Composition of interleukin-23 receptor peptide inhibitors

Abstract

To provide compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salt or solvate forms thereof, corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation and related diseases and disorders.SOLUTION: A composition comprises: a peptide of a specific sequence or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 0.1% to about 15% (w / w) of the composition; and one or more pharmaceutically acceptable excipients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application is a U.S. Provisional Patent Application No. 63 / 1, filed on November 20, 2020. Patent No. 16,568 and U.S. Provisional Patent Application No. 63 / 275 filed on November 3, 2021. , claiming priority under No. 222, these are incorporated herein by reference in their entirety for all purposes. It can be done.

[0002] (Sequence Listing) This application includes a sequence listing that has been submitted electronically in ASCII format, and the sequence listing This entire document is incorporated herein by reference. Created on November 9, 2021. The SCII copy is named 056365_518001WO_SL_ST25.txt Its size is 1,202 bytes.

[0003] (Field of invention) The present invention relates to interleukin for the treatment of autoimmune inflammation and related diseases and disorders. Peptide inhibitors of the Interleukin-23 Receptor (IL-23R) or the drug Pharmacologically acceptable salt or solvate forms, corresponding pharmaceutical compositions, methods and / or uses Regarding use. [Background technology]

[0004] Interleukin-23 (IL-23) cytokines are involved in multiple sclerosis. Asthma, rheumatoid arthritis, psoriatic arthritis, psoriasis, and inflammatory bowel disease (Inflammatory Bowel Disease) Owel disease (IBD), for example, autoimmune inflammation such as ulcerative colitis and Crohn's disease. It is believed to play an important role in the pathogenesis of related diseases and disorders. Studies in sexual and chronic mouse models have revealed that IL-23R and The main roles of downstream effector cytokines have been clarified. IL-23R plays a variety of roles. It is expressed in adaptive and innate immune cells, and adaptive and innate immune cells are abundant in the gut. Th17 cells, γδT cells, and natural killer (NK) cells are released. This may include, but is not limited to, dendritic cells, macrophages, and innate lymphoid cells. i. In IBD patients, IL-23R gene expression and protein level on the intestinal mucosal surface It has been found that the IL level rises. IL-23 responds to IL-6 to IL-22, IL -17, and pathogenic CD4 that produces tumor necrosis factor (TNF) + This effect is thought to be mediated by promoting the development of T cell populations.

[0005] IL-23 is produced in large quantities in the intestines, where T helper 1 (Th1) and By influencing Th17-related cytokines, T cell-dependent and T cell-dependent colitis In addition to regulating the balance between tolerance and immunity through independent pathways, it also favors inflammation. It is thought to play an important role in suppressing regulatory T cell responses in the gut. In addition, Polymorphisms in the IL-23 receptor (IL-23R) are associated with inflammatory bowel disease (I This is associated with increased susceptibility to BD, and this can lead to problems with gut homeostasis. The important role of the IL-23 pathway has been further established.

[0006] Psoriasis (PsO2) is a chronic skin disease that affects approximately 2% to 3% of the general population. ) has been shown to be mediated by the body's T-cell inflammatory response mechanism. IL-23 is It is reported that chronic autoimmune inflammation is caused by the induction of interleukin-17. By regulating T memory cells and maintaining them through macrophage activation, psoriasis One of several interleukins considered to be key players in the pathogenesis of the disease It has two properties. The expression of IL-23 and IL-23R is increased in the tissues of psoriasis patients. It has been shown that antibodies that neutralize IL-23 are effective in the development of psoriasis in animal models of psoriasis. It showed IL-23-dependent inhibition. In addition, the IL-23 antibody guselkumab was found in human It is approved by the FDA for the treatment of moderate to severe psoriasis vulgaris in [country / region].

[0007] IL-23 has a unique p19 subunit and interferon-γ , IFN-γ) producing T Helper 1, T Helper 1, T H 1) Cytoca involved in cell development A heterodimer composed of the p40 subunit shared with IL-12, which is the in Both IL-23 and IL-12 contain the p40 subunit, but they are different. It has phenotypic characteristics. For example, animals lacking IL-12 are prone to inflammatory autoimmune diseases. Although prone to it, IL-23-deficient animals likely have a higher incidence of CNS in IL-23-deficient animals. CD4 that produces IL-6, IL-17, and TNF + Due to a decrease in the number of T cells, It is resistant. IL-23 is composed of IL-12Rβ1 and IL-23R subunits. It binds to IL-23R, a heterodimeric receptor. Through this combination, the Jak-stat signaling molecules, Jak2, Tyk2, and Stat are involved. 1. Stat3, Stat4, and Stat5 are activated, but this is compared to IL-12. Therefore, Stat4 activation is substantially weak, and different DNA-binding Stat4 responds to IL-23. The t complex is formed. IL-23R constitutively associates with Jak2 and with Stat3. It associates in a ligand-dependent manner. IL-12 primarily acts on naive CD4(+) T cells. In contrast, IL-23 preferentially acts on memory CD4(+) T cells.

[0008] To inhibit the IL-23 pathway for use in the treatment of IL-23-related diseases and disorders. Attempts have been made to identify the therapeutic area that binds to IL-23 or IL-23R. Several antibodies have been identified, and these antibodies bind to the p40 subunit of IL-23. It contains the antibody ustekinumab, which is moderate to severe. Severe psoriasis vulgaris, active psoriatic arthritis, moderate to severe active Crohn's disease, and moderate It has been approved for the treatment of severe active ulcerative colitis. More recently, IL- polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R are also This is defined (see, for example, U.S. Patent Application Publication No. 2013 / 0029907). iakinumab (i.e., an antibody that also targets the common p40 subunit), Also, tildrakizumab, guselkumab, MEDI2070, and B I-655066 (i.e., for example, targeting the unique p19 subunit of IL-23) Clinical trials of antibodies in Crohn's disease or psoriasis are in the treatment of human inflammatory diseases. This highlights the potential of blocking IL-23 signaling. While these findings are promising, Challenges remain regarding the successful delivery of the drug to its target. This improves the treatment of intestinal inflammation, including intestinal diseases such as Crohn's disease, ulcerative colitis, and related disorders. It is possible.

[0009] Therapeutic agents are delivered to treat IL-23 and / or IL-23R-related diseases, particularly inflammatory bowel disease. (IBD), ulcerative colitis, Crohn's disease (CD), psoriasis, or psoriatic Autoimmune inflammation in the intestinal tract and other areas, including but not limited to arthritis. To treat and prevent the disease, it is necessary to develop effective pharmaceutical vehicles such as pharmaceutical compositions. There is still a need for this in the field of technology. [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] The present invention relates to a peptide inhibitor or a pharmaceutically acceptable salt or solvate thereof. By providing compositions, these needs are addressed, and pharmaceutical compositions are - Binds to IL-23R, binds to IL-23, and facilitates IL-23 receptor-mediated IL-23 receptor activity. Inhibiting the Gnar signaling pathway and / or the IL-23 pathway can lead to inflammatory diseases or disorders (i.e., e.g., For example, this may include psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. However, it treats inflammatory diseases or disorders (but is not limited to these), - Inflammatory diseases or disorders may be moderate to severe and may be suitable for oral administration. This includes, but is not limited to, the diseases or disorders listed above.

[0011] In addition, pharmaceutical compositions for the specific targeting of IL-23R from the luminal side of the intestine, and corresponding The method and / or use of this method provides therapeutic benefits to IBD patients suffering from local inflammation of the intestinal tissue. It can be provided.

[0012] This invention aims to overcome these and other problems encountered in the art. ru. [Means for solving the problem]

[0013] In general, the present invention relates to the treatment of autoimmune inflammation and related diseases and disorders. Leukin-23 receptor (IL-23R) peptide inhibitors or pharmaceutically acceptable salts thereof Or relating to solvates, corresponding pharmaceutical compositions, methods and / or uses.

[0014] The present invention relates to a composition as described herein, having the following structure: Peptide 1: Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[ 3-Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1), or This relates to compositions comprising a pharmaceutically acceptable salt or solvate form thereof.

[0015] [ka]

[0016] The present invention relates to a composition, wherein the SEQ ID NO: is present in an amount of about 0.1% to about 15% (w / w) of the composition. One peptide or a pharmaceutically acceptable salt or solvate thereof, and one or more The present invention provides a composition comprising a pharmaceutically acceptable excipient.

[0017] The present invention relates to a peptide inhibitor of the interleukin-23 receptor (IL-23R) or the This relates to compositions in the form of pharmaceutically acceptable salts or solvates.

[0018] The present invention relates to a composition, wherein the SEQ ID NO: is present in an amount of about 0.1% to about 15% (w / w) of the composition. 1 peptide or its pharmaceutically acceptable salt or solvate form, and about 10% to about 60 A % (w / w) amount of an absorption enhancer and one or more pharmaceutically acceptable excipients, The present invention provides a composition containing the following:

[0019] The present invention relates to a composition having an internal phase, which is about 0.1% to about 15% (w / w) of the composition A quantity of the peptide of SEQ ID NO: 1, and a quantity of caprin in the composition of approximately 20% to approximately 45% (w / w) An internal phase containing sodium phosphate, and an external phase disposed on top of the internal phase, which is microcrystalline cellulose. The present invention provides a composition comprising an external phase, which includes the above.

[0020] The present invention relates to a composition comprising the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. The present invention provides a composition comprising a solvate form and a 50 mM pH 7.4 phosphate-buffered aqueous solution. do.

[0021] The present invention relates to a method for producing tablets, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, and Capri Sodium phosphate and, A step of granulating a mixture, In the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and Hydrophilic silica The steps include adding to form the internal phase, This is a step in which the external phase is compressed onto the internal phase. The external phase includes a step of compression containing silicified microcrystalline cellulose, The steps include applying a sub-coating to the outer phase, The steps include applying an enteric coating on top of a sub-coating to form a tablet, This provides a method that includes [something].

[0022] In some embodiments, a method for making tablets is The peptide of sequence number 1, sodium caprate, A step of granulating a mixture, In the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and Hydrophilic silica The steps include adding to form the internal phase, This is a step in which the external phase is compressed onto the internal phase. The external phase includes a step of compression containing silicified microcrystalline cellulose, The steps include applying a sub-coating to the outer phase, The steps include applying an enteric coating on top of a sub-coating to form a tablet, Includes.

[0023] The present invention is a product for treating inflammatory diseases or disorders, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, and Capri Granulating a mixture containing sodium phosphate, In the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and Hydrophilic silica Adding to form the internal phase, This involves compressing the outer phase onto the inner phase, where the outer phase is silicified microcrystalline cellulose. Compression, including the use of , Applying a sub-coating on top of the outer phase, Applying an enteric coating on top of a sub-coating to form a tablet, The product is prepared by the following method.

[0024] The present invention relates to a method for treating inflammatory diseases, as described herein, , administering a therapeutically effective amount of the composition of the present invention to a subject or patient in need of such treatment The present invention provides a method that includes the following:

[0025] The present invention relates to a method for treating inflammatory bowel disease (IBD), which requires treatment of the disease. The present invention provides a method comprising administering a therapeutically effective amount of a composition to a target subject or patient.

[0026] The present invention relates to the manufacture of pharmaceuticals for treating inflammatory bowel disease (IBD), and the combination of the present inventions. Provides the use of the finished product.

[0027] The present invention relates to a method for treating psoriasis or psoriatic arthritis in a subject, wherein the subject is treated The present invention provides a method comprising administering an effective amount of the composition described herein.

[0028] The present invention relates to the composition of the present invention in the manufacture of a pharmaceutical product for treating psoriasis or psoriatic arthritis. To provide the use of an item.

[0029] The present invention relates to a method for inhibiting IL-23 receptors for the treatment of inflammatory diseases or disorders. If such inhibition is necessary, the systemically active petech of SEQ ID NO: 1 is used in the target or patient. deliver a butylate or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. It concerns the method by which it is done.

[0030] The present invention relates to an IL-23 receptor for treating inflammatory diseases or disorders. Systemic inhibition of IL-23 signaling, or the IL-23 pathway, or pharmacology A method for selectively blocking, and for patients who need it, a therapeutically effective dose of SEQ ID NO: 1. Peptide or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. This relates to a method that involves oral administration.

[0031] The present invention relates to the treatment of inflammatory diseases or disorders, and relates to the blood, blood circulation, tissue, skin, or A method for inhibiting or blocking IL-23 receptors in joints, which requires For patients who have this condition, an oral therapeutically effective dose of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable equivalent. The present invention relates to a method comprising administering a salt or solvate, or a pharmaceutical composition thereof.

[0032] This invention relates to IL-23 receptors in tissues selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting, and for patients who require such inhibition, an oral dose that is therapeutically effective. A quantity of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, or The present invention relates to a method comprising administering a pharmaceutical composition.

[0033] The present invention is a method for inhibiting IL-23 receptors in gastrointestinal tissue, and For patients requiring inhibition, an oral dose of the therapeutically effective amount of the peptide of SEQ ID NO: 1 or its medicinal properties The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form.

[0034] This invention relates to the production of IL-17A in tissues selected from blood, skin, cartilage, or synovial membrane. A method to inhibit life, and for patients who require such inhibition, oral dose therapy is available. Administer an effective dose of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form. Regarding methods, including how to do something.

[0035] The present invention is a method for inhibiting the production of IL-17A in gastrointestinal tissue, and For patients requiring inhibition of the drug, an oral therapeutically effective dose of the peptide of SEQ ID NO: 1 or its The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form.

[0036] This invention relates to the production of IL-17F in tissues selected from blood, skin, cartilage, or synovial membrane. A method to inhibit life, and for patients who require such inhibition, oral dose therapy is available. Administer an effective dose of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form. Regarding methods, including how to do something.

[0037] The present invention is a method for inhibiting the production of IL-17F in gastrointestinal tissue, and For patients requiring inhibition of the drug, an oral therapeutically effective dose of the peptide of SEQ ID NO: 1 or its The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form.

[0038] This invention relates to the production of IL-22 in tissues selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting, and for patients who require such inhibition, an oral dose that is therapeutically effective. Administer an amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof. Regarding methods, including the act of doing so.

[0039] The present invention is a method for inhibiting the production of IL-22 in gastrointestinal tissue, and For patients requiring inhibition, an oral dose of the therapeutically effective amount of the peptide of SEQ ID NO: 1 or its medicinal properties The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form. [Brief explanation of the drawing]

[0040] [Figure 1] The X-ray powder diffraction spectrum of the peptide of SEQ ID NO: 1, as prepared by the procedure of Example 1, is shown. [Figure 2] This graph shows the oral doses of the peptide of SEQ ID NO: 1 in relation to interleukin-17A levels (0.03-100 mg / kg, po) in rat blood after stimulation of rat blood with 4 ng / mL IL-23 plus 4 ng / mL IL-1β. [Figure 3] This graph shows the oral doses of the peptide of Sequence ID No. 1 in rat blood, corresponding to interleukin-17A levels (0.03-100 mg / kg, po), after stimulation of rat blood with 20 ng / mL IL-23 plus 4 ng / mL IL-1β. [Figure 4] This graph shows the oral doses of the peptide of Sequence ID No. 1 in rat blood, corresponding to interleukin-17A levels (0.03–100 mg / kg, po), after stimulation of rat blood with 100 ng / mL IL-23 plus 4 ng / mL IL-1β. [Figure 5] This graph shows the oral doses of the peptide of SEQ ID NO: 1 in relation to interleukin-17A levels (0.03-100 mg / kg, po) in rat blood after stimulation of rat blood with 4 ng / mL of IL-1β. [Figure 6] This shows the interleukin-17A levels in IL-23-stimulated rat blood versus 10 mg / kg oral administration of the peptide of Sequence ID No. 1 (labeled "Formulation (I)") at 2 and 6 hours after administration. [Figure 7]This shows changes in cutaneous interleukin-17A (IL-17A) gene expression in rats after intradermal administration of naiveté or recombinant rat IL-23, oral administration of vehicle or SEQ ID NO: 1 peptide (1, 3, 10, 30, 100, 300 mg / kg BID), or intraperitoneal administration of anti-IL-23 or isotype antibodies. [Figure 8] This shows changes in cutaneous interleukin-17F (IL-17F) gene expression in rats after intradermal administration of naiveté or recombinant rat IL-23, oral administration of vehicle or SEQ ID NO: 1 peptide (1, 3, 10, 30, 100, 300 mg / kg BID), or intraperitoneal administration of anti-IL-23 or isotype antibodies. [Figure 9] This shows changes in cutaneous interleukin-22 (IL-22) gene expression in rats after intradermal administration of naiveté or recombinant rat IL-23, oral administration of vehicle or SEQ ID NO: 1 peptide (1, 3, 10, 30, 100, 300 mg / kg BID), or intraperitoneal administration of anti-IL-23 or isotype antibodies. [Figure 10] This shows the ear thickness of rats after naiveté, intradermal administration of recombinant rat IL-23, oral administration of vehicle or SEQ ID NO: 1 peptide (1, 3, 10, 30, 100, 300 mg / kg bid), or intraperitoneal administration of anti-IL-23 or isotyped antibodies. [Figure 11] This shows the time course of weight gain in naivet, or weight loss in rats after intracolonic administration of TNBS, and oral administration of water (days 2-6) or the peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, 1, 3, and 10 mg / kg / day, day 2-6). [Figure 12]Shows the change in colon weight / length ratio in naive rats or in rats after intracolonic administration of TNBS and oral administration of water (-2 days to 6 days) or the peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, 1, 3, and 10 mg / kg / day, -2 days to 6 days). [Figure 13] Shows the change in colon inflammation score in naive rats or in rats after intracolonic administration of TNBS and oral administration of water or the peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, 1, 3, and 10 mg / kg / day, -2 days to 6 days). [Figure 14] Shows the percent inhibition (mean ± SE) of IL-23-induced IFNγ production data from multiple indicated time points at day 1 and day 10 in the MAD cohort relative to baseline. [Figure 15] Shows the percent inhibition (mean ± SEM) of IL-23-induced pSTAT3 data from multiple indicated time points at day 1 and day 10 in the 25 mg MAD cohort.

Mode for Carrying Out the Invention

[0041] I. Overview Generally, the present invention relates to a peptide inhibitor of interleukin-23 receptor (IL-23R) or a pharmaceutically acceptable salt or solvate form thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders.

[0042] The present invention is a pharmaceutical composition as described herein, wherein the chemical structure is the peptide of SEQ ID NO: 1 shown below Ac-[Pen] * -N-T-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N- * 3-Pal]-Sarc-NH2( *Pen-Pen form disulfide bond) (SEQ ID NO: 1)

[0043] [ka] This relates to pharmaceutical compositions comprising the pharmaceutically acceptable salt or solvate form thereof.

[0044] The peptide of Sequence ID No. 1 is published in International Publication No. 2021 / 146441 and the U.S. Patent Application Publication. It was previously described as peptide #104 in issue 2021 / 0261622, These disclosures are incorporated herein by reference in their entirety.

[0045] The present invention relates to pharmaceutical compositions disclosed herein for the treatment of inflammatory bowel disease (IBD), ulcers, etc. This may include, but is not limited to, psoriatic colitis, Crohn's disease (CD), psoriasis, or psoriatic arthritis. Methods or uses for the treatment of various autoimmune inflammations and related diseases and disorders that are not permitted. This relates to preferred pharmaceutical compositions.

[0046] Each aspect of the present invention as defined in this section or any other section is defined by definition and and limitations, for example, the definitions and limitations set out in sections I to VI of this specification, and first Definitions and limitations described throughout the disclosure, specification, and claims filed in the patent application. It can be incorporated.

[0047] II. Definition "A", "an", or "a(n)" refers to a group of substituents or a "group of substituents" in this specification. When used in writing, it is an indefinite article meaning at least one.

[0048] When referring to a value, "approximately" includes 10% of the stated value plus or minus 10% of the stated value. For example, Approximately 50% includes the range of 45% to 55%, and approximately 20 molar equivalents are in the range of 18 to 22 molar equivalents. It includes the bounds. Therefore, when referring to a range, "approximately" means each upper limit and of the range described. This refers to a range of + / - 10% for each of the listed values, from approximately 1 to approximately 3 (weight / weight). The ratio of quantities includes the range of 0.9 to 3.3. However, in the case of mass units, "approximately" The term "plus" or "minus" means plus or minus 5 mg. For example, a mass of approximately 10 mg means 5 mg This refers to a range of up to 15 mg, while a mass of approximately 50 mg refers to a range of 45 mg to 55 mg.

[0049] An "absorption enhancer" (AE) is an agent that enhances the mucosal absorption of drugs in the gastrointestinal tract. Components that improve or facilitate this, for example, permeation enhancers (PE) or This refers to an intestinal permeability enhancer. As has been conventionally understood in this technology, a permeability enhancer The aim is to improve the oral delivery of therapeutic drugs with poor bioavailability. It is a drug that can increase the paracellular and / or transcellular passage of drugs. A pharmaceutical excipient that can increase permeability is called an "absorption modifier excipient." It is called a firming excipient (AME). In oral compositions, for example, Humectants (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., It can be used as macrogol glyceride, and in particular, in compositions, BioAbay It may be included as PE to improve durability. PE is how PE is paracellular or These can be classified in terms of whether they alter barrier integrity via transcellular pathways. Furthermore, the terms "absorption enhancer" or "AE" are synonymous with the terms "penetration enhancer" or "PE". It is thought that this is the case.

