Formulations of lipidated peptide inhibitors of 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 of the oral pharmaceutical formulations for increasing the bioavailability of the lipidated peptides and / or for treating autoimmune inflammation and related diseases and disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 480,068, filed on January 16, 2023, which is incorporated herein by reference in its entirety.

[0003] Incorporation of Sequence Listing

[0004] A sequence listing in ST.26 XML format, named 739658_NTT-4253PC_SL.xml, created on January 12, 2024, comprising 137,953 bytes, was prepared in accordance with 37 CFR 1.822 to 1.824, and is filed concurrently with the filing of this application, the entire text of which is incorporated herein by reference. Technical Field

[0005] 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 thereof and an absorption enhancer, and methods and / or uses of the oral pharmaceutical formulations for increasing the bioavailability of the lipidated peptide and / or for treating autoimmune inflammation and related diseases and disorders. Background Art

[0006] The interleukin-23 (IL-23) cytokine has been implicated as a key player 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 major role for the interleukin-23 receptor (IL-23R) and downstream effector cytokines in disease pathogenesis.

[0007] Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for the treatment of IL-23-related diseases and disorders. Recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, e.g., U.S. Patent Application Publication No. US2013 / 0029907). Clinical trials conducted with briakinumab (e.g., also targeting the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (e.g., targeting the unique p19 subunit of IL-23) in Crohn's disease or psoriasis have highlighted the potential of IL-23 signaling blockade in the treatment of human inflammatory diseases. Although these findings are promising, there are still challenges in successfully delivering such therapeutic agents to the target. Effective delivery can improve the treatment of intestinal inflammation, such as intestinal diseases, including Crohn's disease, ulcerative colitis, and related conditions.

[0008] Lipidation of therapeutically useful polypeptides can provide advantageous physicochemical properties compared to corresponding unmodified polypeptides. Lipidated polypeptides can exhibit improved half-life, reduced immunogenicity, enhanced intracellular uptake and / or enhanced transepithelial delivery.

[0009] 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-related diseases, particularly those associated with autoimmune inflammation, such as diseases in the intestine, which may include but are not limited to inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease (CD), psoriasis or psoriatic arthritis, etc.

[0010] The present disclosure is directed to overcoming these and other problems encountered in the prior art. Summary of the Invention

[0011] In general, the present disclosure relates to oral pharmaceutical compositions comprising lipidated peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts, solvates and / or other forms thereof, and methods and / or uses of the oral pharmaceutical compositions for increasing the bioavailability of lipidated peptides and / or for treating autoimmune inflammation and related diseases and disorders.

[0012] In some embodiments, the present disclosure relates to an oral pharmaceutical formulation comprising (1) an absorption enhancer and (2) a lipidated peptide comprising 9 to 20 amino acids; wherein the lipidated peptide is cyclized to form a ring, wherein the ring comprises 4 to 14 amino acids; and wherein the ratio of the absorption enhancer to the lipidated peptide is no greater than 50:1 (w / w).

[0013] The present disclosure relates to oral pharmaceutical compositions 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 as provided herein, as described herein, corresponding pharmaceutical compositions, methods for treating autoimmune inflammatory diseases and related disorders, and / or uses.

[0014] The present disclosure relates to oral pharmaceutical formulations comprising an absorption enhancer as provided herein and a lipidated peptide as provided herein.

[0015] The present disclosure relates to oral pharmaceutical compositions comprising a compound having the formula:

[0016] or a pharmaceutically acceptable salt or solvate form thereof, wherein the variables are as defined and provided herein.

[0017] 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 ratio (w / w) of about 1 to about 200.

[0018] The present disclosure relates to methods as provided herein for treating diseases or disorders associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R), comprising administering an effective amount of an oral pharmaceutical formulation as provided herein.

[0019] The present disclosure relates to methods for increasing the bioavailability of a compound in an oral pharmaceutical formulation as 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 as provided herein. DETAILED DESCRIPTION

[0020] I. Overview

[0021] In general, the present disclosure relates to oral pharmaceutical formulations comprising lipidated peptide inhibitors of interleukin-23 receptor (IL-23R), or pharmaceutically acceptable salts or solvates thereof, and an absorption enhancer, and methods and / or uses of the oral pharmaceutical formulations for increasing the bioavailability of the lipidated peptides and / or for treating autoimmune inflammation and related diseases and disorders.

[0022] II. Definitions

[0023] 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.

[0024] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art.

[0025] When referring to a value, "about" includes the stated value + / - 10%. For example, about 50% includes a range of 45% to 55%, and about 20 molar equivalents includes a range of 18 molar equivalents to 22 molar equivalents. Thus, when referring to a range, "about" refers to the stated value + / - 10% of each end of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0026] "Absorption enhancer" (AE) refers to an ingredient that improves or promotes mucosal absorption of a drug in the gastrointestinal tract, such as, but not limited to, a permeation enhancer (PE) or intestinal permeation enhancer. As commonly understood in the art, a permeation enhancer is an agent intended to improve the oral delivery of a therapeutic drug and help increase bioavailability. PE is able to increase the intercellular and / or transcellular passage of a drug. Pharmaceutical excipients that can increase permeation have been referred to as "absorption modifying excipients" (AME). AME can be used in oral compositions, for example as a wetting agent (sodium lauryl sulfate), an antioxidant (e.g., EDTA), and an emulsifier (e.g., polyethylene glycol glycerides), and can be included in compositions specifically as PE to improve bioavailability. PE can be classified according to how it alters barrier integrity through paracellular or transcellular pathways. In the present disclosure, the term "absorption enhancer" or AE is considered synonymous with the term "permeation enhancer" or PE.

[0027] "Administering" refers to administering a composition of the present disclosure to a subject.

[0028] As used herein, a "composition" is intended to encompass a product comprising a specified active ingredient (API) as described herein and a pharmaceutically acceptable excipient, carrier, or diluent, such as in the specified amounts defined throughout the initially filed disclosure, the product resulting from the combination of specified components (such as the specified ingredients in the specified amounts as described herein).

[0029] "Intestinal permeation enhancer (IPE)" refers to a component that improves the bioavailability of a component with poor bioavailability. Suitable representative IPEs for use in the present disclosure include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroidal detergents, acylcarnitines and alkanoylcholines, N-acetylated α-amino acids and N-acetylated non-α-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, a suitable IPE for use in the present disclosure may be sodium caprate.

[0030] A "joint" refers to the tissue that connects one bone to another in the human body. Examples of tissue encompassed by the term "joint" include, but are not limited to, tendons, cartilage, ligaments, and synovium. Synovial fluid adjacent to any of the aforementioned tissues is considered part of the "joint" herein.

[0031] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds used as lubricants may also have the properties of glidants. Examples of lubricants may include, but are not limited to, talc, silicon dioxide, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0032] "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 administering a pharmaceutical composition as provided herein. Additional non-limiting examples can include but are not limited to humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other mammals. In some aspects, the patient is a human.

[0033] 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., it is 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 listed in the LS Pharmacopoeia or other generally recognized pharmacopoeias.

[0034] The compositions or pharmaceutical compositions of the present disclosure may be in various pharmaceutically acceptable forms, including but not limited to liquid compositions, tablet or matrix compositions, capsule compositions, and the like.

[0035] "Sodium decanoate" or "NaC10" refers to a substance with the molecular formula C 10 H 19 NaO2 and the IUPAC compound sodium decanoate of the following structural formula:

[0036]

[0037] As used herein, "solvate" means 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 some cases, the solvate will be capable of being isolated. The term "solvate" is intended to encompass both solution-phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include hydrates.

[0038] "Therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease or condition, or that shows a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of the specific drug to which it refers to provide the desired therapeutic effect. The precise amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The precise amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, for example, 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, 20th edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins Press).

[0039] The term "treat" or "treating" or "treatment" is defined as applying or administering a therapeutic agent, i.e., a compound or formulation of the present disclosure, to a patient suffering from a disorder or disease, or symptoms thereof, as described herein, or applying or administering a therapeutic agent to a tissue or cell line isolated from the patient (e.g., for diagnosis or ex vivo application); applying or administering with the purpose of curing, healing, alleviating, relieving, altering, remedying, improving, ameliorging, or influencing the disorder or disease, its symptoms, or the likelihood of developing the disorder or disease. Such treatments may be modified or improved based on knowledge gained from the field of pharmacogenomics.

[0040] As used herein, the term "prevent" or "preventing" means that a disease or disorder does not develop if it has not already occurred, or that the disorder or disease does not develop further if it has already occurred. The ability to prevent some or all symptoms associated with a disorder or disease is also contemplated.

[0041] As used in the specification and claims, as used herein, "comprises," "including," "having," "may," "contains" and variations thereof are intended to be open transitional phrases, terms or words that require the presence of the named features, groups, components or steps and do not exclude the presence of other features, groups, components or steps. For example, the language "a peptide of formula (A) comprising 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 17 (A)" means amino acids X3 to X 17 In addition, the peptide may include, but is not limited to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N-terminal 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.), etc. The terms "comprising," "including," "having," "may," or "containing" may include embodiments encompassed by the terms "consisting essentially of" or "consisting of."

[0042] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and generally 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.).

[0043] Naturally occurring L-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid designations of Table 1. The corresponding D-amino acids are represented by lowercase single-letter amino acid designations or by the three-letter or uppercase single-letter amino acid designations of Table 1 preceded by the letter "D" (e.g., r, dR, or D-Arg).

[0044] Table 1: Naturally occurring amino acids

[0045]

[0046]

[0047] 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). When referred to using single-letter abbreviations, D-amino acids can be indicated in lowercase by convention. For example, D-arginine can be represented as "arg" or "r". Alternatively, a lowercase "d" in front of an amino acid can be used to indicate that it is in the D isomeric form, for example, D-lysine can be represented by dK.

[0048] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full names (e.g., sarcosine, ornithine, etc.), the commonly employed three-letter or four-letter codes for their residues are adopted, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0049] The amino acid in its D-isomeric form may be positioned at any of the positions in the IL-23R inhibitors described herein (e.g., X3-X3 where present in the molecule). 17 In some embodiments, the D-isomeric form of an amino acid may be positioned only at X3, X5, X6, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X30, X40, X50, X60, X70, X80, X90, X11, X12, X13, X14, X 13 In other embodiments, the amino acid in the D-isomeric form may be positioned only at X3, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X30, X40, X50, X60, X70, X80, X90, X10, X11, X12, X13, X14, X15 13 In other embodiments, the amino acid in its D-isomeric form may be positioned only at X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X30, X31, X40, X50, X60, X70, X80, X90, X10, X11, X12, X13, X1 13 In other embodiments, the D-isomeric form of an amino acid may be located only at X3, and optionally at one additional position. In other embodiments, the D-isomeric form of an amino acid may be located only at X3, and optionally at two or three additional positions. In other embodiments, the D-isomeric form of an amino acid may be located only at positions X3 through X3, and optionally at two or three additional positions. 17 In other embodiments, the D-isomer form of an amino acid may be positioned only at positions X3 to X4 occurring in the IL-23R inhibitors described herein. 17 For example, there are only three or four locations X3 to X 15The IL-23R inhibitors described herein may have D-forms of amino acids present at three or four of these positions. In other embodiments, the D-isomer forms of amino acids may be located only at positions X3 through X4 present in the IL-23R inhibitors described herein. 17 Five or six of them.

[0050] Peptides can be naturally occurring, synthetically produced or recombinantly expressed. Peptides can also include other groups that modify the amino acid chain, such as functional groups added via post-translational modification. Examples of post-translational modifications include but are not limited to acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, prenylation, lipidation, phosphopantetheinylation, phosphorylation, selenylation and C-terminal amidation. The term peptide also includes peptides that comprise amino terminal and / or carboxyl terminal modifications. The modification of the terminal amino group includes but is not limited to deamination, N-low alkyl, N-di-low alkyl and N-acyl modifications. The modification of the terminal carboxyl group includes but is not limited to amide, low alkyl amide, dialkyl amide and low alkyl ester modifications (for example, wherein low alkyl is C1-C4 alkyl). The term peptide also includes modifications, such as but not limited to those mentioned above, where the amino acid modification falls between the amino and carboxyl terminal.

[0051] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. The sequences disclosed herein are sequences to which "-OH" moieties or "-NH2" moieties are incorporated at the carboxyl end (C-terminus) of the sequence. In such cases, and unless otherwise indicated, "-OH" or "-NH2" moieties at the C-terminus of the sequence indicate hydroxyl groups or amino groups corresponding to formic acid (COOH) or amide groups (CONH2) groups present at the C-terminus, respectively. In each sequence disclosed herein, the "-OH" moiety at the C-terminus can replace the "-NH2" moiety at the C-terminus, and vice versa.

[0052] As used herein, the phrase "amino acid," "amino acid residue," or "residue" refers to an amino acid, modified amino acid, amino acid analog, or amino acid mimetic that is incorporated into a peptide via an amide bond or an amide bond mimetic.

[0053] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions recommended by the IUPAC Organic Nomenclature Commission and the IUPAC-IUB Biochemical Nomenclature Commission, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)", Biochemistry, Vol. 14, No. 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 those recommended, this will be made clear to the reader. In amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-" or brackets, e.g., lysine is shown as [K].

[0054] Those skilled in the art will appreciate that certain amino acids and other chemical moieties are modified when combined with another molecule. For example, an amino acid side chain can be modified when forming an intramolecular bridge with another amino acid side chain, for example, one or more hydrogens can be removed or replaced by a bond.

