z 脂質 is.

[0087] In some embodiments of the peptide of formula (B), X 13 are E, K(Ac), K(d), KZ peg , K(NMeAc), Dab(NMecarn), E(OAll), KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 In some embodiments, X 13 is E, K(Ac), K(d), K(NMeAc), Dab(NMecarn), E(OAll). In some embodiments, X 13 is KZ リピド , Dab-Z リピド , NMeK-Z リピド In some embodiments, X 13 is E. In some embodiments, X 13 is K(Ac). In some embodiments, X 13 is K(d). In some embodiments, X 13 is KZ peg In some embodiments, X 13 is K(NMeAc). In some embodiments, X 13 is Dab(NMecarn). In some embodiments, X 13 is E(OAll). In some embodiments, X 13 is KZ 脂質 In some embodiments, X 13 Dab-Z 脂質 In some embodiments, X 13 is NMeK-Z リピド is.

[0088] In some embodiments of the peptide of formula (B), X 14 , N, KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 In some embodiments, X 14 is KZ 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 In some embodiments, X 14is N. In some embodiments, X 14 is KZ 脂質 In some embodiments, X 14 is NMeK-Z 脂質 In some embodiments, X 14 Dab-Z 脂質 is.

[0089] In some embodiments of the peptide of formula (B), X 16 are Sar, NMeK(d), and KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 In some embodiments, X 16 is Sar or NMeK(d). In some embodiments, X 16 is KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X 16 is Sar. In some embodiments, X 16 is NMeK(d). In some embodiments, X 16 is KZ 脂質 In some embodiments, X 16 Dab-Z 脂質 In some embodiments, X 16 is NMeK-Z 脂質 In some embodiments, X 16 does not exist.

[0090] In some embodiments of the peptide of formula (B), X 17 is KZ 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 In some embodiments, X 17 is KZ 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 In some embodiments, X 17 is KZ 脂質 In some embodiments, X17 Dab-Z 脂質 In some embodiments, X 17 is NMeK-Z 脂質 In some embodiments, X 17 does not exist.

[0091] In some embodiments of the peptide of formula (B), R 2a are CONH2, CONMe2, and CONH-Z peg , or CO-Z 脂質 In some embodiments, R 2a is a C-terminal capping group. In some embodiments, R 2a is CONH, CONMe. In some embodiments, R 2a is CONH-Z peg or CO-Z 脂質 In some embodiments, R 2a is CONH. In some embodiments, R 2a is CONMe. In some embodiments, R 2a is CONH-Z peg In some embodiments, R 2a CO-Z 脂質 is.

[0092] In some embodiments, X4 and X9 are linked via a disulfide bond.

[0093] In some embodiments, X4 is Abu and X9 is C. In some embodiments, X4 is Abu and X9 is aMeC. In some embodiments, X4 is Abu and X9 is Pen.

[0094] In some embodiments, X4 is C and X9 is C. In some embodiments, X4 is C and X9 is aMeC. In some embodiments, X4 is C and X9 is Pen.

[0095] In some embodiments, X4 is Pen and X9 is C. In some embodiments, X4 is Pen and X9 is aMeC. In some embodiments, X4 is Pen and X9 is Pen.

[0096] In some embodiments, X4 is aMeC and X9 is C. In some embodiments, X4 is aMeC and X9 is aMeC. In some embodiments, X4 is aMeC and X9 is Pen.

[0097] In some embodiments, X4 is Pen(oXyl) and X9 is C. In some embodiments, X4 is Pen(oXyl) and X9 is aMeC. In some embodiments, X4 is Pen(oXyl) and X9 is Pen.

[0098] In some embodiments, X4 is Pen(mXyl) and X9 is C. In some embodiments, X4 is Pen(mXyl) and X9 is aMeC. In some embodiments, X4 is Pen(mXyl) and X9 is Pen.

[0099] In some embodiments, X4 is Pen(pXyl) and X9 is C. In some embodiments, X4 is Pen(pXyl) and X9 is aMeC. In some embodiments, X4 is Pen(pXyl) and X9 is Pen.

[0100] In some embodiments, X4 is 4AminoPro and X9 is D. In some embodiments, X4 is 4AminoPro and X9 is E. In some embodiments, X4 is 4AminoPro and X9 is hE.

[0101] In some embodiments, X4 is Dap and X9 is D. In some embodiments, X4 is Dap and X9 is E. In some embodiments, X4 is Dap and X9 is hE.

[0102] In some embodiments, X4 is Pra and X9 is Dap(N3). In some embodiments, X4 is aG and X9 is aG.

[0103] In some embodiments, the peptide is cyclized via a bond between two amino acid residues (eg, at X4 and X9) having a structure selected from the following:

[0104] [Table 2-1]

[0105] [Table 2-2]

[0106] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9 having a structure selected from the following:

[0107] [Table 3]

[0108] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9 having the following structure:

[0109] [ka]

[0110] In some embodiments, the peptide comprises X and X having the structure: 10 This includes the bond between

[0111] [ka]

[0112] In some embodiments, the peptide is cyclized to form a first ring, and the first ring comprises 4 to 11 or 14 amino acids. In some embodiments, the first ring comprises 4 to 9 or 11 amino acids. In some embodiments, the first ring comprises 4, 6, or 10 amino acids. In some embodiments, the first ring comprises 4 amino acids. In some embodiments, the first ring comprises 5 amino acids. In some embodiments, the first ring comprises 6 amino acids. In some embodiments, the first ring comprises 7 amino acids. In some embodiments, the first ring comprises 8 amino acids. In some embodiments, the first ring comprises 9 amino acids. In some embodiments, the first ring comprises 10 amino acids. In some embodiments, the first ring comprises 11 amino acids. In some embodiments, the first ring comprises 14 amino acids.

[0113] In some embodiments, the first ring comprises a bond between two amino acids having a structure selected from the following:

[0114] [Table 4-1]

[0115] [Table 4-2]

[0116] [Table 4-3]

[0117] [Table 4-4]

[0118] [Table 4-5]

[0119] [Table 4-6]

[0120] In some embodiments, the first ring comprises a bond between the N-terminus of the peptide and an amino acid, which has a structure selected from the following:

[0121] [Table 5]

[0122] In some embodiments, the first ring is between X4 and X9, between X4 and X 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X3 and X 13 and between X6 and X9.

[0123] In some embodiments, the first ring is between X4 and X9, between X4 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and between X6 and X9.

[0124] In some embodiments, a first ring is formed between X4 and X9. In some embodiments, a first ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, a first ring is formed between X4 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0125] In some embodiments, the first ring is composed of X and X 13 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0126] In some embodiments, the first ring comprises X and X 10 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0127] In some embodiments, the first ring comprises X and X 13 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0128] In some embodiments, the first ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, the first ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0129] In some embodiments, the peptide is further cyclized to form a second ring, wherein the second ring comprises 4 to 14 amino acids. In some embodiments, the peptide is further cyclized to form a second ring, wherein the second ring comprises 4 to 11 or 14 amino acids. In some embodiments, the second ring comprises 4 to 9 or 11 amino acids. In some embodiments, the second ring comprises 4, 6, 10, or 11 amino acids. In some embodiments, the second ring comprises 4 amino acids. In some embodiments, the second ring comprises 5 amino acids. In some embodiments, the second ring comprises 6 amino acids. In some embodiments, the second ring comprises 7 amino acids. In some embodiments, the second ring comprises 8 amino acids. In some embodiments, the second ring comprises 9 amino acids. In some embodiments, the second ring comprises 10 amino acids. In some embodiments, the second ring comprises 11 amino acids. In some embodiments, the second ring comprises 14 amino acids.

[0130] In some embodiments, the second ring comprises a bond between two amino acids having a structure selected from the following:

[0131] [Table 6-1]

[0132] [Table 6-2]

[0133] [Table 6-3]

[0134] [Table 6-4]

[0135] [Table 6-5]

[0136] [Table 6-6]

[0137] In some embodiments, the second ring comprises a bond between the N-terminus of the peptide and an amino acid, which has a structure selected from the following:

[0138] [Table 7]

[0139] In some embodiments, the second ring is between X4 and X9, between X4 and X 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X3 and X 13 and between X6 and X9.

[0140] In some embodiments, the second ring is a ring consisting of X and X 10 Between or X3 and X 13In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 Between or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles. 10 Between or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 Between or X3 and X 13 It is formed between.

[0141] In some embodiments, a second ring is formed between X4 and X9. In some embodiments, a second ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. In some embodiments, a second ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0142] In some embodiments, the second ring is a ring formed from X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0143] In some embodiments, the second ring is a ring consisting of X and X 10 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0144] In some embodiments, the second ring is a ring consisting of X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0145] In some embodiments, a second ring is formed between X6 and X9. In some embodiments, a second ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, a second ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0146] In some embodiments, the second ring is X 13and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the N-terminus of the peptide.

[0147] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0148] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0149] In some embodiments, the first ring is connected to X and X via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. 13 and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 and between X6 and X9.

[0150] In some embodiments, the first ring is connected to X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 and between X6 and X9.

[0151] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0152] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0153] In some embodiments, the peptide comprises at least one polyethylene glycol chain, hi some embodiments, the peptide comprises no more than five, no more than four, no more than three, no more than two, or no more than one polyethylene glycol chain.

[0154] In some embodiments, each polyethylene glycol chain independently terminates in an ammonium group of a methyl group. In some embodiments, the polyethylene glycol chain terminates in an ammonium group. In some embodiments, the polyethylene glycol chain terminates in a methyl group.

[0155] In some embodiments, the peptide has the following structure:

[0156] [ka] and a polyethylene glycol chain having the formula: Z A is -OCH3, -N + (CH3)3,

[0157] [ka] and n is an integer from 2 to 24.

[0158] In some embodiments, the peptide has the following structure:

[0159] [ka] The polyethylene glycol chain has the formula:

[0160] In some embodiments, the peptide has the following structure:

[0161] [ka] and a polyethylene glycol chain having the formula: Z A -N + (CH3)3, n is an integer from 2 to 24.

[0162] In some embodiments, n is an integer from 2 to 15. In some embodiments, n is an integer from 2 to 5. 2. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 14. In some embodiments, n is 14. In some embodiments, n is 15.

[0163] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a polyethylene glycol chain.

[0164] Non-limiting examples of polyethylene glycol chains are provided in Table A.

[0165] [Table 8-1]

[0166] [Table 8-2]

[0167] [Table 8-3]

[0168] In some embodiments, the peptide comprises at least one lipophilic substituent. In some embodiments, the peptide comprises one lipophilic substituent. In some embodiments, the peptide comprises no more than three, no more than two, or no more than one lipophilic substituent. In some embodiments, the peptide comprises no more than one lipophilic substituent.

[0169] In some embodiments, the peptide has the following structure:

[0170] [ka] and a lipophilic substituent having the formula: Z B teeth,

[0171] [ka] and Z C is Z C1 , Z C2 , or Z C3 and Z C1 teeth,

[0172] [ka] and Z C2 teeth,

[0173] [ka] and Z C3 teeth,

[0174] [ka] and Z D teeth,

[0175] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa, independently for each occurrence,

[0176] [ka] and p is independently at each occurrence 0, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; v is 0 or 1, w is independently 0 or 1 at each occurrence.