[0050] "Administering" refers to administering the composition of the present invention to a subject.

[0051] As used herein, “composition” refers to a specific active product composition as described herein. Active Product Ingredient (API), and pharmaceutically acceptable excipients, carriers, or This includes a diluent in a specific amount defined, for example, throughout the entire disclosure initially filed. A product, and a specific component such as a specific amount of a specific ingredient as described herein. It is intended to encompass the products resulting from the combination of these elements.

[0052] As used herein, "gastrointestinal tissue" refers to all tissues, including the organs of the gastrointestinal tract. "Digestive tract tissue" is defined solely as the combination of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. This includes, but is not limited to, weaving.

[0053] A "disintegrant" is a substance that promotes the disintegration of a composition when it comes into contact with a liquid. This refers to pharmaceutical excipients incorporated into substances. For example, disintegrants are used in the preparation of tablets. A pharmaceutically acceptable drug in which the tablet disintegrates upon contact with moisture, releasing the medicinal substance. It is a drug that causes this. An example of a disintegrant is cross-linked polyvinylpyrrolidone (cross Povidone), cross-linked carboxymethylcellulose sodium (croscarmellose sodium) Examples include cross-linked polymers containing (m), modified starch, sodium starch glycolate, etc. These are possible, but not limited to them.

[0054] "Displaced on top of" means that one phase or coating is on top of another phase or coating. This refers to an upward placement. Such a placement conforms to the shape of the underlying phase or coating. This allows for the layering of the phase and coating, and as a result, substantial space between the phase and coating. Leave no gaps.

[0055] "Enteric coating" is a commonly applied coating used for the delayed release of active ingredients. This refers to any of the polymer coatings that have been conventionally understood in the art. As such, enteric coatings generally prevent the dissolution or breakdown of oral medications in the gastric environment. This is a polymer barrier applied to oral medications. It protects the drug from stomach acid. To protect the stomach from the harmful effects of drugs, or after the stomach (usually in the upper tract of the intestines) ) Helps by either releasing the drug. Some drugs are affected by the pH of stomach acid. It needs to be stable and protected from degradation. Enteric coating is also important (for gastric-resistant drugs). This is an effective method for obtaining the drug target. Such delayed release is typically p It is H-dependent, and the pH in the intestinal tract, which differs from the pH in the stomach, allows for further release of the active ingredient. To enable. Generally, suitable materials used for enteric coatings are fatty acids, wax. This may include, but is not limited to, sucrose, shellac, plastics, and plant fibers. Enteric coating materials such as cellulose phthalate acetate, polyvinyl alcohol phthalate, and Sierra cellulose acetate The present invention may include, but is not limited to, trimalate and film resin. Examples of additional enteric coatings for use include aloylic acid esters. Cellulose acetate phthalate (CAP), poly(methacrylic) Methyl methacrylate (-co-methacrylate), poly(vinyl acetate phthalate) Acetate Phthalate, PVAP, Cellulose Acetate Trimelitate cetate (trimellitate, CAT), and hydroxypropyl methylcellulose phthalate Products based on (Hydroxypropyl Methylcellulose Phthalate, HPMCP, etc.) These are some examples, but are not limited to them.

[0056] "Outer phase" refers to the bulk portion of the core structure that exists between the inner phase and the outer coating of the composition. It refers to minutes. The foreign minister itself can be thought of as a coating, but the foreign minister is generally just a coat It may be thicker than the fining, thereby imparting a significant structure / dimension to the composition.

[0057] A "lubricant" is a substance added to a powder to improve its flowability and / or lubricity. This refers to lubricants such as magnesium stearate, fumed silica, and starch. Examples include, but are not limited to, talc.

[0058] "Granulated mixture" refers to a mixture of two or three or more drugs, specifically two or three or more The process involves mixing the drugs and granulating two or more of these drugs together into a fine particle form. This refers to a mixture made by two or three or more drugs. The present invention provides a particulate material composed of an agent. For example, in the present invention, the composition is: This may include, but is not limited to, a granular mixture of peptide 1 and sodium caprate. No. Such granular mixtures are the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt. Alternatively, it is formed in a solvate form and a particulate form containing sodium caprate.

[0059] "Hydrophilic silica" is a solid used as a fluidizing agent (anticaking), adsorbent, and desiccant. This refers to pharmaceutical excipients that can be used in product form. Hydrophilic silica also contributes to the mechanical stability of the composition. It can be used to increase the properties and decay rate. Hydrophilic silica is fumed. This can be done, in other words, this is a pyrogenic process for producing silica nanoparticles. This refers to the production of hydrophilic silica by fumed silica. The particle size of fumed silica can vary, 5 This may include, but is not limited to, sizes such as nm to 100 nm or 5 to 50 nm. The particles do not need to be porous, and the size is 50-1000m. 2 / g or 50-600m 2 / g table It may have an area, but is not limited to these. An example of hydrophilic silica is approximately 200 m². 2 / Aerosil 200, which has a specific surface area of ​​g, is one example.

[0060] "Internal phase" refers to the central part of the composition. In this embodiment, the internal phase is the active ingredient. This is the location where the peptide of Sequence ID No. 1 of the present invention exists or may exist.

[0061] An "Intestinal Permeation Enhancer (IPE)" is a drug that enhances the bioavailability of the intestinal permeable system. This refers to a component that improves the bioavailability of a component that already has bioavailability. Typical IPEs suitable for use in the present invention include various surfactants, fatty acids, and medium-chain glycerides. Lido, steroid detergent, acylcarnitine and alkanoylcholine, N-acetylated alkanoylcholine Alpha-amino acids and N-acetylated non-alpha-amino acids, as well as chitosan and other mucosal-adhering substances. This includes, but is not limited to, adhesive polymers. For example, suitable for use in the present invention. The IPE can be sodium caprate.

[0062] A "joint" or "joints" is a structure in the human body that connects one bone to another. It refers to the tissue that connects to bone. The terms "joint" or "joints" are used to describe this. Examples of tissues included include tendons, cartilage, ligaments, and synovial membranes, but are not limited to these. It is not determined. The synovial fluid adjacent to any of the above tissues is considered part of the “joint”. This is considered herein.

[0063] A "lubricant" refers to a substance added to a formulation to reduce friction. Functional compounds can also possess lubricating properties. Examples of lubricants include: Talc, silica, and vegetable stearin, magnesium stearate, or stearic acid Examples include, but are not limited to, fats such as those listed above.

[0064] "Microcrystalline cellulose" or "MCC (Microcrystalline Cellulose)" refers to refined wood This refers to pharmaceutical-grade cellulose manufactured from wood pulp. MCC is unmodified or chemically modified. It can be modified, for example, silicified microcrystalline cellulose. It can be llulose (SMCC). MCC can function as a volume expander. Due to the favorable compressibility characteristics of MCC, it can assist in tablet formation. Cut.

[0065] "Patient" or "Subject" means a living organism, and a living organism is provided herein. Humans suffering from or susceptible to a disease or condition that can be treated by the administration of such pharmaceutical composition. This includes, but is not limited to, the subjects. Further non-limiting examples include humans and other mammals. These could include cattle, rats, mice, dogs, monkeys, and other mammals, but these It is not limited to this. In some embodiments, the patient is a human being.

[0066] "Medically acceptable" means that the carrier, diluent, or excipient is not a component of the composition of the present invention. It must be compatible with the active ingredients or components, that is, it must be useful, safe, non-toxic, and medical. This means that it is pharmaceutically acceptable. According to the present invention, pharmaceutically acceptable means that it is pharmaceutically acceptable in animals In particular for use in humans, USPharmacopoeia or As described in other generally recognized pharmacopoeias, approved or appropriable It means to do something.

[0067] The composition or pharmaceutical composition of the present invention may be in different pharmaceutically acceptable forms, and different medical Pharmacologically acceptable forms include liquid compositions, tablets or matrix compositions, and capsule compositions. This includes, but is not limited to, objects.

[0068] When the composition is a tablet composition, the tablet may contain two or more different phases. It is possible for two or more different phases to include an inner phase and an outer phase that may contain a core. The tablet composition may also contain one or more coatings, but is not limited to this. It is not determined.

[0069] "Silicified microcrystalline cellulose" or "SMCC" refers to co-treated microcrystalline cellulose. This refers to fine particle aggregates of silicon dioxide and silicon dioxide. SMCC suitable for use in the present invention is fine It may contain silicon dioxide in an amount of approximately 0.1% to approximately 20% by weight of crystalline cellulose, however Not limited to this, silicon dioxide has an average primary particle size of approximately 1 nanometer (n The particle size can be approximately 100 micrometers (μm). For example, Silicon dioxide makes up about 0.5% to about 10% of silicified microcrystalline cellulose, or microcrystalline cells. It can contain approximately 1.25% to 5% by weight relative to the loin. Also, carboxymethyl dioxide Ion particles can have a particle size of approximately 5 nm to approximately 40 μm or approximately 5 nm to approximately 50 μm. It can. Silicon dioxide is about 10m 2 / g~about 500m 2 / g, or approximately 50m 2 / g ~ approx. 5 00m 2 / g, or approximately 175m 2 / g~about 350m 2 It can have a surface area of ​​ / g. Silicified microcrystalline cellulose is a trademark of PROSOLV®, a registered trademark of Penwest. Several suppliers known to those skilled in the art, including Pharmaceuticals, Inc. It is commercially available from [company name]. PROSOLV (registered trademark) is, for example, PROSOLV (registered trademark). (Mark) SMCC 50, PROSOLV (Registered Trademark) SMCC 90, and PROSOLV (Registered Trademark) Available in several grades, including HD. Other products are SMCC. This includes, but is not limited to, 50LD, SMCC HD90, and SMCC 90LM. It will not be done.

[0070] "Sodium caprate" or "NaC10" refers to a substance with the molecular formula C 10H 19 NaO2 and This refers to sodium decanoate, an IUPAC compound having the following structural formula.

[0071] [ka]

[0072] As used herein, "solvate" refers to the compound of the present invention and one or more solvent components. This refers to a physical association with a child. This physical association involves variations in the degree of bonding, including hydrogen bonding. In some cases, solvates are isolateable. The term "solvate" refers to a solution that is incompatible with a solution. The definition shall include both the mediator and the isolable solvate. The definition shall not be limited to suitable solvates. One example is a hydrate.

[0073] "Sorbitol" refers to the sugar alcohol D-glucitol, and the sugar alcohol D-glucitol Citol can function as a binder to promote the adhesion of components in tablet compositions.

[0074] "Sub-coating" refers to any number of film layers placed on top of the outer layer, The film layer can provide one or more benefits, for example, making the composition easier to swallow. To provide a smooth tablet surface, it contains coloring to aid in tablet identification and moisture absorption. It provides a rear layer and a high tensile strength outer layer for the tablet. Such a sub-coating is Polyvinyl alcohol (PVA) and polyethylene glycol (Poly This may include, but is not limited to, graft copolymers with thylene glycol (PEG). Not provided. Commercial products that provide sub-coatings are OPADRY® and OP This includes product lines under product names such as AGLOS®. Sub-coatings are one or It can be further covered by two or more additional coatings.

[0075] "Therapeutic effective dose" means the amount that treats or relieves the identified disease or condition, This refers to the amount of a compound or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutic effective dose" refers to a non-toxic but sufficient amount of a particular drug, within the scope of the meaning of therapeutic effective dose. Furthermore, the therapeutically effective dose refers to the amount sufficient to provide the desired therapeutic effect. The exact amount required depends on factors such as the patient's overall health and age. It varies from elephant to elephant. The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques. This can be confirmed (for example, Lieberman, Pharmaceutical D osage Forms(vols.1-3,1992), Lloyd,The Art ,Science and Technology of Pharmaceutica l Compounding (1999), Pickar, Dosage Calcul ations (1999), and Remington: The Science and Practice of Pharmacy,20th Edition,2003, Gennaro, Ed., Lippincott, Williams & Wilkin (See s).

[0076] "To treat," "to treat," and "treatment" refer to the success or failure of treatment, This refers to any sign of remission of a disease or condition, and the sign may be objective or subjective. Target parameters, for example, remission, reduction of symptoms, or injury to the patient, pathological condition, Or to make the condition more acceptable, to slow down the rate of degeneration or decline, To minimize the debilitating effects of the final point, and to improve the patient's physical or mental health. This includes the treatment or remission of symptoms, which may be based on objective or subjective parameters. Observational or subjective parameters are determined by physical examination, neuropsychiatric examination, and / or psychiatric assessment. Includes the result of the value.

[0077] The abbreviation "(w / w)" means "weight for weight" or " The phrase "weight by weight," that is, the set disclosed herein The weight or mass of the constituent components of the composition relative to the total weight of the finished product, or by weight. It refers to the proportion of a particular substance in a mixture that is being measured. Therefore, the quantity is unitless (un It is unitless, or unitless, and is the weight percentage of the constituent components relative to the total weight of the composition. This expresses a percentage. For example, a 2% (w / w) solution means that 2 grams of solute are in 100 grams of solution. This means it is dissolved.

[0078] Systemic routes of administration, as traditionally understood in the fields of medicine or pharmacy, refer to the routes of drug delivery. A pharmaceutical composition or preparation, or other substance, enters the circulatory system, and as a result, various body tissues and refers to a route of administration in which the organs are exposed to the drug, preparation or other substance, or the administration It is defined as a route. As is conventionally understood in the art, administration is via Oral administration (the drug or oral preparation is ingested by mouth and absorbed through the gastrointestinal tract), enteral administration ( Drug absorption also occurs throughout the gastrointestinal tract), or parenteral administration (generally by injection, infusion, Alternatively, it can be performed through transplantation or other means.

[0079] The "systemically active" peptide drug therapy of the present invention generally refers to peptide activity This refers to treatment with a pharmaceutical composition containing the component, and in treatment, the peptide undergoes immediate metabolism and / or resist elimination, various systems such as the cardiovascular system, respiratory system, gastrointestinal system, nervous system, or immune system This results in exposure to the peptide in body tissues and organs.

[0080] In this invention, systemic drug activity also refers to the ability to travel through the bloodstream and affect various body tissues and... This refers to treatments that use substances that reach and affect cells in organs. Systemic active drugs are all It is transported to the site of action of the embolic active drug and acts throughout the body, causing inflammatory diseases. It attacks the physiological processes involved in rubbing.

[0081] Bioavailability refers to the ability of the active portion (drug or metabolite) to enter the systemic circulation. This refers to the degree and rate to which the drug accesses the site of action. The results are influenced by the characteristics of the dosage form, and these characteristics are partially related to the design and manufacture of the dosage form. It depends on.

[0082] Mai. Pharmaceutical composition In general, the present invention relates to autoimmune inflammation and related diseases and disorders as defined herein. Interleukin-23 receptor (IL-23R) peptide inhibitors for the treatment of harm This refers to compositions in the form of pharmaceutically acceptable salts or solvates, corresponding pharmaceutical compositions, and methods. , and / or relating to use.

[0083] In one embodiment, the present invention relates to the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof or The present invention provides a composition in solvate form.

[0084] In another aspect, the composition of the present invention Ac-[Pen] * -N-T-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N- 3-Pal]-Sarc-NH2( * Pen-Pen * Defined as the form (disulfide bond), and having the following chemical structure shown below, the peptide of SEQ ID NO: 1 Relates to its pharmaceutically acceptable salt or solvate form.

[0085]

Chemical Structure

[0086] form may exist in any form, for example, as a pharmaceutically acceptable salt, hydrate, or other solvate. In some aspects, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form may be provided in crystalline form, amorphous form, or semi-crystalline form. In one aspect of the composition, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate

[0087] form is in salt form. In one aspect of the composition, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form is acetate. In another aspect of the composition, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form is bisacetate. In another aspect of the composition, the acetate form of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form is in amorphous form. In another aspect of the composition, the acetate form of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form is in amorphous form. In another aspect of the composition, the SEQ ID NO: 1 The acetate form of peptide number 1 or its pharmaceutically acceptable salt or solvate form. It is an acetate salt. In another embodiment of the composition, the acetate form of the peptide of SEQ ID NO: 1 or The pharmaceutically acceptable salt or solvate form is bisacetate. In yet another embodiment, In this invention, the acetate of the composition is in an amorphous form. In another embodiment of the composition, SEQ ID NO: 1 The peptide or its pharmaceutically acceptable salt or solvate form is the solvate form. In another embodiment of the composition, the acetate form of the peptide of SEQ ID NO: 1 is acetate solvated. It is an object.

[0088] The present invention relates to compositions that may be liquid or solid compositions.

[0089] The compositions of the present invention achieve the intended purpose or pharmaceutically effective effect in the subject or patient. It may be administered by any means according to therapeutic administration. Examples include oral, parenteral, Administration methods include subcutaneous, intravenous, intramuscular, intraperitoneal, percutaneous, topical, buccal, or ocular routes. In some embodiments, the administration of the compositions of the present invention is adapted for oral administration. In other embodiments, the administration of the composition is by intravenous administration.

[0090] In another aspect, the present invention relates to a composition comprising about 0.1% to about 15% (w / w) of the composition. an amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, and 1 The present invention provides a composition comprising one or more pharmaceutically acceptable excipients.

[0091] In another aspect, the present invention relates to a composition comprising about 0.1% to about 20% (w / w) of the composition. an amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, and 1 To provide a composition comprising one or two or more pharmaceutically acceptable excipients.

[0092] In another aspect, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof has the following structure.

[0093]

Chemical formula

[0094] In another aspect, the peptide of SEQ ID NO: 1 has the following structure.

[0095]

Chemical formula

[0096] In another aspect, the present invention provides a composition comprising the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof and a 50 mM aqueous phosphate buffer solution at pH 7.4. To provide a composition.

[0097] In another aspect, the present invention provides a composition comprising the peptide of SEQ ID NO: 1 and a 50 mM aqueous phosphate buffer solution at pH 7.4.

[0098] In another aspect, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof may be present in any amount from about 0.1% to about 15% (w / w) of the composition. For example , the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof is about 0.5% to about 15% (w / w) of the composition, or about 1% to about 10%, or about 0.5% to about 5%, or about 0.5% to about 3%, or about 1% to about 3%, or about 1.5% to about 2.5%, or about 1 It may be present in amounts of 0.5% to approximately 2.0% (w / w). In another embodiment, the peptide of SEQ ID NO: 1. Or the pharmaceutically acceptable salt or solvate form thereof, in an amount of approximately 1% to approximately 5% (w / w). It may exist in another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof In one embodiment, the solvate form may be present in an amount of approximately 1.8% (w / w). In another embodiment, the sequence number The peptide of 1 or its pharmaceutically acceptable salt or solvate form is approximately 7.1% (w / It may be present in the amount of w). In another embodiment, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable form The salt or solvate form may be present in an amount of approximately 10.7% (w / w).

[0099] In another embodiment, the peptide of SEQ ID NO: 1 is present in any of 0.1 to 15% (w / w) of the composition. It can be present in such amounts. For example, the peptide of SEQ ID NO: 1 may be present in 0.5-15% (w / w), or 1-10%, or 0.5-5%, or 0.5-3%, or 1-3%, or 1. It may be present in amounts of 5-2.5% or 1.5-2.0% (w / w). In another embodiment, the sequence Peptide number 1 may be present in amounts of 1-5% (w / w). For example, peptide number 1 Tide is present in approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% of the composition. Amounts containing 11%, 12%, 13%, 14%, or approximately 15% (w / w), and in between these amounts. It may be present in any of the fractional amounts. In another embodiment, the peptide of SEQ ID NO: 1 is present at approximately 1.8% ( It can exist in w / w quantities.

[0100] In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof The form can exist in any absolute amount. For example, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable form. The acceptable salt or solvate form is 1 mg to 1000 mg, or 1 to 500 mg, or It may be present in amounts of 1 to 100 mg, 10 to 50 mg, or 20 to 30 mg. Another embodiment Therefore, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form is 1 It may be present in amounts of 0 mg to 50 mg. In another embodiment, the peptide of SEQ ID NO: 1 or its pharmaceutical product. The generally acceptable salt or solvate form may be present in an amount of 20-40 mg. Therefore, the peptide of Sequence ID No. 1 or its pharmaceutically acceptable salt or solvate form is 2 It may be present in amounts of 0 to 30 mg. In yet another embodiment, the peptide of SEQ ID NO: 1 or its pharmaceutical product. The generally acceptable salt or solvate forms are approximately 10 mg, 15 mg, 20 mg, and 25 mg. , 30mg, 35mg, 40mg, 45mg, or 50mg, 100mg, 300mg, Or it may be present in an amount of 1000 mg, and the amount is any amount between these and a fraction of these amounts. Includes a number. In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof or The solvate form may be present in an amount of approximately 25 mg.