[0055] 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 front or end of a chemical group are for convenience; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure represents the point of attachment of the group. A dotted line indicates an optional bond. Unless chemically or structurally required, the order in which the chemical groups are written or the point at which they are attached to the rest of the molecule does not indicate or imply directionality. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and the two can be attached in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule, for example, at the aryl or alkyl portion of the group. Prefixes such as "C u-v " or (C u -C v ) indicates that the following group has u to v carbon atoms. For example, "C 1-6 "C1-C6 alkyl" and "C1-C6 alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

[0056] The term "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group can have 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, but are not limited to, 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, -CH2CH2CH2CH2CH 3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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 refers to C (1-6) In another embodiment, alkyl refers to C (1-4) In another embodiment, alkyl refers to C (1-3) alkyl.

[0057] The term "alkylene" refers to a divalent alkyl group, for example, an alkylene group can have 1 to 10 carbon atoms (ie, (C1-C 10 ) 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.

[0058] Furthermore, within the scope of the present invention, any element, particularly when referred to with respect to the peptides of the present disclosure or pharmaceutically acceptable salts thereof, is intended to encompass all isotopes or isotopic mixtures of said element (naturally occurring or synthetically produced) in its natural abundance or in its 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 (ie, tritium or T). In some embodiments, the compounds described herein include 2 H (i.e. deuterium) isotopes. For example, -C (1-6) Alkyl groups include not only -CH3 but also CD3; not only CH2CH3 but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C, and 15 O and 16 O and 17 O and 18 O. The isotope may be radioactive or non-radioactive. The radiolabeled compounds of the present disclosure may include a radioisotope selected from the group consisting of: 3 H. 11 C. 18 F. 35 S. 122 I. 123 I. 125 I. 131 I. 75 Br, 76 Br, 77 Br and 82 Br. Preferably, the radioisotope is selected from 3 H. 11 C and 18 F's group.

[0059] As used herein, the terms "lipophilic substituent", "lipid chain" and "lipid moiety" refer to substituents comprising 4 to 40 carbon atoms, 8 to 25 carbon atoms or 12 to 22 carbon atoms. The lipophilic substituent can be attached to the amino group of the peptide (e.g., the ε-amino group of a lysine residue) through the carboxyl group of the lipophilic substituent. The lipophilic substituent can optionally include one or more spacers (e.g., a polyethylene glycol chain or γ-glutamic acid having 2 or more repeated -CH2CH2O- units). In some embodiments, the lipophilic substituent comprises a straight or branched alkyl or alkylene group. In some embodiments, the lipophilic substituent is an acyl group of a straight or branched fatty acid.

[0060] As used herein, the term "lipidated peptide" refers to a peptide comprising one or more lipophilic substituents as described herein. The lipophilic substituents of the lipidated peptide can be conjugated to the N-terminus, C-terminus or amino acid side chains, for example.

[0061] The abbreviation "(w / w)" refers to the phrase "weight to weight" or "weight to weight," i.e., the ratio of a particular substance within a mixture, as measured by the weight or mass or weight amount of a component of a composition disclosed herein relative to the total weight of the composition. Thus, the quantity is unit-less or unitless and represents the weight percent 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.

[0062] Systemic administration routes, as conventionally understood in the medical or pharmaceutical arts, refer to or are defined as routes by which a drug, pharmaceutical composition or formulation, or other substance is administered into the circulatory system such that various body tissues and organs are exposed to the drug, formulation, or other substance. As conventionally understood in the art, administration can be by oral administration (wherein the drug or oral formulation is taken orally and absorbed via the gastrointestinal tract), enteral administration (drug absorption also occurs via the gastrointestinal tract), or parenteral administration (usually by injection, infusion, or implantation, etc.).

[0063] As used in the present disclosure, "systemically active" peptide drug therapy generally refers to treatment by means of a pharmaceutical composition comprising a peptide active ingredient, wherein the peptide resists immediate metabolism and / or excretion, resulting in its exposure to various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous, or immune systems.

[0064] Systemic drug activity in this disclosure also refers to treatment with substances that travel through the bloodstream, reach and affect cells in various body tissues and organs. Systemically active drugs are transported to their sites of action and act throughout the body to attack the physiological processes that cause inflammatory diseases.

[0065] Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation and thereby reaches the site of action. The bioavailability of a drug is influenced by the properties of the dosage form, which depends in part on its design and manufacture.

[0066] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions recommended by the IUPAC Organic Nomenclature Commission and the IUPAC-IUB Biochemical Nomenclature Commission, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)", Biochemistry, Vol. 14, No. 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 those recommended, this will be made clear to the reader. In amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-".

[0067] III. Compounds

[0068] The present disclosure relates to oral pharmaceutical formulations comprising one or more lipidated cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) as provided herein, or pharmaceutically acceptable salts thereof, and one or more enhancers as provided herein.

[0069] Some embodiments relate to an oral pharmaceutical formulation comprising: an absorption enhancer; and a lipidated peptide.

[0070] In some embodiments, the present disclosure provides an oral pharmaceutical formulation comprising (1) an absorption enhancer and (2) a lipidated peptide comprising 9 to 20 amino acids; wherein the lipidated peptide is cyclized to form a ring, wherein the ring comprises 4 to 14 amino acids; and wherein the ratio of the absorption enhancer to the lipidated peptide is no greater than 50:1 (w / w).

[0071] In some embodiments, the lipidated peptide comprises 12 to 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.

[0072] In some embodiments, the lipidated peptide is an inhibitor of the interleukin-23 receptor.

[0073] In some embodiments, the lipidated peptide comprises a helical structure.

[0074] In some embodiments, the lipidated peptide is cyclized to form a ring, wherein the ring comprises 4 to 11 or 14 amino acids. In some embodiments, the ring comprises 4 to 9 or 11 amino acids. In some embodiments, the ring comprises 4, 6 or 10 amino acids. In some embodiments, the ring comprises 4 amino acids. In some embodiments, the ring comprises 6 amino acids. In some embodiments, the ring comprises 10 amino acids.

[0075] In some embodiments, the lipidated peptide comprises the amino acid sequence of Formula (A):

[0076] R1a -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), or a pharmaceutically acceptable salt thereof, wherein:

[0077] R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ;

[0078] X3 is any amino acid or absent;

[0079] X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0080] X5 is any amino acid;

[0081] X6 is any amino acid;

[0082] X7 is 7MeW, W, or does not exist;

[0083] X8 is any amino acid;

[0084] X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3);

[0085] X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z 脂质 , APEG3F or AEF-Z 脂质 ;

[0086] X 11 is any amino acid;

[0087] X 12 is any amino acid;

[0088] X 13 is any amino acid;

[0089] X 14 is any amino acid;

[0090] X 16 is any amino acid;

[0091] X 17 is any amino acid or absent;

[0092] R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z 脂质 ;

[0093] Z peg is independently at each occurrence a polyethylene glycol chain;

[0094] Z 脂质 is independently at each occurrence a lipophilic substituent;

[0095] wherein the peptide comprises a bond between residues at X4 and X9; and

[0096] The polypeptide is contained in a group consisting of R1, X3, X5, X6, X8, X 10 、X 12 、X 13 、X 14 、X 16 、X 17 or at least one lipophilic substituent at the position of R2.

[0097] In some embodiments, the lipidated peptide comprises the amino acid sequence of Formula (A):

[0098] 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),

[0099] or a pharmaceutically acceptable salt thereof, wherein:

[0100] R 1a It is MeCO, Z peg , Z 脂质 , succiniccarn, 5cpaCO, or AEEP-Z 脂质 ;

[0101] X3 is R, KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0102] X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0103] X5 is N, N(NMe2), K(d), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0104] X6 is T, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ;

[0105] X7 is 7MeW, W, or does not exist;

[0106] X8 is K(Ac), K(d), K(NMeAc), Q, KZ 脂质 , KZ peg 、NMeK-Z 脂质 , Dab-Z 脂质 , Dab(NMecarn) or Dab-Z peg ;

[0107] X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3);

[0108] X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z 脂质 , APEG3F or AEF-Z 脂质 ;

[0109] X 11 is substituted or unsubstituted 2Nal or substituted or unsubstituted 3Quin;

[0110] X 12 It's THP, KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0111] X 13 is E, K(Ac), K(d), KZ peg ,K(NMeAc),Dab(NMecarn),E(OAll),KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0112] X 14 It's N, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ;

[0113] X 16 It is Sar, NMeK(d), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0114] X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0115] R 2a CONH2, CONMe2, CONH-Z peg or CO-Z 脂质 ;

[0116] Z peg is independently at each occurrence a polyethylene glycol chain;

[0117] Z 脂质 is independently at each occurrence a lipophilic substituent;

[0118] wherein the peptide comprises a bond between residues at X4 and X9.

[0119] In some embodiments, for Formula (A), X7 is substituted or unsubstituted W. In some embodiments, X7 is 7(3NacPh)W, 7BrW, 7MeW, or W. In some embodiments, X7 is 7MeW.

[0120] In some embodiments, R 1a It is MeCO, Z peg or Z 脂质 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 In some embodiments, X 10 It is AEF-Z 脂质 In some embodiments, X 11 is substituted or unsubstituted 2Nal or substituted or unsubstituted 3Quin. 11 is substituted or unsubstituted 2Nal. In some embodiments, X 12 is THP. In some embodiments, X 12 It is THP-Z 脂质 In some embodiments, X 13 is E. In some embodiments, X13 It's EZ 脂质 In some embodiments, X 14 Is N. In some embodiments, X 14 It's NZ 脂质 In some embodiments, X 16 Is Sar. In some embodiments, X 16 is NMeK(d). In some embodiments, X 16 It's KZ 脂质 In some embodiments, X 16 It's Dab-Z 脂质 In some embodiments, X 16 It is NMeK-Z 脂质 In some embodiments, X 17 It's KZ 脂质 In some embodiments, X 17 It's Dab-Z 脂质 In some embodiments, X 17 It is NMeK-Z 脂质 In some embodiments, X 17 In some embodiments, R 2a is CONH2. In some embodiments, R 2a is CONMe2. In some embodiments, R 2a CONH-Z peg In some embodiments, R 2a CO-Z 脂质 .

[0121] In some embodiments, the lipidated peptide comprises an amino acid sequence of Formula (B):

[0122] 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), or a pharmaceutically acceptable salt thereof, wherein:

[0123] R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ;

[0124] X3 is any amino acid or absent;

[0125] X4 is any amino acid;

[0126] X5 is any amino acid;

[0127] X6 is any amino acid;

[0128] X7 is 7MeW or W;

[0129] X8 is any amino acid;

[0130] X9 is any amino acid;

[0131] X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z peg 、TMAPF-Z 脂质 、APEG3F、AEF-Z peg or AEF-Z 脂质 ;

[0132] X 11 is any amino acid;

[0133] X 12 is any amino acid;

[0134] X 13 is any amino acid;

[0135] X 14 is any amino acid;

[0136] X 16 is any amino acid;

[0137] X 17 is any amino acid or absent;

[0138] R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z 脂质 ;

[0139] Z peg is independently at each occurrence a polyethylene glycol chain;

[0140] Z 脂质 is independently at each occurrence a lipophilic substituent;

[0141] wherein the polypeptide is contained in a 1a ,X3,X4 X5,X6,X8,X9 X 10 、X 11 、X 12 、X 13 、X 14 、X 16 、X 17 or R2a at least one lipophilic substituent or polyethylene glycol chain at position ; and

[0142] wherein the peptide is cyclized to form a first loop, wherein the first loop comprises 4 to 14 amino acids.

[0143] In some embodiments of the peptide of Formula (B),

[0144] R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ;

[0145] X3 is r, k(d), kZ 脂质 , dab-Z 脂质 、NMek-Z 脂质 or does not exist;

[0146] X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0147] X5 is E, N, N(NMe2), K(d), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0148] X6 is T, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ;

[0149] X7 is 7MeW or W;

[0150] X8 is K(Ac), K(d), K(NMeAc), Q, KZ 脂质 , KZ peg 、NMeK-Z 脂质 , Dab-Z 脂质 , Dab(NMecarn) or Dab-Z peg ;

[0151] X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3);

[0152] X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z peg 、TMAPF-Z 脂质 、APEG3F、AEF-Z peg or AEF-Z 脂质 ;

[0153] X 11 It is 2Nal or 6OH2Nal;

[0154] X 12 It's THP, KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0155] X 13 is E, K(Ac), K(d), KZ peg ,K(NMeAc),Dab(NMecarn),E(OAll),KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 ;

[0156] X 14 It's N, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ;

[0157] X 16 It is Sar, NMeK(d), KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0158] X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0159] R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z 脂质 ;

[0160] Z peg is independently at each occurrence a polyethylene glycol chain;

[0161] Z 脂质 is independently at each occurrence a lipophilic substituent;

[0162] wherein the peptide comprises a bond between residues at X4 and X9; and

[0163] wherein the polypeptide is contained in a 1a 、X3、X5、X6、X8、X 10 、X 12 、X 13 、X14 、X 16 、X 17 or R 2a At least one lipophilic substituent at the position of, or at least one lipophilic substituent selected from R 1a , X8, X 10 、X 13 or R 2a The polyethylene glycol chain is positioned at the position of .

[0164] In some embodiments of the peptide of Formula (B),

[0165] R 1a It is MeCO, Z peg , Z 脂质 or 5cpaCO;

[0166] X3 is r, k(d), kZ 脂质 , dab-Z 脂质 、NMek-Z 脂质 or does not exist;

[0167] X4 is Pen;

[0168] X5 is E, N, N(NMe2), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ;

[0169] X6 is T;

[0170] X7 is 7MeW;

[0171] X8 is K(Ac), K(d), K(NMeAc), KZ 脂质 , KZ peg 、NMeK-Z 脂质 , Dab-Z lipids or Dab-Z peg ;

[0172] X9 is Pen;

[0173] X 10 AEF, TMAPF, APEG3F, AEF-Z peg or AEF-Z 脂质 ;

[0174] X 11 It is 2Nal or 6OH2Nal;

[0175] X 12 It is THP;

[0176] X 13 It is E, K(Ac), KZ peg、K(NMeAc)、KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂 quality;

[0177] X 14 It is N;

[0178] X 16 Is Sar or NMeK-Z 脂质 ;

[0179] X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist;

[0180] R 2a CONH2, CONMe2, CONH-Z peg or CO-Z 脂质 ;

[0181] wherein the peptide comprises a disulfide bond between residues at X4 and X9; and

[0182] wherein the polypeptide is contained in a 1a , X3, X5, X8, X 10 、X 13 、X 16 、X 17 or R 2a At least one lipophilic substituent at the position of, or at least one lipophilic substituent selected from R 1a , X8, X 10 、X 13 or R 2a The polyethylene glycol chain is positioned at the position of .