[0177] In some embodiments, the peptide has the following structure:

[0178] [ka] and a lipophilic substituent having the formula: Z C2 teeth,

[0179] [ka] and ZD teeth

[0180] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa is

[0181] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; w is independently 0 or 1 at each occurrence.

[0182] In some embodiments, the peptide has the following structure:

[0183] [ka] The lipophilic substituent comprises:

[0184] In some embodiments, the peptide has the following structure:

[0185] [ka] The lipophilic substituent comprises:

[0186] In some embodiments, the peptide has the following structure:

[0187] [ka] The lipophilic substituent comprises:

[0188] In some embodiments, the peptide has the following structure:

[0189] [ka] The lipophilic substituent comprises:

[0190] In some embodiments, the peptide has the following structure:

[0191] [ka] The lipophilic substituent comprises:

[0192] In some embodiments, the peptide has the following structure:

[0193] [ka] The lipophilic substituent comprises:

[0194] In some embodiments, the peptide has the following structure:

[0195] [ka] and a lipophilic substituent having the formula: Z B teeth,

[0196] [ka] and Z C is Z C1 , Z C2 , or Z C3 and Z C1 teeth,

[0197] [ka] and Z C2 teeth,

[0198] [ka] and Z C3 teeth,

[0199] [ka] and Z D teeth,

[0200] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa, independently for each occurrence,

[0201] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; v is 0 or 1, w is independently 0 or 1 at each occurrence.

[0202] In some embodiments, the peptide has the following structure:

[0203] [ka] and a lipophilic substituent having the formula: Z C2 teeth,

[0204] [ka] and Z D teeth,

[0205] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa is

[0206] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; w is independently 0 or 1 at each occurrence.

[0207] In some embodiments, the peptide has the following structure:

[0208] [ka] The lipophilic substituent comprises:

[0209] In some embodiments, the peptide has the following structure:

[0210] [ka] The lipophilic substituent comprises:

[0211] In some embodiments, the peptide has the structure:

[0212] [ka] The lipophilic substituent comprises:

[0213] In some embodiments, the peptide has the following structure:

[0214] [ka] The lipophilic substituent comprises:

[0215] In some embodiments, the peptide has the following structure:

[0216] [ka] The lipophilic substituent comprises:

[0217] In some embodiments, the peptide has the following structure:

[0218] [ka] The lipophilic substituent comprises:

[0219] In some embodiments, Z c teeth,

[0220] [ka] is.

[0221] In some embodiments, Z D teeth,

[0222] [ka] is.

[0223] In some embodiments, Z D teeth,

[0224] [ka] is.

[0225] In some embodiments, Z E is —H. In some embodiments, Z E is —COOH. In some embodiments, Z E is tetrazolyl.

[0226] In some embodiments, Z F is —H. In some embodiments, Z F is -CH3.

[0227] In some embodiments, Xaa is independently at each occurrence:

[0228] [ka] is.

[0229] In some embodiments, Xaa is

[0230] [ka] is.

[0231] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0232] In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

[0233] In some embodiments, r is an integer between 10 and 20. In some embodiments, r is 10. In some embodiments, r is 11. In some embodiments, r is 12. In some embodiments, r is 13. In some embodiments, r is 14. In some embodiments, r is 15. In some embodiments, r is 16. In some embodiments, r is 17. In some embodiments, r is 18. In some embodiments, r is 19. In some embodiments, r is 20.

[0234] In some embodiments, w is 0. In some embodiments, w is 1.

[0235] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a lipophilic substituent.

[0236] In some embodiments, the lipophilic substituent is selected from Table B1.

[0237] [Table 9-1]

[0238] [Table 9-2]

[0239] [Table 9-3]

[0240] [Table 9-4]

[0241] [Table 9-5]

[0242] [Table 9-6]

[0243] [Table 9-7]

[0244] Further non-limiting examples of lipophilic substituents are provided in Table B2.

[0245] [Table 10-1]

[0246] [Table 10-2]

[0247] [Table 10-3]

[0248] [Table 10-4]

[0249] [Table 10-5]

[0250] [Table 10-6]

[0251] [Table 10-7]

[0252] [Table 10-8]

[0253] In some embodiments, the lipophilic substituent is selected from PEG2PEG2GolAC18OH, PEG2PEG2SP6gEC18OH, PEG2PEG6gEC18OH, PEG2PEG2gE(c)C18OH, PEG2PEG2gEC18OH, or PEG12gEC18OH.

[0254] In particular, the present disclosure relates to oral pharmaceutical formulations comprising lipidated cyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, wherein each lipidated cyclic peptide is a compound having a formula identified in Table 1.

[0255] [Table 11-1]

[0256] [Table 11-2]

[0257] [Table 11-3]

[0258] [Table 11-4]

[0259] [Table 11-5]

[0260] [Table 11-6]

[0261] Table 11-7

[0262] Table 11-8

[0263] Table 11-9

[0264] Table 11-10

[0265] Table 11-11

[0266] Table 11-12

[0267] Table 11-13

[0268] Table 11-14

[0269] Table 11-15

[0270] Table 11-16

[0271] Table 11-17

[0272] Table 11-18

[0273] Table 11-19

[0274] Table 11-20

[0275] Table 11-21

[0276] Table 11-22

[0277] Table 11-23

[0278] Table 11-24

[0279] Table 11-25

[0280] Table 11-26

[0281] Table 11-27

[0282] Table 11-28

[0283] Table 11-29

[0284] Table 11-30

[0285] Table 11-31

[0286] Table 11-32

[0287] Table 11-33

[0288] Table 11-34

[0289] Table 11-35

[0290] Table 11-36

[0291] Table 11-37

[0292] [Table 11-38]

[0293] [Table 11-39]

[0294] [Table 11-40]

[0295] In the peptide sequences shown above, when a particular residue is followed by a number in parentheses, that residue is linked to another residue in the sequence designated by the same number. For example, in the sequence MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-K(PEGNMegENMeC18OH)-CONH2 (SEQ ID NO: 40), the two Pen(3) residues are linked to each other.

[0296] synthesis The compounds or lipidated peptides described herein can be synthesized by a number of techniques known to those of skill in the art. In certain aspects, the monomer subunits are synthesized and purified using the techniques described in the accompanying Examples.

[0297] In some embodiments, the present disclosure provides methods of producing a compound of the present disclosure (or a monomeric subunit thereof), comprising chemically synthesizing a peptide having an amino acid sequence described herein, including, but not limited to, any of the amino acid sequences shown in Formulas I-V or the compounds of Table 1 herein. In some embodiments, a portion of the peptide is recombinantly synthesized instead of chemically synthesized. In some embodiments, the method of producing the compound further comprises cyclizing the compound precursor after the constituent subunits have been joined. In certain embodiments, cyclization is achieved via any of the various methods described herein.

[0298] The present disclosure may include, but is not limited to, polynucleotides and vectors (e.g., expression vectors) that encode portions of the amino acid sequences of the compounds described herein, e.g., in the accompanying Examples or Table 1.

[0299] The present disclosure further describes the synthesis of the lipid adduct compounds described herein, such as the compounds of Formulas I-V and Table 1.

[0300] In some embodiments, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked to one another to form a compound of the present disclosure.

[0301] In some embodiments, one or more of the amino acid residues or amino acid monomers are covalently linked to one another and lipidated at an intermediate oligomeric stage, followed by attachment of additional amino acids and cyclization to form the compounds of the present disclosure.

[0302] In some aspects, cyclic peptides are synthesized and then lipidated to form compounds of the present disclosure. Exemplary synthetic methods are described in the Examples.

[0303] The present disclosure further describes the synthesis of compounds described herein, such as compounds of Formulas I-V and those in Table 1. Exemplary synthetic methods are described in the Examples.

[0304] IV. Pharmaceutical Compositions In general, the present disclosure relates to oral pharmaceutical formulations comprising a lipidated peptide inhibitor of interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer, and methods and / or uses thereof for increasing the bioavailability of the lipidated peptide and / or for treating autoimmune inflammation and related diseases and disorders.

[0305] In one aspect, the present disclosure provides an oral pharmaceutical formulation comprising one or more inhibitors of the present disclosure, one or more absorption enhancers provided herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0306] The pharmaceutically acceptable carrier, diluent, or excipient may be a solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride.

[0307] The lipidated peptides of the present disclosure provided herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, in neutral form. Pharmaceutically acceptable salts are neutral, non-toxic salts of compounds that have the desired pharmacological activity in neutral form. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne, hexyne-1,4-diol, hexyne-2 ... Suitable pharmaceutically acceptable salts include benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0308] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + (wherein X is C1-C4 alkyl). Base addition salts such as sodium salts or potassium salts are also included.

[0309] The present disclosure relates to an oral pharmaceutical composition comprising an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and therefore may be useful for increasing the half-life of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0310] Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, can be useful in positron emission topography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0311] In some embodiments, the present disclosure provides an oral pharmaceutical formulation comprising an absorption enhancer provided herein and a lipidated peptide provided herein.

[0312] In some embodiments, the peptide in the oral pharmaceutical formulations provided herein comprises an amino acid sequence of Formula (A).

[0313] In some embodiments, the peptide in the oral pharmaceutical formulations provided herein comprises an amino acid sequence of Formula (B).

[0314] In some embodiments, the peptide in the oral pharmaceutical formulation provided herein is

[0315] [ka]

[0316] [ka] or a compound having the formula or a pharmaceutically acceptable salt or solvate form thereof; During the ceremony, L is -O-, -S-, or -SS-; R1, R2, R3, R4, R5, R6, R8, R9, and R 10 are each independently H, CH3, -C(=O)CH3, or -C(=O)NHR 11 ,

[0317] [ka] -C(=O)CH(R 12 )CONH2, R 14 , -(CH2) n NHR 12 , -(CH2) n C(=O)NHR 12 , -(CH2) n C(=O)OR 12 , -C(=O)(CH2)nNHR 12, or -C(=O)(CH2) n OR 12 and R7 is -(CH2) p NHR 13 or -(CH2) q NHC(=NH)NH2, each m, n, p, and q is independently 1, 2, 3, 4, or 5; Each R 11 , R 12 , R 13 , and R 14 is independently H or a lipid moiety.