[0101] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The form of the mediator is approximately 1 mg to 1000 mg, or approximately 1 to 500 mg, or approximately 1 to 10 It may be present in amounts of 0 mg, approximately 10 to approximately 50 mg, or approximately 20 to approximately 30 mg. Another embodiment So, what is the amount of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form? The amount may range from approximately 1 mg to approximately 1000 mg. In another embodiment, the peptide of SEQ ID NO: 1 or its The pharmaceutically acceptable amount of salt or solvate form may range from approximately 10 mg to approximately 300 mg. In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvation thereof. The amount in physical form is approximately 25 mg to approximately 150 mg. In another embodiment, the peptide of SEQ ID NO: 1. Or the amount of its pharmaceutically acceptable salt or solvate form is approximately 25 mg to approximately 100 mg It may be. In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof The amount of the solvate form may be about 25 mg. In some embodiments, the peptide of SEQ ID NO: 1 The amount of tide or its pharmaceutically acceptable salt or solvate form is approximately 100 mg. In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof. The amount of substance may be approximately 150 mg.

[0102] In general, the pharmaceutical compositions of the present invention utilize conventional materials and techniques known in the fields of pharmacy and formulation. It can be formed into different dosage forms prepared using the technique, and the technique is such as mixing and blending. This includes, but is not limited to, the law and techniques described throughout this disclosure. Furthermore, the pharmaceutical composition used to form the dosage form may also contain suitable adjuvants and carriers. This may include, but is not limited to, excipients or stabilizers, and may be in solid or liquid dosage forms. It can be in solid or liquid form, and the solid or liquid dosage forms include tablets, capsules, powders, and solutions. This may include, but is not limited to, a suspension or emulsion. According to the present invention, a solid unit The dosage form may be other conventional types known in the art.

[0103] Furthermore, the solution is suitable for use in the present invention, and the solution is, for example, water, physiological saline, Aqueous dextrose and related sugar solutions, as well as glycol buffers, such as propylene glycol. It may be present in, but is not limited to, a glycol or polyethylene glycol buffer. Liquid carriers, particularly preferred liquid carriers for injectable solutions, under normal storage and usage conditions. These preparations contain preservatives to prevent microbial growth.

[0104] The composition of the present invention may contain various other pharmaceutically acceptable components or excipients, The constituent components or excipients are, for example, lubricants, disintegrants, binders, drying agents, fillers, and This includes, but is not limited to, other components or excipients. These components are It will be stated in the details.

[0105] According to the present invention, compositions such as those described herein are suitable for use in the present invention. It may contain any amount of at least one filler. In some embodiments, the present invention The composition consists of alpha-cellulose, beta-cellulose, gamma-cellulose, starch, and chemicals. Starch, sorbitol, mannitol, lactose, dextrose, sucrose, 2 One or two of the following: calcium phosphate, calcium triphosphate, or calcium carbonate This may include, but is not limited to, the above.

[0106] Typical fillers for use in the compositions of the present invention include starch, lactitol, and larvae. Cactose, inorganic calcium salts, microcrystalline cellulose, sucrose, and combinations thereof This may include, but is not limited to, the following for use in the compositions of the present invention. The fillers or diluents are typically used in the formulation of pharmaceutical compounds, in the art. The present invention may include, but is not limited to, conventionally known fillers or diluents. Examples of such fillers or diluents for use include sugars, such as lactose. dextrose, glucose, sucrose, cellulose, starch, and carbohydrate derivatives Body, (including dextrose and maltodextrin) polysaccharides, (mannitol, xylitol Polyols (including sorbitol), cyclodextrin, calcium carbonate, carbon Examples include magnesium oxide, microcrystalline cellulose, and combinations thereof. The invention is not limited to these. In some embodiments, such a suitable addition for use in the present invention may be found. Fillers or diluents include lactose, microcrystalline cellulose, and combinations thereof. These may be, but are not limited to, several types of microcrystalline cellulose as specified herein. Suitable for use in the compositions described above, for example, microcrystalline cellulose is MIC PH101, PH1 02, PH103, PH105, PH 112, PH113, PH200, and PH30 1. Selected from other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. These may be, but are not limited to, the fillers suitable for use in the present invention. It may contain microcrystalline cellulose (AVICEL PH102). In another embodiment, the present invention may contain A suitable filler for use in this context is one containing microcrystalline cellulose (AVICEL PH101). obtain.

[0107] In some embodiments, the fillers for use in the present invention are described herein. Sea urchin, approximately 1% to approximately 99% (w / w) of the composition, or approximately 1% to approximately 50% of the composition, Approximately 1% to approximately 25%, or approximately 1% to approximately 20%, or approximately 1% to approximately 10%, or 2 It may be present in amounts of approximately 8% or 3% to 5% (w / w).

[0108] In another embodiment, the filler for use in the present invention is as defined herein. Sea urchin, 1-99% (w / w) of the composition, or 1-50%, or 1-25% of the composition, Or 1-20%, or 1-10%, or 2-8%, or 3-5% (w / Such fillers may also be present in amounts of w). It is present in amounts of %, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or approximately 10% (w / w). The amount obtained may include any of these fractional amounts as defined, but these Not limited.

[0109] In some embodiments, the composition may further include microcrystalline cellulose. In that embodiment, the composition may further contain silicified microcrystalline cellulose, but to Not limited to, in some embodiments, the composition may include alphacellulose, betacellulose. Gammacellulose, starch, modified starch, sorbitol, mannitol, lactol Sucrose, dextrose, calcium diphosphate, calcium triphosphate, or carbonate It may further contain one or more of the following: calcium, etc. In some embodiments, The composition may further contain mannitol. In some embodiments, the composition is so It can also contain rubitol.

[0110] In some embodiments, microcrystalline cellulose is present in an amount of about 1 to about 25% (w / w) of the composition. It can be. In some embodiments, microcrystalline cellulose is present in the internal phase of the composition. It can be present in an amount of approximately 1% to approximately 25% (w / w) of the composition. Several embodiments So, microcrystalline cellulose makes up about 1% to about 10% (w / ) of the composition in the internal phase of the composition. It can be present in the amount w). In some embodiments, microcrystalline cellulose is in the composition In the internal phase, it can be present in an amount of approximately 21.3% (w / w) of the composition. In that embodiment, microcrystalline cellulose constitutes approximately 3.9% (w) of the composition in the internal phase of the composition. It can exist in the quantity of / w).

[0111] In some embodiments, the composition may further comprise silicified microcrystalline cellulose. In some embodiments, silicified microcrystalline cellulose is SMCC 50, SMCC 50L This could be D, SMCC 90, SMCC HD90, or SMCC 90LM, etc. This is not limited to these. In some embodiments, silicified microcrystalline cellulose is SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90 It could be LM, but is not limited to these. Not bound by theory, but silicified microcrystalline cells The enteric coating is early due to sodium caprate present in the internal phase. It is thought to protect against erosion. Silicified microcrystalline cellulose is preferred for use in the present invention. It may be present in any appropriate amount. For example, SMCC may be present in about 1 to about 99% (w / w) of the composition. ), or about 10-50% of the composition, or about 25-60%, or about 20-5% 0%, or approximately 25-45%, or approximately 30-40%, or approximately 35-37% It can be present in a % (w / w) amount. SMCC makes up about 30% (w / w) of the composition. or 31%, 32%, 33%, 34%, 35%, 36%, 36.1%, 36.2% of the composition %, 36.3%, 36.4%, 36.5%, 36.6%, 36.7%, 36.8%, 36 It may be present in amounts of 0.9%, 37%, 38%, 39%, or more than approximately 40% (w / w). Yes, it is possible. In some embodiments, silicified microcrystalline cellulose makes up about 25-60% of the composition. It can be a quantity of (w / w).

[0112] The composition may also contain a binder. A binder for use in the composition of the present invention. The agent contains a binder commonly used in pharmaceutical formulations. Examples of binders include (hydroxypropylcellulose, hydroxypropylmethyl (Containing cellulose, methylcellulose, and sodium carboxymethylcellulose) Lurose derivative, glycol, sucrose, dextrose, corn syrup, (Akashi (Contains polysaccharides, corn syrup, tragacanth, guar, alginate, and starch) Starch, pregelatinized starch, modified corn starch, gelatin, polyvinyl pylori Examples include DON, polyethylene, polyethylene glycol, and combinations thereof. Obtain, but not limited to these.

[0113] In some embodiments, the composition of the present invention may contain sorbitol. For example, the present invention may contain For use in the composition, sorbitol is present in an amount of about 1% to about 99% (w / w), or in the composition Approximately 1% to 50% of the material, or approximately 1% to 25%, or approximately 5% to 25%, or Approximately 5% to 20%, or approximately 5% to 15%, or approximately 8% to 12% (w / w) It may be present in an amount of . In some embodiments, the composition may also be present in about 5% to about 15% (w Contains sorbitol in the amount of / w)

[0114] In some embodiments, for use in the present invention, sorbitol is present in 1 to 9 parts of the composition. 9% (w / w), or 1-50%, 1-25%, or 5-25% of the composition. Alternatively, it may be present in amounts of 5-20%, 5-15%, or 8-12% (w / w). Obtain. In another embodiment, sorbitol is present in an amount of about 5% (w / w) of the composition, or 6% of the composition. 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10. 5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 1 It can be present in amounts of 4%, or approximately 15% (w / w). In some embodiments, The composition also contains sorbitol in an amount of 5% to 15% (w / w) of the composition. In some embodiments, the composition also contains sorbitol in an amount of about 10.7% (w / w) of the composition.

[0115] In some embodiments, the lubricant may include, but is not limited to, magnesium stearate. It is not possible. The lubricant is present in an amount of 0.1% to 10% (w / w) of the composition, or 0.1% to 5% of the composition. Alternatively, it may be present in amounts of 0.1% to 1%, or 0.1% to 0.5% (w / w). Yes, it is possible. In some embodiments, the lubricant is present in an amount of 0.1% to 0.5% (w / w) of the composition. It may be present. The lubricant may also be present in about 0.10% (w / w) of the composition, or 0. 11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24 %, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or approximately 0.3 It can be present in an amount of 0% (w / w). In some embodiments, the lubricant is present in an amount of about 0.25 It may be present in an amount of %(w / w). In some embodiments, the lubricant is present in about 0.5%(w / w) It may be present in small amounts. In some embodiments, the lubricant is present in amounts of about 0.25% (w / w) of stearyl. It is magnesium phosphate.

[0116] In other embodiments, when the composition is a tablet composition, the composition may include a two-phase structure. However, it is not limited to this, and in a two-phase structure, the outer phase contains microcrystalline cellulose, and the inner phase The phase includes the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate form thereof. .

[0117] In some embodiments, the compositions of the present invention are intended to deliver or use the absorption enhancer. Absorption depends on the use and / or for the treatment of specific indications as defined in this invention. The use of accelerators may be omitted or excluded.

[0118] In other embodiments, the preferred composition of the present invention is administered together with an absorption enhancer such as an intestinal permeability enhancer. When this is done, it may show improved bioavailability.

[0119] In some embodiments, the composition of the present invention may include an absorption or permeation enhancer. In addition, the absorption or permeation enhancer may be in the following forms: zwitterionic, cationic, anionic, or The absorbance or permeation enhancer may be nonionic, but is not limited to these properties. In one embodiment, the absorbance or permeation enhancer is nonionic. It is an intestinal permeability or absorption enhancer. In some embodiments, the absorption enhancer is sodium caprate. Um, sodium caprylate, sodium myristate, sodium palmitate, or Caprates, caprylates, myristates, and other salt forms including sodium stearate. This can be selected from medium-chain saturated fatty acids such as palmitate or stearate, however These are not the only options.

[0120] Other absorption or permeation enhancers include citric acid or citrate, for example, sodium citrate. M, tartaric acid or tartaric acid salts, salicylic acid or its derivatives or salicylates, fats Acid-acylated amino acids, alkyl saccharides, C8-o alkyl polysaccharides, n-oc Chil-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-te Tradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, lauric acid Sucrose, sucrose myristate, sucrose palmitate, sucrose coconut fatty acid , sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mo Notetradecanoate, coco-glucoside, cyclodextrin, alkanoyl carnitine For example, lauroyl carnitine, myristoyl carnitine, or palmitoyl carnitine. Lunithine, lauroyl carnitine chloride, myristoyl carnitine chloride, or Palmitoyl carnitine chloride; sodium lauryl alanine, N-dodecanoyl-L -Alanine, sodium lauroyl asparagine, N-dodecanoyl-L-asparagine , sodium lauroyl aspartate, N-dodecanoyl-L-aspartate, lauroyl Sodium lauroylcysteine, N-dodecanoyl-L-cysteine, lauroyl glutamate Sodium Glutamate, N-Dodecanoyl-L-Glutamate, Sodium Lauroyl Glutamate M, N-dodecanoyl-L-glutamine, lauroylglycine sodium, N-dodecano Il-L-glycine, lauroylhistidine sodium, N-dodecanoyl-L-histidine Din, sodium lauroyl isoleucine, N-dodecanoyl-L-isoleucine, lauroyl Sodium lauroyl leucine, N-dodecanoyl-L-leucine, lauroyl methionine Thorium, N-dodecanoyl-L-methionine, sodium lauroylphenylalanine , N-dodecanoyl-L-phenylalanine, sodium lauroylpropionate, N- Dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-se Phosphorus, sodium lauroylthreonine, N-dodecanoyl-L-threonine, lauroy Tryptophan sodium, N-dodecanoyl-L-tryptophan, lauroyl tyrofoam Sodium cinnabar, N-dodecanoyl-L-tyrosine, sodium lauroyl valine, N- Dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L- Sarcosine, sodium alanine caprate, N-decanoyl-L-alanine, caprin Sodium asparagine acid, N-decanoyl-L-asparagine, asparagine caprate Sodium phosphate, N-decanoyl-L-aspartic acid, cysteine ​​sodium caprate M, N-decanoyl-L-cysteine, sodium capric glutamate, N-decano Il-L-glutamic acid, sodium glutamate caprate, N-decanoyl-L-glutamic acid Tamin, sodium capric acid, N-decanoyl-L-glycine, capric acid Sodium styidine, N-decanoyl-L-histidine, sodium isoleucine caprate Um, N-decanoyl-L-isoleucine, sodium capric acid leucine, N-decano Il-L-leucine, sodium caprate methionine, N-decanoyl-L-methionine , sodium phenylalanine caprate, N-decanoyl-L-phenylalanine, Sodium propionate prate, N-decanoyl-L-proline, Serinyl caprate Thorium, N-decanoyl-L-serine, threonine sodium caprate, N-decanoyl Il-L-threonine, tryptophan sodium caprate, N-decanoyl-L- Liptophan, sodium tyrosine caprate, N-decanoyl-L-tyrosine, capri Sodium valine phosphate, N-decanoyl-L-valine, sodium sarcosinate caprate N-decanoyl-L-sarcosine, oleoyl-sarcosine sodium, N-decyl leucoyl Sodium stearoyl glutamate (e.g., Amisoft HS) -1 1 P), myristoyl glutamate sodium (e.g., Amisoft MS -1 1) Sodium lauroyl glutamate (e.g., Amisoft LS-1) 1) Sodium cocoyl glutamate (e.g., Amisoft CS-1 1), co Coilglycine sodium (e.g., Am lite GCS-1 1), N-decyl hydroxypropyl glycine Sodium cocoyl glycinate, sodium cocoyl glutamate, Sodium uroylalanine, N-dodecanoyl-L-alanine, lauroyl asparagus Sodium lauroyl aspartate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate Um, N-dodecanoyl-L-aspartic acid, sodium lauroylcysteine, N- Dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl -L-glutamic acid, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid Min, Lauroyl Glycinate Sodium, N-Dodecanoyl-L-Glycine, Lauroyl Hy Sodium stidine, N-dodecanoyl-L-histidine, sodium lauroyl isoleucine Lium, N-dodecanoyl-L-isoleucine, sodium lauroylleucine, N-do Decanoyl-L-leucine, Lauroylmethionine sodium, N-Dodecanoyl-L- Methionine, sodium lauroylphenylalanine, N-dodecanoyl-L-phenyl Alanine, sodium lauroylpropionate, N-dodecanoyl-L-proline, laur Sodium lauroylserine, N-dodecanoyl-L-serine, sodium lauroylthreonine Um, N-dodecanoyl-L-threonine, lauroyltryptophan sodium, N- Dodecanoyl-L-tryptophan, Lauroyl tyrosine sodium, N-Dodecanoyl -L-tyrosine, lauroyl valine sodium, N-dodecanoyl-L-valine, N-do Decanoyl-L-sarcosine, alanine caprate sodium, N-decanoyl-L-a Ranine, sodium caprate asparagine, N-decanoyl-L-asparagine, cap Sodium aspartate phosphate, N-decanoyl-L-aspartic acid, capric acid Sodium stain, N-decanoyl-L-cysteine, sodium capric glutamate Um, N-decanoyl-L-glutamic acid, sodium glutamate caprate, N-decanoyl-L-glutamic acid Noyl-L-glutamine, sodium capric acid, N-decanoyl-L-glycine N-, histidine caprate sodium, N-decanoyl-L-histidine, caprate Soleucine sodium, N-decanoyl-L-isoleucine, capric acid leucine sodium M, N-decanoyl-L-leucine, sodium caprate methionine, N-decanoyl -L-methionine, sodium phenylalanine caprate, N-decanoyl-L-phenophosphate Nylalanine, sodium capric proline, N-decanoyl-L-proline, capri Sodium serine acid, N-decanoyl-L-serine, sodium caprate threonine N-decanoyl-L-threonine, sodium tryptophan caprate, N-decano Il-L-tryptophan, tyrosine sodium caprate, N-decanoyl-L-tyrosine N-Valine sodium caprate, N-decanoyl-L-valine, sarcosine caprate Sodium, sodium oleoylsarcosinate, and any of the above compounds Fatty acid acylated amino acids, including but not limited to pharmaceutically acceptable salts; or alpha Canoyl sarcosinate (for example, lauroyl sarcosinate sodium, etc.) (Glucosinate), or C8~C 20 20 standard acylated alkanates Alkyl saccharides (for example, Mult) are one of the alpha-amino acids that make up an protein. itrope (trademark) 1620-LQ-(MV), etc. C1~C 20 Alkylsaccharide ; or n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-mal Toside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-malto Sodium sucrose, sucrose laurate, sucrose myristate, sucrose palmitate, coconut Sucrose fatty acids, sucrose mono-dodecanoate, sucrose monotridecanoate , sucrose mono-tetradecanoate, coco-glucoside, alkylsaccharide, cyclamate Rodextrin (e.g., alpha-cyclodextrin, beta-cyclodextrin) , gamma-cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl Pyrbeta-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino] Caprylic acid, N-[8-(2-hydroxybenzoyl)amino]caprylate, N-[8 -(2-hydroxybenzoyl)amino]caprylate sodium, "SNAC (Sodium N -[8-(2-hydroxybenzoyl)amino]caprylate) also known as, Cium chelate compounds (for example, ethylenediaminetetraacetic acid) Acid, EDTA), cremophor EL (also known as "Kolliphor EL") (CAS number 61791-12-6), chitosan, N,N,N-trimethyl chitosan , benzalkonium chloride, bestatin, or alkanol (for example, ethanol, Decanol), Caprylocaproyl polyoxylglyceride (e.g., caprylocaproyl Lupolyoxyl-8 glyceride, LABRASOL (registered trademark) or ACCONON (registered trademark) (Registered trademark) Available as MC8-2), Ethyl caprylate, Glyceryl monolaurate, Lysophosphatidylcholine, menthol, C2o alkylamine, C8~C 20 Alke Nylamines (e.g., oleylamines), phosphatidylcholine, poloxamers, polyamines Teylene glycol monolaurate, polyoxyethylene, polypropylene glycol mono Laurate, polysorbate (e.g., polysorbate 80), cholic acid (or cholic acid Salts, e.g., sodium cholate), deoxycholates (e.g., sodium deoxycholate) Sodium lye, sodium glycocholate, sodium glycodeoxycholate, lauryl sulfur Sodium lauryl sulfate (SDS), sodium decyl sulfate, octyl sulfate Sodium phosphate, sodium laureth sulfate, N-lauryl sarcosinate, decyl trimeth Ammonium bromide, benzyldimethyldodecylammonium chloride, myristyl Trimethylammonium chloride, dodecylpyridinium chloride, or decyl ammonium This may include, but is not limited to, thioammoniopropanesulfonate.