[0183] In some embodiments of the peptide of Formula (B), R 1a It is MeCO, Z peg , Z 脂质 Or 5cpaCO. In some embodiments, R 1a is an N-capping group. In some embodiments, R 1a is MeCO. In some embodiments, R 1a is 5cpaCO. In some embodiments, R 1a It's Z peg In some embodiments, R 1a It's Z 脂质 .

[0184] In some embodiments of the peptide of Formula (B), X3 is r, k(d), kZ 脂质 , dab-Z 脂质、NMek-Z 脂质 In some embodiments, X3 is r, k(d) or is absent. In some embodiments, X3 is kZ 脂质 , dab-Z 脂质 or NMek-Z 脂质 In some embodiments, X3 is r. In some embodiments, X3 is k(d). In some embodiments, X3 is kZ 脂质 In some embodiments, X3 is dab-Z 脂质 In some embodiments, X3 is NMek-Z 脂质 In some embodiments, X3 is absent.

[0185] In some embodiments of the peptide of Formula (B), X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is 4-aminoPro. 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.

[0186] In some embodiments of the peptide of formula (B), X5 is E, N, N(NMe2), K(d), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 In some embodiments, X5 is E, N, N(NMe2) or K(d). In some embodiments, X5 is KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 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 脂质 In some embodiments, X5 is Dab-Z 脂质 In some embodiments, X5 is NMeK-Z 脂质 .

[0187] In some embodiments of the peptide of formula (B), X6 is T, KZ 脂质 、NMeK-Z脂质 or Dab-Z 脂质 In some embodiments, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 In some embodiments, X6 is T. In some embodiments, X6 is KZ 脂质 In some embodiments, X6 is NMeK-Z 脂质 In some embodiments, X6 is Dab-Z 脂质 .

[0188] 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.

[0189] In some embodiments of the peptide of formula (B), X8 is K(Ac), K(d), K(NMeAc), Q, KZ 脂质 , KZ peg 、NMeK-Z 脂质 , Dab-Z 脂质 , 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 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 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 脂质 In some embodiments, X8 is KZ peg In some embodiments, X8 is NMeK-Z 脂质 In some embodiments, X8 is Dab-Z 脂质 In some embodiments, X8 is Dab(NMecarn). In some embodiments, X8 is Dab-Z peg .

[0190] In some embodiments of the 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).

[0191] In some embodiments of the peptide of Formula (B), X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z peg 、TMAPF-Z 脂质 、APEG3F、AEF-Z peg or AEF-Z 脂质 In some embodiments, X 10 is AEF, TMAPF, AEF(d) or APEG3F. In some embodiments, X 10 It is TMAPF-Z peg or AEF-Z peg In some embodiments, X 10 It is TMAPF-Z 脂质 or AEF-Z 脂质 In some embodiments, X 10 In some embodiments, X 10 is TMAPF. In some embodiments, X 10 is AEF(d). In some embodiments, X 10 It is TMAPF-Z peg In some embodiments, X 10 It is TMAPF-Z 脂质 In some embodiments, X 10 is APEG3F. In some embodiments, X 10 It is AEF-Z peg In some embodiments, X 10 It is AEF-Z 脂质 .

[0192] In some embodiments of the peptide of Formula (B), X 11 Is 2Nal or 6OH2Nal. In some embodiments, X 11 In some embodiments, X 11 It's 6OH2Nal.

[0193] In some embodiments of the peptide of Formula (B), X12 It's THP, KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 In some embodiments, X 12 It's KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 In some embodiments, X 12 is THP. In some embodiments, X 12 It's KZ 脂质 In some embodiments, X 12 It's Dab-Z 脂质 In some embodiments, X 12 It is NMeK-Z 脂质 .

[0194] In some embodiments of the peptide of Formula (B), X 13 is E, K(Ac), K(d), KZ peg ,K(NMeAc),Dab(NMecarn),E(OAll),KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 In some embodiments, X 13 is E, K(Ac), K(d), K(NMeAc), Dab(NMecarn), E(OAll). In some embodiments, X 13 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 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 It's 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 It's KZ 脂质 In some embodiments, X 13 It's Dab-Z 脂质 In some embodiments, X 13 It is NMeK-Z 脂质 .

[0195] In some embodiments of the peptide of Formula (B), X 14 It's N, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 In some embodiments, X 14 It's KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 In some embodiments, X 14 Is N. In some embodiments, X 14 It's KZ 脂质 In some embodiments, X 14 It is NMeK-Z 脂质 In some embodiments, X 14 It's Dab-Z 脂质 .

[0196] In some embodiments of the peptide of Formula (B), X 16 It is Sar, NMeK(d), KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 In some embodiments, X 16 Is Sar or NMeK(d). In some embodiments, X 16 It's KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 In some embodiments, X 16 Is Sar. In some embodiments, X 16 is NMeK(d). In some embodiments, X 16 It's KZ 脂质 In some embodiments, X 16 It's Dab-Z 脂质 In some embodiments, X 16 It is NMeK-Z 脂质 In some embodiments, X 16 Does not exist.

[0197] In some embodiments of the peptide of Formula (B), X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 In some embodiments, X 17 It's KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 In some embodiments, X17 It's KZ 脂质 In some embodiments, X 17 It's Dab-Z 脂质 In some embodiments, X 17 It is NMeK-Z 脂质 In some embodiments, X 17 Does not exist.

[0198] In some embodiments of the peptide of Formula (B), R 2a CONH2, CONMe2, CONH-Z peg or CO-Z 脂质 In some embodiments, R 2a is a C-terminal capping group. In some embodiments, R 2a is CONH2, CONMe2. In some embodiments, R 2a It is CONH-Z peg or CO-Z 脂质 In some embodiments, R 2a is CONH2. In some embodiments, R 2a is CONMe2. In some embodiments, R 2a CONH-Z peg In some embodiments, R 2a CO-Z 脂质 .

[0199] In some embodiments, X4 and X9 are linked by a disulfide bond.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] In some embodiments, X4 is 4-aminoPro and X9 is D. In some embodiments, X4 is 4-aminoPro and X9 is E. In some embodiments, X4 is 4-aminoPro and X9 is hE.

[0208] 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.

[0209] In some embodiments, X4 is Pra and X9 is Dap(N3).In some embodiments, X4 is aG and X9 is aG.

[0210] In some embodiments, the peptide is cyclized via a bond between two amino acid residues (e.g., at X4 and X9) and has a structure selected from the group consisting of:

[0211]

[0212]

[0213]

[0214] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9, having a structure selected from the group consisting of:

[0215]

[0216] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9, having the following structure:

[0217]

[0218] In some embodiments, the peptide comprises a peptide having the structure 10 The key between:

[0219]

[0220] In some embodiments, the peptide is cyclized to form a first loop, wherein the first loop comprises 4 to 11 or 14 amino acids. In some embodiments, the first loop comprises 4 to 9 or 11 amino acids. In some embodiments, the first loop comprises 4, 6, or 10 amino acids. In some embodiments, the first loop comprises 4 amino acids. In some embodiments, the first loop comprises 5 amino acids. In some embodiments, the first loop comprises 6 amino acids. In some embodiments, the first loop comprises 7 amino acids. In some embodiments, the first loop comprises 8 amino acids. In some embodiments, the first loop comprises 9 amino acids. In some embodiments, the first loop comprises 10 amino acids. In some embodiments, the first loop comprises 11 amino acids. In some embodiments, the first loop comprises 14 amino acids.

[0221] In some embodiments, the first loop comprises a bond between two amino acids having a structure selected from the group consisting of:

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229] In some embodiments, the first loop comprises a bond between the N-terminus of the peptide and an amino acid and has a structure selected from the group consisting of:

[0230]

[0231]

[0232] In some embodiments, the first ring is between X4 and X9, X4 and X 13 , X5 and X 10 , X3 and X 13In some embodiments, the first ring is formed between X4 and X9, 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 , X5 and X 10 , X3 and X 13 In some embodiments, the first ring is formed between X4 and X9, X4 and X9 via a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 , X5 and X 10 , X3 and X 13 Or formed between X6 and X9.

[0233] In some embodiments, the first ring is between X4 and X9, X4 and X 13 In some embodiments, the first ring is formed between X4 and X9, 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 In some embodiments, the first ring is formed between X4 and X9, X4 and X9 via a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 Or formed between X6 and X9.

[0234] In some embodiments, the first ring is formed between X4 and X9. In some embodiments, the first 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, the first ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0235] In some embodiments, the first ring is between X4 and X 13 In some embodiments, the first ring is formed between X4 and X4 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 X4 and X through a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 Formed between.

[0236] In some embodiments, the first ring is between X5 and X 10 In some embodiments, the first ring is formed between X5 and X5 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 X5 and X5 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 10 Formed between.

[0237] In some embodiments, the first ring is between X3 and X 13 In some embodiments, the first ring is formed between X3 and X3 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 X3 and X3 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 13 Formed between.

[0238] In some embodiments, the first ring is formed between X6 and X9. 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 disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. In some embodiments, the first ring is formed between X6 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0239] In some embodiments, the peptide is further cyclized to form a second loop, wherein the second loop comprises 4 to 14 amino acids. In some embodiments, the peptide is further cyclized to form a second loop, wherein the second loop comprises 4 to 11 or 14 amino acids. In some embodiments, the second loop comprises 4 to 9 or 11 amino acids. In some embodiments, the second loop comprises 4, 6, 10 or 11 amino acids. In some embodiments, the second loop comprises 4 amino acids. In some embodiments, the second loop comprises 5 amino acids. In some embodiments, the second loop comprises 6 amino acids. In some embodiments, the second loop comprises 7 amino acids. In some embodiments, the second loop comprises 8 amino acids. In some embodiments, the second loop comprises 9 amino acids. In some embodiments, the second loop comprises 10 amino acids. In some embodiments, the second loop comprises 11 amino acids. In some embodiments, the second loop comprises 14 amino acids.

[0240] In some embodiments, the second loop comprises a bond between two amino acids and has a structure selected from the group consisting of:

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] In some embodiments, the second loop comprises a bond between the N-terminus of the peptide and an amino acid and has a structure selected from the group consisting of:

[0249]

[0250]

[0251] In some embodiments, the second ring is between X4 and X9, X4 and X 13 , X5 and X 10 , X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, 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 , X5 and X 10 , X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, X4 and X9 via a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 , X5 and X 10 , X3 and X 13 Or formed between X6 and X9.

[0252] In some embodiments, the second ring is between X5 and X 10 or X3 and X 13 In some embodiments, the second ring is formed between X5 and X5 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 10 or X3 and X 13 In some embodiments, the second ring is formed between X5 and X5 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 10 or X3 and X 13 In some embodiments, the second ring is formed between X5 and X5 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 10 or X3 and X 13 Formed between.

[0253] In some embodiments, the second ring is formed between X4 and X9. In some embodiments, the 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, the second ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0254] In some embodiments, the second ring is between X4 and X 13 In some embodiments, the second ring is formed between X4 and X5 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 X4 and X through a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 Formed between.

[0255] In some embodiments, the second ring is between X5 and X 10 In some embodiments, the second ring is formed between X5 and X5 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 X5 and X5 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 10 Formed between.

[0256] In some embodiments, the second ring is between X3 and X 13 In some embodiments, the second ring is formed between X3 and X3 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 X3 and X3 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 13 Formed between.

[0257] In some embodiments, the second ring is formed between X6 and X9. In some embodiments, the second ring is formed between X6 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, the second ring is formed between X6 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0258] In some embodiments, the second ring is in X 13In some embodiments, the second ring is formed between X and the N-terminus of the peptide 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 loop is formed between X and the N-terminus of the peptide via a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole. 13 Formed between the N-terminus of the peptide.

[0259] In some embodiments, the first ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylenes, and triazoles; and the second ring is formed between X3 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylenes, and triazoles. 13 Between X5 and X 10 Between, X 10 With X 13 Between, or X 13 Formed between the N-terminus of the peptide.

[0260] In some embodiments, the first ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles; and the second ring is formed between X3 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles. 13 Between X5 and X 10 Between, X 10 With X 13 Between or X 13 between the N-terminus of the peptide.

[0261] In some embodiments, the first ring is connected to X4 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 and the second ring is formed between X5 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 or between X6 and X9.

[0262] In some embodiments, the first ring is connected to X4 via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole. 13 and the second ring is formed between X5 and X via a linker selected from the group consisting of disulfide, thioether, amide, olefin and triazole 10 or between X6 and X9.

[0263] 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 disulfides, thioethers, amides, alkenes, ethers, alkylenes, and triazoles; and the second ring is formed between X3 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylenes, and triazoles. 13 Between X4 and X 13 Between X5 and X 10 Between, X 10 With X 13 Between, or X 13 Formed between the N-terminus of the peptide.

[0264] In some embodiments, the first ring is formed between X6 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles; and the second ring is formed between X3 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles. 13 Between X4 and X 13 Between X5 and X 10 Between, X 10 With X 13 Between, or X 13 between the N-terminus of the peptide.

[0265] In some embodiments, the peptide comprises at least one polyethylene glycol chain. In 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.

[0266] In some embodiments, each polyethylene glycol chain independently terminates in an ammonium group or 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.

[0267] In some embodiments, the peptide comprises a polyethylene glycol chain having the following structure:

[0268]

[0269] in:

[0270] Z A -OCH3, -N + (CH3)3, and

[0271] n is an integer from 2 to 24.