[0318] In some embodiments, the peptide in the oral pharmaceutical formulation provided herein is

[0319] [ka] is a compound having the formula:

[0320] In some embodiments, the peptide in the oral pharmaceutical formulation provided herein is

[0321] [ka] is a compound having the formula:

[0322] In some embodiments, the peptide in the oral pharmaceutical formulation provided herein is

[0323] [ka] is a compound having the formula:

[0324] In some embodiments, each lipid moiety is independently selected from groups Z1-Z5: The Z1 is

[0325] [ka] wherein: PEG is -OCH2CH2-, n' is 0 or 2 to 24, and when n' is 0, this group does not exist and is replaced by a bond; m' is 0 or 2 to 24, and when m' is 0, this group does not exist and is replaced by a bond; v' is independently selected at each occurrence from the range of 1 to 4; v" is independently selected at each occurrence from the range of 0 to 4, and when v" is 0, the group is replaced by a bond; X is gE, dgE, 4SB, P, PPP, gE-(c), gE-(C), sp6, gDab, eK, Trx, or absent; o' is 6 to 18, Y is gE, sp6, GolA, Pro, D-Pro, meG, Dab, Trx, or absent; U is hydrogen or methyl; V is -COOH, tetrazole, GolB, mXOH, pXOH, O-phenyl, carnitine, d-carnitine, or hydrogen; The Z2 is

[0326] [ka] and During the ceremony, PEG is -OCH2CH2-, n' is 0 or 2 to 24, and when n' is 0, this group does not exist and is replaced by a bond; m' is independently selected at each occurrence from 0 or the range of 2 to 24, and when m' is 0, this group is replaced by a bond; v' is independently selected at each occurrence from the range of 1 to 4; v" is independently selected at each occurrence from the range of 0 to 4, and when v" is 0, the group is replaced by a bond; p' is 1 to 3; V' is sp6 or gEgE, X is gE, dgE, 4SB, P, PPP, gE-(c), gE-(C), sp6, gDab, eK, Trx, or absent; Y is gE, sp6, GolA, Pro, D-Pro, meG, Dab, Trx, or absent; X is Trx, U is hydrogen or methyl; o' is 6 to 18, V is -COOH, tetrazole, GolB, mXOH, pXOH, O-phenyl, carnitine, d-carnitine, or hydrogen; Z3 is -gE-C(O)(CH2) 6-10 CH3, or -gE-C(O)(CH2) 11-18 CH3, Z4 is -C(O)(CH2) 6-18 COOH or -C(O)(CH2) 6-18 COO(C1-4 alkyl), The Z5 is

[0327] [ka] wherein: n'' and m'' are independently selected from the range of 0 to 24; X is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx; Y is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx; Xaa is a diamino-carboxylic acid.

[0328] In some embodiments, each lipid moiety of a peptide in an oral pharmaceutical formulation provided herein is

[0329] [ka] wherein: ZB teeth,

[0330] [ka] and Z C is Z C1 , Z C2 , or Z C3 and Z C1 teeth,

[0331] [ka] and Z C2 teeth,

[0332] [ka] and Z C3 teeth,

[0333] [ka] and Z D teeth,

[0334] [ka] and Z E is -H, -COOH, phenoxy, or tetrazolyl; Z F is -H or -CH3, Xaa a is expressed independently for each occurrence,

[0335] [ka] and p a is independently 0, 1, 2, 3, 4, 5, or 6 for each occurrence; q a is 1, 2, 3, 4, 5, or 6, r a is an integer between 6 and 24, v a is 0 or 1, w a is independently 0 or 1 for each occurrence.

[0336] In some embodiments, the lipid moiety is one of a Peg moiety and a Peg-modified monomer as shown in Table 2D.

[0337] In some embodiments, R2 is methyl.

[0338] In some embodiments, R3 is H.

[0339] In some embodiments, R4 is H.

[0340] In some embodiments, R5 is H.

[0341] In some embodiments, R8 is H.

[0342] In some embodiments, R4 is H.

[0343] In some embodiments, R9 is H.

[0344] In some embodiments, R 10 is -C(=O)CH3.

[0345] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0346] [ka] It has the formula:

[0347] In some embodiments, R7 is -(CH2)q C(=O)NH)NH2. In some embodiments, q is 3.

[0348] In some embodiments, the compound is

[0349] [ka] It has the formula:

[0350] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0351] [ka] It has the formula (SEQ ID NO: 1).

[0352] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the formula of Formula II, wherein R6 is -C(=O)CH3. In some embodiments, R7 is -(CH2) p NHR 12 In some embodiments, p is 4.

[0353] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0354] [ka] It has the formula:

[0355] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0356] [ka] (SEQ ID NO: 2),

[0357] [ka] (SEQ ID NO: 3),

[0358] [ka] (SEQ ID NO: 4),

[0359] [ka] (SEQ ID NO: 5),

[0360] [ka] (SEQ ID NO: 6), or

[0361] [ka] (SEQ ID NO: 8).

[0362] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0363] [ka] It has the formula:

[0364] In some embodiments, R1 is

[0365] [ka] In some embodiments, m is 4.

[0366] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0367] [ka] (SEQ ID NO: 7).

[0368] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is

[0369] [ka] (SEQ ID NO: 2),

[0370] [ka] (SEQ ID NO: 3),

[0371] [ka] (SEQ ID NO: 4),

[0372] [ka] (SEQ ID NO: 5),

[0373] [ka] (SEQ ID NO: 6),

[0374] [ka] (SEQ ID NO: 8),

[0375] [ka] (SEQ ID NO: 1), or

[0376] [ka] (SEQ ID NO: 7).

[0377] In some embodiments, the peptide in the oral pharmaceutical formulations provided herein is selected from the group consisting of SEQ ID NOs: 1-40.

[0378] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate form thereof is present in the oral pharmaceutical compositions provided herein in an amount of about 0.1% to about 15% (w / w) of the oral pharmaceutical formulation. In some embodiments, the weight ratio (w / w) of the absorption enhancer to the compound or a pharmaceutically acceptable salt or solvate form thereof in the oral pharmaceutical compositions provided herein ranges from about 1 to about 200. In some embodiments, the weight ratio (w / w) of the absorption enhancer to the compound or a pharmaceutically acceptable salt or solvate form thereof ranges from about 1 to about 100. In some embodiments, the weight ratio (w / w) of the absorption enhancer to the compound or a pharmaceutically acceptable salt or solvate form thereof ranges from about 1 to about 20. In some embodiments, the weight ratio (w / w) of the absorption enhancer to the compound or a pharmaceutically acceptable salt or solvate form thereof ranges from about 1 to about 10.

[0379] In some embodiments, the ratio of absorption enhancer to lipidated peptide is 50:1 (w / w) or less. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 40:1 (w / w) or less. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 30:1 (w / w) or less. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 20:1 (w / w) or less.

[0380] In some embodiments, the ratio of absorption enhancer to lipidated peptide is 3:1 (w / w) or greater. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 5:1 (w / w) or greater. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 7:1 (w / w) or greater. In some embodiments, the ratio of absorption enhancer to lipidated peptide is 9:1 (w / w) or greater.

[0381] In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 3:1 (w / w) and 50:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 3:1 (w / w) and 30:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 4:1 (w / w) and 40:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 5:1 (w / w) and 50:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 3:1 (w / w) and 15:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 15:1 (w / w) and 30:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 30:1 (w / w) and 50:1 (w / w).

[0382] In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 5:1 (w / w) and 15:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is between 9:1 (w / w) and 11:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is about 10:1 (w / w).

[0383] In some embodiments, the ratio of absorption enhancer to lipidated peptide is about 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86: 5:1, 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, or 50:1 (w / w).

[0384] In some embodiments, the absorption enhancer is present in the formulation in an amount greater than 200 mg. In some embodiments, the absorption enhancer is present in the formulation in an amount greater than 250 mg. In some embodiments, the absorption enhancer is present in the formulation in an amount less than 1000 mg. In some embodiments, the absorption enhancer is present in the formulation in an amount less than 700 mg. In some embodiments, the absorption enhancer is present in the formulation in an amount between 200 mg and 1000 mg. In some embodiments, the absorption enhancer is present in the formulation in an amount between 250 mg and 700 mg.

[0385] In some embodiments, the absorption enhancer in the oral pharmaceutical compositions provided herein comprises one or more of sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acids, sucrose laurate, sodium octanoate, labrasol, and lauroyl-L-carnitine (LC). In some embodiments, the absorption enhancer comprises sodium salcaprozate (SNAC). In some embodiments, the absorption enhancer comprises lauroyl-L-carnitine (LC). In some embodiments, the absorption enhancer comprises sodium octanoate. In some embodiments, the absorption enhancer comprises sodium labrasol. In some embodiments, the absorption enhancer comprises sodium caprate. In some embodiments, the sodium caprate is present in an amount of about 1% to about 99% (w / w). In some embodiments, the sodium caprate has a purity of at least 98%.

[0386] In some embodiments, the oral pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients.

[0387] In some embodiments, the oral pharmaceutical formulation improves the oral bioavailability of the compound. In some embodiments, the oral pharmaceutical formulation improves the oral bioavailability of the compound by about 2 to about 500 fold. In some embodiments, the oral pharmaceutical formulation improves the oral bioavailability of the compound by about 2 to about 250 fold.

[0388] The present disclosure also provides a method for increasing the bioavailability of a compound in an oral pharmaceutical formulation provided herein in a subject, the method comprising orally administering the compound or a pharmaceutically acceptable salt or solvate thereof and an absorption enhancer. In some embodiments, the method includes orally administering the compound or a pharmaceutically acceptable salt or solvate thereof and an absorption enhancer, the absorption enhancer comprising one or more of sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acid, sucrose laurate, sodium octanoate, Labrasol, and lauroyl-L-carnitine (LC). In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof and the absorption enhancer are co-administered. In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof and the enhancer are co-administered in a pharmaceutically acceptable formulation provided herein.

[0389] The present disclosure also provides methods of using the oral pharmaceutical formulations provided herein for the preparation of a medicament for the treatment of an inflammatory disorder or an autoimmune inflammatory disorder. In some embodiments, the oral pharmaceutical formulations provided herein are used to treat multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis ulcerata ... vulgaris), or psoriatic erythroderma), atopic dermatitis, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease. In some embodiments, the disease or disorder is selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), and psoriatic arthritis (PsA).

[0390] The present disclosure also provides methods for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), comprising administering an effective amount of an oral pharmaceutical formulation provided herein. In some embodiments, the disease or disorder is associated with autoimmune inflammation. In some embodiments, the disease or disorder is multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis ulcerata ... vulgaris, or psoriatic erythroderma), atopic dermatitis, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease. In some embodiments, the disease or disorder is associated with ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

[0391] Generally, the oral pharmaceutical compositions of the present disclosure can be formed into different dosage forms prepared using conventional materials and techniques known in the fields of pharmacy and formulation, including, but not limited to, techniques such as mixing, blending, and the like, and as described throughout this disclosure. Furthermore, the pharmaceutical compositions used to form dosage forms can also include, but are not limited to, suitable adjuvants, carriers, excipients, stabilizers, and the like, and can be in solid or liquid form, such as, but not limited to, solid or liquid dosage forms, which can include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions. According to the present disclosure, the solid unit dosage form can be of other conventional types known in the art.

[0392] Additionally, liquid solutions are suitable for use in the present disclosure, and can be in, for example, but not limited to, water, saline, aqueous dextrose and related sugar solutions, and glycol buffers, such as propylene glycol or polyethylene glycol, buffers, and the like, which are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0393] Oral pharmaceutical compositions of the present disclosure may contain a variety of other pharmaceutically acceptable components or excipients, including, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients, such as those described herein.