[0121] In some embodiments, the absorption or permeation enhancer is sodium caprate, sodium caprylate Sodium palmitate, sodium stearate, sodium citrate, saline Sodium cylate, sodium salcaprozate (SNAC), Polyethylene glycol (PEG)-modified medium-chain triglycerides of capric acid and caprylic acid Cerides (for example, LABRASOL®, imported from Gattefosse, USA) (Possible to use), sucrose laurate, or lauroyl-L-carnitine (Lauroyl- L-carnitine, LC, e.g., PEPTELLIGENCE (registered trademark), E This may include, but is not limited to, products such as (available from Interis BioPharma, NJ, USA). These are not limited to these. In some embodiments, the absorption enhancer is sodium caprate, cap Sodium lylate, sodium palmitate, sodium stearate, sodium citrate Um, sodium salicylate, sodium salcaprozate (SNAC), capric acid and Polyethylene glycol (PEG)-modified medium-chain fatty acid triglycerides of caprylic acid, lau It is sucrose phosphate or lauroyl-L-carnitine (LC). In several embodiments, The absorption or permeation enhancer is polyethylene glycol (PE) containing capric acid and caprylic acid. G) It can be a modified medium-chain fatty acid triglyceride.

[0122] In another aspect, the present invention relates to a composition comprising about 0.1% to about 15% (w / w) of the composition. an amount of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, and about An absorption or permeation enhancer in an amount of 10% to approximately 60% (w / w), and one or more pharmaceutically active ingredients The present invention relates to a composition comprising acceptable excipients.

[0123] In another aspect, the present invention relates to a composition comprising about 0.1% to about 15% (w / w) of the composition. an amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, and The present invention relates to a composition comprising an extractive agent and one or more pharmaceutically acceptable excipients. .

[0124] In other embodiments, the absorption or permeation enhancer used is sodium salcaprozate. Obtain. In some embodiments, the absorption or permeation enhancers used are capric acid and caprylic acid. Acids may contain polyethylene glycol (PEG)-modified medium-chain fatty acid triglycerides, etc. , but not limited to these.

[0125] In some embodiments, the absorption or permeation enhancer used in the composition of the present invention is a cap. It may be, but is not limited to, sodium phosphate.

[0126] In another aspect, the present invention relates to a composition comprising about 0.1% to about 15% (w / w) of the composition. an amount of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, and The product contains approximately 20% to 45% (w / w) of sodium caprate and microcrystalline cellulose. The present invention provides a composition containing S and

[0127] In another embodiment, the present invention relates to a composition, wherein the composition is comprised of 0.1% to 15% (w / w) of the composition. The peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof, and 20% to 45% (w) of the composition The present invention provides a composition comprising sodium caprate in an amount of / w and microcrystalline cellulose. ru.

[0128] In some embodiments, sodium caprate is present in a composition of approximately 1% to approximately 99% (w / w). , or about 5% to about 50% (w / w) of the composition, or about 10% to about 50% (w / w), Or approximately 20% to approximately 50% (w / w), or approximately 30% to approximately 50% (w / w), if Approximately 30% to 40% (w / w), or approximately 32% to 38% (w / w), or It can be present in the composition in an amount of approximately 35% to approximately 36% (w / w). In this embodiment, sodium caprate is present in an amount of approximately 30% to approximately 40% (w / w).

[0129] In some embodiments, sodium caprate is present in the composition at a concentration of 1-99% of the composition. (w / w), or 5-50% (w / w) or 10-50% (w / w) of the composition, Alternatively, 20-50% (w / w), or 30-50% (w / w), or 30-40 Amounts of % (w / w), or 32-38% (w / w), or 35-36% (w / w). It can exist in some forms. In some embodiments, sodium caprate is present in 30-40% It is present in (w / w) amounts. For example, sodium caprate makes up about 30% of the composition, 31% %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% ( It can exist in w / w quantities, and such quantities include any fractional amounts between these. In some embodiments, sodium caprate is present in an amount of approximately 32% to approximately 38% (w / w). It can be present. In some embodiments, sodium caprate is present at about 35.7% (w It can exist in the quantity of / w).

[0130] In one embodiment, for use in the composition of the present invention, sodium caprate is used in small amounts. 98%, 98.2%, 98.4%, 98.6%, 98.8%, 99.0%, 99.5% It may have a purity of %, or at least 99.9%. It is not bound by any theory, however Higher purity of sodium caprate is equivalent to lower technical grade sodium caprate. For example, compared to sodium caprate with a purity of 90% or 95%, improved It can provide iodine availability. In some embodiments, sodium caprate The um has a purity of at least 98% for use in the present invention.

[0131] In another embodiment, for use in the present invention, sodium caprate is approximately 10 nm The average particle size may be approximately 150 micrometers. In some embodiments, the present invention Sodium caprate particles suitable for use in this application range from approximately 1 micrometer to approximately 150 micrometers. It may have an average diameter of chromate. In some embodiments, such sodium caprate Um particles can have an average diameter of approximately 50 micrometers to approximately 150 micrometers. In other embodiments, sodium caprate particles are flat, ranging in size from about 10 nm to about 5 micrometers. They may have a uniform diameter. In some embodiments, the sodium caprate particles are approximately 50 nm to approximately It may have an average diameter of 1 micrometer. In some embodiments, sodium caprate is used. The particles may have an average diameter of approximately 100 nm to 800 nm.

[0132] In some embodiments, sodium caprate may be supplied in various particle sizes. In some embodiments, sodium caprate particles are 10 nm to 150 micrometers in size. It can have an average diameter. In some embodiments, sodium caprate particles are 1 They can have an average diameter of several micrometers to 150 micrometers. In this embodiment, the sodium caprate particles are 50 micrometers to 150 micrometers in size. It can have an average diameter of 1. It can have an average diameter of 0 nm to 5 micrometers. In some embodiments, Sodium phosphate particles can have an average diameter of 50 nm to 1 micrometer. In some embodiments, sodium caprate particles are 100 nm to about 800 nm in size. It can have an average diameter.

[0133] In another embodiment, sodium caprate is suitable for use in the composition of the present invention. It can exist in any of the following forms. In some embodiments, sodium caprate exists in crystalline form. It can be in an amorphous or semi-crystalline form. In some embodiments, crystalline caprin The use of sodium acid enhances the bioavailability of the peptide in SEQ ID NO: 1. This is possible. In some embodiments, the use of amorphous sodium caprate is as described in SEQ ID NO: 1. The bioavailability of butylene can be enhanced. In some embodiments, semicrystalline The use of sodium caprate increases the bioavailability of the peptide of SEQ ID NO: 1. It can be strengthened.

[0134] In some embodiments, the use of crystalline sodium caprate is equivalent to the peptide of SEQ ID NO: 1 or This may enhance the bioavailability of its pharmaceutically acceptable salt or solvate form. In some embodiments, the use of amorphous sodium caprate is used for the peptide of SEQ ID NO: 1. or enhance the bioavailability of its pharmaceutically acceptable salt or solvate form. Obtain. In some embodiments, the use of semicrystalline sodium caprate is obtained. Increase the bioavailability of tides or their pharmaceutically acceptable salts or solvates. It can be strengthened.

[0135] In another embodiment, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof The form and sodium caprate are specified herein for use or suitability in the present invention. They can be combined in any preferred form as defined. In some embodiments, the array Peptide No. 1 or its pharmaceutically acceptable salt or solvate form, and capric acid Sodium can form a mixture or a granular mixture.

[0136] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The mediated form and sodium caprate form a mixture or granular mixture.

[0137] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The mediated form and sodium caprate form a mixture.

[0138] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The mediator form and sodium caprate form a granular mixture. In some embodiments The peptide and sodium caprate of SEQ ID NO: 1 can be in the form of a granular mixture. ru.

[0139] Therefore, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form The substance and sodium caprate can be mixed to form a granular mixture. The granulated mixture consists of particles having any of the average diameters suitable for use in the composition of the present invention. It can be formed from. For example, the particles of the granulated mixture are about 100 nm to about 5 micrometers. The average diameter of the particles can be approximately 1 micrometer to 150 micrometers. It can have an average diameter of chromate. In some embodiments, the composition of the present invention The particles of the granulated mixture have an average diameter of approximately 200 nanometers to approximately 1 micrometer. obtain.

[0140] In some embodiments, the peptide of SEQ ID NO: 1 and sodium caprate are mixed. A granular mixture can be formed. In some embodiments, the peptide of SEQ ID NO: 1 and Sodium caprate forms a granular mixture. In some embodiments, the granular mixture The particles of an object can have an average diameter of 100 nm to 5 micrometers. Furthermore, it can have an average diameter of 1 micrometer to 150 micrometers. In some embodiments, the particles of the granulated mixture are 200 nanometers to 1 micrometer in size. It can have an average diameter.

[0141] In other embodiments, when the composition is a tablet composition, the composition may include a two-phase structure. Not limited to this, in a two-phase structure, the outer phase contains microcrystalline cellulose, and microcrystalline cellulose Lurose, along with sodium caprate present in the endophase, can ensure proper intestinal delivery. It can act as a protective barrier between the enteric coating and the surrounding area.

[0142] In another embodiment, the inner phase is approximately 1.8% (w / w) of the peptide of Sequence ID No. 1 or its medicinal properties. Pharmacologically acceptable salt or solvate form, and about 35.7% (w / w) of caprin It may contain sodium phosphate.

[0143] In another embodiment, the inner phase contains approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1, and approximately 3 It may contain 5.7% (w / w) of sodium caprate.

[0144] In some embodiments, the present invention relates to a composition, which is an internal phase, and which comprises about 0.1% of the composition. ~Approximately 15% (w / w) of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or This is in solvate form, and sodium caprate in an amount of about 20% to about 45% (w / w) of the composition. An inner phase containing mu, and an outer phase disposed on the inner phase, which contains microcrystalline cellulose. The present invention provides a composition comprising a phase.

[0145] In some embodiments, the present invention relates to a composition, which is an internal phase, and which comprises about 0.1% of the composition. ~Approximately 10% (w / w) of the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or This is in solvate form, and sodium caprate in an amount of about 20% to about 45% (w / w) of the composition. An inner phase containing mu, and an outer phase disposed on the inner phase, which contains microcrystalline cellulose. The present invention provides a composition comprising a phase.

[0146] In some embodiments, the present invention relates to a composition, which is an internal phase, comprising 0.1% of the composition. 10% (w / w) of the peptide of SEQ ID NO: 1, and 20% to 45% (w / w) of the composition An internal phase containing an amount of sodium caprate, and an external phase disposed on top of the internal phase, which is microcrystalline The present invention provides a composition comprising an outer phase containing crystalline cellulose.

[0147] The internal phase may contain various other pharmaceutically acceptable components or excipients, and such components or Excipients include, for example, lubricants, disintegrants, binders, desiccants, fillers, and other constituents. This includes, but is not limited to, ingredients or excipients.

[0148] Typical disintegrants suitable for use in the present invention include agar, alginic acid, calcium carbonate, Microcrystalline cellulose, croscarmellose sodium, crospovidone, polarinyl Potassium, sodium starch glycolate, potato or tapioca starch, other Starch, pregelatinized starch, clay, other algins, other celluloses, gum (gellan gum) It may include, for example, low-substituted hydroxypropyl cellulose, or mixtures thereof, The invention is not limited to these. In some embodiments, a disintegrant suitable for use in the present invention is a disintegrant. This may include, but is not limited to, roscarmellose sodium. Such disintegrants are Approximately 1% to approximately 99% (w / w) of the composition of the present invention, or approximately 1% to 50% of the composition, Approximately 1% to approximately 25%, or approximately 1% to approximately 20%, or approximately 1% to approximately 10%, or approximately It may be present in amounts of 2% to approximately 8%, or approximately 4% to approximately 6% (w / w). Suitable disintegrants for use are also present in the composition at approximately 1% (w / w), 2%, 3%, 4%, 5%, and 6%. It may be present in amounts of 7%, 8%, 9%, or about 10% (w / w), and the amount may be between these. This includes, but is not limited to, any of the fractional amounts. In some embodiments, the disintegrant is the present It can be present in an amount of approximately 1% to approximately 10% (w / w) of the composition of the element.

[0149] In some embodiments, the disintegrant is present in an amount of 1-99% (w / w) of the composition, or 1-5% of the composition. 0%, or 1-25%, or 1-20%, or 1-10%, or 2-8% It may be present in an amount of %, or 4-6% (w / w). Disintegrant for use in the present invention Also, approximately 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, and 9% of the composition. It may be present in an amount of approximately 10% (w / w), and the amount may include any fractional amount between these. However, it is not limited to these. In some embodiments, the disintegrant is present in the internal phase of the composition. It may be present in the composition in an amount of 1-10% (w / w). In some embodiments, the disintegrant is present in the composition In the internal phase of a substance, it may be present in an amount of about 5% (w / w) of the composition of the present invention.

[0150] In another embodiment, the composition of the present invention or any amount of hydrophilic silica for the purposes of the present invention This may include, but is not limited to, hydrophilic silica, approximately 200m 2 Specific surface area / g Aerosil 200, which has a product, is an example. A substitute for hydrophilic silica is tal. Sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate Cium, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof This may include, but is not limited to, things like [examples of examples].

[0151] In some embodiments, the composition of the present invention may further include hydrophilic silica. In one embodiment, Hydrophilic silica is present in the composition of the present invention at a concentration of about 0.1% to about 10% (w / w), or about 0.1% to about 5% of the composition, or about 0.1% to about 2%, or about 0 0.1% to approximately 1.5%, or approximately 0.1% to approximately 1%, or approximately 0.3% to approximately 0.7% ( It may be present in an amount of w / w. In another embodiment, the composition of the present invention may be present in about 0.1% to about 0.1% of the composition. It may further contain 1.5% (w / w) of hydrophilic silica. In another embodiment, the composition of the present invention The composition may further contain hydrophilic silica in an amount of approximately 1.0% (w / w).

[0152] In one embodiment, hydrophilic silica is present in the composition of the present invention in an amount of 0.1 to 1 0% (w / w), or 0.1% to 5%, or 0.1% to 2%, or 0% of the composition. Amounts of 1% to 1.5%, or 0.1% to 1%, or 0.3% to 0.7% (w / w). It may exist in such quantities. For example, the hydrophilic silica used in this invention is present in an amount of about 0.1% of the composition. 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1 They may be present in amounts of 0.0% or 1.5% (w / w), and such amounts are defined as these It includes any fractional amount between the two. In another embodiment, the composition of the present invention is 0.1% to 1% of the composition. It may further contain 0.5% (w / w) of hydrophilic silica. In a further embodiment, the composition of the present invention The composition may further contain hydrophilic silica in an amount of approximately 0.5% (w / w).

[0153] In some embodiments, the composition may further include hydrophilic silica in its internal phase. In that embodiment, the composition contains approximately 0.1% to approximately 1.5% (w / w) of hydrophilic silica It may further contain . In some embodiments, the composition is in an amount of about 0.5% (w / w) of the composition. It may further contain hydrophilic silica.

[0154] The internal phase is a small effective therapeutic amount for use in a composition, as determined by the present invention. It may contain, but is not limited to, one disintegrant. Suitable for use in the present invention. Typical disintegrants include starch, clay, cellulose, alginate, and gum, and cross-linking agents. This includes, but is not limited to, cellulose, polymers, and combinations thereof. Not limited to, other typical disintegrants suitable for use in the present invention include microcrystalline cellulose. Croscarmellose sodium, alginic acid, sodium alginate, crospovid N, cellulose, agar and related gums, sodium starch glycolate, corn starch Potato starch, sodium starch glycolate, Veegum HV, methyl Cellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar This may include, but is not limited to, m, and combinations thereof.

[0155] In some embodiments, the disintegrant is present in the internal phase at about 1% to about 10% of the composition of the present invention. It may be present in an amount of w / w. In some embodiments, the disintegrant is present in the internal phase, as part of the present invention. It can be present in the final product in an amount of approximately 5.0% (w / w).

[0156] In another embodiment, the internal phase of the composition of the present invention is approximately 1% to approximately 10% (w / w) of the composition. Disintegrant, approximately 1% to approximately 10% (w / w) of the composition of microcrystalline cellulose, approximately 0 Hydrophilic silica in an amount of 0.1% to approximately 1.5% (w / w), or approximately 5% to approximately 15% (w / w) of the composition. It may further contain at least one of the sorbitols in the amount of / w.

[0157] In yet another embodiment, the internal phase of the composition undergoes decay in an amount of about 1% to about 10% (w / w) of the composition. The agent, approximately 1% to approximately 10% (w / w) of the composition, microcrystalline cellulose, approximately 0.1% of the composition Approximately 1.5% (w / w) of hydrophilic silica, and approximately 5% to 15% (w / w) of the composition. It may further contain an amount of sorbitol.

[0158] In another embodiment, the internal phase of the composition of the present invention is decayed in an amount of 1% to 10% (w / w) of the composition. Microcrystalline cellulose in an amount of 1% to 10% (w / w) of the agent and composition, and 0.1% to 1% of the composition. 0.5% (w / w) of hydrophilic silica, or 5% to 15% (w / w) of the composition of sol It may further contain at least one of the bitols.

[0159] In yet another embodiment, the internal phase of the composition is a disintegrant in an amount of 1% to 10% (w / w) of the composition. Microcrystalline cellulose in an amount of 1% to 10% (w / w) of the composition, and 0.1% to 1.5% of the composition. Hydrophilic silica in %(w / w) amounts, and sorbite in 5% to 15%(w / w) amounts of the composition It may further include .

[0160] In some embodiments, the internal phase of the composition of the present invention is approximately 3.9% (w / w) of microcrystalline material. Cellulose, approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w / w) of The compound further contains a disintegrant and at least one of approximately 0.5% (w / w) hydrophilic silica. It is visible.

[0161] In some embodiments, the internal phase of the composition is approximately 3.9% (w / w) of microcrystalline cellulose. S, approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w / w) of disintegrant, It may also further contain approximately 0.5% (w / w) of hydrophilic silica.

[0162] In some embodiments, the internal phase of the composition is Avicel PH101 at approximately 3.9% (w / w) and approximately 10.7% (w / w) Sorbitol, approximately 5.0% (w / w) of croscarmellose sodium, and approximately 0 It may further contain 0.5% (w / w) of Aerosil 200.

[0163] The outer phase microcrystalline cellulose is any microcrystalline cellulose known in the art. It may include cellulose. In some embodiments, the outer phase microcrystalline cellulose is silicified microcrystalline cellulose. It may contain crystalline cellulose (SMCC). In some embodiments, silicified microcrystalline cellulose. The available options are SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, and This may include, but is not limited to, SMCC 90LM and others.

[0164] In some embodiments, for use in the present invention, the microcrystalline cellulose of the outer phase is It may be microcrystalline cellulose (SMCC) with any particle size (i.e., the present invention) It may have a particle size suitable for use for the purpose of the external phase. It contains silicified microcrystalline cellulose in an amount of approximately 25% to approximately 45% (w / w) of the composition. In several embodiments, the outer phase consists of silicified microcrystalline cells in an amount of approximately 27.7% (w / w) of the composition. Contains rose. In some embodiments, the external phase is about 31.0% (w / w) of the composition. Contains ionized microcrystalline cellulose. In some embodiments, the outer phase constitutes about 59.6% of the composition. It contains silicified microcrystalline cellulose in w / w amounts.

[0165] In some embodiments, the outer phase is silicified microcrystalline in an amount of 25-45% (w / w) of the composition. Contains cellulose. In some embodiments, the outer phase is present in an amount of about 36.6% (w / w) of the composition. It contains silicified microcrystalline cellulose.

[0166] The Foreign Minister may include various other pharmaceutically acceptable excipients or components, and such pharmaceutically acceptable excipients or The constituent components may include lubricants, disintegrants, binders, desiccants, fillers, and other constituent components. However, it is not limited to these. For use in the present invention, the disintegrant is in the composition. , 0.1-10% (w / w) of the composition, or 0.1-5%, or 0.1-2% of the composition %, or 0.1-1.5%, or 0.1-1%, or 0.1-0.4% (w It may be present in amounts of / w). For example, hydrophilic silica may be present in amounts of about 0.1%, 0.2%, 0% of the composition. 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8% It can be present in amounts of 0.9%, 1.0%, or 1.5% (w / w), and the amount is This includes any of the divisions between these as defined herein. In some embodiments, The foreign phase may further contain a disintegrant. In some embodiments, the foreign phase is 0.1% to 1% of the composition. It may further contain 0.5% (w / w) of hydrophilic silica. In some embodiments, the outer phase is combined The resulting product may further contain a disintegrant in an amount of approximately 0.25% (w / w).

[0167] In the present invention, the external phase is suitable for use in compositions such as those described herein. It may contain any amount of lubricant. Examples of lubricants suitable for use in the present invention include magnesium carbonate. Nesium, magnesium lauryl sulfate, calcium silicate, talc, fumed carbon dioxide Examples include, but are not limited to, the element I and combinations thereof. Suitable lubricants include magnesium stearate, calcium stearate, stearic acid, Sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, Magnesium uryl sulfate, sodium benzoate, colloidal silicon dioxide, magnesium oxide Um, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate, polyethylene Includes ylene glycol, sodium acetate, sodium chloride, and combinations thereof. Obtain, but not limited to these.