[0272] In some embodiments, the peptide comprises a polyethylene glycol chain having the following structure:

[0273]

[0274] In some embodiments, the peptide comprises a polyethylene glycol chain having the following structure:

[0275]

[0276] in:

[0277] Z A Yes-N + (CH3)3; and

[0278] n is an integer from 2 to 24.

[0279] 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.

[0280] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a polyethylene glycol chain.

[0281] Non-limiting examples of polyethylene glycol chains are provided in Table A.

[0282] Table A. Exemplary polyethylene glycol chains

[0283]

[0284]

[0285]

[0286]

[0287] 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.

[0288] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0289]

[0290] in:

[0291] Z B yes

[0292] Z C It's Z C1 , Z C2 or Z C3 ;

[0293] Z C1 yes

[0294] Z C2 yes

[0295] Z C3 yes

[0296] Z D yes

[0297] Z E is -H, -COOH or tetrazolyl;

[0298] Z F is -H or -CH3;

[0299] Xaa is independently

[0300] p is independently 0, 1, 2, 3, 4, 5, or 6 at each occurrence;

[0301] q is 1, 2, 3, 4, 5, or 6;

[0302] r is an integer from 6 to 24;

[0303] v is 0 or 1; and

[0304] w is independently 0 or 1 at each occurrence.

[0305] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0306]

[0307] in:

[0308] Z C2 yes

[0309] Z D yes

[0310] ZE is -H, -COOH or tetrazolyl;

[0311] Z F is -H or -CH3;

[0312] Xaa is

[0313] p is independently 1, 2, 3, 4, 5, or 6 at each occurrence;

[0314] q is 1, 2, 3, 4, 5, or 6;

[0315] r is an integer from 6 to 24; and

[0316] w is independently 0 or 1 at each occurrence.

[0317] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0318]

[0319] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0320]

[0321] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0322]

[0323] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0324]

[0325] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0326]

[0327] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0328]

[0329] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0330]

[0331] in:

[0332] Z B yes

[0333] Z C It's Z C1 , Z C2 or Z C3 ;

[0334] Z C1 yes

[0335] Z C2 yes

[0336] Z C3 yes

[0337] Z D yes

[0338] Z E is -H, -COOH or tetrazolyl;

[0339] Z F is -H or -CH3;

[0340] Xaa is independently

[0341] p is independently 1, 2, 3, 4, 5, or 6 at each occurrence;

[0342] q is 1, 2, 3, 4, 5, or 6;

[0343] r is an integer from 6 to 24;

[0344] v is 0 or 1; and

[0345] w is independently 0 or 1 at each occurrence.

[0346] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0347]

[0348] in:

[0349] Z C2 yes

[0350] Z D yes

[0351] Z E is -H, -COOH or tetrazolyl;

[0352] Z F is -H or -CH3;

[0353] Xaa is

[0354] p is independently 1, 2, 3, 4, 5, or 6 at each occurrence;

[0355] q is 1, 2, 3, 4, 5, or 6;

[0356] r is an integer from 6 to 24; and

[0357] w is independently 0 or 1 at each occurrence.

[0358] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0359]

[0360] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0361]

[0362] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0363]

[0364] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0365]

[0366] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0367]

[0368] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0369]

[0370] In some embodiments, Z c yes

[0371] In some embodiments, Z D yes

[0372] In some embodiments, Z D yes

[0373] In some embodiments, Z Eis -H. In some embodiments, Z E In some embodiments, Z E It is a tetrazolyl group.

[0374] In some embodiments, Z F is -H. In some embodiments, Z F It is -CH3.

[0375] In some embodiments, Xaa at each occurrence is independently

[0376] In some embodiments, Xaa is

[0377] 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.

[0378] 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.

[0379] 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.

[0380] In some embodiments, w is 0. In some embodiments, w is 1.

[0381] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a lipophilic substituent.

[0382] In some embodiments, the lipophilic substituent is selected from Table Bl.

[0383] Table B1. Exemplary lipophilic substituents

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393] Further non-limiting examples of lipophilic substituents are provided in Table B2.

[0394] Table B2. Exemplary lipophilic substituents

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405] In some embodiments, the lipophilic substituent is selected from PEG2PEG2GolAC18OH, PEG2PEG2SP6gEC18OH, PEG2PEG6gEC18OH, PEG2PEG2gE(c)C18OH, PEG2PEG2gEC18OH, or PEG12gEC18OH.

[0406] Specifically, the present disclosure relates to oral pharmaceutical formulations comprising lipidated cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, wherein each lipidated cyclic peptide is a compound having the formula as identified in Table 1.

[0407] Table 1. Compounds

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448] In the peptide sequences shown above, when a number in parentheses follows a particular residue, that residue is linked to another residue in the sequence denoted by the same number. For example, in the sequence MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-K(PEG12NMegENMeC18OH)-CONH2 (SEQ ID NO:40), two Pen(3) residues are linked to each other.

[0449] synthesis

[0450] The compounds or lipidated peptides described herein can be synthesized by a number of techniques known to those skilled in the art. In certain aspects, monomeric subunits are synthesized and purified using the techniques described in the accompanying examples.

[0451] In some aspects, the present disclosure provides a method for producing a compound of the present disclosure (or its monomeric subunit), the method comprising chemically synthesizing a peptide having an amino acid sequence as described herein, including but not limited to any of the amino acid sequences set forth in the compounds of Formula I to Formula V or Table 1 herein. In some aspects, a portion of the peptide is recombinantly synthesized rather than chemically synthesized. In some aspects, the method for producing the compound further comprises cyclizing the compound precursor after the component subunits have been connected. In particular aspects, cyclization is accomplished via any of the various methods described herein.

[0452] The present disclosure may include, but is not limited to, polynucleotides and vectors (eg, expression vectors) encoding a portion of the amino acid sequence of a compound described herein, such as in the accompanying Examples or Table 1.

[0453] The present disclosure further describes the synthesis of lipidated compounds described herein, such as compounds of Formula I to Formula V and compounds of Table 1.

[0454] In some aspects, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked to each other to form the compounds of the disclosure.

[0455] In some aspects, one or more of the amino acid residues or amino acid monomers are covalently linked to each other and lipidated at an intermediate oligomer stage prior to attachment of additional amino acids and cyclization to form the compounds of the disclosure.

[0456] In some aspects, cyclic peptides are synthesized and then lipidated to form compounds of the disclosure. Exemplary synthetic methods are described in the following examples.

[0457] This disclosure further describes the synthesis of compounds described herein, such as compounds of Formulas I through V and compounds of Table 1. Exemplary synthetic methods are described in the following Examples.

[0458] IV. Pharmaceutical Compositions

[0459] In general, the present disclosure relates to oral pharmaceutical formulations comprising lipidated peptide inhibitors of interleukin-23 receptor (IL-23R), or pharmaceutically acceptable salts or solvates thereof, and an absorption enhancer, as well as methods and / or uses thereof for increasing the bioavailability of the lipidated peptides and / or for treating autoimmune inflammatory and related diseases and disorders.

[0460] In one aspect, the present disclosure provides oral pharmaceutical formulations comprising one or more inhibitors of the present disclosure and one or more absorption enhancers as provided herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0461] The pharmaceutically acceptable carrier, diluent or excipient may be a solid, semisolid or liquid filler, diluent, encapsulating material or any type of formulation aid. Protection against the action of microorganisms may 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, sodium chloride, etc.

[0462] The lipidated peptides of the present disclosure as provided herein can be prepared and / or formulated as pharmaceutically acceptable salts or neutral forms when appropriate. Pharmaceutically acceptable salts are non-toxic salts of neutral forms of compounds that have the desired pharmacological activity of the neutral form. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared into pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butynes, thiazolinones ... The pharmaceutically acceptable salts of the present invention include, for example, benzoic acid salt, benzoylmethanesulfonate ...

[0463] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and NX4. + (wherein X is C1-C4 alkyl). Also included are base addition salts such as sodium or potassium salts.

[0464] The present disclosure relates to oral pharmaceutical compositions comprising an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by 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 used to increase the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, 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 methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0465] Examples of isotopes that may be incorporated into the compounds of the present disclosure also 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 used for positron emission tomography (PET) studies to examine 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 methods analogous to those described in the examples set forth below using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed.

[0466] In some embodiments, the present disclosure provides oral pharmaceutical formulations comprising an absorption enhancer as provided herein and a lipidated peptide as provided herein.

[0467] In some embodiments, the peptide in the oral pharmaceutical formulation as provided herein comprises the amino acid sequence of Formula (A).

[0468] In some embodiments, the peptide in the oral pharmaceutical formulation as provided herein comprises the amino acid sequence of Formula (B).

[0469] In some embodiments, the peptide in the oral pharmaceutical formulations as provided herein is a compound having the formula:

[0470]

[0471]

[0472] or a pharmaceutically acceptable salt or solvate thereof,

[0473] in:

[0474] L is -O-, -S-, or -SS-;

[0475] R1, R2, R3, R4, R5, R6, R8, R9 and R 10 are independently H, CH3, -C(=O)CH3, -C(=O)NHR 11 、 -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)nNHR12 or -C(=O)(CH2) n OR 12 ;

[0476] R7 is -(CH2) p NHR 13 or -(CH2) q NHC(=NH)NH2;

[0477] each m, n, p and q are independently 1, 2, 3, 4 or 5;

[0478] Each R 11 、R 12 、R 13 and R 14 is independently H or a lipid moiety.

[0479] In some embodiments, the peptide in the oral pharmaceutical formulations provided herein for the peptide is a compound having the formula:

[0480]

[0481] In some embodiments, the peptide in the oral pharmaceutical formulations as provided herein is a compound having the formula:

[0482]

[0483] In some embodiments, the peptide in the oral pharmaceutical formulations as provided herein is a compound having the formula:

[0484]

[0485] In some embodiments, each lipid moiety is independently selected from the group Z1 to Z5:

[0486] Z1 is

[0487]

[0488] in:

[0489] PEG is -OCH2CH2-;

[0490] n' is 0 or 2 to 24, when n' is 0, the group is absent and is replaced by a bond;

[0491] m' is 0 or 2 to 24. When m' is 0, the group is absent and is replaced by a bond;

[0492] v' is independently selected at each occurrence from the range of 1 to 4;

[0493] v" is independently selected at each occurrence from the range of 0 to 4, when v" is 0, the group is replaced by a bond;

[0494] X is gE, dgE, 4SB, P, PPP, gE-(c), gE-(C), sp6, gDab, eK, Trx, or absent;

[0495] o' is 6 to 18;

[0496] Y is gE, sp6, GolA, Pro, D-Pro, meG, Dab, Trx, or absent;

[0497] U is hydrogen or methyl;

[0498] V is -COOH, tetrazole, GolB, mXOH, pXOH, O-phenyl, carnitine, d-carnitine, or hydrogen;

[0499] Z2 is

[0500]

[0501] in:

[0502] PEG is -OCH2CH2-;

[0503] n' is 0 or 2 to 24, when n' is 0, the group is absent and is replaced by a bond;

[0504] m' is independently selected at each occurrence from 0 or from the range of 2 to 24, when m' is 0, the group is replaced by a bond;

[0505] v' is independently selected at each occurrence from the range of 1 to 4;

[0506] v" is independently selected at each occurrence from the range of 0 to 4, when v" is 0, the group is replaced by a bond;

[0507] p' is 1 to 3;

[0508] V' is sp6 or gEgE;

[0509] X is gE, dgE, 4SB, P, PPP, gE-(c), gE-(C), sp6, gDab, eK, Trx, or absent;

[0510] Y is gE, sp6, GolA, Pro, D-Pro, meG, Dab, Trx, or absent;

[0511] X is Trx;

[0512] U is hydrogen or methyl;

[0513] o' is 6 to 18;

[0514] V is -COOH, tetrazole, GolB, mXOH, pXOH, O-phenyl, carnitine, d-carnitine, or hydrogen;

[0515] Z3 is -gE-C(O)(CH2) 6-10 CH3 or -gE-C(O)(CH2) 11-18 CH3;

[0516] Z4 is -C(O)(CH2) 6-18 COOH or -C(O)(CH2) 6-18 COO(C1-4 alkyl);

[0517] The Z5 is

[0518]

[0519] in:

[0520] n" and m" are independently selected from the range of 0 to 24;

[0521] X is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx;

[0522] Y is absent or selected from the group consisting of E, dgE, 4SB, gE-(c), gE-(C), sp6, gDab, eK, or Trx; and

[0523] Xaa is diaminocarboxylic acid.

[0524] In some embodiments, each lipid portion of a peptide in an oral pharmaceutical formulation as provided herein is

[0525]

[0526] in:

[0527] Z B yes

[0528] Z C It's Z C1 , Z C2 or Z C3 ;

[0529] Z C1 yes

[0530] Z C2 yes

[0531] Z C3 yes

[0532] Z D yes

[0533] Z E is -H, -COOH, phenoxy or tetrazolyl;

[0534] Z F is -H or -CH3;

[0535] Xaa a In each occurrence, independently

[0536] p a is, independently at each occurrence, 0, 1, 2, 3, 4, 5, or 6;

[0537] q a is 1, 2, 3, 4, 5, or 6;

[0538] r a is an integer from 6 to 24;

[0539] v a is 0 or 1; and

[0540] w a is independently 0 or 1 at each occurrence.

[0541] In some embodiments, the lipid moiety is one of a Peg moiety and a Peg-modified monomer as shown in Table 2D.

[0542] In some embodiments, R2 is methyl.

[0543] In some embodiments, R3 is H.

[0544] In some embodiments, R4 is H.

[0545] In some embodiments, R5 is H.

[0546] In some embodiments, R8 is H.

[0547] In some embodiments, R4 is H.

[0548] In some embodiments, R9 is H.