[0394] In some aspects, the oral pharmaceutical compositions of the present disclosure may not include or may exclude the use of an absorption enhancer, depending on the intended delivery or use of the absorption enhancer and / or for the treatment of a particular indication as defined in this disclosure.

[0395] In other aspects, suitable oral pharmaceutical compositions of the present disclosure may exhibit improved bioavailability when administered with absorption enhancers, such as, but not limited to, intestinal permeation enhancers.

[0396] In some aspects, the oral pharmaceutical compositions of the present disclosure may include an absorption or permeation enhancer. When present, the absorption or permeation enhancer may be, but is not limited to, the following forms: zwitterionic, cationic, anionic, or nonionic. In one aspect, the absorption or permeation enhancer is an intestinal permeation or absorption enhancer. In some aspects, the absorption enhancer may be selected from, but is not limited to, medium-chain saturated fatty acids such as caprate, caprylate, myristate, palmitate, or stearate, including salt forms such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate.

[0397] Other absorption or permeation enhancers include citric acid or citrates, such as sodium citrate, tartaric acid or tartrates, salicylic acid or its derivatives or salicylates, fatty acid acylated amino acids, alkyl saccharides, C8-o alkyl polysaccharides, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose coconut, sucrose monododecanoate, mono sucrose monophosphate, sucrose monoisopropyl ether ... Sucrose tridecanoate, sucrose monotetradecanoate, coco-glucoside, cyclodextrin, alkanoylcarnitines such as lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine, lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride, fatty acid acylated amino acids such as, but not limited to, sodium lauroylalaninate, N-dodecanoyl-L-alanine, sodium lauroylasparaginate, N-dodecanoyl-L-asparagine, sodium lauroylaspartate , N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl propionate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate,N-Dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-Dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-Dodecanoyl-L-sarcosine, sodium caprylate alaninate, N-Decanoyl-L-alanine, sodium caprylate asparaginate, N-Decanoyl-L-asparagine, sodium caprylate aspartate, N-Decanoyl-L-aspartic acid, caprate cysteine Sodium caprate, N-decanoyl-L-cysteine, sodium caprylate glutamate, N-decanoyl-L-glutamic acid, sodium caprylate glutaminate, N-decanoyl-L-glutamine, sodium caprylate glycinate, N-decanoyl-L-glycine, sodium caprylate histidinate, N-decanoyl-L-histidine, sodium caprylate isoleucinate, N-decanoyl-L-isoleucine, caprine Sodium caprylate leucinate, N-decanoyl-L-leucine, sodium caprylate methioninate, N-decanoyl-L-methionine, sodium caprylate phenylalaninate, N-decanoyl-L-phenylalanine, sodium caprylate propionate, N-decanoyl-L-proline, sodium caprylate serinate, N-decanoyl-L-serine, sodium caprylate threoninate, N-decanoyl-L-threonine, sodium caprylate tryptophanate, N-decanoyl-L-tryptophan, sodium caprylate tyrosinate, N-decanoyl-L-tyrosine, sodium caprylate valinate, N-decanoyl-valine, sodium caprylate sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decyl leucine, sodium stearoyl glutamate (e.g., from Amisoft HS-11P), sodium myristoyl glutamate (e.g., Amisoft MS-11), sodium lauroyl glutamate (e.g., Amisoft LS-11), sodium cocoyl glutamate (e.g., Amisoft CS-11), sodium cocoyl glycinate (e.g., Am lite GCS-11), sodium N-decyl leucine, sodium cocoyl glycinate, sodium cocoyl glutamate,Sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, la Sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl propionate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, lauroyl Sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium caprylate alaninate, N-decanoyl-L-alanine, sodium caprylate asparaginate, N-decanoyl-L-asparagine, sodium caprylate aspartate, N-decanoyl N-decanoyl-L-aspartic acid, capric acid cysteine ​​sodium, N-decanoyl-L-cysteine, capric acid glutamic acid sodium, N-decanoyl-L-glutamic acid, capric acid glutamic acid sodium, N-decanoyl-L-glutamine, capric acid glycinate sodium, N-decanoyl-L-glycine, capric acid histidinate sodium, N-decanoyl-L-histidine, capric acid isoleucinate sodium, N-decanoyl-L-isoleucine, capric acid leucinate sodium, N-decanoyl-L-leucine,Sodium caprylate methioninate, N-decanoyl-L-methionine, sodium caprylate phenylalaninate, N-decanoyl-L-phenylalanine, sodium caprylate prolinate, N-decanoyl-L-proline, sodium caprylate serinate, N-decanoyl-L-serine, sodium caprylate threoninate, N-decanoyl-L-threonine, sodium caprylate tryptophanate, N-decanoyl-L-tryptophan, sodium caprylate tyrosinate, N-decanoyl-L-tyrosinate cin, capric acid sodium valinate, N-decanoyl-L-valine, capric acid sodium sarcosinate, oleoyl sodium sarcosinate, and pharmaceutically acceptable salts of any of the above compounds; or alkanoyl sarcosinates (e.g., lauroyl sarcosinates such as sodium lauroyl sarcosinate), or one of the 20 standard proteinogenic alpha-amino acids acylated with a C8-C20 alkanoic acid, an alkyl saccharide (e.g., Multitrope™ 1620-LQ -(MV); or n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, cocoglucoside, alkyl saccharides, cyclodextrins (e.g., alpha-cyclodextrins), cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino]caprylic acid, N-[8-(2-hydroxybenzoyl)amino]caprylate, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also known as "SNAC"), calcium chelating compounds (e.g., ethylenediaminetetraacetic acid (EDTA), cremophor EL (also known as "Kolliphor EL"),CAS No. 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, or alkanol (e.g., ethanol, decanol), caprylocaproyl polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride, available as LABRASOL® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C-2o alkyl acrylate The surfactant may include, but is not limited to, amine, C8-C20 alkenylamine (e.g., oleylamine), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (e.g., polysorbate 80), cholic acid (or cholate salts, e.g., sodium cholate), deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, or decyldimethylammoniopropanesulfonate.

[0398] In some embodiments, absorption or permeation enhancers may include, but are not limited to, sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acid (e.g., LABRASOL®, available from Gattefosse, USA), sucrose laurate, or lauroyl-L-carnitine (LC, e.g., PEPTELLIGENCE®, available from Enteris BioPharma, NJ, USA). In some embodiments, the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acids, sucrose laurate, or lauroyl-L-carnitine (LC). In some embodiments, the absorption or permeation enhancer can be polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acids.

[0399] In other embodiments, the absorption or permeation enhancer used may be sulcaprozate sodium. In some embodiments, the absorption or permeation enhancer used may include, but is not limited to, polyethylene glycol (PEG)-modified medium-chain fatty acid triglycerides of capric and caprylic acids.

[0400] In some aspects, the absorption or permeation enhancer used in the compositions of the present disclosure can be, but is not limited to, sodium caprate.

[0401] In another aspect, the present disclosure provides an oral pharmaceutical composition comprising an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt or solvate form thereof, in an amount of about 0.1% to about 15% (w / w) of the composition.

[0402] In some embodiments, sodium caprate may be present in the composition in an amount of about 1% to about 99% (w / w) of the composition.

[0403] In one embodiment, for use in the oral pharmaceutical compositions of the present disclosure, sodium caprate can have a purity of at least 98%, 98.2%, 98.4%, 98.6%, 98.8%, 99.0%, 99.5%, or at least 99.9%. Without being bound by any theory, higher purity sodium caprate can provide improved bioavailability compared to lower technical grade sodium caprate, e.g., sodium caprate of 90% or 95% purity. In some embodiments, sodium caprate for use in the present disclosure has a purity of at least 98%.

[0404] In another embodiment, sodium caprate can be present in any form adapted for use in the oral pharmaceutical compositions of the present disclosure. In some embodiments, sodium caprate can be in crystalline, amorphous, or semi-crystalline form. In some embodiments, the use of crystalline sodium caprate can enhance the bioavailability of the IL-23R inhibitors of the present disclosure. In some embodiments, the use of amorphous sodium caprate can enhance the bioavailability of the IL-23R inhibitors of the present disclosure. In some embodiments, the use of semi-crystalline sodium caprate can enhance the bioavailability of the IL-23R inhibitors of the present disclosure.

[0405] In some embodiments, the use of crystalline sodium caprate may enhance the bioavailability of the disclosed IL-23R inhibitors or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the use of amorphous sodium caprate may enhance the bioavailability of the disclosed IL-23R inhibitors or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the use of semi-crystalline sodium caprate may enhance the bioavailability of the disclosed IL-23R inhibitors or pharmaceutically acceptable salts or solvates thereof.

[0406] In some embodiments, the peptide has SEQ ID NO: 1. In some embodiments, the peptide has SEQ ID NO: 2. In some embodiments, the peptide has SEQ ID NO: 3. In some embodiments, the peptide has SEQ ID NO: 4. In some embodiments, the peptide has SEQ ID NO: 5. In some embodiments, the peptide has SEQ ID NO: 6. In some embodiments, the peptide has SEQ ID NO: 7. In some embodiments, the peptide has SEQ ID NO: 8.

[0407] V. Methods of Treatment and / or Use In one aspect, the present disclosure relates to a method or use for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein. In some aspects, the present disclosure provides a method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein. Inflammatory diseases suitable for treatment with a formulation or composition of the present disclosure may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA).

[0408] In some aspects, the present disclosure provides methods or uses for treating a subject suffering from a condition or indication associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject a composition of the present disclosure. In some aspects, methods or uses for treating a subject suffering from a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the individual a composition of the present disclosure in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. In some aspects, the inhibition of IL-23 binding to IL-23R occurs specifically in a particular organ or tissue of the subject, for example, the organ or tissue includes, but is not limited to, organs such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0409] In some embodiments, the methods or uses of the present disclosure can comprise providing a composition of the present disclosure to a subject in need thereof, hi some embodiments, the subject in need thereof has been diagnosed or determined to be at risk for developing an IL-23 / IL-23R-associated disease or disorder.

[0410] Each aspect of the disclosure defined in this section or any other section may incorporate definitions and limitations, such as those set forth in Sections I-V of this specification, as well as those set forth throughout the originally filed disclosure, specification, and claims. [Example]

[0411] The following examples illustrate the present invention. These examples are not intended to limit the scope of the disclosure, but rather to provide guidance to those skilled in the art for preparing and using the disclosed compounds, compositions, and methods. Although specific embodiments of the disclosure have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the present invention.

[0412] Some abbreviations useful in describing this invention are defined below in Tables 2A-2G.