[0168] The Foreign Minister may include at least one disintegrant in any preferred amount according to the present invention. In one embodiment, the disintegrant may include croscarmellose sodium. For use, the disintegrant is used in the composition at a concentration of approximately 0.1% to approximately 10% (w / w) of the composition. Or about 0.1% to about 5% of the composition, or about 0.1% to about 2%, or about 0.1% Approximately 1.5%, or approximately 0.1% to 1%, or approximately 0.1% to 0.4% (w / w) It may be present in an amount of . In another embodiment, a suitable disintegrant is about 1% (w / w), 2% of the composition. It can be present in amounts of 3%, 4%, 5%, 6%, 7%, 8%, 9%, or approximately 10% (w / w). However, the amount is not limited to these, and the amount may be any of the amounts between these as defined in the present invention. Including the amount of division. In another aspect of the present invention, the disintegrant is in the outer phase of the composition, about 1 It may exist in an amount of approximately 10% (w / w), but is not limited to this. In other forms, decay The agent may be present in the external phase of the composition in an amount of approximately 5.0% (w / w) of the composition.

[0169] In another embodiment, the outer phase may also contain any amount of hydrophilic silica according to the present invention. Water-based silica is approximately 200m 2 An example using Aerosil 200, which has a specific surface area of ​​1 / g. As shown, suitable substitutes for hydrophilic silica for use in the present invention are talc, ferro Sodium cyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, 2 Contains silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof. However, it is not limited to these. Hydrophilic silica is present in the composition at a concentration of about 0.1 to 1% of the composition. 0% (w / w), or about 0.1-5% of the composition, or about 0.1-2%, or about 0 Amount of 0.1-1.5%, or approximately 0.1-1%, or approximately 0.3-0.7% (w / w) It can exist in amounts of 0.1%, 0.2%, 0.3%, and 0% of the composition. 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or 1.5% It can exist in (w / w) quantities, and such quantities include any fractional amounts between these two. .

[0170] In some embodiments, the external phase of the compositions disclosed herein is about 0.1% by weight of the composition. Lubricant in an amount of approximately 0.5% by weight, disintegrant in an amount of approximately 1% to approximately 10% by weight of the composition, or combination At least one of the hydrophilic silica in an amount of approximately 0.1% to 1.5% by weight of the product is further It can be included in.

[0171] In some embodiments, the external phase of the composition is in an amount of about 0.1% to about 0.5% by weight of the composition. Lubricant, disintegrant in an amount of about 1% to about 10% by weight of the composition, and about 0.1% by weight of the composition It may further contain approximately 1.5% by weight of hydrophilic silica.

[0172] In some embodiments, the external phase of the composition disclosed herein is 0.1% by weight of the composition. 0.5% by weight of lubricant, 1% to 10% by weight of disintegrant of the composition, or 0% of the composition It further contains at least one of hydrophilic silica in an amount of 0.1% to 1.5% by weight. can.

[0173] In some embodiments, the outer phase of the composition is a lubricant in an amount of 0.1% to 0.5% by weight of the composition. Disintegrant in an amount of 1% to 10% by weight of the composition, and disintegrant in an amount of 0.1% to 1.5% by weight of the composition It may further contain a certain percentage of hydrophilic silica.

[0174] In some embodiments, the external phase of the compositions disclosed herein is about 5.0% (w / w) A certain amount of disintegrant, approximately 0.5% (w / w) of hydrophilic silica, and approximately 0.25% (w / w) It may further contain at least one of the lubricants in a given quantity.

[0175] In some embodiments, the outer phase of the composition is approximately 36.6% (w / w) of silicified microcrystalline material. Cellulose, approximately 5.0% (w / w) of disintegrant, approximately 0.5% (w / w) of hydrophilic cellulose Contains licorice and approximately 0.25% (w / w) of lubricant.

[0176] In some embodiments, the external phase of the composition is approximately 36.6% (w / w) of SMCC HD 90, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5% (w / w) Aerosil 200 in an amount of ) and magnesium stearate in an amount of approximately 0.25% (w / w) It may contain nesium.

[0177] In some embodiments, the composition of the present invention may be in the form of tablets or capsules, but these may be The dosage form may be any form not limited to this. In some embodiments, the composition may be a tablet or capsule composition. It is possible. In some embodiments, the composition may be a tablet composition. In this embodiment, such a tablet composition may contain an amount of a unit dose size, and the unit dose size The amount may range from approximately 25 mg to approximately 2000 mg, or from approximately 500 mg to approximately 2000 mg. The compositions of the present invention may be any preferred size according to the present invention. For example, 25, 50, 75, 100, 110, 120, 130, 140, 150, 16 0, 170, 180, 190, 200, 250, 300, 350, 400, 450, 50 0, 550, 600, 650, 700, 750, 800, 850, 900, 950, 10 50, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 14 50, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 18 Dosages such as 50, 1900, 1950, or 2000 milligrams (mg) The amount may be a tablet or capsule, but is not limited thereto. In one embodiment, the combination of the present invention The products are available as tablets of 25 mg, 50 mg, 100 mg, or 1400 mg, respectively. The tablets may be taken once or twice a day, or as determined by medical necessity. It may be administered, but is not limited to these. In some embodiments, the composition may be approximately 500 mg The unit dose size may be approximately 2000 mg. In some embodiments, the composition is approximately 14 The unit dose size could be 00 mg.

[0178] In some embodiments, such tablet compositions are used in units of 500 mg to approximately 2000 mg. May include quantity and size. The tablet composition may be any of the preferred sizes according to the present invention, for example ba, 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 1 70, 180, 190, 200, 250, 300, 350, 400, 450, 500, 5 50, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, The tablets may be 1900, 1950, or 2000 mg, but are not limited to these. In some embodiments, the composition is a 1400 mg tablet.

[0179] Tablets formed from the composition of the present invention are administered in a manner that is required and acceptable to the patient. Depending on the frequency, it may be administered as a single or multiple dose, and such tablets are for specific diseases. Contains a quantity or amount of active agent sufficient to effectively treat the condition. Therefore, in one embodiment, the present invention relates to the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable form. A composition for oral administration in the form of a salt or solvate, comprising approximately 0.05 to approximately 30 mg This relates to a composition that can be taken in a daily dose of / kg body weight / day. In some embodiments, the dose The dosage can be approximately 0.1 mg to approximately 20 mg / kg body weight / day. In other embodiments, the dosage The dosage can be approximately 0.1 mg to approximately 5 mg / kg body weight / day. In another embodiment, the dosage This can range from approximately 0.1 mg to approximately 1 mg / kg body weight / day.

[0180] In some embodiments, the present invention relates to a composition for oral administration of the peptide of SEQ ID NO: 1. This refers to compositions that can be ingested at a daily dose of 0.05 to 30 mg / kg body weight / day. In some cases, the dosage can be 0.1 mg to 20 mg / kg body weight / day. In another embodiment, the dosage may be 0.1 mg to 5 mg / kg body weight / day. In this embodiment, the dosage can be 0.1 mg to 1 mg / kg body weight / day.

[0181] In some embodiments, the present invention relates to an internal phase comprising an amount of about 1.8% (w / w) of the sequence number 1 peptide or its pharmaceutically acceptable salt or solvate form, and about 35.7% ( An inner phase containing an amount of sodium caprate (w / w), and an outer phase containing approximately 36.6% (w / w) sodium caprate. The present invention provides a composition comprising an outer phase containing silicified microcrystalline cellulose HD90 in an amount of / w) do.

[0182] In some embodiments, the present invention relates to an internal phase comprising an amount of about 1.8% (w / w) of the sequence number The inner phase contains peptide 1 and approximately 35.7% (w / w) of sodium caprate. The outer layer contains approximately 36.6% (w / w) of silicified microcrystalline cellulose HD90. The present invention provides a composition containing a foreign substance.

[0183] In some embodiments, the composition, In the internal phase, approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1 and approximately 35.7% ( A granular mixture with sodium caprate in w / w amounts, approximately 3.9% (w / w) of fine Crystalline cellulose, approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w / w) The inner phase contains an amount of disintegrant and approximately 0.5% (w / w) of hydrophilic silica, The outer phase disposed on top of the core, containing approximately 36.6% (w / w) of silicified microcrystalline sediment Lurose, approximately 5.0% (w / w) of disintegrant, approximately 0.5% (w / w) of hydrophilic silica The outer phase contains a substance and approximately 0.25% (w / w) of lubricant, It can include...

[0184] In some embodiments, the composition, In the internal phase, approximately 7.1% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and , a granular mixture with approximately 35.7% (w / w) of sodium caprate, approximately 3.9% ( Microcrystalline cellulose in w / w amounts, Approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w / w) of croscarmellose. Mellose sodium, approximately 0.5% (w / w) of colloidal anhydrous silica, and approximately 0.2 The inner phase contains 5% (w / w) magnesium stearate, External phase, approximately 31.0% (w / w) of silicified microcrystalline cellulose, approximately 5.0% (w / w) amount of croscarmellose sodium, approximately 0.5% (w / w) amount of colloid Contains anhydrous silica and approximately 0.25% (w / w) of magnesium stearate. In terms of, It can include...

[0185] In some embodiments, the composition, In the internal phase, approximately 10.7% (w / w) of the acetate form of the peptide of SEQ ID NO: 1. And a granular mixture with approximately 35.7% (w / w) of sodium caprate, approximately 3.9% (w / w) amount of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w / w) of croscarmellose. It contains melose sodium and approximately 0.5% (w / w) of colloidal anhydrous silica. In terms of, External phase, approximately 27.7% (w / w) of silicified microcrystalline cellulose, approximately 5.0% (w / w) amount of croscarmellose sodium, approximately 0.5% (w / w) amount of colloid Contains anhydrous silica and approximately 0.25% (w / w) of magnesium stearate. In terms of, It can include...

[0186] In some embodiments, the composition, In the internal phase, approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1 and approximately 35.7% ( A granular mixture with sodium caprate in w / w amounts, approximately 3.9% (w / w) of A vicel PH101, approximately 10.7% (w / w) of sorbitol, approximately 5.0% (w Croscarmellose sodium in an amount of (w / w), and approximately 0.5% (w / w) of Aero The inner phase contains sil 200, The Minister of Foreign Affairs stated that the amount of SMCC HD90 was approximately 36.6% (w / w), and approximately 5.0% (w / w) amount of croscarmellose sodium, approximately 0.5% (w / w) amount of Aerosil The external phase contains 200 and approximately 0.25% (w / w) of magnesium stearate. , It can include...

[0187] In some embodiments, the internal phase of the composition contains about 1.8% (w / w) of the peptide of SEQ ID NO: 1. Contains sodium caprate in acetate form and approximately 35.7% (w / w) of sodium caprate. The outer phase can be made of approximately 36.6% (w / w) silicified microcrystalline cellulose HD90. Includes.

[0188] The compositions of the present invention may also use, but are not limited to, silicified microcrystalline cellulose. Silicated microcrystalline cellulose is in contact with sodium caprate and enteric coating. By effectively reducing the enteric coating integrity for proper intestinal delivery, This can impart specific stability to the composition. Also, the peptide of SEQ ID NO: 1 or its pharmaceutically The bioavailability of the acceptable salt or solvate form is that of an absorption enhancer, for example, Improved bioavailability through the use of permeability enhancers such as sodium caprate. This can be demonstrated, in particular, sodium caprate with a purity greater than 98%. This can improve bioavailability. Bioavailability is also affected by capric acid. The use of specific sizes of sodium particles and the degree of crystallinity of the sodium caprate source And it can be improved.

[0189] In some embodiments, the internal phase contains approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of cete form and approximately 35.7% (w / w) sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, approximately 10.7% (w / w) of sol Bitol, approximately 5.0% (w / w) of disintegrant, and approximately 0.5% (w / w) of hydrophilicity. It can contain silica, and the outer phase is approximately 36.6% (w / w) of silicified microcrystalline cellulose. - Approximately 5.0% (w / w) of disintegrant, approximately 0.5% (w / w) of hydrophilic silica, It also contains approximately 0.25% (w / w) of lubricant.

[0190] In some embodiments, the composition, In the internal phase, approximately 1.8% (w / w) of the acetate form of the peptide of SEQ ID NO: 1 and , a granular mixture with approximately 35.7% (w / w) of sodium caprate, approximately 3.9% ( Microcrystalline cellulose in w / w amounts, approximately 10.7% (w / w) amounts of sorbitol, approximately 5 0.0% (w / w) of croscarmellose sodium, and approximately 0.5% (w / w) The inner phase contains colloidal anhydrous silica, External phase, approximately 36.6% (w / w) of silicified microcrystalline cellulose, approximately 5.0% (w / w) amount of croscarmellose sodium, approximately 0.5% (w / w) amount of colloid Contains anhydrous silica and approximately 0.25% (w / w) of magnesium stearate. In terms of, It can include...

[0191] In some embodiments, the internal phase contains approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of cete form and approximately 35.7% (w / w) sodium caprate. Approximately 3.9% (w / w) of Avicel PH101, approximately 10.7% (w / w) Sorbitol, approximately 5.0% (w / w) of croscarmellose sodium, and approximately 0 It can contain 0.5% (w / w) of Aerosil 200, and the foreign minister is approximately 36.6 % (w / w) amount of SMCC HD90, approximately 5.0% (w / w) amount of croscarmellol Sodium, approximately 0.5% (w / w) of Aerosil 200, and approximately 0.25% Contains (w / w) magnesium stearate.

[0192] In some embodiments, the internal phase contains approximately 7.1% (w / w) of the peptide of SEQ ID NO: 1. It can be in the form of a cete, and can contain approximately 35.7% (w / w) of sodium caprate. The outer phase contains approximately 30.75% (w / w) of silicified microcrystalline cellulose HD90. .

[0193] In some embodiments, the internal phase contains approximately 10.0% (w / w) of the peptide of SEQ ID NO: 1. It is in acetate form and contains approximately 35.7% (w / w) of sodium caprate. The outer phase contains approximately 30.75% (w / w) of silicified microcrystalline cellulose HD90. nothing.

[0194] In some embodiments, the internal phase contains approximately 7.1% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of cete form and approximately 35.7% (w / w) sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, approximately 10.7% (w / w) of sol Bitol, approximately 5.0% (w / w) of disintegrant, approximately 0.5% (w / w) of hydrophilic silica It can contain a lubricant in an amount of approximately 0.25% (w / w), and the external phase is approximately 30.75% Silicified microcrystalline cellulose in (w / w) amounts, approximately 5.0% (w / w) amount of disintegrant, approximately 0 It contains 0.5% (w / w) of hydrophilic silica and approximately 0.5% (w / w) of lubricant.

[0195] In some embodiments, the internal phase contains approximately 10.0% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of acetate and approximately 35.7% (w / w) sodium caprate. The substance contains approximately 3.9% (w / w) of microcrystalline cellulose and approximately 10.7% (w / w) of sorbate. Rubitol, approximately 5.0% (w / w) of disintegrant, approximately 0.5% (w / w) of hydrophilic sulfate It can contain licorice and a lubricant in an amount of about 0.25% (w / w), and the external phase is about 30.75 % (w / w) amount of silicified microcrystalline cellulose, approximately 5.0% (w / w) amount of disintegrant, approximately It contains 0.5% (w / w) of hydrophilic silica and approximately 0.5% (w / w) of lubricant.

[0196] In some embodiments, the internal phase contains approximately 7.1% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of cete form and approximately 35.7% (w / w) sodium caprate. Approximately 3.9% (w / w) of Avicel PH101, approximately 10.7% (w / w) Sorbitol, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5 %(w / w) of Aerosil 200 and approximately 0.25%(w / w) of Stear It can contain magnesium phosphate, and the external phase contains approximately 30.75% (w / w) of SMC. C HD90, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5% (w / w) Aerosil and approximately 0.5% (w / w) Magnesium Stearate Contains zinc.

[0197] In some embodiments, the internal phase contains approximately 10.0% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of acetate and approximately 35.7% (w / w) sodium caprate. The substance contains approximately 3.9% (w / w) of Avicel PH101, and approximately 10.7% (w / w) of A certain amount of sorbitol, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0. 5% (w / w) of Aerosil 200 and approximately 0.25% (w / w) of steroids It can contain magnesium sulfate, and the external phase contains approximately 30.75% (w / w) of SM. CC HD90, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5 % (w / w) Aerosil and approximately 0.5% (w / w) Magnesium Stearate Contains nesium.

[0198] In some embodiments, the internal phase contains approximately 7.1% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of cete form and approximately 35.7% (w / w) sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, approximately 10.7% (w / w) of sol Bitol, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5% (w / w) Colloidal anhydrous silica in an amount of (w / w), and approximately 0.25% (w / w) of stearic acid It can contain magnesium, and the outer phase contains approximately 31.0% (w / w) of silicified microcrystalline sediment. Lurose, approximately 5.0% (w / w) of croscarmellose sodium, approximately 0.5% (w / w) Colloidal anhydrous silica in an amount of (w / w), and approximately 0.25% (w / w) of stearic acid Contains magnesium.

[0199] In some embodiments, the internal phase contains approximately 10.7% (w / w) of the peptide of SEQ ID NO: 1. A granular mixture of acetate and approximately 35.7% (w / w) sodium caprate. The substance contains approximately 3.9% (w / w) of microcrystalline cellulose and approximately 10.7% (w / w) of sorbate. Rubitol, approximately 5.0% (w / w) of croscarmellose sodium, and approximately 0.5 It can contain % (w / w) amount of colloidal anhydrous silica, and the outer phase is approximately 27.7% (w / w). Silicified microcrystalline cellulose in an amount of (w / w), and approximately 5.0% (w / w) of croscarmellol Sodium, approximately 0.5% (w / w) of colloidal anhydrous silica, and approximately 0.25% ( Contains magnesium stearate in w / w amounts.

[0200] In some embodiments, the composition contains approximately 16.3% (w / w) of the peptide of SEQ ID NO: 1. It contains an acetate form and approximately 50.0% (w / w) of sodium caprate. This can be done. In some embodiments, the composition contains about 6.0% (w / w) of polyethylene. Poly(propylene glycol)-block-poly(ethylene glycol)-block-poly(ethylene Glycol, approximately 15.2% (w / w) of mannitol, and approximately 10.0% (w / w) ) an amount of disintegrant, approximately 1.0% (w / w) of hydrophilic silica, and approximately 1.5% (w / w) The composition further comprises an amount of lubricant and, in some embodiments, an amount of about 6.0% (w / w). Kolliphor P188 contains approximately 15.2% (w / w) of mannitol, and approximately 10.0% (w / w) of croscarmellose sodium and approximately 1.0% (w / w) A quantity of Aerosil 200 and approximately 1.5% (w / w) of magnesium stearate. It can further include and

[0201] In some embodiments, the internal phase contains approximately 1.8% (w / w) of the peptide of SEQ ID NO: 1. Ceteate form, and approximately 21.3% (w / w) of microcrystalline cellulose, approximately 10.7% ( (w / w) amount of sorbitol, approximately 2.5% (w / w) amount of croscarmellose sodium M, approximately 0.5% (w / w) of hydrophilic silica, and approximately 0.25% (w / w) of ste It can contain magnesium allate, and the outer phase contains approximately 59.6% (w / w) silicification. Microcrystalline cellulose HD90, approximately 2.5% (w / w) of croscarmellose sodium M, approximately 0.5% (w / w) of hydrophilic silica, and approximately 0.25% (w / w) of ste Contains magnesium allate.

[0202] coating In some embodiments, the composition is disposed on top of the composition. The rimmer may further include a sub-coating. In some embodiments, the composition is external The phase may include a sub-coating of PVA-PEG graft copolymer disposed on top of the phase. Yes, it is possible. This coating acts as a smooth surface to aid in swallowing tablets. It is possible. The coating also provides a platform for further layers. This can be achieved, and the further layer may include an enteric coating placed on top of the subcoating. Yes, it is possible. In some embodiments, the sub-coating may also be used for coloring for tablet identification. Vehicles can be provided. Other coatings include HPMC, HPC, PVA, and This may include, but is not limited to, coatings based on Eudragit E. .

[0203] Sub-coatings may include products of the OPADRY® class, optional. It can be present in the desired amount. In some embodiments, the subcoating is about 1% It can be present in an amount of approximately 10% (w / w). In some embodiments, subcoating The ing is used in an amount of approximately 1% to approximately 3% (w / w) relative to the combined inner and outer phases of the composition. It can exist. For example, the subcoating can be approximately 1%, 1.5%, 2.0%, 2%. It can be present in amounts containing 0.5% and approximately 3%, and the amount may be any of the amounts between these two. This includes the amount of separation. In one embodiment, the subcoating may be present in an amount of about 3%.

[0204] In some embodiments, the subcoating is present in an amount of 1% to 10% (w / w). This is possible. In some embodiments, the subcoating is the combined internal phase of the composition It can exist in an amount of 1% to 3% (w / w) relative to the outer phase. For example, subcoat The compound is present in amounts of approximately 1%, 1.5%, 2.0%, 2.5%, and 3%. The amount may include any fractional amount between these.