[0549] In some embodiments, R 10 It is -C(O)CH3.

[0550] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0551]

[0552] In some embodiments, R7 is -(CH2) q C(=O)NH)NH2. In some embodiments, q is 3.

[0553] In some embodiments, the compound has the formula:

[0554]

[0555] Formula III.

[0556] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0557]

[0558] (SEQ ID NO: 1).

[0559] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula II, wherein R6 is -C(=O)CH3. In some embodiments, R7 is -(CH2) p NHR 12 In some embodiments, p is 4.

[0560] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0561]

[0562] Formula IV.

[0563] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0564]

[0565]

[0566]

[0567]

[0568]

[0569] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0570]

[0571] In some embodiments, wherein R1 is In some embodiments, m is 4.

[0572] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0573]

[0574] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula:

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583] In some embodiments, the peptide in the oral pharmaceutical formulation as provided herein is selected from the group consisting of SEQ ID NOs: 1-40.

[0584] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is present in an oral pharmaceutical composition as provided herein in an amount of about 0.1% (w / w) 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 thereof, in the oral pharmaceutical composition as provided herein is in the range of 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 thereof, is in the range of 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 thereof, is in the range of 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 thereof, is in the range of about 1 to about 10.

[0585] In some embodiments, the ratio of absorption enhancer to lipidated peptide is no more than 50:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no more than 40:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no more than 30:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no more than 20:1 (w / w).

[0586] In some embodiments, the ratio of absorption enhancer to lipidated peptide is no less than 3:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no less than 5:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no less than 7:1 (w / w). In some embodiments, the ratio of absorption enhancer to lipidated peptide is no less than 9:1 (w / w).

[0587] 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).

[0588] 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).

[0589] 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 or 50:1 (w / w).

[0590] 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.

[0591] In some embodiments, the absorption enhancer in the oral pharmaceutical composition as provided herein includes one or more of sodium caprylate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, saprolactam sodium (SNAC), polyethylene glycol (PEG)-modified medium-chain fatty acid triglycerides of capric and caprylic acid, sucrose laurate, sodium octanoate, labrasol, and lauroyl-L-carnitine (LC). In some embodiments, the absorption enhancer includes saprolactam sodium (SNAC). In some embodiments, the absorption enhancer includes lauroyl-L-carnitine (LC). In some embodiments, the absorption enhancer includes sodium caprylate. In some embodiments, the absorption enhancer includes sodium labrasol. In some embodiments, the absorption enhancer includes sodium caprate. In some embodiments, sodium caprate is present in an amount of about 1% (w / w) to about 99% (w / w). In some embodiments, sodium caprate has a purity of at least 98%.

[0592] In some embodiments, the oral pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients.

[0593] 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-fold to about 500-fold. In some embodiments, the oral pharmaceutical formulation improves the oral bioavailability of the compound by about 2-fold to about 250-fold.

[0594] The present disclosure also provides a method for increasing the bioavailability of a compound in an oral pharmaceutical formulation as provided herein in a subject, the method comprising oral administration of the compound or its pharmaceutically acceptable salt or solvate form, and an absorption enhancer. In some embodiments, the method includes an absorption enhancer, which includes one or more of sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium saporisate (SNAC), a medium-chain fatty acid triglyceride of capric and caprylic acid modified by polyethylene glycol (PEG), sucrose laurate, sodium caprylate (sodium octanoate), labrasol, and lauroyl-L-carnitine (LC). In some embodiments, the compound or its pharmaceutically acceptable salt or solvate form is co-administered with an absorption enhancer. In some embodiments, the compound or its pharmaceutically acceptable salt or solvate form is co-administered with an enhancer in a pharmaceutically acceptable formulation as provided herein.

[0595] The present disclosure also provides methods for preparing a medicament for treating an inflammatory disorder or an autoimmune inflammatory disorder using an oral pharmaceutical formulation as provided herein. In some embodiments, an oral pharmaceutical formulation as provided herein is used to prepare a medicament for treating autoimmune inflammation and related diseases and disorders, including but not limited to multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, youth 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 innate immune disorders 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, or erythrodermic psoriasis), atopic dermatitis, atopic 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 following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, 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).

[0596] The present disclosure also provides 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 as 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, young adult 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 innate immune disorders 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, palmar erythroderma, cerebrospinal fluid, inflammatory bowel disease (IBD), inflammatory bowel disease (IBD), juvenile IBD, juvenile 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 innate immune disorders 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, pust Plantar pustulosis, psoriasis vulgaris or erythrodermic psoriasis), atopic dermatitis, atopic 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 following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, 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).

[0597] Generally speaking, the oral pharmaceutical compositions of the present disclosure can be prepared into different dosage forms, which are prepared using conventional materials and techniques known in the art of medicine and formulation, which may include, but are not limited to, techniques such as mixing, blending, etc., as well as as described throughout this disclosure. In addition, the pharmaceutical composition used to form the dosage form may also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, and may be in solid or liquid form, such as solid or liquid dosage forms, which may include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions, etc. According to the present disclosure, the solid unit dosage form may be other conventional types known in the art.

[0598] In addition, suitable for use in the present disclosure are solutions, which may be, but are not limited to, water, saline, aqueous dextrose solutions and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol, buffered solutions, etc. are preferred liquid carriers, especially for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0599] The oral pharmaceutical compositions of the compositions of the present disclosure may include various other pharmaceutically acceptable components or excipients, such as, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients, etc. These components are described herein.

[0600] In some aspects, the oral pharmaceutical compositions of the present disclosure may not include or may exclude the use of absorption enhancers, depending on their intended delivery or use and / or for the treatment of a specific indication as defined in the present disclosure.

[0601] In other aspects, suitable oral pharmaceutical compositions of the present disclosure may exhibit improved bioavailability when administered in conjunction with absorption enhancers, such as, but not limited to, intestinal permeation enhancers.

[0602] In some aspects, the oral pharmaceutical composition of the present disclosure may include an absorption or penetration enhancer. When present, the absorption or penetration enhancer can be, but is not limited to, the following forms: zwitterions, cations, anions, or non-ions. In one aspect, the absorption or penetration enhancer is an intestinal permeation or absorption enhancer. In some aspects, the absorption enhancer can 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) and the like.

[0603] Other absorption or penetration enhancers may include, but are not limited to, citric acid or a citrate such as sodium citrate, tartaric acid or a tartrate, salicylic acid or a derivative thereof, or a salicylate, fatty acid acylated amino acids, alkyl sugars, C8-o alkyl polysaccharides, n-octyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, n-tetradecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monolaurate, sucrose monotridecanoate, sucrose monotetradecanoate, coconut glucoside, cyclodextrins, alkanoylcarnitines such as lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine, lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride, fatty acid acylated amino acids,Including but not limited to sodium lauroyl alanine, N-lauroyl-L-alanine, sodium lauroyl asparagine, N-lauroyl-L-asparagine, sodium lauroyl aspartate, N-lauroyl-L-aspartic acid, sodium lauroyl cysteine, N-lauroyl-L-cysteine, sodium lauroyl glutamate, N-lauroyl-L-glutamic acid, sodium lauroyl glutamine, N-lauroyl-L-glutamine, sodium lauroyl glycinate, N-lauroyl-L-glycine, sodium lauroyl histidine, N-lauroyl-L-histidine, sodium lauroyl isoleucine, N-lauroyl-L-isoleucine, Sodium lauroyl leucine, N-lauroyl-L-leucine, sodium lauroyl methionine, N-lauroyl-L-methionine, sodium lauroyl phenylalanine, N-lauroyl-L-phenylalanine, sodium lauroyl propionate, N-lauroyl-L-proline, sodium lauroyl serine, N-lauroyl-L-serine, sodium lauroyl threonine, N-lauroyl-L-threonine, sodium lauroyl tryptophan, N-lauroyl-L-tryptophan, sodium lauroyl tyrosine, N-lauroyl-L-tyrosine, sodium lauroyl valine, N-lauroyl-L-valine, sodium lauroyl sarcosinate, N-lauroyl- L-sarcosine, sodium decanoate alanine, N-decanoyl-L-alanine, sodium decanoate asparagine, N-decanoyl-L-asparagine, sodium decanoate aspartate, N-decanoyl-L-aspartic acid, sodium decanoate cysteine, N-decanoyl-L-cysteine, sodium decanoate glutamate, N-decanoyl-L-glutamic acid, sodium decanoate glutamine, N-decanoyl-L-glutamine, sodium decanoate glycinate, N-decanoyl-L-glycine, sodium decanoate histidine, N-decanoyl-L-histidine, sodium decanoate isoleucine, N-decanoyl-L-isoleucine, sodium decanoate leucine, N-decanoyl-L-leucine, Sodium methionine decanoate, N-decanoyl-L-methionine, sodium phenylalanine decanoate, N-decanoyl-L-phenylalanine, sodium decanoate propionate, N-decanoyl-L-proline, sodium decanoyl serine, N-decanoyl-L-serine, sodium decanoate threonine, N-decanoyl-L-threonine, sodium decanoate tryptophan, N-decanoyl-L-tryptophan, sodium decanoate tyrosine, N-decanoyl-L-tyrosine, sodium decanoate valine, N-decanoyl-L-valine, sodium decanoate sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decyl leucine, sodium stearoyl glutamate (e.g., Amisoft HS-1 1P), Sodium Myristoyl Glutamate (e.g., Amisoft MS-1 1), Sodium Lauroyl Glutamate (e.g., Amisoft LS-1 1), Sodium Cocoyl Glutamate (e.g., Amisoft CS-1 1), Sodium Cocoyl Glycinate (e.g.,Am lite GCS-1 1), Sodium N-Decyl Leucine, Sodium Cocoyl Glycinate, Sodium Cocoyl Glutamate, Sodium Lauroyl Alanine, N-Lauroyl-L-Alanine, Sodium Lauroyl Asparagine, N-Lauroyl-L-Asparagine, Sodium Lauroyl Aspartate, N-Lauroyl-L-Aspartic Acid, Sodium Lauroyl Cysteine, N-Lauroyl-L-Cysteine, Sodium Lauroyl Glutamate, N-Lauroyl-L-Glutamate, Sodium Lauroyl Glutamine, N-Lauroyl-L-Glutamine, Sodium Lauroyl Glycinate, N-Lauroyl-L-Glycine, Sodium Lauroyl Histidine, N-Lauroyl-L-Histidine, Sodium Lauroyl Isoleucine, N-Lauroyl-L-Isoleucine Leucine, Sodium Lauroyl Leucine, N-Lauroyl-L-Leucine, Sodium Lauroyl Methionine, N-Lauroyl-L-Methionine, Sodium Lauroyl Phenylalanine, N-Lauroyl-L-Phenylalanine, Sodium Lauroyl Propionate, N-Lauroyl-L-Proline, Sodium Lauroyl Serine, N-Lauroyl-L-Serine, Sodium Lauroyl Threonine, N-Lauroyl-L-Threonine, Sodium Lauroyl Tryptophan, N-Lauroyl-L-Tryptophan, Sodium Lauroyl Tyrosine, N-Lauroyl-L-Tyrosine, Sodium Lauroyl Valine, N-Lauroyl-L-Valine, N-Lauroyl-L-Sarcosine, Sodium Decanoyl Alanine, N-Decanoyl-L-Alanine Acid, Sodium Asparagine Decanoate, N-Decanoyl-L-Asparagine, Sodium Aspartate Decanoate, N-Decanoyl-L-Aspartic Acid, Sodium Cysteine ​​Decanoate, N-Decanoyl-L-Cysteine, Sodium Glutamate Decanoate, N-Decanoyl-L-Glutamic Acid, Sodium Glutamine Decanoate, N-Decanoyl-L-Glutamine, Sodium Glycinate Decanoate, N-Decanoyl-L-Glycine, Sodium Histidine Decanoate, N-Decanoyl-L-Histidine, Sodium Isoleucine Decanoate, N-Decanoyl-L-Isoleucine, Sodium Leucine Decanoate, N-Decanoyl-L-Leucine, Sodium Methionine Decanoate, N-Decanoyl-L-Methionine, Sodium Phenylalanine Decanoate, N-Decanoyl-L-Phenylalanine, sodium decanoate proline, N-decanoyl-L-proline, sodium decanoate serine, N-decanoyl-L-serine, sodium decanoate threonine, N-decanoyl-L-threonine, sodium decanoate tryptophan, N-decanoyl-L-tryptophan, sodium decanoate caseinate, N-decanoyl-L-tyrosine, sodium decanoate valine, N-decanoyl-L-valine, sodium decanoate sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts of any of the foregoing compounds; or alkanoyl sarcosinate (e.g., lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or one of the 20 standard proteinogenic α-amino acids acylated with a C8-C20 alkanoic acid), an alkyl saccharide (e.g., a C1-C20 alkyl saccharide,Such as Multitrope™ 1620-LQ-(MV); or n-octyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, n-tetradecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-myristate, coco-glucoside, alkyl sugars, cyclodextrins (e.g., α-cyclodextrin , β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-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), polyoxyethyl castor oil (also known as "Kolliphor EL"; CAS No. 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin or alkanols (e.g., ethanol, decanol), caprylocaproyl polyoxylglycerides (such as caprylocaproyl polyoxy-8 glyceride; trade names, or MC8-2), ethyl caprylate, monolaurin, lysophosphatidylcholine, menthol, C-2o alkylamine, C8-C20 alkenylamine (e.g., oleylamine), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (e.g., polysorbate 80), cholic acid (or cholate, e.g., sodium cholate), sodium deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium lauryl ether sulfate, N-lauroyl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride or decyldimethylaminopropanesulfonate, etc.