[0413] [Table 12-1]

[0414] [Table 12-2]

[0415] [Table 12-3]

[0416] [Table 12-4]

[0417] [Table 12-5]

[0418] [Table 12-6]

[0419] [Table 12-7]

[0420] [Table 13]

[0421] Table 14-1

[0422] Table 14-2

[0423] Table 14-3

[0424] Table 14-4

[0425] Table 14-5

[0426] Table 14-6

[0427] Table 14-7

[0428] Table 14-8

[0429] Table 14-9

[0430] Table 14-10

[0431] Table 14-11

[0432] Table 14-12

[0433] Table 14-13

[0434] Table 14-14

[0435] Table 14-15

[0436] Table 14-16

[0437] Table 14-17

[0438] Table 14-18

[0439] Table 14-19

[0440] Table 14-20

[0441] Table 14-21

[0442] Table 14-22

[0443] Table 14-23

[0444] Table 14-24

[0445] Table 14-25

[0446] Table 14-26

[0447] Table 14-27

[0448] Table 14-28

[0449] Table 14-29

[0450] Table 14-30

[0451] Table 14-31

[0452] Table 14-32

[0453] Table 14-33

[0454] Table 14-34

[0455] Table 14-35

[0456] Table 14-36

[0457] Table 14-37

[0458] Table 14-38

[0459] Table 14-39

[0460] Table 14-40

[0461] Table 14-41

[0462] Table 14-42

[0463] Table 14-43

[0464] Table 14-44

[0465] Table 14-45

[0466] Table 14-46

[0467] Table 14-47

[0468] Table 14-48

[0469] Table 14-49

[0470] Table 14-50

[0471] Table 14-51

[0472] Table 14-52

[0473] Table 14-53

[0474] Table 14-54

[0475] Table 14-55

[0476] Table 14-56

[0477] Table 14-57

[0478] Table 14-58

[0479] Table 14-59

[0480] Table 14-60

[0481] [Table 14-61]

[0482] [Table 14-62]

[0483] [Table 14-63]

[0484] In some embodiments, both naturally occurring L-amino acids and D-amino acids are represented by either the conventional three-letter or uppercase single-letter amino acid symbols in Table 2C-a. In some embodiments, D-amino acids are represented by lowercase single-letter amino acid symbols corresponding to the single-letter symbols in Table 2C or Table 2C-a, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0485] [Table 15]

[0486] As used herein, the term "L-amino acid" refers to the "L" isomeric form of an amino acid, and conversely, the term "D-amino acid" refers to the "D" isomeric form of an amino acid (e.g., (D)Asp or D-Asp, (D)Phe, or D-Phe). Any L-amino acid residue may be substituted with the D-isomer form of the amino acid residue, so long as the peptide retains the desired function. D-amino acids, when referred to using single-letter abbreviations, may by convention be designated by a lowercase letter. For example, D-arginine may be designated as "arg" or "r". Alternatively, a lowercase "d" may be used before an amino acid to indicate its D-isomer form, for example, D-lysine may be designated as dK.

[0487] For less common or non-naturally occurring amino acids, when not referred to by their full name (e.g., sarcosine, ornithine, etc.), the frequently used three- or four-letter abbreviation for the residue is used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0488] Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also contain additional groups that modify the amino acid chain, such as functional groups added by post-translational modifications. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation. The term "peptide" also includes peptides containing modifications of the amino and / or carboxy termini. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., lower alkyl is C1-C4 alkyl). The term "peptide" also includes modifications of amino acids between the amino and carboxy termini, such as, but not limited to, those described above.

[0489] [Table 16-1]

[0490] [Table 16-2]

[0491] Table 16-3

[0492] Table 16-4

[0493] Table 16-5

[0494] Table 16-6

[0495] Table 16-7

[0496] Table 16-8

[0497] Table 16-9

[0498] Table 16-10

[0499] Table 16-11

[0500] Table 16-12

[0501] Table 16-13

[0502] Table 16-14

[0503] Table 16-15

[0504] Table 16-16

[0505] Table 16-17

[0506] Table 16-18

[0507] Table 16-19

[0508] Table 16-20

[0509] Table 16-21

[0510] Table 16-22

[0511] Table 16-23

[0512] Table 16-24

[0513] Table 16-25

[0514] Table 16-26

[0515] Table 16-27

[0516] Table 16-28

[0517] Table 16-29

[0518] Table 16-30

[0519] Table 16-31

[0520] Table 16-32

[0521] Table 16-33

[0522] Table 16-34

[0523] Table 16-35

[0524] Table 16-36

[0525] Table 16-37

[0526] Table 16-38

[0527] Table 16-39

[0528] Table 16-40

[0529] Table 16-41

[0530] Table 16-42

[0531] Table 16-43

[0532] Table 16-44

[0533] Table 16-45

[0534] Table 16-46

[0535] Table 16-47

[0536] Table 16-48

[0537] Table 16-49

[0538] Table 16-50

[0539] Table 16-51

[0540] Table 16-52

[0541] Table 16-53

[0542] Table 16-54

[0543] Table 16-55

[0544] Table 16-56

[0545] Table 16-57

[0546] Table 16-58

[0547] Table 16-59

[0548] Table 16-60

[0549] Table 16-61

[0550] Table 16-62

[0551] Table 17-1

[0552] [Table 17-2]

[0553] [Table 18]

[0554] The amino acid structures provided in Table 2G below are presented without a stereochemical designation at the alpha carbon. However, it is understood that these amino acids exist as either L- or D-amino acids. For example, "Dap" represents the L-stereoisomer:

[0555] [ka] or the D-stereoisomer (e.g., when referred to as "dap," "dDap," or "D-Dap"):

[0556] [ka] may be present in the peptides of the present disclosure as

[0557] [Table 19-1]

[0558] [Table 19-2]

[0559] [Table 19-3]

[0560] [Table 19-4]

[0561] [Table 19-5]

[0562] [Table 19-6]

[0563] Example 1. HOC18gEPEG2PEG2-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (disulfide bond formation) (SEQ ID NO: 1)

[0564] [ka]

[0565] Synthesis of intermediate 1-1 Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (110 μmol, 100–200 mesh; loading 0.33 mmol / g) in a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, the side-chain protecting groups were tert-butyl for Thr and Glu, trityl for Pen and Asn, tert-butoxycarbonyl for AEF, and Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg. All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were performed using a 5-fold excess of activated amino acid over the resin's free amino groups at 90 °C for 3 min under microwave irradiation. Amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Double acylation reactions were performed for 3Pya and 2Nal. Fmoc deprotection was performed using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was performed manually (PEG2, PEG2, and gE (Fmoc-Glu-OtBu) residues) using DIC-HOAT (6 equivalents, 1:1:1) at room temperature. C18OH (18-(tert-butoxy)-18-oxooctadecanoic acid) was coupled at room temperature using DIC-HOAT (6 equivalents, 1:1:1), and complete acylation was monitored by the ninhydrin test.

[0566] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 15 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give the desired intermediate 1-1 (78.1% yield). 132 H 200 N 28 O 33 LCMS analysis for S2 calculated: 2771.32, found: 924.7 (M+3) 3+ .

[0567] HOC18gEPEG2PEG2-r-Pen * -NT-7MeW-K(Ac)-Pen * Synthesis of -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 1) Intermediate 1-1 was dissolved in ACN / H2O (1 mg / ml). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 × 40 mm, 300 Å, 15 μm). Mobile phase A: + 0.1% TFA, mobile phase B: acetonitrile (ACN) + 0.1% TFA. The following gradient of eluent B was used: 25% B over 5 min to 25% B over 25 min to 40% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (22% yield). C 132 H 198 N 28 O 33LCMS analysis for S2 calculated: 2769.32, found: 1386.1 (M+2) 2+ .

[0568] Example 2. MeCO-k(PEGPEGGolACOH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 2)

[0569] [ka]

[0570] The compounds were prepared according to the same procedure as in Example 1, etc. The compound of SEQ ID NO: 2 was prepared. 141 H 217 N 28 O 35 S2 + LCMS analysis calculated: 2771.33, found: 1386.55 (M+2) 2+ .

[0571] Example 3. MeCO-k(PEGPEGSP6gECOH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 3)

[0572] [ka]

[0573] Synthesis of intermediate 3-1 Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (110 μmol, 100-200 mesh; loading 0.34 mmol / g) in a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, side-chain protecting groups were tert-butyl for Thr and Glu, trityl for Pen and Asn, and tert-butoxycarbonyl for AEF. The N-terminal D-Lys was protected with an orthogonal DDe protecting group.

[0574] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90 °C for 3 min under MW irradiation using a 5-fold excess of activated amino acids relative to the resin's free amino groups. Amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Double acylation reactions were carried out for 3 Pya and 2 Nal. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was carried out manually using 10 equivalents of acetic anhydride in DMF.

[0575] At the end of the solid-phase peptide assembly, the resin was treated with 100 mL of a 3% hydrazine solution in DMF. The solution was drained, and the resin was washed with DCM (3 × 5 mL) and DMF (5 × 5 mL). Further side-chain derivatization was performed manually at room temperature using DIC-HOAT (3 equiv., 1:1:1) (PEG2, PEG2, Fmoc-SP6 ((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N-(carboxymethyl)-N,N-dimethylethan-1-aminium), and gE (Fmoc-Glu-OtBu) residues). C18OH (18-(tert-butoxy)-18-oxooctadecanoic acid) was coupled at room temperature using DIC-HOAT (6 equiv., 1:1:1), and complete acylation was monitored by the ninhydrin test.

[0576] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 15 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give the desired intermediate 3-1 (80% yield). C140H215N28O35S2+ LCMS analysis calculated: 2914.52, found: 972.5 (M+3). 3+ .

[0577] MeCO-k(PEG2PEG2SP6gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * Synthesis of -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 3) Intermediate 3-1 was dissolved in ACN / H2O (1 mg / ml). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 x 40 mm, 300 Å, 15 μm). Mobile phase A: +0.1% TFA, mobile phase B: acetonitrile (ACN) +0.1% TFA. The following gradient of eluent B was used: 25% B over 5 min to 25% B over 25 min to 40% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (35% yield). C 140 H 213 N 28 O 35 S2 + LCMS analysis calculated: 2912.52, found: 1456.6 (M+2) 2+ .

[0578] Example 4. MeCO-k(PEGPEGECOH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 4)

[0579] [ka]

[0580] Synthesis of intermediate 4-1 Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (110 μmol, 100-200 mesh; loading 0.33 mmol / g) in a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, side-chain protecting groups were tert-butyl for Thr, trityl for Pen and Asn, and tert-butoxycarbonyl for AEF. The N-terminal D-Lys was protected with an orthogonal DDe protecting group.

[0581] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90 °C for 3 min under MW irradiation using a 5-fold excess of activated amino acids relative to the resin's free amino groups. Amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Double acylation reactions were performed for 3 Pya and 2 Nal. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was performed manually using 10 equivalents of acetic anhydride in DMF. At the end of solid-phase peptide assembly, the resin was treated with 100 mL of a 3% hydrazine solution in DMF. The solution was drained, and the resin was washed with DCM (3 × 5 mL). The deprotection step was repeated, followed by washing the resin with DCM (5 × 5 mL) and DMF (5 × 5 mL). Further side chain derivatization was performed manually (PEG2, PEG2, and gE (Fmoc-Glu-OtBu) residues) using DIC-HOAT (3 equiv., 1:1:1) at room temperature. C18OH (18-(tert-butoxy)-18-oxooctadecanoic acid) was coupled using DIC-HOAT (6 equiv., 1:1:1) at room temperature, and complete acylation was monitored by the ninhydrin test.