[0205] In some embodiments, the composition may include a sub-coating disposed on the outer phase. Yes, it is possible. In some embodiments, the composition is an enteric coating placed on top of a subcoating. It can also include coatings. These combined coatings provide a moisture barrier. It can be provided, and in the case of enteric coating, it allows for the delivery of tablet contents to the intestinal tract. This allows for changes in pH in the intestinal tract, which enables the release of the tablet contents.

[0206] In some embodiments, the composition is an enteric coating disposed on top of a subcoating. Includes. In some embodiments, the enteric coating allows the tablet contents to be kept within a pH range of about 5 to about 8. Selected to provide release of substances. In some embodiments, enteric coatings are pH 5.5 Enteric coating. The enteric coating is made of cellulose phthalate acetate (CAP). ), poly(methacrylate-co-methacrylate methyl methyl methacrylate, cellulose acetate trimelite CAT, poly(vinyl acetate phthalate) (PVAP), or hydroxypropyl acetate This may include substances based on methylcellulose phthalate (HPMCP), etc. It is possible, but not limited to these. In some embodiments, the enteric coating is about 1%~ It can be present in an amount of approximately 15% (w / w). In some embodiments, enteric coating The compound is present in an amount of approximately 5% to approximately 15% (w / w) of the combined internal and external phases of the composition. This is possible. In one embodiment, the enteric coating may be present in an amount of approximately 12%. Cut.

[0207] In some embodiments, enteric coating allows for the release of tablet contents within a pH range of 5-8. Selected to provide. In some embodiments, the enteric coating is pH 5.5 enteric. It is a coating. Enteric coatings are made of cellulose phthalate acetate (CAP), poly( Methyl methacrylate-co-methacrylate, cellulose acetate trimellitate (CA T), poly(vinyl acetate phthalate) (PVAP), or hydroxypropyl methyl This may include a cellulose phthalate (HPMCP) based product, but Not limited to these. In some embodiments, the enteric coating is 1% to 15% (w / w) It can be present in amounts such as the above. In some embodiments, the enteric coating is of the composition It can constitute 5% to 15% (w / w) of the combined internal and external phases. For example, the amount of enteric coating is approximately 5%, 6%, 7%, 8%, 9%, 10%, 11%. The amount may be 12%, 13%, 14%, or 15% (w / w), and this amount is This includes fractions of .

[0208] In some embodiments, the composition contains about 3% (w / w) of OPADRY® Q X Pink sub-coating and approximately 12% (w / w) of ACRYL-EZE (registered trademark) It may further include a white enteric coating.

[0209] In some embodiments, the tablet composition of the present invention contains at least about 1% to about 10% (w / w) It may have bioavailability. Bioavailability refers to the bioavailability for oral administration. Area Under Curve (AUC) was measured using the AUC obtained by intravenous administration. It is possible. For example, bioavailability is approximately 1%, 2%, 3%, 4%, 5%, 6%. The amount may be 7%, 8%, 9%, or about 10%. In some embodiments, the tablet composition of the present invention It may have a bioavailability ranging from approximately 10% to approximately 50%.

[0210] In some embodiments, the tablet composition of the present invention has an area under the curve (AUC) for oral administration. )Measured using AUC for intravenous administration, such as 1% to 10% (w / w) It may have bioavailability. For example, bioavailability is about 1%, 2%, It may be 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Therefore, bioavailability can range from 10% to 50%. In some aspects The composition has a bioavailability of at least 1-10%.

[0211] IV. Methods or processes for preparing tablets or dosage forms According to the present invention, the composition is defined throughout this disclosure as having an active main component ( That is, the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form) and , additional pharmaceutically acceptable ingredients (i.e., may include, but is not limited to, absorption enhancers) It is composed of (a component), an adjuvant, a carrier, an excipient, or a stabilizer. The percentage of the active principal ingredient (API) in the composition of the present invention or The amount, of course, varies as the amount of active compound in such therapeutically useful compositions. The present invention provides a dosage suitable for administration to the target or patient. The actual preferred dosage of the API used in the product depends on the specific composition of the formulation. It is reasonable to expect variations depending on the substance, mode of administration, specific site of administration, and the host being treated. This should be understood. The selection of the most appropriate initial dose for a particular patient includes, but is not limited to, body weight. It is determined by experts using well-known medical principles.

[0212] Furthermore, the oral tablet dosage form of the present invention has a surface layer coated with an enteric coating. Furthermore, enteric coating is an enteric coating as defined in the definitions section of this specification. This is possible, but not limited to, an oral tablet dosage form, a core component, a separate continuous layer These may be formulated, or in combination thereof, but are not limited to the core, other layers, etc. The tablet components have different release-regulating component properties based on the gastrointestinal environment, pH, or time. It may have. Therefore, the oral tablet dosage form of the present invention may also be coated with a pH-sensitive polymer. It can be done.

[0213] Tablets containing the composition of the present invention are produced using a conventional tablet forming apparatus known in the art. Tablets can be prepared using a tablet forming apparatus that can use a compactor and rollers, etc. .

[0214] In some embodiments, the present invention is a method, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, and Capri Granulating a mixture containing sodium phosphate, The granulated mixture is supplemented with microcrystalline cellulose, sorbitol, a disintegrant, and hydrophilic silica. In addition, forming an internal phase, This involves compressing the outer phase onto the inner phase, where the outer phase is silicified microcrystalline cellulose. Compression, including the use of , Applying a sub-coating on top of the outer phase, Applying an enteric coating on top of a sub-coating to form a tablet, Provides a way to include it.

[0215] In some embodiments, the present invention relates to a tablet comprising the peptide of SEQ ID NO: 1 or its pharmaceutically active ingredient It may include a salt or solvate form that is permissible for use with sodium caprate. The process involves granulating the mixture, and adding microcrystalline cellulose and sorbitol to the granulated mixture. A process of forming an inner phase by adding a disintegrant and hydrophilic silica, and an outer phase on top of the inner phase. A compression process in which the outer phase contains silicified microcrystalline cellulose. The process of compression, the process of applying the sub-coating on top of the outer phase, and the intestine The process involves applying a soluble coating on top of a sub-coating to form a tablet, and by We provide tablets that are manufactured using [the specified method / technology].

[0216] In some embodiments, the present invention relates to a method for the peptide of SEQ ID NO: 1 or its pharmaceutically acceptable properties A mixture containing a salt or solvate form acceptable to the law, and sodium caprate, is granulated. The process involves granulation, and the granulated mixture contains microcrystalline cellulose, sorbitol, a disintegrant, and a parenteral compound. The process involves adding aqueous silica to form the internal phase and then compressing the external phase onto the internal phase. Therefore, the external phase contains silicified microcrystalline cellulose and is compressed. Applying a sub-coating on top of the outer phase, and applying an enteric coating as a sub-coating. The present invention provides a method which may include applying to form a tablet.

[0217] In some embodiments, the present invention is a tablet, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, Sodium caprate and, A process of granulating a mixture, including In the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and Hydrophilic silica The process of adding to form the internal phase, A process in which the outer phase is compressed onto the inner phase, wherein the outer phase is silicified microcrystalline se The compression process, including the use of lurose, The process of applying a sub-coating on top of the outer phase, The process of applying an enteric coating on top of a sub-coating to form a tablet, Regarding tablets manufactured by [company name / method].

[0218] Each aspect of the present invention as defined in this section or any other section is defined by definition and and limitations, for example, the definitions and limitations set out in sections I to VI of this specification, and first Definitions and limitations described throughout the disclosure, specification, and claims filed in the patent application. It can be incorporated.

[0219] V. Methods and / or Uses of Treatment In one embodiment, the present invention relates to a method or use for treating an inflammatory disease in a subject. A method or Regarding use. In some embodiments, the present invention is for treating inflammatory diseases in a subject. A method comprising administering a therapeutically effective amount of the composition of the present invention to a subject. The present invention provides for use in treating inflammatory diseases such as inflammatory bowel disease (IBD). ), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) This may include, but is not limited to, psoriatic arthritis (pSA), etc. It will not be done.

[0220] In some embodiments, the present invention relates to conditions or adaptations associated with IL-23 or IL-23R. Subjects suffering from a disorder (e.g., activation of the IL-23 / IL-23R signaling pathway) A method or use for treating a disease comprising administering the composition of the present invention to a subject. , provides a method or use. In some embodiments, improper, uncontrolled, or increased A state characterized by IL-23 or IL-23R activity or signaling A method or use for treating a subject suffering from an indication, in which the individual, in the subject A sufficient amount to (partially or completely) inhibit the binding of IL-23 to IL-23R. A method or use is provided which includes administering the composition of the present invention. In some embodiments, Inhibition of IL-23 binding to IL-23R is particularly effective in the specific organ or tissue of the target. This occurs, for example, in the organ or tissue in question: stomach, small intestine, large intestine / colon, intestinal mucosa, muco This includes, but is not limited to, organs such as the lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels. It is not determined.

[0221] In some embodiments, the methods or uses of the present invention are intended for those who require them. It may include providing a composition of the following: The subjects are those at risk of developing diseases or disorders associated with IL-23 / IL-23R. They have been diagnosed or determined to have been diagnosed.

[0222] In general, the present invention is a. Oral peptides that systemically activate the interleukin-23 receptor (IL-23R) Administration of a drug inhibitor or a pharmaceutically acceptable salt or solvate thereof, b. Administration of the corresponding pharmaceutical composition, c. Here, each of a and b above may be optionally selected as an absorption enhancer. Enhancer (AbE) can be used, and d. Methods and / or uses for the treatment of IL-23-driven diseases, wherein IL-23-driven Mobile diseases include autoimmune inflammation and related diseases and disorders as defined herein. Methods and / or uses obtained, but not limited to these. Regarding.

[0223] According to the present invention, systemic drug activity or pharmacological activity is related to various degrees of inflammation. This program is intended for individuals with varying degrees of disease or disability severity, and covers a wide range of inflammatory disease or disability severity levels. Those who have inflammatory diseases or disorders include, but are not limited to, inflammatory diseases or disorders. This may include diseases such as psoriasis, psoriatic arthritis, ulcerative colitis, and inflammatory bowel disease. These are not the only options.

[0224] In particular, the present invention is Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[ 3-Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) or The pharmaceutically acceptable salt or solvate or With respect to the corresponding pharmaceutical compositions, these are peptides having systemic activity, The peptide is the IL-23 receptor (IL-23R), and IL-23 is transmitted via the IL-23 receptor. Systemically inhibiting or pharmacologically blocking signal transduction, or the IL-23 pathway, that is, It is directly coupled to the IL-23R subunit, thereby allowing the IL-23 to be used with the IL-23. It prevents binding to the receptor and affects proximal IL-23R signaling and downstream effector function. Inhibition of (for example, this may include, but is not limited to, cytokine secretion) It occurs as a result.

[0225] Furthermore, the present invention relates to Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac )]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[TH P]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphological disulfide (Conjugation) (SEQ ID NO: 1) or its pharmaceutically acceptable salt or solvate form (i.e., (A systemically active peptide inhibitor of the interleukin-23 receptor (IL-23R)) Oral administration of the corresponding pharmaceutical composition, method for the treatment of IL-23-driven diseases And / or in relation to use, IL-23-driven diseases are autoimmune diseases as defined herein. This may include, but is not limited to, inflammatory diseases and related illnesses and disorders.

[0226] According to the present invention, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof and / or a corresponding For each of the preparations or pharmaceutical compositions, "systemic activity" refers to blood activity that extends beyond the gastrointestinal tract. It blocks IL-23 receptors (IL-23R) in fluids and tissues, and therefore IL-23 It is defined as the inhibition of signal transduction.

[0227] In one embodiment, the present invention demonstrates its effectiveness through distribution in the body and treatment of bodily organ systems. Regarding systemic activity, efficacy is observed in skin and joint-related disorders, namely psoriasis or psoriatic-related disorders. This may include, but is not limited to, "skin efficacy or joint efficacy" in the treatment of arthritis, etc. stomach.

[0228] Generally, conventionally known peptide therapies must be administered intravenously or intramuscularly. Most peptide drugs (e.g., insulin) are metabolized in the intestines, therefore Therefore, when administered orally, it has no therapeutic effect. In contrast, the sequence numbers disclosed herein The peptide formulation of No. 1 achieves sufficient systemic concentration of the peptide of SEQ ID NO: 1 after oral administration. It has been shown that this inhibits IL-23R, resulting in pharmacological effects.

[0229] Furthermore, the present invention relates to the peptide inhibitor Ac-[Pen] * -NT-[W(7-Me)]- [Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-N al]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen type A disulfide bond (SEQ ID NO: 1) or a pharmaceutically acceptable salt as described herein. This further includes pharmaceutical compositions or formulations containing, with and without, such permeation enhancers. These formulations may be used in any indication where a higher plasma concentration is required.

[0230] Information supporting the above is illustrated in the examples and throughout this application.

[0231] In one aspect, the present invention relates to various therapeutic methods of use as described herein, Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3 -Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) ) or its pharmaceutically acceptable salts or solvates and / or their corresponding pharmaceutical compositions Regarding use.

[0232] In one embodiment, the present invention is a method for treating a systemic disease or disorder in a subject. The target is given a therapeutically effective amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. To administer a solvate orally to treat a systemic disease or disorder in the subject. This includes methods.

[0233] In one embodiment, the present invention provides a method for treating systemic diseases or disorders in a subject. A method for delivering a sufficient systemic level of therapeutic agent to a subject, wherein the subject receives a therapeutically effective amount of therapeutic agent. It is administered orally, thereby providing sufficient treatment for systemic diseases or disorders in the subject. This includes providing a systemic level of therapeutic agent, where the therapeutic agent is the peptide of SEQ ID NO: 1 or its medicinal properties. This relates to a method for obtaining a pharmaceutically acceptable salt or solvate.

[0234] In some aspects of the present invention, the systemic disease or disorder is psoriasis or psoriatic arthritis. In some embodiments, the systemic disease or disorder is psoriasis. The disease or disorder is psoriatic arthritis.

[0235] In one embodiment, the present invention involves contacting the target skin with a therapeutically effective amount of the peptide of SEQ ID NO: 1. A method comprising administering to a target a therapeutically effective amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable amount thereof. The salt or solvate is administered orally, thereby allowing the peptide of SEQ ID NO: 1 to reach the target skin. Regarding methods, including contact with

[0236] In one embodiment, the present invention reduces skin inflammation in subjects suffering from psoriasis or psoriatic arthritis. A method for which the target skin is subjected to a therapeutically effective amount of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable amount thereof. The process involves contacting the salt or solvate of the product with a therapeutically effective amount of the peptide of SEQ ID NO: 1. The drug or a pharmaceutically acceptable salt or solvate thereof is administered orally, thereby the sequence Peptide number 1 comes into contact with the target skin, thereby reducing inflammation in the target skin. Regarding methods, including the act of doing so.

[0237] In some aspects of the present invention, the peptide of SEQ ID NO: 1 is absorbed and circulated systemically. , and make contact with the target skin.

[0238] In one embodiment, the present invention relates to IL-23 receptor inhibition for the treatment of inflammatory diseases or disorders. A method for providing systemically active peptide drugs to patients who need them. Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[ 3-Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1)

[0239] [ka] This is carried out by oral delivery of the pharmaceutically acceptable salt or solvate form. Regarding the method.

[0240] In another embodiment, the present invention relates to IL-23 receptor inhibition for the treatment of inflammatory diseases or disorders. A method for that purpose, for patients who need it, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W( 7-Me)]-[Lys(Ac)]-[Pen] *-Phe[4-(2-aminoethoxy] )]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * P en-Pen form disulfide bond) (SEQ ID NO: 1)

[0241] [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, an absorption enhancer and [c] at least one pharmaceutically acceptable excipient, The present invention relates to a method that involves orally delivering a pharmaceutical composition containing [a specific substance].

[0242] In another embodiment, the present invention relates to IL-23 receptor inhibition for the treatment of inflammatory diseases or disorders. A method for that purpose, - A systemically active peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof, -The corresponding pharmaceutical composition is, For the treatment of inflammatory diseases or disorders, directly affecting the blood, blood circulation, tissues, skin, or joints. By means of delivery via contact, or via blood, blood circulation, tissue, skin, or joints. .

[0243] In another embodiment, the present invention relates to the treatment of inflammatory diseases or disorders. ● IL-23 receptor (IL-23R), ● IL-23 signaling via the IL-23 receptor, or ● IL-23 route A method for systemically inhibiting or pharmacologically blocking a substance, which requires For patients, A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W(7-M e)]-[Lys(Ac)]-[Pen] *-Phe[4-(2-aminoethoxy)]- [2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen- Pen-type disulfide bond) (SEQ ID NO: 1)

[0244] [ka] A method relating to the oral administration of the pharmaceutically acceptable salt or solvate form thereof. do.

[0245] In another embodiment, the present invention relates to the treatment of inflammatory diseases or disorders. ● IL-23 receptor (IL-23R), ● IL-23 signaling via the IL-23 receptor, or ● IL-23 route A method for systemically inhibiting or pharmacologically blocking a substance, which requires For patients, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W( 7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy] )]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * P en-Pen form disulfide bond) (SEQ ID NO: 1)

[0246] [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, with or without an absorption enhancer. [c] at least one pharmaceutically acceptable excipient, The present invention relates to a method comprising orally administering a pharmaceutical composition containing [a specific compound].

[0247] In another aspect, the present invention relates to the treatment of inflammatory diseases or disorders, blood, blood circulation, tissue a method for targeting inhibition or blockade of IL-23 receptors in the skin or joints. So, for patients who need this, an oral dose of a therapeutically effective amount of the peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-( 2-aminoethoxy)-[2-Nal]-[THP]-EN-[3-Pal]-Sa rc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1)

[0248] [ka] A method comprising administering the pharmaceutically acceptable salt or solvate form thereof. .

[0249] In another aspect, the present invention relates to the treatment of inflammatory diseases or disorders, blood, blood circulation, tissue A method for inhibiting or blocking IL-23 receptors in the skin or joints, For patients who need it, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W( 7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy] )]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * P en-Pen form disulfide bond) (SEQ ID NO: 1)

[0250] [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, an absorption enhancer and [c] at least one pharmaceutically acceptable excipient, The present invention relates to a method comprising administering an oral dose of a therapeutically effective amount of a pharmaceutical composition containing [a specific compound].

[0251] In other embodiments, for the treatment of inflammatory diseases or disorders, the blood, blood circulation, tissue, skin, or This invention relates to a method for inhibiting or blocking IL-23 receptors in joints, and otherwise is true. Methods defined for the present invention, including those discussed in detail herein, for example, The methods defined in include or encompass the following aspects or embodiment definitions, or It is understood that the following aspects or embodiment definitions are intended to be incorporated. ● IL-23 receptor (IL-23R) inhibition or blockade is effective in the gastrointestinal tract and beyond. In weaving, ● Systemic pharmacodynamic activity in the blood is directly proportional to systemic exposure in human subjects. ●Target blocking level is IC 50 Predicted by the value, ● Sufficient exposure to systemically active peptide levels is sufficient for at least 24 hours of IC (Acquisition Control). 50 It is super, ● The target blocking level is in the picomolar range of ICs. 50 Determined by the value, ● Systemic exposure is required for inhibitory activity in the blood, and / or ● The pharmacological activity of a drug in blood, plasma, or serum is determined by the systemic exposure of the drug. It is measured or detected as a function of dew and potency.

[0252] Each aspect of the present invention relates to psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. Inflammation selected from diseases and / or inflammatory diseases or disorders of moderate to severe severity. It is intended to be suitable for sexually transmitted diseases or disorders.

[0253] According to embodiments of the present invention as defined throughout this disclosure, a systemically active pe Petit Do is ●Within a dosage range of approximately 1 mg to approximately 1000 mg, ●Within a dosage range of approximately 25 mg to approximately 100 mg, ● If necessary, 10 mg, 25 mg, or 50 mg once or twice daily. At a specific dose, ● A dose of 10 mg once a day or 10 mg twice a day, ● A dose of 25 mg once a day or 25 mg twice a day, ● May be administered in doses of 50 mg once daily or 50 mg twice daily, and / or ● 50 mg is administered once or twice a day, but is not limited to these doses, within a 24-hour period. Over 50% inhibition is observed during the interval.

[0254] According to embodiments of the present invention as defined throughout this disclosure, a systemically active pe Petit Do is ● If necessary, approximately 10 mg, 25 mg, or 50 mg once or twice a day. At a specific dose, ● A dose of approximately 10 mg once a day or approximately 10 mg twice a day, ● A dose of approximately 25 mg once a day or approximately 25 mg twice a day, These may be administered, but are not limited to them.

[0255] In one embodiment, the present invention relates to IL in a tissue selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting the -23 receptor, which is administered orally to patients who require it. Therapeutic effective dose of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(A c)-[Pen] *-Phe[4-(2-aminoethoxy)]-[2-Nal]-[T HP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphological disulfide Administer the drug (sequence number 1) or a pharmaceutically acceptable salt or solvate thereof. Regarding methods, including the act of doing so.