[0604] In some aspects, absorption or permeation enhancers may include, but are not limited to, sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium saporin (SNAC), polyethylene glycol (PEG)-modified medium chain fatty acid triglycerides of capric and caprylic acid (such as those available from Gattefosse, USA), and ), sucrose laurate, or lauroyl-L-carnitine (LC, such as available from Enteris BioPharma, NJ, USA ) etc. In some respects, the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sabolisha sodium (SNAC), the medium chain fatty acid triglyceride of capric acid and caprylic acid modified by polyethylene glycol (PEG), sucrose laurate or lauroyl-L-carnitine (LC). In some respects, the absorption or penetration enhancer can be the medium chain fatty acid triglyceride of capric acid and caprylic acid modified by polyethylene glycol (PEG).

[0605] In other aspects, the absorption or penetration enhancer used can be sabolixa sodium.In some aspects, the absorption or penetration enhancer used can include but is not limited to polyethylene glycol (PEG) modified medium chain fatty acid triglycerides of capric acid and caprylic acid, etc.

[0606] 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.

[0607] 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 thereof, in an amount of about 0.1% (w / w) to about 15% (w / w) of the composition.

[0608] In some aspects, sodium caprate can be present in the composition in an amount from about 1% (w / w) to about 99% (w / w) of the composition.

[0609] In one aspect, for use in oral pharmaceutical compositions of the present disclosure, sodium decanoate 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 decanoate can provide improved bioavailability compared to lower technical grade sodium decanoate (such as 90% or 95% pure sodium decanoate). In some aspects, sodium decanoate for use in the present disclosure has a purity of at least 98%.

[0610] In another aspect, sodium decanoate can be in any form suitable for use in the oral pharmaceutical compositions of the present disclosure. In some aspects, sodium decanoate can be in a crystalline form, an amorphous form, or a semi-crystalline form. In some aspects, the use of crystalline sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure. In some aspects, the use of amorphous sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure. In some aspects, the use of semi-crystalline sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure.

[0611] In some aspects, the use of crystalline sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the use of amorphous sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In some aspects, the use of semicrystalline sodium decanoate can improve the bioavailability of the IL-23R inhibitors of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof.

[0612] 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.

[0613] V. Methods of treatment and / or uses

[0614] In one aspect, the present disclosure relates to a method or use for treating an inflammatory disease in a subject, the method or use comprising administering a therapeutically effective amount of a composition disclosed herein to the subject. In some aspects, the present disclosure provides a method for treating an inflammatory disease in a subject, the method comprising administering a therapeutically effective amount of a composition disclosed herein to the subject. Suitable inflammatory diseases treated with the formulations or compositions 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), etc.

[0615] In some aspects, the present disclosure provides methods or uses for treating a subject having a condition or indication associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), wherein the methods or uses comprise administering a composition of the present disclosure to the subject. In some aspects, a method is provided for treating a subject having a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, the method comprising administering to the subject a composition of the present disclosure in an amount sufficient to inhibit (partially or completely) the binding of IL-23 to IL-23R in the subject. In some aspects, the inhibition of IL-23 binding to IL-23R occurs in a specific organ or tissue of the subject, i.e., for example, these organs or tissues include, but are 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.

[0616] In some aspects, the methods or uses of the present disclosure may comprise providing a composition of the present disclosure to a subject in need thereof. In some aspects, the subject in need thereof has been diagnosed with or has been determined to be at risk of developing a disease or condition associated with IL-23 / IL-23R.

[0617] Each aspect of the disclosure defined in this section or any other section can be incorporated into definitions and limitations such as those set forth in Sections I through V herein, and throughout the originally filed disclosure, specification, and claims.

[0618] VI. Examples

[0619] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present disclosure. Although specific aspects of the present disclosure have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention.

[0620] Certain abbreviations that may be used to describe the present invention are defined below in Tables 2A-2G below.

[0621] Table 2A. Amino acid abbreviations

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631] Table 2B. Abbreviations for Substituents, Reagents, and Solvents

[0632]

[0633]

[0634] Table 2C. Amino acid monomers

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707] In some embodiments, naturally occurring L- and D-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid designations of Table 2C-a. In some embodiments, D-amino acids are represented by lowercase single-letter amino acid designations corresponding to the single-letter designations of 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.

[0708] Table 2C-a: Naturally occurring amino acids

[0709]

[0710] 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). An amino acid residue in the D isomeric form can replace any L-amino acid residue as long as the peptide retains the desired function. When referred to using single-letter abbreviations, D-amino acids can be indicated in lower case by convention. For example, D-arginine can be represented as "arg" or "r". Alternatively, a lower case "d" in front of an amino acid can be used to indicate that it is in the D isomeric form, for example, D-lysine can be represented by dK.

[0711] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full names (e.g., sarcosine, ornithine, etc.), the commonly employed three-letter or four-letter codes for their residues are adopted, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0712] Peptides can be naturally occurring, synthetically produced or recombinantly expressed. Peptides can also include other groups that modify the amino acid chain, such as functional groups added via post-translational modification. Examples of post-translational modifications include but are not limited to acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, prenylation, lipidation, phosphopantetheinylation, phosphorylation, selenylation and C-terminal amidation. The term peptide also includes peptides that comprise amino terminal and / or carboxyl terminal modifications. The modification of the terminal amino group includes but is not limited to deamination, N-low alkyl, N-di-low alkyl and N-acyl modifications. The modification of the terminal carboxyl group includes but is not limited to amide, low alkyl amide, dialkyl amide and low alkyl ester modifications (for example, wherein low alkyl is C1-C4 alkyl). The term peptide also includes modifications, such as but not limited to those mentioned above, where the amino acid modification falls between the amino and carboxyl terminal.

[0713] Table 2D. Peg moieties and Peg-modified monomers

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787] Table 2E. Non-limiting N-terminal modifications

[0788]

[0789]

[0790]

[0791] Table 2F. Non-limiting C-terminal modifications

[0792]

[0793] The amino acid structures provided in Table 2G below are presented without a stereochemical indicator at the α-carbon; however, it is understood that these amino acids exist as either L-amino acids or D-amino acids. For example, "Dap" can be an L-stereoisomer:

[0794]

[0795] or exists in the peptides of the present disclosure as the D-stereoisomer (e.g., when referred to as "dap," "dDap," or "D-Dap"):

[0796]

[0797] Table 2G. Monomer abbreviations

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805] Example 1.HOC18gEPEG2PEG2-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)- Synthesis of N-3Pya-Sar-CONH2 (*Pen-Pen forms a disulfide bond) (SEQ ID NO: 1)

[0806]

[0807] Intermediate 1-1

[0808] Synthesis of intermediate 1-1

[0809] 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) on ​​a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During the solid phase assembly of the peptides, the side chain protecting groups were: tert-butyl for Thr and Glu; trityl for Pen and Asn; tert-butyloxy-carbonyl 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 at 90°C under MW irradiation for 3 min, with a 5-fold excess of activated amino acids compared to the free amino groups on the resin. Amino acids were activated with equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF. A double acylation reaction was performed on 3Pya and 2Nal. Fmoc deprotection was performed using 20% ​​(v / v) piperidine in DMF. Capping of free amino groups (PEG2, PEG2, and gE (Fmoc-Glu-OtBu) residues) was performed manually using DIC-HOAT (6 equivalents, 1:1:1) at room temperature. C18OH (18-(tert-butyloxy)-18-oxooctadecanoic acid) was coupled using DIC-HOAT (6 equivalents, 1:1:1) at room temperature, and complete acylation was monitored by the ninhydrin test.

[0810] 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% H2O, 2.5% TIPS, 5% phenol) at room temperature for about 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide precipitate was washed with fresh cold diethyl ether to remove the organic scavenger. This process was repeated twice. The final precipitate was dried, resuspended in H2O and acetonitrile 1:1+0.1% TFA and stirred overnight. The mixture was then lyophilized to obtain the desired intermediate 1-1 (78.1% yield). LCMS: C132 H 200 N 28 O 33 The analytical calculated value of S2 is 2771.32; the measured value is 924.7 (M+3) 3+ .

[0811] HOC18gEPEG2PEG2-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N-3Pya- Sar-CONH2(SEQ ID NO:1)

[0812] Intermediate 1-1 was dissolved in ACN / H2O (1 mg / mL). Saturated iodoacetic acid solution was then added dropwise with stirring until the yellow color persisted. The reaction was complete within 30 minutes (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the product was purified by preparative filtration using a Waters DeltaPak C4 (200 mm × 40 mm, The cyclized peptide was purified by reverse phase HPLC (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 to 25% B in 5 minutes, to 40% B in 25 minutes, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (22% yield). LCMS: C 132 H 198 N 28 O 33 The analytical calculated value of S2 is 2769.32; the measured value is 1386.1 (M+2) 2+ .

[0813] Example 2. MeCO-k(PEG2PEG2GolAC18OH)-Pen*-NT-7MeW-K(Ac)-Pen*-AEF-2Nal- THP-K(Ac)-N-3Pya-Sar-CONH2(*Pen-Pen forms disulfide bond)(SEQ Synthesis of ID NO:2)

[0814]

[0815] Intermediate 2-1

[0816] The compound was prepared according to a procedure similar to that of Preparation Example 1. Preparation of the compound of SEQ ID NO: 2. LCMS: C 141 H 217 N 28 O 35 S2 + The analytical calculated value is 2771.33; the measured value is 1386.55 (M+2) 2+ .

[0817] Example 3. MeCO-k(PEG2PEG2SP6gEC18OH)-Pen* -NT-7MeW-K(Ac)-Pen * -AEF-2Nal- THP-K(Ac)-N-3Pya-Sar-CONH2(*Pen-Pen forms disulfide bond)(SEQ Synthesis of ID NO:3)

[0818]

[0819] Synthesis of intermediate 3-1

[0820] 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) on ​​a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During solid-phase peptide assembly, side chain protecting groups included tert-butyl for Thr and Glu, trityl for Pen and Asn, and tert-butyloxycarbonyl for AEF. The N-terminal D-Lys residue was protected with an orthogonal DDe protecting group.

[0821] All amino acids were dissolved in DMF at a 0.4 M concentration. Acylation reactions were performed at 90°C under MW irradiation for 3 minutes, with a 5-fold excess of activated amino acids relative to resin free amino groups. Equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF were used to activate the amino acids. Double acylation of 3Pya and 2Nal was performed. Fmoc deprotection was performed using 20% ​​(v / v) piperidine in DMF. Free amino groups were capped manually using 10 equivalents of acetic anhydride in DMF.

[0822] At the end of the peptide assembly on the solid phase, the resin was treated with 100 mL of 3% hydrazine 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 (PEG2, PEG2, Fmoc-SP6 ((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N-(carboxymethyl)-N,N-dimethyleth-1-aminium) and gE (Fmoc-Glu-OtBu) residues) was performed manually using DIC-HOAT (3 equivalents, 1:1:1) at room temperature. C18OH (18-(tert-Butoxy)-18-oxooctadecanoic acid) was coupled using DIC-HOAT (6 equivalents, 1:1:1) at room temperature, and complete acylation was monitored by ninhydrin test.

[0823] 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% H2O, 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 precipitate was washed with fresh cold diethyl ether to remove the organic scavenger. This process was repeated twice. The final precipitate was dried, resuspended in H2O and acetonitrile 1:1 + 0.1% TFA and stirred overnight. The mixture was then lyophilized to give the desired intermediate 3-1 (80% yield). LCMS: Analytical calculation for C140H215N28O35S2+ was 2914.52; found 972.5 (M+3) 3+ .

[0824] MeCO-k(PEG2PEG2SP6gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K (Ac)-N-3Pya-Sar-CONH2(SEQ Synthesis of ID NO:3)

[0825] Intermediate 3-1 was dissolved in ACN / H2O (1 mg / mL). Saturated iodoacetic acid solution was then added dropwise with stirring until the yellow color persisted. The reaction was complete within 30 minutes (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the product was purified by filtration using a preparative Waters DeltaPak C4 (200 mm × 40 mm, The cyclized peptide was purified by reverse phase HPLC (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 to 25% B in 5 minutes, to 40% B in 25 minutes, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (35% yield). LCMS: C 140 H 213 N 28 O 35 S2 + The analytical calculated value is 2912.52; the measured value is 1456.6 (M+2) 2+ .

[0826] Example 4. MeCO-k(PEG2PEG2gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP- K(Ac)-N-3Pya-Sar-CONH2(*Pen-Pen forms disulfide bond)(SEQ Synthesis of ID NO:4)

[0827]

[0828] Intermediate 4-1

[0829] Synthesis of intermediate 4-1

[0830] 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) on ​​a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During solid-phase peptide assembly, side chain protecting groups included tert-butyl for Thr, trityl for Pen and Asn, and tert-butyloxycarbonyl for AEF. The N-terminal D-Lys residue was protected with an orthogonal DDe protecting group.

[0831] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were performed at 90°C under MW irradiation for 3 minutes, with a 5-fold excess of activated amino acids relative to the free amino groups on the resin. Amino acids were activated with equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF. Double acylation reactions were performed on 3Pya and 2Nal. Fmoc deprotection was performed using 20% ​​(v / v) piperidine in DMF. Free amino groups were capped manually using 10 equivalents of acetic anhydride in DMF. At the end of peptide assembly on the solid phase, the resin was treated with 100 mL of 3% hydrazine 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 (PEG2, PEG2, and gE(Fmoc-Glu-OtBu) residues) was performed manually using DIC-HOAT (3 equivalents, 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.

[0832] 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 15mL TFA solution (v / v) (87.5% TFA, 5% H2O, 2.5% TIPS, 5% phenol) at room temperature for about 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135mL). After centrifugation, the peptide precipitate was washed with fresh cold diethyl ether to remove the organic scavenger. This process was repeated twice. The final precipitate was dried, resuspended in H2O and acetonitrile 1:1+0.1% TFA and stirred overnight. The mixture was then lyophilized to obtain the desired intermediate 4-1 (89% yield). LCMS: C 134 H 202 N26 O 34 The analytical calculated value of S2 is 2785.3; the measured value is 1393.4 (M+2) 2+ .