[0582] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 15 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give the desired intermediate 4-1 (89% yield). C 134 H 202 N 26 O 34 LCMS analysis for S2 calculated: 2785.3, found: 1393.4 (M+2) 2+ .

[0583] MeCO-k(PEG2PEG2gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 4) Intermediate 4-1 was dissolved in ACN / HO (5 mg / ml). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 × 40 mm, 300 Å, 15 μm). Mobile phase A: + 0.1% TFA, mobile phase B: acetonitrile (ACN) + 0.1% TFA. The following gradient of eluent B was used: 25% B over 5 min to 25% B over 25 min to 40% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (28% yield): C 134 H 200 N 26 O 34 LCMS analysis for S2 calculated: 2783.34, found: 1392.4 (M+2) 2+ .

[0584] Example 5. MeCO-k(PEG2PEG6gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 5)

[0585] [ka]

[0586] The compound of SEQ ID NO: 5 was prepared according to a procedure similar to that used to prepare Example 1, etc. The compound of SEQ ID NO: 5 was prepared in 13% yield. 141 H 217 N 28 O 35 S2 + LCMS analysis calculated: 2973.58, found: 1487.5 (M+2) 2+ .

[0587] Example 6. MeCO-k(PEGPEGgE(c)C18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 6)

[0588] [ka]

[0589] Synthesis of intermediate 6-1 Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (110 μmol, 100-200 mesh; loading 0.33 mmol / g) in a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, side-chain protecting groups were tert-butyl for Thr and Glu, trityl for Pen and Asn, and tert-butoxycarbonyl for AEF. D-Lys was protected with the orthogonal DDe protecting group.

[0590] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90 °C for 3 min under MW irradiation using a 5-fold excess of activated amino acids relative to the resin's free amino groups. Amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Double acylation reactions were carried out for 3 Pya and 2 Nal. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was carried out manually using 10 equivalents of acetic anhydride in DMF. At the end of solid-phase peptide assembly, the resin was treated with 100 mL of a 3% hydrazine solution in DMF. The solution was drained, and the resin was washed with DCM (5 × 5 mL) and DMF (5 × 5 mL). Further side chain derivatization was performed manually using DIC-HOAT (3 equivalents, 1:1:1) at room temperature (PEG2, PEG2, and gE ((S,E)-4-((Fmoc)amino)-5-oxo-5-(prop-1-en-1-yloxy)pentanoic acid) residues). C18OH (18-(tert-butoxy)-18-oxooctadecanoic acid) was coupled at room temperature using DIC-HOAT (6 equivalents, 1:1:1), and complete acylation was monitored by the ninhydrin test. The resin was then treated with 0.25 equivalents of Pd tetrakis, 24 equivalents of phenylsilane in 5 ml of DCM (dry) for 30 minutes under N2 atmosphere (the process was repeated twice), and washed with DCM, DMF, and a solution of 0.5% sodium dimethyldithiocarbamate (0.5%) and DIPEA (0.5%) in DMF. The resin was then manually preactivated with HATU (1.2 eq.) and dipea (2 eq.) and left under stirring for 10 min. Amino-carnitine (2 eq.; (R)-2-amino-4-(tert-butoxy)-N,N,N-trimethyl-4-oxobutan-1-aminium) was added. The reaction was complete after 2 h (monitored by test cleavage).

[0591] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 15 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give intermediate 6-1 (73.6% yield). C 141 H 217 N 28 O 35 S2 + LCMS analysis calculated: 2928.55, found: 1464.74 (M+2) 2+ .

[0592] MeCO-k(PEG2PEG2gE(c)C18OH)-Pen * -NT-7MeW-K(Ac)-Pen * Synthesis of -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 6) Intermediate 6-1 was dissolved in ACN / H2O (1 mg / ml). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 × 40 mm, 300 Å, 15 μm). Mobile phase A: +0.1% TFA, mobile phase B: acetonitrile (ACN) +0.1% TFA. The following gradient of eluent B was used: 20% B over 5 min to 20% B over 25 min to 35% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (20% yield). C 141 H 215 N 28 O 35 S2 +LCMS analysis calculated for: 2926.55, found 1463.9 (M+2) 2+ .

[0593] Example 7. MeCO-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-EN-3Pya-Sar-K(PEG2PEG2gEC18OH)-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 7)

[0594] [ka]

[0595] Synthesis of intermediate 7-1 Intermediate 7-1 was synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (110 μmol, 100-200 mesh; loading 0.33 mmol / g) in a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, the side-chain protecting groups were tert-butyl for Thr and Glu, trityl for Pen and Asn, tert-butoxycarbonyl for AEF, and Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg. The C-terminal Lys was protected with an orthogonal DDe protecting group.

[0596] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out using a 5-fold excess of activated amino acids relative to the resin's free amino groups under microwave irradiation at 90 °C for 3 min. The amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Double acylation reactions were carried out for 3 Pya and 2 Nal. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was carried out manually using 10 equivalents of acetic anhydride in DMF. At the end of solid-phase peptide assembly, the resin was treated with 100 mL of a 3% hydrazine solution in DMF. The solution was drained, and the resin was washed with DCM (3 × 5 mL). The deprotection step was repeated, and then the resin was washed with DCM (5 × 5 mL) and DMF (5 × 5 mL). Further side chain derivatization was carried out using standard coupling conditions on a Cem Liberty Blue microwave peptide synthesizer with a 5-fold excess of activated building blocks (Fmoc-PEG2, Fmoc-PEG2, and Fmoc-gE (Fmoc-Glu-OtBu)) and equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF. C18OH (18-(tert-butoxy)-18-oxooctadecanoic acid) was coupled manually at room temperature using DIC-HOAT (3 equivalents, 1:1:1), and complete acylation was monitored by the ninhydrin test.

[0597] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 15 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give the desired intermediate 7-1 (50% yield). C 137 H 207 N29 O 36 LCMS analysis for S2 calculated: 2900.45, found: 967.8 (M+3) 3+ .

[0598] MeCO-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-EN-3Pya-Sar-K(PEG2PEG2gEC18OH)-CONH2( * Synthesis of Pen-Pen (forms disulfide bond) (SEQ ID NO: 7) Intermediate 7-1 was dissolved in ACN / H2O (1 mg / ml). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 x 40 mm, 300 Å, 15 μm). Mobile phase A: +0.1% TFA, mobile phase B: acetonitrile (ACN) +0.1% TFA. The following gradient of eluent B was used: 25% B over 5 min to 25% B over 25 min to 40% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (5% yield). C 137 H 205 N 29 O 36 LCMS analysis calculated for S2: 2898.43, found: 1450.0 (M+2) 2+ .

[0599] Example 8. MeCO-k(PEG12gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * Synthesis of -AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 8)

[0600] [ka]

[0601] Peptide assembly: Peptides were synthesized by solid-phase peptide synthesis (SPPS) using Fmoc chemistry. Peptide assembly was performed on a Biotage Syro II parallel peptide synthesizer with Rink Amide MBHA resin (0.15 mmol, 0.65 mmol / g). The side-chain protecting groups used were tert-butyl (tBu) for Thr and Glu, trityl (Trt) for Pen and Asn, tert-butoxycarbonyl (Boc) for AEF, Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg, and Dde for the N-terminal Lys. Fmoc-protected amino acids (5 equiv., 0.75 mmol, 5 mL, 0.5 M in DMF) were coupled at room temperature for 1 h using HATU (5 equiv., 0.75 mmol, 1.56 mL, 0.48 M in DMF) and NMM (10 equiv., 1.5 mmol, 0.75 mL, 2 M in DMF). Fmoc deprotection was carried out by treating the resin with 40% piperidine in DMF for 3 min, followed by further treatment with 20% piperidine in DMF for 9 min. Capping of the free terminal amino group was carried out by treating the resin with a solution of acetic anhydride:NMM:DMF (2:2:6, 5 mL) at room temperature for 20 min. The Dde group was then deprotected by treating the resin with 2% hydrazine in DMF (5 mL) at room temperature for 10 min. The solution was drained, followed by the addition of fresh solution for 10 min. The resin was drained and washed with DMF and DCM. Side chain derivatization was carried out on a Biotage Syro II peptide synthesizer using the conditions described above.

[0602] Disulfide formation: After assembly, the resin-bound peptide was treated with a solution of iodine (4 equiv.) in DMF and allowed to mix for 1 h at room temperature. The resin was washed with 1 M sodium ascorbate in DMF, DMF, and DCM and dried.

[0603] Cleavage and purification: The peptide was cleaved from the solid support and deprotected by treating the resin with cleavage cocktail (5 mL, 92.5% TFA, 2.5% water, 2.5% TIPS, 2.5% DODT) at 42 °C for 30 min on a CEM Razor cleavage station. The resin was filtered and washed with cleavage cocktail (2 mL). The peptide was precipitated by adding cold MTBE to the filtrate. After centrifugation, the peptide pellet was washed twice with fresh cold MTBE. The dried pellet was dissolved in water and acetonitrile (1:1 + 0.1% TFA) and lyophilized. The crude peptide was then purified by reverse-phase HPLC using a Waters Xbridge CSH C18 OBD 19 × 150 mm column. Mobile phase A: water + 0.1% TFA, mobile phase B: acetonitrile + 0.1% TFA. Gradient: 35% B to 40% B over 10 min, flow rate 25 mL / min. The pure fractions were combined and lyophilized to give the desired product (12% yield). LCMS analysis calculated for C149H231N25O41S2: 3090.62, found 1546.6 (M+2H). 2+ , 1031.6(M+3H) 3+ , 774.0(M+4H) 4+ .

[0604] Example 9: Pharmacokinetic study of the compositions described and provided herein after a single intravenous, oral (PO), intraduodenal (ID), or intracolonic (IC) administration to rats. The compositions were administered to male Sprague-Dawley rats via intravenous, oral, or intracolonic routes of administration. The compositions were administered at doses of 0.5 mg / kg (IV), 5 mg / kg (ID), or 10 mg / kg (PO or IC) and dose volumes of 1 mL / kg (IV), 5 mg / kg (ID), or 10 mg / mL (PO or IC). Plasma was collected and treated with 5% (volume %) protease inhibitor. Samples were collected as follows: IV sampling time points: 0.08, 0.25, 0.5, 1, 3, 6, 8, 12, 24 hours post-dose, and PO, ID, and IC sampling time points: 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose. Plasma was analyzed by LC-MS / MS for parent compound concentration (ng / mL), and concentration data and pharmacokinetic parameters were calculated. The following table illustrates the data. PK data for the compound of SEQ ID NO: 7 in rats given an intraduodenal (ID) dose of 5 mg / kg with 100 mg / kg of absorption enhancer, as shown below:

[0605] [Table 20]

[0606] SNAC, sodium caprate powder, Labrasol oil, lauroyl-L-carnitine, and sodium octanoate significantly improved the AUC of SEQ ID NO: 7 following intraduodenal (ID) dosing in rats, as shown in the table below. last Unexpectedly and surprisingly, sodium caprate powder and Labrasol oil significantly increased the AUC of SEQ ID NO: 7. last increased approximately 7-fold and 10-fold, respectively.