[0256] In one embodiment, the present invention uses blood, skin, cartilage, or synovial membrane, selected individually or separately. The present invention relates to a tissue that is blood. In some embodiments, the present invention relates to a tissue that is blood. In some embodiments, the present invention relates to a tissue that is skin. In some embodiments, the present invention relates to cartilage. The present invention relates to a tissue that is synovial. In some embodiments, the present invention relates to a tissue that is synovial.

[0257] In another aspect, the present invention relates to a method for inhibiting IL-23 receptors in gastrointestinal tissue. Therefore, in patients who require inhibition, an oral dose of a therapeutically effective amount of peptide Ac-[ Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe [4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal ]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) or The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form of [the substance].

[0258] In one embodiment, the digestive tract tissue consists of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. Selected from the group, together, individually, or separately. In some embodiments, gastrointestinal tissue The mouth is the mouth. In some embodiments, the digestive tract tissue is the esophagus. In some embodiments, The digestive tract tissue is the stomach. In some embodiments, the digestive tract tissue is the small intestine. In some embodiments, the gastrointestinal tissue is the large intestine. In some embodiments, the gastrointestinal tissue is the duodenum. Yes, in some embodiments, the digestive tract tissue is the anus.

[0259] In one embodiment, the present invention relates to IL in a tissue selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting the production of -17A, which is administered orally to patients who require such inhibition. The therapeutically effective dose of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Ly s(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal] -[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen Morphology (rufid bond) (SEQ ID NO: 1) or its pharmaceutically acceptable salt or solvate form is administered. Regarding methods, including giving.

[0260] In another aspect, the present invention relates to a method for inhibiting the production of IL-17A in gastrointestinal tissue. The law involves administering an oral dose of a therapeutically effective amount of peptide Ac- [Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Ph e[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pa] l]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form thereof.

[0261] IL-17A can be measured by any method known in the art, and antibody Alternatively, antigen-binding biochemical assays, such as enzyme-linked immunosorbent assays. This may include a nosorbent assay (ELISA) or radiometric assay as described herein. The methods described include, for example, the methods in the examples.

[0262] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The method and / or use of the mediator is at IL-17A level in the area where it is required. To reduce the amount of IL-17A. In some embodiments, the reduction of IL-17A is achieved by the peptide of SEQ ID NO: 1 or The IL-17A level after administration of the pharmaceutically acceptable salt or solvate, before administration or It is measured by comparing it to the control IL-17A level without administration. In some embodiments, IL-17A levels may be measured in vivo, ex vivo, or in vitro. In some aspects, the IL-17A level is about 5% to about 95%, for example, about 10%. Reduced by approximately 90%, 20% to 80%, 30% to 80%, or 30% to 70%. For example, IL-17A levels can be reduced by approximately 20% to 80%. According to the report, the IL-17A levels are approximately 10%, 20%, 30%, 40%, and 50%. It will be reduced by approximately 60%, 70%, 80%, or 90%.

[0263] In one embodiment, the present invention relates to IL in a tissue selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting the production of -17F, which is administered orally to patients who require such inhibition. The therapeutically effective dose of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Ly s(Ac)]-[Pen] *-Phe[4-(2-aminoethoxy)]-[2-Nal] -[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen Morphology (rufid bond) (SEQ ID NO: 1) or its pharmaceutically acceptable salt or solvate form is administered. Regarding methods, including giving.

[0264] In another aspect, the present invention relates to a method for inhibiting the production of IL-17F in gastrointestinal tissue. The law involves administering an oral dose of a therapeutically effective amount of peptide Ac- [Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Ph e[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pa] l]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form thereof.

[0265] IL-17F can be measured by any method known in the art, and the antibody Alternatively, antigen-binding biochemical assays, such as enzyme-linked immunosorbent assays (ELISA), or reagents. This may include a radiation assay, and the methods described herein, for example, the method of the Examples include.

[0266] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The method and / or use of the mediator is required at the IL-17F level in the subject where it is needed. Reduces IL-17F. In some embodiments, the reduction of IL-17F is due to the peptide of SEQ ID NO: 1 or The IL-17F level after administration of the pharmaceutically acceptable salt or solvate, before administration or It is measured by comparing it to the control IL-17F level without administration. In some embodiments, IL-17F levels may be measured in vivo, ex vivo, or in vitro. In some aspects, the IL-17F level is about 5% to about 95%, for example, about 10%. Reduced by approximately 90%, 20% to 80%, 30% to 80%, or 30% to 70%. For example, IL-17F levels can be reduced by approximately 20% to 80%. According to the description, the IL-17F levels are approximately 10%, 20%, 30%, 40%, and 50%. It will be reduced by approximately 60%, 70%, 80%, or 90%.

[0267] In one embodiment, the present invention relates to IL in a tissue selected from blood, skin, cartilage, or synovial membrane. A method for inhibiting the production of -22, which is administered orally to patients who require such inhibition. A therapeutically effective amount of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys (Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]- [THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen form diss Administer a filtrate bond (SEQ ID NO: 1) or a pharmaceutically acceptable salt or solvate thereof. Regarding methods, including how to do something.

[0268] In another embodiment, the present invention relates to a method for inhibiting the production of IL-22 in gastrointestinal tissue. Therefore, in patients who require inhibition, an oral dose of a therapeutically effective amount of peptide Ac-[ Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe [4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal ]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1) or The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate form of [the substance].

[0269] IL-22 expression can be measured by any method known in the art, and anti Body or antigen-binding biochemical assays, for example, enzyme-linked immunosorbent assays (ELISA) or Radiometric assays may include methods described herein, such as the method of the Examples. Includes.

[0270] In some embodiments, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solution thereof. The method and / or use of the mediator is necessary for the IL-22 expression level in the target population. Reduces bell. In some embodiments, the reduction of IL-22 expression is due to the peptide of SEQ ID NO: 1. Or the IL-22 expression level after administration of a pharmaceutically acceptable salt or solvate thereof, It is measured by comparing it to the control IL-22 expression level before administration or without administration. In several embodiments, IL-22 expression levels were measured in vivo, ex vivo, or in vitro. It can be measured. In some embodiments, IL-22 expression levels range from about 5% to about 95%, for example. For example, approximately 10% to 90%, approximately 20% to 80%, approximately 30% to 80%, or approximately 30% to It can be reduced by 70%. For example, IL-22 expression levels can be reduced by approximately 20% to 80%. In some aspects, IL-22 expression levels are approximately 10%, 20%, 30%, and 4%. It is reduced by 0%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, or approximately 90%.

[0271] In other embodiments, conventionally known assays are newly developed for use in the present invention. The assay may include, but is not limited to, a PD biomarker assay. Iomarker assays are functions of systemic exposure and potency of a drug, measured in blood / plasma / serum. To detect / quantify the pharmacological activity of a drug in the present invention, the compound or pharmaceutical It can be used in a generally acceptable salt or a corresponding pharmaceutical composition or formulation.

[0272] In some aspects, the disease or disorder is autoimmune inflammation and related diseases and disorders. For example, autoimmune inflammation and related diseases and disorders include multiple sclerosis, asthma, and rheumatic diseases. Arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease Ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spinal cord syndrome) This may include, but is not limited to, spondyloarthritis, psoriatic arthritis, or psoriasis.

[0273] In some embodiments, the disease or disorder is psoriasis (e.g., psoriasis vulgaris, guttate psoriasis, reverse psoriasis) (Pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, ectopic Acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), seronegative joints Enteropathy associated with the disease, microscopic colitis, collagen colitis, eosinophilic gastroenteritis / esophagitis, radiation Innate immunity such as in colitis associated with chemotherapy or leukocyte adhesion deficiency-1 Colitis associated with the disorder, chronic granulomatous disease, glycogen storage disease type 1b, Hermanskie-Pudl K syndrome, Chediak-Higashi syndrome, Wiscot-Aldrich syndrome, sac inflammation, rectum Sac inflammation, gastrointestinal cancer, pancreatitis, and insulin ulcers resulting from colectomy and ileostomy. Diabetes dependence, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-associated enteropathy, bile duct Select from periarthritis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease. It may be done or chosen.

[0274] In one embodiment, the present invention relates to a method for treating autoimmune inflammation and related diseases and disorders. or use of an autoimmune inflammatory bowel disease (IB) that causes autoimmune inflammation and related diseases and disorders. D) Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis This may include, but is not limited to, methods and / or uses such as (PsA). In some cases, inflammatory diseases include inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. It is psoriasis or psoriatic arthritis.

[0275] In some embodiments, the present invention relates to subjects requiring treatment for inflammatory bowel disease (IBD). A method or use for treating the same in which the composition of the present invention is administered to the subject The present invention provides a method or use that includes doing so. In some embodiments, the present invention relates to the subject A method for treating inflammatory bowel disease (IBD), wherein a therapeutically effective amount of the present invention is given to the subject. The present invention provides a method comprising administering a substance. In some embodiments, IBD is ulcerative colitis. It is enteritis. In some forms, IBD is Crohn's disease.

[0276] In some embodiments, the present invention relates to the manufacture of pharmaceuticals for treating inflammatory bowel disease (IBD). The present invention provides a method or use of the composition in the present invention.

[0277] In another embodiment, the present invention relates to subjects in need of treatment for inflammatory bowel disease (IBD). A method for treating the same, comprising administering a therapeutically effective amount of the composition disclosed herein to the subject. The present invention relates to methods, including giving. In some embodiments, IBD is Crohn's disease or ulcer It is a type of colitis. In some aspects, IBD is Crohn's disease. In some aspects IBD is ulcerative colitis.

[0278] In some embodiments, the present invention relates to the manufacture of pharmaceuticals for treating inflammatory bowel disease (IBD). This specification provides for the use of the compositions disclosed herein in the context of [the relevant field].

[0279] In some embodiments, the present invention relates to subjects in need of treatment for psoriasis or psoriatic arthritis. A method for treating the condition, comprising administering a therapeutically effective amount of the composition of the present invention to the subject. This concerns methods, including the following.

[0280] In some embodiments, the present invention relates to the manufacture of a pharmaceutical product for treating psoriasis or psoriatic arthritis. This specification provides for the use of the compositions disclosed herein.

[0281] In some embodiments, the present invention relates to a method for treating inflammatory bowel disease (IBD) in a subject. or use comprising administering a therapeutically effective amount of the composition disclosed herein. Regarding laws or uses. In some embodiments, according to the treatment of a patient, a composition in tablet form is used. A method or use of the present invention, comprising administering orally once, twice, or three times a day. In this context, IBD is Crohn's disease or ulcerative colitis.

[0282] Each aspect of the present invention as defined in this section or any other section is defined by definition and and limitations, for example, the definitions and limitations set out in Sections II to VI of this Specified Specified, and most The definitions and limitations described throughout the initial filing of the disclosure, specification, and claims. It is possible to incorporate fixed values. [Examples]

[0283] VI. In describing the present invention, the abbreviations and symbols used herein are those of the fields of chemistry and biology. The common use of such abbreviations and symbols by those skilled in the art shall be followed. Specifically, the following abbreviations are It may be used in the examples and throughout this specification.

[0284] [Table 1]

[0285] Example 1. Preparation of amorphous acetate form of the peptide of SEQ ID NO: 1 Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[ 3-Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1)

[0286] [ka]

[0287] The synthesis of the amorphous acetate form of the peptide of SEQ ID NO: 1 is described in U.S. Patent Application Publication No. 2021. According to Example 1B of No. / 0261622, using the FMOC solid-phase peptide synthesis technique, Prepared.

[0288] Using standard FMOC-protected synthesis conditions reported in the literature, the peptide was synthesized using Rink The peptide was constructed in Amide MBHA resin. The constructed peptide was cleaved with a strong acid, and then... Then, it was isolated from the resin and protecting group by precipitation. Oxidation is performed, followed by reverse-phase HPLC (RPHPLC) and counter-ion iodine. Purification was carried out by exchange of ions. The final product was obtained by freeze-drying the pure fraction.

[0289] 10g of Rink Amide MBHA solid phase resin (0.66 mmol) which is a swelling resin. (g load) filter frit, ground glass joint, vacuum side arm and The mixture was transferred to a 250 mL peptide container equipped with [a specific component]. The resin was washed three times with DMF.

[0290] Step 1: Linking of FMOC-Sarc-OH: Deprotection of the resin-bonded FMOC group, 2 Adding 20% ​​4-methyl-piperidine in DMF by volume to the swollen resin, and Shake for 3-5 minutes before delivery, and add a 4-methylpiperidine solution in a volume equal to 2 volumes of the second resin bed. This was achieved by adding and shaking for an additional 20-30 minutes. After deprotection, The resin was washed three times with DMF while shaking. FMOC-Sarc-OH (3 equivalents, 6. Dissolve 2g of (2g) together with Oxyma (4.5 equivalents, 4.22g) in 100mL of DMF. The solution was dissolved. The acid was pre-activated by shaking for 15 minutes before adding it to the deprotected resin. This was achieved by adding DIC (3.9 equivalents, 4 mL). Subsequently, additional DIC was added. An aliquot (2.6 equivalents, 2.65 mL) was added after approximately 15 minutes of coupling. The progress was monitored using a colorimetric Kaiser test. Once it was determined that the reaction was complete, the resin was then removed. Before initiating the deprotection / coupling cycle, the device was washed three times with DMF while shaking.

[0291] Step 2: Linking FMOC-3Pal-OH: Deprotect FMOC, two consecutive resins Add 20% 4-methyl-piperidine to the floor volume of DMF, for 3-5 minutes in the first application, and then again in the second application. This was achieved again by adding the resin for 20-30 minutes and draining it during the process. Before ligation with protected 3-pyridylalanine (3Pal), Washed 3 times. FMOC-3Pal-OH (3 equivalents, 7.8g) was added to Oxyma (4.5 It was dissolved in DMF along with the equivalent amount (4.22 g). DIC (3.9 equivalents) for 15 minutes. Pre-activation with 4 mL was performed before adding to the Sarc-amide resin. After 15 minutes, An additional aliquot of DIC (2.6 equivalents, 2.65 mL) was added to the reaction. Kaiser Once the reaction is complete, as determined by the test, the resin will proceed to the next deprotection / coupling cycle. Before starting, I washed it again three times with DMF.

[0292] Step 3: Linking FMOC-Asn(Trt)-OH: Link FMOC to resin bond 3Pa Removed from the N-terminus of l and washed as described above. FMOC-Asn(Trt)-OH(2 Add (equivalent to 8g) together with Oxyma (3 equivalents, 2.81g) in 100mL of DMF. Dissolved. DIC (2.6 equivalents, 2.65 mL) was mixed with 3Pal-Sarc-amide resin. Before adding to the solution, it was added for approximately 15 minutes to pre-activate the acid. After approximately 15 minutes, DIC An additional aliquot (1.4 equivalents, 1.43 mL) was added to the reaction. Kaiser test Therefore, once the reaction is complete as determined, the resin is released to initiate the next deprotection / coupling cycle. Before that, I washed it three times with DMF.

[0293] Step 4: Linking FMOC-Glu(OtBu)-OH: Link FMOC to resin bonded as Paragine was removed from the N-terminus, and the resin was washed with DMF as described above. FMOC-Gl u(OtBu)-OH (2 equivalents, 5.91g) and Oxyma (3 equivalents, 2.81g) Together, they were dissolved in 100 mL of DMF. DIC (2.6 equivalents, 2.65 mL) Before adding to the Asn(Trt)-3Pal-Sarc-amide resin, leave it in the acid for about 15 minutes. It was added for pre-activation. After about 15 minutes, an additional aliquot of DIC (1.4 equivalents) was added. 1.43 mL was added to the reaction. The reaction was completed as determined by the Kaiser test. The resin was then washed three times with DMF before starting the next deprotection / coupling cycle.

[0294] Step 5: Linking FMOC-THP-OH: Link FMOC to the N-terminus of the resin-bound peptide. Removed from the resin and washed as described above. FMOC-THP-OH (3 equivalents, 7.3 Dissolve 6g of (4.5 equivalents, 4.22g) of Oxyma in 100mL of DMF. It was dissolved. DIC (3.9 equivalents, 4 mL) was mixed with Glu(OtBu)-Asn(Trt)- Before adding to the 3Pal-Sarc-amide resin, pre-activate the acid for approximately 15 minutes. It was added. After about 15 minutes, an additional aliquot of DIC (2.6 equivalents, 2.65 mL) was added. It was added to the reaction. Once the reaction was complete, as determined by the Kaiser test, the resin was then added. Before initiating the deprotection / coupling cycle, it was washed three times with DMF.

[0295] Step 6: Linking of FMOC-L-Ala(2-naphthyl)-OH(Nal): FMO ¹C was removed from the N-terminus of the resin-bound peptide, and the resin was washed as described above. FMOC -L-Ala(2-naphthyl)-OH (3 equivalents, 8.66g) and Oxyma (4.5 equivalents) It was dissolved in 100 mL of DMF along with (4.22 g). DIC (3.9 equivalents, 4 mL) THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-A It was added to the mid resin for approximately 15 minutes to pre-activate the acid. After approximately 15 minutes... An additional aliquot of DIC (2.6 equivalents, 2.65 mL) was added. Kaiser test Therefore, once the reaction is complete as determined, the resin is released to initiate the next deprotection / coupling cycle. Before doing that, I washed it again three times with DMF.

[0296] Step 7: FMOC-4-[2-(Boc-amino-ethoxy)]-L-phenyl Lanin(FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phen Linking of ylalanine (FMOC-AEF): FMOC is linked to the N-terminus of the resin-bound peptide. Removed from the edge, and the resin was washed as described above. FMOC-4-[2-(Boc-amino -Ethoxy)-L-phenylalanine (3 equivalents, 10.8g) It was dissolved in 100 mL of DMF along with the equivalent amount (4.22 g). DIC (3.9 equivalents) , 4 mL) Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-S It was added for approximately 15 minutes to pre-activate the acid before adding it to the arc-amide resin. After 15 minutes, an additional aliquot of DIC (2.6 equivalents, 2.65 mL) was added to the reaction. Once the reaction is complete, as determined by the Kaiser test, the resin is then deprotected / bonded to the next stage. Before starting the binding cycle, the tubes were washed three times with DMF.

[0297] Step 8: Bonding FMOC-Pen(Trt)-OH: Bond FMOC with resin-bonded peptide The N-terminus of the ion was removed, and the resin was cleaned as described above. FMOC-Pen(Trt)- Combine OH (3 equivalents, 12.14g) with Oxyma (4.5 equivalents, 4.22g) and 1 It was dissolved in 00 mL of DMF. DIC (3.9 equivalents, 4 mL) was added to AEF-Nal- To THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin Before addition, the acid was pre-activated for approximately 15 minutes. After approximately 15 minutes, the DIC was added. An aliquot (2.6 equivalents, 2.65 mL) was added to the reaction. The Kaiser test was performed. Once the reaction is complete as determined, the resin is released before starting the next deprotection / coupling cycle. Then, it was washed again three times with DMF.

[0298] Step 9: Linking FMOC-Lys(Ac)-OH: Linking FMOC to the resin-bound peptide. The N-terminus was removed, and the resin was washed as described above. FMOC-Lys(Ac)-OH (2 equivalents, 5.4g) together with Oxyma (3 equivalents, 2.81g) in 100mL of D It was dissolved in MF. DIC (2.6 equivalents, 2.65 mL) was added to Pen(Trt)-AE F-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-A It was added to the mid resin for approximately 15 minutes to pre-activate the acid. After approximately 15 minutes... An additional aliquot of DIC (1.4 equivalents, 1.43 mL) was added to the reaction. - Once the reaction is complete as determined by the test, the resin is released into the next deprotection / coupling cycle. Before starting, the system was washed again three times with DMF.

[0299] Step 10: Linking FMOC-7-Me-Trp-OH: Link FMOC to resin-bonded peptide The cydone was removed from the N-terminus, and the resin was washed as described above. FMOC-7-Me-Trp -OH (2 equivalents, 5.81g) together with Oxyma (3 equivalents, 2.81g), 100 It was dissolved in mL of DMF. DIC (2.6 equivalents, 2.65 mL) was mixed with Lys(Ac) -Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt) -3Pal-Sarc-amide resin requires pre-activation of the acid for approximately 15 minutes before addition. It was added to the solution. After about 15 minutes, an additional aliquot of DIC (1.4 equivalents, 1.43 mL) was added. , was added to the reaction. Once the reaction was complete, as determined by the Kaiser test, the resin was used. Before starting the next deprotection / coupling cycle, the system was washed again three times with DMF.