[0833] MeCO-k(PEG2PEG2gEC18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-K(Ac)-N- 3Pya-Sar-CONH2 (*Pen-Pen forms a disulfide bond) (SEQ ID NO:4)

[0834] Intermediate 4-1 was dissolved in ACN / H2O (5 mg / mL). Saturated iodoacetic acid solution was then added dropwise with stirring until the yellow color persisted. The reaction was complete within 30 minutes (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the product was purified by filtration using a preparative Waters DeltaPak C4 (200 mm × 40 mm, The cyclized peptide was purified by reverse phase HPLC (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 to 25% B in 5 minutes, to 40% B in 25 minutes, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (28% yield): LCMS: C 134 H 200 N 26 O 34 The analytical calculated value of S2 is 2783.34; the measured value is 1392.4 (M+2) 2+ .

[0835] Example 5. MeCO-k(PEG2PEG6gEC18OH)-Pen*-NT-7MeW-K(Ac)-Pen*-AEF-2Nal- THP-K(Ac)-N-3Pya-Sar-CONH2(*Pen-Pen forms disulfide bond)(SEQ Synthesis of ID NO:5)

[0836]

[0837] Intermediate 5-1

[0838] The compound of SEQ ID NO: 5 was prepared according to a procedure similar to that of Preparation Example 1. The compound of SEQ ID NO: 5 was prepared with a yield of 13%. LCMS: C 141 H 217 N 28 O 35 S2 + The analytical calculated value is 2973.58; the measured value is 1487.5 (M+2) 2+ .

[0839] Example 6. MeCO-k(PEG2PEG2gE(c)C18OH)-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal- Synthesis of THP-K(Ac)-N-3Pya-Sar-CONH2 (*Pen-Pen forms a disulfide bond) (SEQ ID NO: 6)

[0840]

[0841] Intermediate 6-1

[0842] Synthesis of intermediate 6-1

[0843] 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) on ​​a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During solid-phase peptide assembly, side chain protecting groups included tert-butyl for Thr and Glu, trityl for Pen and Asn, and tert-butyloxycarbonyl for AEF. D-Lys was protected with an orthogonal DDe protecting group.

[0844] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90°C under MW irradiation for 3 minutes with a 5-fold excess of activated amino acids relative to the free amino groups on the resin. The amino acids were activated with equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF. Double acylation reactions were performed on 3Pya and 2Nal. Fmoc deprotection was performed using 20% ​​(v / v) piperidine in DMF. Capping of the free amino groups was performed manually using 10 equivalents of acetic anhydride in DMF. At the end of the peptide assembly on the solid phase, the resin was treated with 100 mL of 3% hydrazine 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 (PEG2, PEG2, and gE ((S,E)-4-((Fmoc)amino)-5-oxo-5-(prop-1-en-1-yloxy)pentanoic acid) residues) was performed manually at room temperature using DIC-HOAT (3 equiv., 1:1:1). C18OH (18-(tert-butyloxy)-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. The resin was then treated with 0.25 equiv. of Pd Tetrakis and 24 equiv. of phenylsilane in 5 ml of anhydrous DCM under N2 for 30 minutes (this process was repeated twice); the resin was 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 stirred for 10 minutes. 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 hours (monitored by assay cleavage).

[0845] 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% H2O, 2.5% TIPS, 5% phenol) at room temperature for about 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide precipitate was washed with fresh cold diethyl ether to remove the organic scavenger. This process was repeated twice. The final precipitate was dried, resuspended in H2O and acetonitrile 1:1+0.1% TFA and stirred overnight. The mixture was then lyophilized to give intermediate 6-1 (73.6% yield). LCMS: C 141 H 217 N 28 O 35 S2 + The analytical calculated value is 2928.55; the measured value is 1464.74 (M+2)2+ .

[0846] MeCO-k(PEG2PEG2gE(c)C18OH)-Pen*-NT-7MeW-K(Ac)-Pen*-AEF-2Nal-THP-K Synthesis of (Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 6)

[0847] Intermediate 6-1 was dissolved in ACN / H2O (1 mg / mL). Saturated iodoacetic acid solution was then added dropwise with stirring until the yellow color persisted. The reaction was complete within 30 minutes (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the product was purified by preparative filtration using a Waters DeltaPak C4 (200 mm × 40 mm, The cyclized peptide was purified by reverse phase HPLC (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 to 20% B in 5 minutes, to 35% B in 25 minutes, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (20% yield). LCMS: C 141 H 215 N 28 O 35 S2 + The analytical calculated value is 2926.55; the measured value is 1463.9 (M+2) 2+ .

[0848] Example 7. MeCO-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-EN-3Pya-Sar-K (PEG2PEG2gEC18OH)-CONH2(*Pen-Pen forms a disulfide bond)(SEQ Synthesis of

[0849]

[0850] Intermediate 7-1

[0851] Synthesis of intermediate 7-1

[0852] 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) on ​​a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During solid-phase peptide assembly, the side chain protecting groups were: tert-butyl for Thr and Glu; trityl for Pen and Asn; tert-butyloxycarbonyl for AEF; and Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg. The C-terminal Lys residue was protected with an orthogonal DDe protecting group.

[0853] All amino acids were dissolved in DMF at a concentration of 0.4 M. The acylation reaction was carried out at 90° C. under microwave (MW) irradiation for 3 minutes, with a 5-fold excess of activated amino acids compared to the free amino groups on the resin. The amino acids were activated with equimolar amounts of 0.5 M DIC in DMF and 1 M Oxyma in DMF. 3Pya and 2Nal were subjected to a double acylation reaction. Fmoc deprotection was performed using a 20% (v / v) piperidine solution in DMF. The free amino groups were capped manually using 10 equivalents of acetic anhydride in DMF. At the end of the peptide assembly on the solid phase, 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 the resin was then washed with DCM (5×5 mL) and DMF (5×5 mL). Further side chain derivatization was performed on a CemLiberty Blue microwave peptide synthesizer using standard coupling conditions 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 using DIC-HOAT (3 equiv, 1:1:1) at room temperature, and complete acylation was monitored by the ninhydrin test.

[0854] 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 15mL TFA solution (v / v) (87.5% TFA, 5% H2O, 2.5% TIPS, 5% phenol) at room temperature for about 1.5 hours. The resin was then filtered and precipitated in cold MTBE (135mL). After centrifugation, the peptide precipitate was washed with fresh cold diethyl ether to remove the organic scavenger. This process was repeated twice. The final precipitate was dried, resuspended in H2O and acetonitrile 1:1+0.1% TFA and stirred overnight. The mixture was then lyophilized to obtain the desired intermediate 7-1 (50% yield). LCMS: C 137 H 207 N 29 O 36 The analytical calculated value of S2 is 2900.45; the measured value is 967.8 (M+3) 3+ .

[0855] MeCO-r-Pen * -NT-7MeW-K(Ac)-Pen * -AEF-2Nal-THP-EN-3Pya-Sar-K (PEG2PEG2gEC18OH)-CONH2(*Pen-Pen forms a disulfide bond)(SEQ ID NO:7)

[0856] Intermediate 7-1 was dissolved in ACN / H2O (1 mg / mL). Saturated iodoacetic acid solution was then added dropwise with stirring until the yellow color persisted. The reaction was complete within 30 minutes (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the product was purified by preparative filtration using a Waters DeltaPak C4 (200 mm × 40 mm, The cyclized peptide was purified by reverse phase HPLC (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 to 25% B in 5 minutes, to 40% B in 25 minutes, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the desired compound (5% yield). LCMS: C 137 H 205 N 29 O 36 The analytical calculated value of S2 is 2898.43; the measured value is 1450.0 (M+2) 2+ .

[0857] Example 8. MeCO-k(PEG12gEC18OH)-Pen*-NT-7MeW-K(Ac)-Pen*-AEF-2Nal-THP-K (Ac)-N-3Pya-Sar-CONH2(SEQ Synthesis of

[0858]

[0859] Peptide Assembly: Peptides were synthesized by solid-phase peptide synthesis (SPPS) using Fmoc chemistry. Peptide assembly was performed on Rink Amide MBHA resin (0.15 mmol, 0.65 mmol / g) on ​​a Biotage Syro II parallel peptide synthesizer. Side chain protecting groups used were: tert-butyl (tBu) for Thr and Glu; trityl (Trt) for Pen and Asn; tert-butyloxycarbonyl (Boc) for AEF; Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg; and Dde for the N-terminal Lys. At room temperature, Fmoc-protected amino acids (5 eq, 0.75 mmol, 1.56 mL, 0.48 M in DMF) were coupled using HATU (5 eq, 0.75 mmol, 1.56 mL, 0.48 M in DMF) and NMM (10 eq, 1.5 mmol, 0.75 mL, 2 M in DMF) for 1 hour. Fmoc deprotection was performed by treating the resin with 40% piperidine in DMF for 3 minutes and then treating it with 20% piperidine in DMF for another 9 minutes. Capping of the free terminal amino group was performed by treating the resin with a solution of acetic anhydride: NMM: DMF (2:2:6, 5) mL) for 20 minutes at room temperature. The Dde group was then deprotected by treating the resin with 2% hydrazine (5 mL) in DMF for 10 minutes at room temperature. The solution was drained and then fresh solution was added for 10 minutes. The resin was drained and washed with DMF and DCM. Side chain derivatization was performed in a Biotage Syro II peptide synthesizer using the above conditions.

[0860] Disulfide formation: After assembly, the resin-bound peptide was treated with iodine (4 eq) in DMF and allowed to mix at room temperature for 1 hour. The resin was washed with 1 M sodium ascorbate in DMF, DMF, and DCM and dried.

[0861] Cleavage and purification: The peptide was cleaved from the solid support and deprotected by treating the resin with cleavage mixture (5 mL, 92.5% TFA, 2.5% water, 2.5% TIPS, 2.5% DODT) for 30 minutes at 42°C on a CEM Razor cleavage station. The resin was filtered and washed with cleavage mixture (2 mL). Cold MTBE was added to the filtrate to precipitate the peptide. After centrifugation, the peptide precipitate was washed twice with fresh cold MTBE. The dried precipitate 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 19x150mm column. Mobile phase A: water + 0.1% TFA, mobile phase B: acetonitrile + 0.1% TFA. Gradient: 35% B to 40% B over 10 minutes, flow rate 25 mL / min. Pure fractions were combined and lyophilized to obtain the desired product (12% yield). LCMS analysis calculated value for C149H231N25O41S2: 3090.62, found: 1546.6 (M+2H) 2+ 、1031.6(M+3H) 3+ 、774.0(M+4H) 4+ .

[0862] Example 9: Pharmacokinetic study of a composition as described and provided herein following a single intravenous, oral (PO), intraduodenal (ID), or intracolonic (IC) administration to rats. The composition was administered to male Sprague-Dawley rats by intravenous, oral, or intracolonic routes of administration. The composition was administered as follows: Dose: 0.5 mg / kg (IV), 5 mg / kg (ID), or 10 mg / kg (PO or IC), Dose volume: 1 mL / kg (IV), 5 mg / kg (ID), or 10 mg / mL (PO or IC). Plasma was collected and treated with 5% (volume %) protease inhibitors. 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. The plasma concentration (ng / mL) of the parent compound was analyzed by LC-MS / MS, and the concentration data and pharmacokinetic parameters were calculated. The data are shown in the table below. The PK data of the compound of SEQ ID NO: 7 and 100 mg / kg absorption enhancer administered intraduodenally (ID) at 5 mg / kg in rats are shown below.

[0863]

[0864]

[0865] SNAC, sodium caprate powder, Labrasol oil, lauroyl-L carnitine, and sodium caprylate significantly increased the AUC of SEQ ID NO: 7 when administered intraduodenally (ID) to rats. last. The results are shown in the table below. Unexpectedly and surprisingly, sodium caprate powder and Labrasol oil increased the AUC of SEQ ID NO: 7. last. Increased by about 7 times and 10 times.

[0866] The following table shows the bioavailability data in rats for compounds of SEQ ID NOs: 1-8 dosed intracolonically (IC) and orally (PO) at 10 mg / kg in the presence and absence of 100 mg / kg sodium decanoate.

[0867]

[0868]

[0869] F%: Bioavailability

[0870] IC / C10: Intracolonic administration of 10 mg / kg of peptide and 100 mg / kg of sodium decanoate.

[0871] PO / C10: Oral administration of 10 mg / kg of peptide and 100 mg / kg of sodium decanoate.

[0872] Unexpectedly and surprisingly, sodium decanoate powder significantly increased the bioavailability of all compounds of SEQ ID NOs: 1-8 by about 2-fold to about 20-fold when co-administered with 100 mg / kg sodium decanoate. Compounds of SEQ ID NOs: 9-40 also exhibited high bioavailability when co-administered with sodium decanoate.

[0873] 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. Pursuant to 37 CFR §1.57(b)(1), Applicants intend that the statement of incorporation by reference

[0874] Reference is made to each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, each of which is expressly identified pursuant to 37 CFR §1.57(b)(2), even if such citation is not immediately adjacent to a specific statement of incorporation by reference. The inclusion of a specific statement of incorporation by reference (if any) within the specification does not in any way diminish this general statement of incorporation by reference. Citation of a reference herein is not intended to be an admission that the reference is relevant prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0875] The present embodiment is not limited to the scope of the specific embodiments described herein. In fact, in addition to those described herein, various modifications will become apparent to those skilled in the art based on the foregoing description. Such modifications are intended to fall within the scope of the embodiments and any appended claims.

[0876] This description is considered sufficient to enable those 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 fall within the scope of this disclosure and any appended claims.

Claims

1. An oral pharmaceutical preparation, comprising: absorption enhancers; and lipidated peptides containing 9 to 20 amino acids; wherein the lipidated peptide is cyclized to form a ring, wherein the ring comprises 4 to 14 amino acids; and wherein the ratio of the absorption enhancer to the lipidated peptide is no greater than 50:1 (w / w).