[0607] The following table illustrates the bioavailability data of compounds of SEQ ID NOs: 1-8 in rats by intracolonic (IC) and oral (PO) dosing at 10 mg / kg in the presence or absence of 100 mg / kg sodium caprate.

[0608] [Table 21-1]

[0609] [Table 21-2] F%: Bioavailability IC / C10: 10 mg / kg peptide administered intracolonically in combination with 100 mg / kg sodium caprate. PO / C10: 10 mg / kg of peptide administered orally in combination with 100 mg / kg of sodium caprate.

[0610] Unexpectedly and surprisingly, sodium caprate powder significantly increased the bioavailability of all compounds of SEQ ID NOS: 1-8 by about 2 to about 20 fold when co-administered with 100 mg / kg sodium caprate. Compounds of SEQ ID NOS: 9-40 also showed high bioavailability when co-administered with sodium caprate.

[0611] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated to be incorporated by reference. In accordance with 37 C.FR § 1.57(b)(1), applicants intend to refer to any individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, each of which is specifically identified in accordance with 37 C.FR § 1.57(b)(2), even if such citation is not immediately adjacent to the dedicated incorporation-by-reference statement. The inclusion of a dedicated incorporation-by-reference statement within this specification does not in any way weaken this general incorporation-by-reference statement. The citation of a reference herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the content or date of these publications or documents.

[0612] The present embodiments are not limited in scope by the specific embodiments described herein. Indeed, various modifications in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the embodiments and any accompanying claims.

[0613] The specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and are within the scope of the disclosure and any appended claims.

Claims

1. an absorption enhancer; and a lipidated peptide comprising 9 to 20 amino acids, the lipidated peptide is cyclized to form a ring, the ring comprising 4 to 14 amino acids; An oral pharmaceutical formulation wherein the ratio of said absorption enhancer to said lipidated peptide is 50:1 (w / w) or less.

2. The lipidated peptide has the formula (A): R １ａ -X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -3Pya-X １６ -X １７ -R ２ａ (A) or a pharmaceutically acceptable salt thereof, During the ceremony, R １ａ is an N-terminal capping group (e.g., MeCO), Z ｐｅｇ , or Z 脂質 and X ３ is any amino acid or is absent, X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is any amino acid, X ６ is any amino acid, X ７ is 7MeW, W or absent, X ８ is any amino acid, X ９ is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X １０ is AEF, TMAPF, AEF(d), TMAPF-Z 脂質 , APEG3F, or AEF-Z 脂質 and X １１ is any amino acid, X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １６ is any amino acid, X １７ is any amino acid or is absent, R ２ａ is a C-terminal capping group (e.g., CONH2), CONH-Z ｐｅｇ , or CO-Z 脂質 and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ and X ９ including bonds between residues in The polypeptide is R １ , X ３ , X ５ , X ６ , X ８ , X １０ , X １２ , X １３ , X １４ , X １６ , X １７ , or R ２ 10. The oral pharmaceutical formulation of claim 1, comprising at least one lipophilic substituent at a position selected from:

3. R １ａ But MeCO, Z ｐｅｇ , Z 脂質 , succiniccarn, 5cpaCO, or AEEP-Z 脂質 and X ３ But R, K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is N, N(NMe ２ ), K(d), K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X ６ But T, K-Z 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X ７ is 7MeW, W or absent, X ８ is K(Ac), K(d), K(NMeAc), Q, K-Z 脂質 , K-Z ｐｅｇ , NMeK-Z 脂質 , Dab-Z 脂質 , Dab(NMecarn), or Dab-Z ｐｅｇ and X ９ is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X １０ However, AEF, TMAPF, AEF(d), TMAPF-Z 脂質 , APEG3F, or AEF-Z 脂質 and X １１ is a substituted or unsubstituted 2Nal or a substituted or unsubstituted 3Quin; X １２ However, THP, K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X １３ But E, K (Ac), K (d), K-Z ｐｅｇ , K (NMeAc), Dab (NMecarn), E (OAll), K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X １４ But N, K-Z 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X １６ is Sar, NMeK(d), K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X １７ But K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R ２ However, CONH2, CONMe2, CONH-Z ｐｅｇ , or CO-Z 脂質 3. The oral pharmaceutical formulation of claim 2, wherein:

4. The lipidated peptide has the formula (B): R １ａ -X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -3Pya-X １６ -X １７ -R ２ａ (B) or a pharmaceutically acceptable salt thereof, During the ceremony, R １ａ is an N-terminal capping group (e.g., MeCO), Z ｐｅｇ , or Z 脂質 and X ３ is any amino acid or is absent, X ４ is any amino acid, X ５ is any amino acid, X ６ is any amino acid, X ７ is 7MeW or W, X ８ is any amino acid, X ９ is any amino acid, X １０ is AEF, TMAPF, AEF(d), TMAPF-Z ｐｅｇ , TMAPF-Z 脂質 , APEG3F, AEF-Z ｐｅｇ , or AEF-Z 脂質 and X １１ is any amino acid, X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １６ is any amino acid, X １７ is any amino acid or is absent, R ２ａ is a C-terminal capping group (e.g., CONH2), CONH-Z ｐｅｇ , or CO-Z 脂質 and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The polypeptide is １ａ , X ３ , X ４ , X ５ , X ６ , X ８ , X ９ , X １０ , X １１ , X １２ , X １３ , X １４ , X １６ , X １７ , or R ２ａ and at least one lipophilic substituent or polyethylene glycol chain at a position selected from 2. The oral pharmaceutical composition of claim 1, wherein the peptide is cyclized to form a first ring, and the first ring comprises 4 to 14 amino acids.

5. 5. The oral pharmaceutical composition of claim 4, wherein the first ring comprises from 4 to 9 or 11 amino acids.

6. The first ring is X ４ and X ９ Between ４ and X １３ Between ５ and X １０ Between ３ and X １３ Between or X ６ and X ９ The oral pharmaceutical composition according to claim 4, which is formed between

7. The first ring is X ４ and X ９ Between ４ and X １３ Between or X ６ and X ９ The oral pharmaceutical composition according to claim 4, which is formed between

8. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X ９ The oral pharmaceutical composition according to claim 7, which is formed between

9. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X １３ The peptide according to claim 7, which is formed between

10. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ６ and X ９ The peptide according to claim 7, which is formed between

11. 11. The peptide of any one of claims 4 to 10, wherein the peptide is further cyclized to form a second ring comprising 4 to 14 amino acids.

12. 12. The peptide of claim 11, wherein the second ring comprises 4, 6, 10, or 11 amino acids.

13. the peptide is further cyclized to form a second ring; the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ３ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １０ and X １３ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １３ and the N-terminus of the peptide.

14. the peptide is further cyclized to form a second ring; the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ６ and X ９ The peptide according to claim 9, which is formed between

15. the peptide is further cyclized to form a second ring; the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ３ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ４ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １０ and X １３ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １３ and the N-terminus of the peptide.

16. R １ａ is an N-terminal capping group (e.g., MeCO), Z ｐｅｇ , or Z 脂質 and X ３ is r, k(d), k-Z 脂質 , dab-Z 脂質 , NMek-Z 脂質 or not present, X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is E, N, N(NMe ２ ), K(d), K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X ６ But T, K-Z 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X ７ is 7MeW or W, X ８ is K(Ac), K(d), K(NMeAc), Q, K-Z 脂質 , K-Z ｐｅｇ , NMeK-Z 脂質 , Dab-Z 脂質 , Dab(NMecarn), or Dab-Z ｐｅｇ and X ９ is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X １０ However, AEF, TMAPF, AEF(d), TMAPF-Z ｐｅｇ , TMAPF-Z 脂質 , APEG3F, AEF-Z ｐｅｇ , or AEF-Z 脂質 and X １１ is 2Nal or 6OH2Nal, X １２ However, THP, K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and 8 １３ The ｐｅｇ 、KKAccc、Dabb(87ecarrnnnn)、(!Allll)、- 脂質 、Dabmﺺ 脂質 、8Me- 脂質 であり、 X １４ But N, K-Z 脂質 , NMeK-Z 脂質 , or Dab-Z 脂質 and X １６ But, Sar, NMeK(d), K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, X １７ But K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R ２ａ is a C-terminal capping group (e.g., CONH2), CONH-Z ｐｅｇ , or CO-Z 脂質 and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z 脂質 is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ and X ９ including bonds between residues in The polypeptide is １ａ , X ３ , X ５ , X ６ , X ８ , X １０ , X １２ , X １３ , X １４ , X １６ , X １７ , or R ２ａ or R １ａ , X ８ , X １０ , X １３ , or R ２ａ The oral pharmaceutical composition according to claim 4, or a pharmaceutically acceptable salt thereof, comprising a polyethylene glycol chain at a position selected from:

17. R １ａ But MeCO, Z ｐｅｇ , Z 脂質 or 5 cpa CO X ３ is r, k(d), k-Z 脂質 , dab-Z 脂質 , NMek-Z 脂質 or not present, X ４ is Pen; X ５ is E, N, N(NMe ２ ), K-Z 脂質 Dab-Z 脂質 or NMeK-Z 脂質 and X ６ But, T, X ７ is 7 MeW, X ８ is K(Ac), K(d), K(NMeAc), K-Z 脂質 K-Z ｐｅｇ NMeK-Z 脂質 Dab-Z 脂質 or Dab-Z ｐｅｇ and X ９ is Pen; X １０ However, AEF, TMAPF, APEG3F, AEF-Z ｐｅｇ , or AEF-Z 脂質 and X １１ is 2Nal or 6OH2Nal, X １２ But it is THP, X １３ But E, K (Ac), K-Z ｐｅｇ , K(NMeAc), K-Z 脂質 , Dab-Z 脂質 , or NMeK-Z 脂質 and X １４ is N, X １６ However, Sar or NMeK-Z 脂質 and X １７ But K-Z 脂質 , Dab-Z 脂質 , NMeK-Z 脂質 or not present, R ２ａ However, CONH2, CONMe2, CONH-Z ｐｅｇ , or CO-Z 脂質 and The peptide is X ４ and X ９ and a disulfide bond between residues in The polypeptide is １ａ , X ３ , X ５ , X ８ , X １０ , X １３ , X １６ , X １７ , or R ２ａ or R １ａ , X ８ , X １０ , X １３ , or R ２ａ 17. The oral pharmaceutical composition of claim 4 or 16, comprising a polyethylene glycol chain at a position selected from:

18. the lipidated peptide 【Chemistry 1】 【Chemistry 2】 a compound having the formula or a pharmaceutically acceptable salt or solvate form thereof; During the ceremony, L is —O—, —S—, or —S—S—; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ８ , R ９ , and R １０ are each independently H, CH ３ , —C(═O)CH ３ , -C(=O)NHR １１ , 【Transformation 3】 -C(=O)CH(R １２ ) CONH ２ , R １４ , -(CH ２ ) ｎ NHR １２ , -(CH ２ ) ｎ C(=O)NHR １２ , -(CH ２ ) ｎ C(=O)OR １２ , -C(=O)(CH ２ ) ｎ NHR １２ , or -C(=O)(CH ２ ) ｎ OR １２ and R ７ is -(CH ２ ) ｐ NHR １３ or -(CH ２ ) ｑ NHC (=NH)NH ２ and each m, n, p, and q is independently 1, 2, 3, 4, or 5; Each R １１ , R １２ , R １３ , and R １４ is independently H or a lipid moiety.