2. The oral pharmaceutical formulation according to claim 1, wherein the lipidated peptide comprises an amino acid sequence of 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), or a pharmaceutically acceptable salt thereof, wherein: R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ; X3 is any amino acid or absent; X4 is 4-aminoPro, 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 does not exist; X8 is any amino acid; X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z 脂质 , APEG3F or AEF-Z 脂质 ; 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 absent; R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z lipids; Z peg is independently at each occurrence a polyethylene glycol chain; Z 脂质 is independently at each occurrence a lipophilic substituent; wherein the peptide comprises a bond between residues at X4 and X9; and The polypeptide is contained in a group consisting of R1, X3, X5, X6, X8, X 10 、X 12 、X 13 、X 14 、X 16 、X 17 or at least one lipophilic substituent at the position of R2.

3. The oral pharmaceutical preparation according to claim 2, wherein: R 1a It is MeCO, Z peg , Z 脂质 , succiniccarn, 5cpaCO, or AEEP-Z 脂质 ; X3 is R, KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist; X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is N, N(NMe2), K(d), K-Z 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X6 is T, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ; X7 is 7MeW, W, or does not exist; X8 is K(Ac), K(d), K(NMeAc), Q, K-Z 脂质 , K-Z peg , NMeK-Z 脂质 , Dab-Z 脂质 , Dab(NMecarn) or Dab-Z peg ; X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 Is AEF, TMAPF, AEF(d), TMAPF-Z 脂质 , APEG3F or AEF-Z 脂质 ; X 11 is substituted or unsubstituted 2Nal or substituted or unsubstituted 3Quin; X 12 It's THP, KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X 13 is E, K(Ac), K(d), KZ peg ,K(NMeAc),Dab(NMecarn),E(OAll),KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist; X 14 It's N, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ; X 16 It is Sar, NMeK(d), KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist; and R2 is CONH2, CONMe2, CONH-Z peg or CO-Z 脂质 .

4. The oral pharmaceutical composition according to claim 1, wherein the lipidated peptide comprises an amino acid sequence of 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), or a pharmaceutically acceptable salt thereof, wherein: R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ; X3 is any amino acid or 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 is AEF, TMAPF, AEF(d), TMAPF-Z peg , TMAPF-Z 脂质 , APEG3F, AEF-Z peg or AEF-Z 脂质 ; 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 absent; R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z lipids; Z peg is independently at each occurrence a polyethylene glycol chain; Z 脂质 is independently at each occurrence a lipophilic substituent; wherein the polypeptide is contained in a 1a ,X3,X4,X5,X6,X8,X9,X 10 、X 11 、X 12 、X 13 、X 14 、X 16 、X 17 or R 2a at least one lipophilic substituent or polyethylene glycol chain at position ; and wherein the peptide is cyclized to form a first loop, wherein the first loop comprises 4 to 14 amino acids.

5. The oral pharmaceutical composition according to claim 4, wherein the first loop comprises 4 to 9 or 11 amino acids.

6. The oral pharmaceutical composition according to claim 4, wherein the first ring is located between X4 and X9, X4 and X 13 , X5 and X 10 , X3 and X 13 Or formed between X6 and X9.

7. The oral pharmaceutical composition according to claim 4, wherein the first ring is located between X4 and X9, X4 and X 13 Or formed between X6 and X9. 8 . The oral pharmaceutical composition according to claim 7 , wherein the first ring is formed between X 4 and X 9 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole.

9. The peptide according to claim 7, wherein the first ring is connected to X4 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 13 Formed between.

10. The peptide according to claim 7, wherein the first ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole.

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

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

13. The peptide of claim 8, wherein the peptide is further cyclized to form a second ring, wherein: The second ring is connected to X3 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 13 formed between; The second ring is connected to X5 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 10 formed between; The second 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. 10 With X 13 between; or The second 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. 13 and the N-terminus of the peptide.

14. The peptide of claim 9, wherein the peptide is further cyclized to form a second ring, wherein: The second ring is connected to X5 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 The second ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole.

15. The peptide of claim 10, wherein the peptide is further cyclized to form a second ring, wherein: The second ring is connected to X3 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 13 formed between; The second ring is connected to X4 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 13 formed between; The second ring is connected to X5 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene and triazole. 10 formed between; The second 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. 10 With X 13 between; or The second 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. 13 and the N-terminus of the peptide.

16. The oral pharmaceutical composition according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: R 1a is an N-terminal blocking group (e.g., MeCO), Z peg or Z 脂质 ; X3 is r, k(d), kZ 脂质 , dab-Z 脂质 、NMek-Z 脂质 or does not exist; X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is E, N, N(NMe2), K(d), K-Z 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X6 is T, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ; X7 is 7MeW or W; X8 is K(Ac), K(d), K(NMeAc), Q, K-Z 脂质 , K-Z peg , NMeK-Z 脂质 , Dab-Z 脂质 , Dab(NMecarn) or Dab-Z peg ; X9 is aMeC, aG, C, D, E, hE, Pen, Dap, or Dap(N3); X 10 is AEF, TMAPF, AEF(d), TMAPF-Z peg , TMAPF-Z 脂质 , APEG3F, AEF-Z peg or AEF-Z 脂质 ; X 11 It is 2Nal or 6OH2Nal; X 12 It's THP, KZ 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X 13 is E, K(Ac), K(d), K-Z peg , K(NMeAc), Dab(NMecarn), E(OAll), K-Z 脂质 , Dab-Z 脂质 , NMeK-Z 脂质 ; X 14 It's N, KZ 脂质 、NMeK-Z 脂质 or Dab-Z 脂质 ; X 16 It is Sar, NMeK(d), KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist; X 17 It's KZ 脂质 , Dab-Z 脂质 、NMeK-Z 脂质 or does not exist; R 2a is a C-terminal capping group (e.g., CONH2), CONH-Z peg or CO-Z lipids; Z peg is independently at each occurrence a polyethylene glycol chain; Z lipid is independently at each occurrence a lipophilic substituent; wherein the peptide comprises a bond between residues at X4 and X9; and wherein the polypeptide is contained in a 1a 、X3、X5、X6、X8、X 10 、X 12 、X 13 、X 14 、X 16 、X 17 or R 2a At least one lipophilic substituent at the position of, or at least one lipophilic substituent selected from R 1a , X8, X 10 、X 13 or R 2a The polyethylene glycol chain is positioned at the position of .

17. The oral pharmaceutical composition according to claim 4 or claim 16, wherein: R 1a It is MeCO, Z peg , Z 脂质 or 5cpaCO; X3 is r, k(d), kZ 脂质 , dab-Z 脂质 , NMek-Z lipids or absent; X4 is Pen; X5 is E, N, N(NMe2), K-Z 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X6 is T; X7 is 7MeW; X8 is K(Ac), K(d), K(NMeAc), K-Z 脂质 , K-Z peg , NMeK-Z 脂质 , Dab-Z 脂质 or Dab-Z peg ; X9 is Pen; X 10 AEF, TMAPF, APEG3F, AEF-Z peg or AEF-Z 脂质 ; X 11 It is 2Nal or 6OH2Nal; X 12 It is THP; X 13 is E, K(Ac), K-Z peg , K(NMeAc), K-Z 脂质 , Dab-Z 脂质 or NMeK-Z 脂质 ; X 14 It is N; X 16 Is Sar or NMeK-Z 脂质 ; X 17 It's KZ 脂质 , Dab-Z 脂质 , NMeK-Z lipid or absent; R 2a CONH2, CONMe2, CONH-Z peg or CO-Z 脂质 ; wherein the peptide comprises a disulfide bond between residues at X4 and X9; and wherein the polypeptide is contained in a 1a , X3, X5, X8, X 10 、X 13 、X 16 、X 17 or R 2a At least one lipophilic substituent at the position of, or at least one lipophilic substituent selected from R 1a , X8, X 10 、X 13 or R 2a The polyethylene glycol chain is positioned at the position of .

18. The oral pharmaceutical formulation according to claim 1, wherein the lipidated peptide is a compound having the following formula: or a pharmaceutically acceptable salt or solvate thereof, in: L is -O-, -S-, or -SS-; R1, R2, R3, R4, R5, R6, R8, R9 and R 10 are independently H, CH3, -C(=O)CH3, -C(=O)NHR 11 、 -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)nNHR12 or -C(=O)(CH2) n OR 12 ; R7 is -(CH2) p NHR 13 or -(CH2) q NHC(=NH)NH2; each m, n, p and q are 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 oral pharmaceutical formulation according to claim 18, wherein the lipidated peptide is a compound having the following formula:

20. The oral pharmaceutical formulation according to claim 18, wherein the compound is a compound having the formula:

21. The oral pharmaceutical formulation according to claim 18, wherein the compound is a compound having the formula:

22. The oral pharmaceutical formulation according to claims 18 to 21, wherein each lipid moiety or lipophilic substituent is independently selected from the group Z1 to Z5: Z1 is Z2 is in: Each PEG is independently –OCH2CH2-; 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' is independently selected at each occurrence from 0 or from the range of 2 to 24, when m' is 0, the group is replaced by a bond; Each v' at each occurrence is independently selected from the range of 1 to 4; Each 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; 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, 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(C 1-4 alkyl); The Z5 is in: 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; and Xaa is diamino-formic acid.

23. The oral pharmaceutical formulation according to claims 18 to 21, wherein each lipid moiety or lipophilic substituent is in: Z B yes Z C is Z C1 , Z C2 or Z C3 ; Z C1 yes Z C2 yes Z C3 yes Z D yes Z E is -H, -COOH, phenoxy or tetrazolyl; Z F is -H or -CH3; Xaa a In each occurrence, independently 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; and w a is independently 0 or 1 at each occurrence.

24. The oral pharmaceutical formulation according to any one of claims 18 to 23, wherein R2 is methyl.

25. The oral pharmaceutical formulation according to any one of claims 18 to 24, wherein R3 is H.

26. The oral pharmaceutical formulation according to any one of claims 18 to 25, wherein R4 is H.

27. The oral pharmaceutical formulation according to any one of claims 18 to 26, wherein R5 is H.

28. The oral pharmaceutical formulation according to any one of claims 18 to 27, wherein R8 is H.

29. The oral pharmaceutical formulation according to any one of claims 18 to 28, wherein R4 is H.

30. The oral pharmaceutical formulation according to any one of claims 18 to 29, wherein R9 is H.

31. The oral pharmaceutical formulation according to any one of claims 18 to 30, wherein R 10 yes- C(=O)CH3.

32. The oral pharmaceutical formulation according to any one of claims 18 to 23, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

33. The oral pharmaceutical formulation according to claim 32, wherein R7 is -(CH2) q C(=O)NH)NH2.

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

35. The oral pharmaceutical formulation of claim 34, wherein the compound has the formula:

36. The oral pharmaceutical formulation of claim 35, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

37. The oral pharmaceutical formulation according to claim 32, wherein R6 is -C(=O)CH3.

38. The oral pharmaceutical formulation according to claim 37, wherein R7 is -(CH2) p NHR 12 .

39. The oral pharmaceutical formulation according to claim 38, wherein p is 4.

40. The oral pharmaceutical formulation of claim 39, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

41. The oral pharmaceutical formulation of claim 40, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

42. The oral pharmaceutical formulation according to any one of claims 18 to 23, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

43. The oral pharmaceutical formulation according to claim 42, wherein R1 is 44. The oral pharmaceutical formulation according to claim 43, wherein m is 4.

45. The oral pharmaceutical formulation of claim 44, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

46. ​​The oral pharmaceutical formulation of claim 19, wherein the compound or a pharmaceutically acceptable salt thereof has the formula:

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

48. The oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the weight ratio (w / w) of the absorption enhancer to the lipidated peptide or a pharmaceutically acceptable salt or solvate thereof is in the range of about 1 to about 200.

49. The oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the weight ratio (w / w) of the absorption enhancer to the lipidated peptide or a pharmaceutically acceptable salt or solvate thereof is in the range of about 1 to about 100.

50. The oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the weight ratio (w / w) of the absorption enhancer to the lipidated peptide or a pharmaceutically acceptable salt or solvate thereof is in the range of about 1 to about 20.

51. The oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the weight ratio (w / w) of the absorption enhancer to the lipidated peptide or a pharmaceutically acceptable salt or solvate thereof is in the range of about 1 to about 10.

52. The oral pharmaceutical formulation according to any one of claims 1 to 47, wherein the ratio of the absorption enhancer to the lipidated peptide is not less than 3:1 (w / w).

53. The oral pharmaceutical formulation of any one of claims 1 to 47, wherein the ratio of the absorption enhancer to the lipidated peptide is between 3:1 (w / w) and 30:1 (w / w).

54. The oral pharmaceutical formulation of claim 4 according to any one of claims 1 to 47, wherein the ratio of the absorption enhancer to the lipidated peptide is between 5:1 (w / w) and 50:1 (w / w).

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

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

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

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, saprolactam sodium (SNAC), polyethylene glycol (PEG)-modified medium chain fatty acid triglycerides of capric and caprylic acid, sucrose laurate, sodium caprylate, labrasol, and lauroyl-L-carnitine (LC).

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

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

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

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

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

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

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

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

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

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

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

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, saprolactam sodium (SNAC), polyethylene glycol (PEG)-modified medium chain fatty acid triglycerides of capric and caprylic acid, sucrose laurate, sodium caprylate, labrasol, and lauroyl-L-carnitine (LC).

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

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

73. 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. The use of claim 73 for the preparation of a medicament for treating autoimmune inflammatory and related diseases and disorders including, but not limited to, multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, young adult 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 innate immune disorders such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, atopic 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 following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

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

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

78. The method of claim 77, wherein the disease or disorder is: multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, young adult 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 innate immune disorders 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, or erythrodermic psoriasis), atopic dermatitis, atopic 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 following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

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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