19. the lipidated peptide 【Chemistry 4】 20. The oral pharmaceutical formulation of claim 18, wherein the compound has the formula:

20. The compound is 【Transformation 5】 20. The oral pharmaceutical formulation of claim 18, wherein the compound has the formula:

21. The compound is 【Transformation 6】 20. The oral pharmaceutical formulation of claim 18, wherein the compound has the formula:

22. Each lipid moiety or lipophilic substituent independently comprises Z １ ~Z ５ is selected from the group Z １ teeth, 【Transformation 7】 and Z ２ teeth, 【Transformation 8】 and During the ceremony, Each PEG is independently —OCH ２ CH ２ - and each n' is independently 0 or ranges from 2 to 24, when n' is 0 the group is absent and is replaced by a bond; each m' at each occurrence is independently selected from 0 or the range of 2 to 24, and when m' is 0, this group is replaced by a bond; each v' is independently selected at each occurrence from the range of 1 to 4; each v" at each occurrence is independently selected from the range of 0 to 4, and when v" is 0, this group is replaced by a bond; p' is 1 to 3; V' is sp6 or gEgE; each X is independently gE, dgE, 4SB, P, PPP, gE-(c), gE-(C), sp6, gDab, eK, Trx, or absent; each Y, is independently gE, sp6, GolA, Pro, D-Pro, meG, Dab, Trx, or absent; T is Trx, each U is independently hydrogen or methyl; each o' is independently 6 to 18; each V is independently —COOH, tetrazole, GolB, mXOH, pXOH, Ophenyl, carnitine, d-carnitine, or hydrogen; Z ３ is -gE-C(O)(CH ２ ) ６～１０ CH ３ , or -gE-C(O)(CH ２ ) １１～１８ CH ３ and Z ４ is -C(O)(CH ２ ) ６～１８ COOH or -C(O)(CH ２ ) ６～１８ COO (C １～４ alkyl), Z ５ teeth, 【Chemistry 9】 wherein: n" and m" are independently selected from the range of 0 to 24; X' is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx; Y' is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx; 22. The oral pharmaceutical formulation of claims 18 to 21, wherein Xaa is a diamino-carboxylic acid.

23. Each lipid moiety or lipophilic substituent is 【Chemistry 10】 and During the ceremony, Z Ｂ teeth, 【Chemistry 11】 and Z Ｃ Is Z Ｃ１ , Z Ｃ２ , or Z Ｃ３ and Z Ｃ１ teeth, 【Chemistry 12】 and Z Ｃ２ teeth, 【Chemistry 13】 and Z Ｃ３ teeth, 【Chemistry 14】 and Z Ｄ teeth, 【Chemistry 15】 and Z Ｅ is —H, —COOH, phenoxy, or tetrazolyl; Z Ｆ is -H or -CH ３ and Xaa ａ is expressed independently for each occurrence, 【Chemistry 16】 and p ａ is independently at each occurrence 0, 1, 2, 3, 4, 5, or 6; q ａ is 1, 2, 3, 4, 5, or 6, r ａ is an integer from 6 to 24, v ａ is 0 or 1, w ａ The oral pharmaceutical formulation of claims 18 to 21, wherein, independently at each occurrence, is 0 or 1.

24. R ２ The oral pharmaceutical formulation according to any one of claims 18 to 23, wherein is methyl.

25. R ３ The oral pharmaceutical formulation of any one of claims 18 to 24, wherein is H.

26. R ４ The oral pharmaceutical formulation of any one of claims 18 to 25, wherein is H.

27. R ５ The oral pharmaceutical formulation of any one of claims 18 to 26, wherein is H.

28. R ８ The oral pharmaceutical formulation of any one of claims 18 to 27, wherein is H.

29. R ４ The oral pharmaceutical formulation of any one of claims 18 to 28, wherein is H.

30. R ９ The oral pharmaceutical formulation of any one of claims 18 to 29, wherein is H.

31. R １０ is -C(=O)CH ３ The oral pharmaceutical formulation according to any one of claims 18 to 30, wherein

32. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 17】 24. An oral pharmaceutical formulation according to any one of claims 18 to 23, having the formula:

33. R ７ But -(CH ２ ) ｑ C(=O)NH)NH ２ 33. The oral pharmaceutical formulation of claim 32, wherein:

34. 34. The oral pharmaceutical formulation of claim 33, wherein q is 3.

35. The compound is [Chemistry 18] 35. The oral pharmaceutical formulation of claim 34 having the formula:

36. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 19】 36. The oral pharmaceutical formulation of claim 35 having the formula:

37. R ６ is -C(=O)CH ３ 33. The oral pharmaceutical formulation of claim 32, wherein:

38. R ７ But -(CH ２ ) ｐ NHR １２ 38. The oral pharmaceutical formulation of claim 37, wherein:

39. 39. The oral pharmaceutical formulation of claim 38, wherein p is 4. 。

40. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 20】 40. The oral pharmaceutical formulation of claim 39 having the formula:

41. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 41. The oral pharmaceutical formulation of claim 40 having the formula:

42. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 26】 24. An oral pharmaceutical formulation according to any one of claims 18 to 23, having the formula:

43. R １ but, 【Chemistry 27】 43. The oral pharmaceutical formulation of claim 42, wherein 。

44. 44. The oral pharmaceutical formulation of claim 43, wherein m is 4. 。

45. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 28】 45. The oral pharmaceutical formulation of claim 44 having the formula:

46. The compound, or a pharmaceutically acceptable salt thereof, 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 20. The oral pharmaceutical formulation of claim 19 having the formula:

47. 2. The oral pharmaceutical formulation of claim 1, wherein the lipidated peptide is selected from the group consisting of SEQ ID NOs: 1-40.

48. 48. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the weight ratio (w / w) of said absorption enhancer to said lipidated peptide or its pharmaceutically acceptable salt or solvate form ranges from about 1 to about 200.

49. 48. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the weight ratio (w / w) of said absorption enhancer to said lipidated peptide or its pharmaceutically acceptable salt or solvate form ranges from about 1 to about 100.

50. 48. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the weight ratio (w / w) of said absorption enhancer to said lipidated peptide or its pharmaceutically acceptable salt or solvate form ranges from about 1 to about 20.

51. 48. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the weight ratio (w / w) of said absorption enhancer to said lipidated peptide or its pharmaceutically acceptable salt or solvate form ranges from about 1 to about 10.

52. 48. An oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the ratio of said absorption enhancer to said lipidated peptide is 3:1 (w / w) or greater.

53. 48. An oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the ratio of said absorption enhancer to said lipidated peptide is from 3:1 (w / w) to 30:1 (w / w).

54. 48. The oral pharmaceutical formulation of claim 4, wherein the ratio of absorption enhancer to lipidated peptide is from 5:1 (w / w) to 50:1 (w / w).

55. 48. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the ratio of said absorption enhancer to said lipidated peptide is about 10:1 (w / w).

56. 56. An oral pharmaceutical formulation according to any one of claims 1 to 55, wherein the absorption enhancer is present in an amount greater than 250 mg.

57. 57. An oral pharmaceutical formulation according to any one of claims 1 to 56, wherein the absorption enhancer is present in an amount of less than 700 mg.

58. 58. The oral pharmaceutical formulation of any one of claims 1 to 57, wherein the absorption enhancer comprises one or more of sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acids, sucrose laurate, sodium octanoate, Labrasol, and lauroyl-L-carnitine (LC).

59. 59. The oral pharmaceutical formulation of any one of claims 1 to 58, wherein the absorption enhancer comprises sulcaprozate sodium (SNAC).

60. 59. The oral pharmaceutical formulation of any one of claims 1 to 58, wherein the absorption enhancer comprises lauroyl-L-carnitine (LC).

61. 59. The oral pharmaceutical formulation of any one of claims 1 to 58, wherein the absorption enhancer comprises sodium octanoate.

62. 59. The oral pharmaceutical formulation of any one of claims 1 to 58, wherein the absorption enhancer comprises labrasol sodium.

63. 59. An oral pharmaceutical formulation according to any one of claims 1 to 58, wherein the absorption enhancer comprises sodium caprate.

64. 64. The oral pharmaceutical formulation of any one of claims 63, wherein the sodium caprate has a purity of at least 98%.

65. 65. The oral pharmaceutical formulation of any one of claims 1 to 64, wherein the oral pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients.

66. 66. The oral pharmaceutical formulation of any one of claims 1 to 65, wherein said oral pharmaceutical formulation improves the oral bioavailability of said compound.

67. 66. The oral pharmaceutical formulation of any one of claims 1 to 65, wherein said oral pharmaceutical formulation improves the oral bioavailability of said compound by about 2 to about 500 fold.

68. 66. The oral pharmaceutical formulation of any one of claims 1 to 65, wherein said oral pharmaceutical formulation improves the oral bioavailability of said compound by about 2 to about 250 fold.

69. 50. A method of increasing the bioavailability of a lipidated peptide of any one of claims 1-47 in a subject, comprising orally administering the compound, or a pharmaceutically acceptable salt or solvate form thereof, and an absorption enhancer.

70. 70. The method of claim 69, wherein the absorption enhancer comprises one or more of sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain triglycerides of capric and caprylic acids, sucrose laurate, sodium octanoate, Labrasol, and lauroyl-L-carnitine (LC).

71. 71. The method of claim 69 or 70, wherein the compound or a pharmaceutically acceptable salt or solvate form thereof and the absorption enhancer are co-administered.

72. 72. The method of any one of claims 69 to 71, wherein the compound or a pharmaceutically acceptable salt or solvate form thereof and the enhancer are co-administered in a pharmaceutically acceptable formulation.

73. 69. Use of an oral pharmaceutical formulation according to any one of claims 1 to 68 for the preparation of a medicament for the treatment of an inflammatory disorder or an autoimmune inflammatory disorder.

74. Multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis ulcerata ... vulgaris), or psoriasis erythrodermic), atopic dermatitis, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholechial inflammation, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

75. 74. The use according to claim 73 for the preparation of a medicament for the treatment of a disease or disorder selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), and psoriatic arthritis (PsA).

76. 69. A method for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), comprising administering to a patient in need thereof an effective amount of the pharmaceutical formulation of any one of claims 1 to 68.

77. 77. The method of claim 76, wherein the disease or disorder is associated with autoimmune inflammation.

78. The disease or disorder may be multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis ulcerata ... vulgaris), or psoriasis erythrodermic), atopic dermatitis, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

79. 79. The method of claim 78, wherein the disease or disorder is associated with ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

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