[0300] Step 11: Linking FMOC-Thr(tBu)-OH: Link FMOC to resin-bonded peptide The tBu was removed from the N-terminus of the tBu and the resin was washed as described above. FMOC-Thr(tBu) -OH (4 equivalents, 10.5g) together with Oxyma (6 equivalents, 5.62g), 100 It was dissolved in mL of DMF. DIC (5.2 equivalents, 5.3 mL) was mixed with 7 MeTrp-L ys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-As Before adding to the n(Trt)-3Pal-Sarc-amide resin, pre-treat with acid for approximately 15 minutes. Added for activation. After about 15 minutes, additional aliquots of DIC (2.6 equivalents, 2. 65 mL was added to the reaction. The reaction was completed as determined by the Kaiser test. The resin was then washed again three times with DMF before starting the next deprotection / coupling cycle.

[0301] Step 12: Linking FMOC-Asn(Trt)-OH: Link FMOC to resin-bonded peptide The cytoplasm was removed from the N-terminus, and the resin was washed as described above. FMOC-Asn(Trt) -OH (4 equivalents, 15.8g) together with Oxyma (6 equivalents, 5.62g), 100 It was dissolved in mL of DMF. DIC (5.2 equivalents, 5.3 mL) was used as Thr(tBu) -7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu (OtBu)-Asn(Trt)-3Pal-Sarc-amide resin before addition, approximately It was added for 15 minutes to pre-activate the acid. After about 15 minutes, an additional aliquot of DIC was added. (2.6 equivalents, 2.65 mL) was added to the reaction. The result was determined by the Kaiser test. Once the reaction is complete, the resin should be refueled with DMF for 3 minutes before starting the next deprotection / coupling cycle. It was washed again.

[0302] Step 13: Linking FMOC-Pen(Trt)-OH: Link FMOC to resin-bonded phenyl(Trt)-OH The cytoplasm was removed from the N-terminus, and the resin was washed as described above. FMOC-Pen(Trt) -OH (2 equivalents, 8.1g) together with Oxyma (3 equivalents, 2.81g) in 100ml It was dissolved in L of DMF. DIC (2.6 equivalents, 2.65 mL) was added to Asn(Trt) -Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Na l-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin Before adding to the solution, it was added for approximately 15 minutes to pre-activate the acid. After approximately 15 minutes, DIC An additional aliquot (2.6 equivalents, 2.65 mL) was added to the reaction. Kaiser test Therefore, once the reaction is complete as determined, the resin is deprotected, and the constructed peptide is deprotected. And before acetic acid capping, the vessels were washed again three times with DMF.

[0303] Step 14: Acetyl capping: Remove FMOC from the N-terminus of the resin-bound peptide. The resin was then washed as described above. 150 mL of Capping Reagent A(THF / acetic anhydride / pyridine, 80:10:10) is used in the constructed Pen(Trt) -Asn(Trt)-Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Tr t)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-S The solution was added to the arc-amide resin and shaken for 30 minutes. The resin was washed three times with DMF, and then... The resin was washed 5 times with DCM. The resin was divided into 5-50 mL centrifuge tubes and cut with TFA. Previously, I left it under vacuum for 1.5 hours.

[0304] Step 15: TFA cleavage and ether precipitation: 200 mL of TFA cleavage cocktail (90 Prepared a solution of 5 / 2.5 / 2.5 TFA / water / tips / DODT. Cut 40 mL. The cocktail was added to each of the five tubes containing the protected resin-bound peptides, and shaken for 2 hours. The resin was saturated. The used resin was filtered and removed, and the filtrate was centrifuged in 18-50 mL for precipitation. The mixture was evenly divided into separate tubes. Cold diethyl ether was added to each to form a white precipitate. Then, the white precipitate was centrifuged. The ether was decanted and discarded, and further Two washes of the precipitate with ether were performed. The resulting white precipitate cake was then placed in a hood. The crude reduced peptide was obtained by drying it overnight inside the room.

[0305] Step 16: Disulfide Oxidation: Oxidize the crude peptide in four 1L batches. Purified. Approximately 2.5 g of crude peptide was dissolved in 1 L of 20% ACN / water. Stirred. However, when a saturated solution of iodine in acetic acid / methanol is used, the yellow / brown color of I2 remains and does not disappear. It was added dropwise to 1 L of peptide solution until the solution was light yellow. The excess I2 was added to a small amount of ascorbic acid. Let it stand for 5 minutes before quenching with vinic acid.

[0306] Step 17: RP-HPLC Purification: Perform RP-HPLC purification immediately after each I2 oxidation. The procedure was carried out using a preparative purification column (Phenomenex, Luna, C18(2), 100 Å). (250 x 50 mm) 20% MPB in MPA (MPA = 0.1% TFA / water, MPB = Equilibrated with 0.1% TFA in ACN at 70 mL / min. 1 L of quenched oxide petroleum Butide was loaded onto an equilibrated column at 70 mL / min. After the solvent leading edge eluted... A gradient of 25-45% MPB at 70 mL / min was applied over 60 minutes. The substance was isolated into fractions, and each was analyzed by analytical RPHPLC. All of the pure fractions were analyzed. The four purification processes are combined, freeze-dried, and the purified T is ready for counterion exchange. I obtained FA salt.

[0307] Step 18: Counterion exchange with acetate: Use the same preparative RP-HPLC column, MP 5% MPB in A (MPA = 0.3% AcOH in water, MPB = 0.3% AcOH in ACN, Equilibration was performed using MPC (0.5 M NH4OAc) in water at a rate of 70 mL / min. Purified peph Tydo TFA salt was dissolved in 50 / 50 ACN / water and diluted to 15% ACN. The solution was loaded onto an equilibrated column at 70 mL / min, and the leading end of the solvent was eluted. The captured peptides were washed with 5% MPB in MPA for 5 minutes. Then the captured peptides Wash the tubing with 5% MPB in MPC at a rate of 70 mL / min for 40 minutes to remove counterions from the acetate. Exchanged with counterions. The captured peptide was washed with 5% MPB in MPA at 70 mL / min for 10 minutes to remove all NH4OAc from the system. Finally, the peptide was eluted over 60 minutes with a gradient of 5 - 70% MPB in MPA and collected in fractions. / min to remove all NH4OAc from the system. Finally, the peptide was eluted over 60 minutes with a gradient of 5 - 70% MPB in MPA and collected in fractions. / min to remove all NH4OAc from the system. Finally, the peptide was eluted over 60 minutes with a gradient of 5 - 70% MPB in MPA and collected in fractions.

[0308] Step 19: Final lyophilization and analysis: The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). u of M + The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1). The collected fractions were analyzed by analytical RP - HPLC, and all fractions with purity greater than 95% were combined. The combined fractions were lyophilized to obtain SEQ ID NO:1 as a white powder with purity greater than 95% as determined by RP - HPLC. Peptide identity was confirmed by LC / MS of the purified amorphous acetate form of the peptide of SEQ ID NO:1, yielding peptide in two charge states, 950 amu M2 / 2 and a molecular ion of 1899 amu. The X - ray powder diffraction spectrum demonstrated the amorphous nature of the product (Figure 1).

[0309] Example 2. Use of phosphate buffer composition The acetate form of the peptide of SEQ ID NO:1 was taken in 50 mM sodium phosphate buffer to a concentration for delivery to the subject in the range of 0.33 mg / mL to 33 mg / mL. The resulting solution can be stored at 2 - 8 °C for up to 4 weeks. The resulting solution can be stored at 2 - 8 °C for up to 4 weeks.

[0310] Example 3. Tablet composition of the acetate form of the peptide of SEQ ID NO:1 A tablet composition containing SEQ ID NO:1 was prepared as described below. [[ID=4!]]

[0311] [Table 2]

[0312] The internal phase contains the acetate form of the peptide of SEQ ID NO: 1, along with the absorption enhancer sodium caprate. It was included together with the peptide and sodium caprate before mixing the components of the internal phase. They were granulated together, and the peptide and sodium caprate were placed in very close proximity. Then, a mixture of the two reagents was obtained as separate granules. Next, the remaining components of the inner phase were added. Next, the outer phase, which was itself produced as cogranules, was pressed together with the inner phase to form the tablet. Formed A. Although not bound by theory, the external phase is that sodium caprate is the final pH level. It is thought to be a barrier that prevents migration to the receptive outer enteric coating. Therefore, Therefore, the external minister physically separated the pH-sensitive outer enteric coating from sodium caprate. It is believed that protecting the tablets in this way improves their stability.

[0313] Subsequently, the above-mentioned combination of internal and external phases in Table 1 that constitute the tablet core are mixed at 3% (w / It was then coated with Opadory QX Pink sub-coating. % (based on core weight of internal phase plus external phase weight w / w) of Acryl-eze (registered trademark) )A functional coating of white delayed-release enteric coating (pH 5.5) It was added on top of the coating.

[0314] Example 4. Acetate tablet composition of the peptide of SEQ ID NO: 1 Another tablet composition containing the acetate form of the peptide of SEQ ID NO: 1 is prepared by a similar procedure. Prepared. This tablet contains magnesium stearate in both the inner and outer phases. .

[0315] [Table 3]

[0316] Example 5. Acetate tablet composition of the peptide of SEQ ID NO: 1 Another tablet composition containing the acetate form of the peptide of SEQ ID NO: 1, in the inner and outer phases, It was prepared as a single phase, as described below.

[0317] [Table 4]

[0318] The tablets contain the acetate form of the peptide of SEQ ID NO: 1, along with the absorption enhancer sodium caprate. It contains together the peptide, sodium caprate, and the remaining ingredients, The mixture was blended. The blend was pressed to form a core tablet.

[0319] Subsequently, the combined inner and outer phases of Table 3 that constitute the tablet core are mixed to approximately 3% (w It was then coated with an Opadory White sub-coating of / w). Then, approximately 4% Acryl-eze (registered trademark) (based on core weight of internal phase plus external phase weight w / w) The functional coating of the delayed-release enteric coating (pH 5.5) is a subcoat. It was added on top of the ing.

[0320] Example 6. Tablet composition of peptide in acetate form of SEQ ID NO: 1 with accelerator. A tablet composition containing the acetate form of SEQ ID NO: 1 with sodium caprate is used in the example. It was prepared using the same procedure as in step 2.

[0321] [Table 5]

[0322] Subsequently, the above-mentioned combination of internal and external phases in Table 4 that constitute the tablet core is mixed to 3% (w / It was then coated with Opadory QX Pink sub-coating. % (based on core weight of internal phase plus external phase weight w / w) of Acryl-eze (registered trademark) )A functional coating of a white delayed-release enteric coating, sub-coating It was added on top of it.

[0323] Example 7. Tablet composition of peptide in acetate form of SEQ ID NO: 1 with accelerator. A tablet composition containing the acetate form of SEQ ID NO: 1 with sodium caprate, similar It was prepared according to the procedure.

[0324] [Table 6]

[0325] Subsequently, the above-mentioned combination of internal and external phases in Table 5 that constitute the tablet core are mixed at 3% (w / It was then coated with Opadory QX Pink sub-coating. % (based on core weight of internal phase plus external phase weight w / w) of Acryl-eze (registered trademark) )A functional coating of a white delayed-release enteric coating, sub-coating It was added on top of it.

[0326] Example 8. Tablet composition of peptide in acetate form of SEQ ID NO: 1 with accelerator. A tablet composition containing the acetate form of SEQ ID NO: 1 with sodium caprate, similar It was prepared according to the procedure.

[0327] [Table 7]

[0328] Example 9. Tablet composition of peptide in acetate form of SEQ ID NO: 1 without accelerator. A tablet composition containing the acetate form of SEQ ID NO: 1 with sodium caprate, similar It was prepared according to the procedure.

[0329] [Table 8]

[0330] Subsequently, the above-mentioned combination of internal and external phases in Table 7 that constitute the tablet core is mixed to 3% (w / It was then coated with Opadory QX Pink sub-coating. % (based on core weight of internal phase plus external phase weight w / w) of Acryl-eze (registered trademark) )A functional coating of a white delayed-release enteric coating, sub-coating It was added on top of it.

[0331] Example 10. Solubility of the acetate form of the peptide of SEQ ID NO: 1 The acetate form of SEQ ID NO: 1, prepared according to Example 1, is used to determine its solubility under various conditions. We evaluated the following. The results are shown in Table 8.

[0332] [Table 9]

[0333] Example 11. Stability of the acetate tablet composition of the peptide of SEQ ID NO: 1. A tablet composition containing the acetate form of SEQ ID NO: 1 was evaluated under stress test conditions.

[0334] Example 12. Rat PK Study 1 In this example, screening of various absorption enhancers was evaluated. The administration of absorption enhancers was... The procedure was performed at a constant concentration of 100 mg / kg, and the SEQ ID NO: 1 (administered at 10 mg / kg) The peptide was evaluated in combination with its acetate form. The acetate of the peptide of SEQ ID NO: 1 The solution of the form was prepared using the same vehicle, but with an absorption enhancer (caprin) included as a control. Formulated without sodium caprate. The following absorption enhancers are used: sodium caprate (NaC1 0) Sodium salcaprozate (SNAC), sucrose laurate, Peptel ligence(Enteris Pharma patent technology - composition not disclosed) The substance and Labrasol were tested. The solution was administered to rats intracolon (intracolon). It was administered by onic (IC) or intraduodenal (ID) injection. Results All absorption enhancers tested showed the same results as the peptide of SEQ ID NO: 1, both after IC and ID administration. The oral bioavailability of the acetate form was increased. NaC10 had the highest Systemic exposure is administered, followed by Peptelligence, then Labrasol, and then Then SNAC, and finally sucrose laurate. Therefore, sodium caprate. It was determined to be a preferred absorption enhancer. The observed plasma concentrations in rats are shown in the table. IC presented in 14 50 Values ​​exceeding (0.054~0.5nM or 0.10~0.47) (ng / mL). Therefore, systemic exposure is likely to be high enough to result in systemic activity. There is.

[0335] The pharmacokinetics of the peptide of SEQ ID NO: 1 were studied at a dose of 10 mg / kg, and at a higher dose of SEQ ID NO: 1. A single dose of 50 mM PBS solution (pH 7.4) containing different absorption enhancers, with and without. Fasted male Sprague Dawley after intra-bidenal (ID) and intra-colon (IC) administration. The study was conducted in rats (n=3 in each group). The following absorption enhancers were used: sodium caprate. Um (NaC10, 100 mg / kg), SNAC (100 mg / kg), laurate Clause (100 mg / kg), Enteris A (Enteris Pharma) We evaluated patented technology (60 mg / kg) and Labrasol (100 mg / kg). Further experimental details, as well as the reference formulation (without absorption enhancer) and 5 after ID and IC administration. Actual average plasma drug activity of SEQ ID NO: 1 for compositions containing different absorption enhancers Table 9 shows a comparison of the state parameters.

[0336] [Table 10] a AUC last Final timestamp for this: 2, 4, 6, 8, or 24 hours

[0337] Example 13. Rat PK Study 2 In this example, the effect of NaC10 concentration was studied. Various concentrations of NaC10 (20 (mg / kg, 50mg / kg, and 200mg / kg) in combination with Sequence ID No. 1 A solution in the form of cetate (10 mg / kg) was administered to rats by IC injection. Results :NaC10, at all concentrations tested, was the total acetate form of the peptide of SEQ ID NO: 1. Although physical exposure increased, the increase given by NaC10 administered at 20 mg / kg was reduced. The absorption enhancement was minimal. The highest absorption enhancement was observed at a NaC10 concentration of 50 mg / kg. The increase in the amount of NaC10 to 100 mg / kg or 200 mg / kg was due to the peptide's cellular activity. It did not further increase oral bioavailability.

[0338] Example 14. Canine PK Study This example shows that a composition containing NaC10 at a dose of 50 mg / kg is used with the PEP of SEQ ID NO: 1. It shows the ability to increase systemic exposure to the acetate form of tide. The peptide of SEQ ID NO: 1 Cetate form (10 mg / kg), NaC10 (50 mg / kg), and other inactive excipients We manufactured tablets containing the agent. We also used Poloxamer P188, which has potential synergistic properties. To determine the effects, the peptides and absorption enhancers were evaluated in combination with NaC10. To ensure proximity, the peptide and absorption enhancer are provided as described in Example 2 above. Co-processed by dry granulation. The tablet core was protected with an immediate-release protection of a PVA-based polymer. It was film-coated in layers. Also, 5.5 (Acryl-EZE) or 7.0 (HP Additional coatings containing pH-responsive polymers that are soluble at pH values ​​higher than MC-AS. We also applied the tasting. In addition, we manufactured a control tablet core (immediate release) without absorption enhancers and studied it. It was administered as a control in the study. Results: NaC10 was found in all tablets to be the same as SEQ ID NO: 1 Systemic exposure to the acetate form of the peptide was increased. It contains NaC10 and Acryl - Tablets coated with Eze (pH 5.5) have the highest bioavailability for peptides. It gives flexibility, and is greater than DR pH7.0, followed by DR pH7.0, IR It was larger than [the original value]. No additional value was observed from the addition of P188.

[0339] Plasma PK of SEQ ID NO: 1, 100 mg of acetate form of SEQ ID NO: 1, without an absorption enhancer. (Without coating and with film coating) and with absorption enhancer (film coating In a study conducted in fasted male dogs after a single PO administration of tablets containing (only those with tinging), The ratio of SEQ ID NO:1 to the absorption enhancer was 1:5 (w:w). It safely passed through the stomach. Two different functional DR film coatings that ensure the same result, one of which is pH 5 To prevent disintegration below 0.5 (to induce dissolution in the upper part of the GI, e.g., the ileum), and another 1 However, it prevents disintegration at pH levels below 7.0 (inducing dissolution in the lower part of the GI, for example, in the colon). We investigated functional DR film coatings (leading to...).

[0340] Table 10 below shows supporting results from canine PK studies. Sodium caprate The 100mg DR tablets are either 100mg tablets without sodium caprate or 10mg tablets. Compared to any of the g / kg solutions, dogs showed higher C after administration. max and A It showed UC. 100 mg DR tablets with sodium caprate showed approximately 6% oral biliary activity. Achieved on-availability, 14 times more than uncoated IR tablets. It was an improvement. Under fasting conditions, dogs were administered composition SEQ ID NO: 1. Ten minutes after administration, 20 mL of 0.1 M HCl / KCl buffer solution with a pH of 1.4 was administered via enteral nutrition. After administering the tablet, an additional 10 mL of water was given. A normal dry diet was given again 2 hours after administration. It opened.

[0341] [Table 11] IR (immediate-release tablets), DR (delayed-release tablets), 1400mg tablet core.

[0342] Example 15. Canine PK Study #2 The pharmacokinetics of the peptide of SEQ ID NO: 1 were studied using 25 mg of the acetate form of SEQ ID NO: 1. One DR FI containing mg of NaC10 with and without (dissolves at pH 5.5 or higher) In fasted and fed male dogs after a single oral administration of lubricating tablets, the following was investigated. A crossover treatment with at least one week of washout between two consecutive treatments. The Zain was applied to the following 12 dogs: (1) fasted dogs, without NaC10, (2 (3) Dogs that ingested, without NaC10, (4) Dogs that fasted, with NaC10, and (5) Dogs that ingested Dogs that ingested the substance had NaC10. In fasted dogs, 10 minutes after administration, the dogs were 20 It accepts mL of 0.1M HCl / KCl buffer pH 1.4 to simulate human stomach and intestinal pH. Following the administration of the tablet, the dog was given an additional 10 mL of water. The dog was then given its usual dry diet. It resumed 4 hours later. For dogs that had ingested the food, 20 minutes before administering the tablet, the dog was given 2 00 mL of standard liquid food was administered via tube feeding. The dog was given whatever it was that day and thereafter. No additional food was given. The actual mean plasma PK parameters for the treatment are shown in Table 11. This will be shown.

[0343] [Table 12] a The data exhibited high variability.

[0344] Example 16. Dose-dependent rat blood activity of the peptide of SEQ ID NO: 1 Systemic pharmacology of orally administered peptide of SEQ ID NO: 1 using a rat whole blood assay. The activity was evaluated. Sprague-Dawley rats were orally administered the peptide of SEQ ID NO: 1. After administration, blood was collected from rats and extracted with rat IL-23 plus IL-1β. In vitro stimulation was performed. The presence of IL-17A was measured using an ELISA assay. -17A production is expected to be suppressed when IL-23 is inhibited. Ssey found that systemic exposure to orally administered peptide SEQ ID NO: 1 was lower than IL-17A Confirm that it is associated with systemic activity, such as that measured by production. Outline of study design The key points are shown in Table 12.

[0345] [Table 13]

[0346] material Table 13 below outlines the materials and kits used in the experiment.

[0347] [Table 14]

[0348] method In each experiment, groups of 5 or 6 female Sprague-Dawley rats were given the following: Table 12 As outlined, an aqueous solution of the peptide of Sequence ID No. 1 or vehicle (water) by body weight The drug was administered. Two or six hours after administration, the animals were euthanized, and their blood was collected based on the following criteria. They were collected in such a way.

[0349] The rats were first euthanized by CO2 asphyxiation, and then their whole blood was collected by closed cardiac puncture. Therefore, the samples were collected in individual heparinized vacuum tankers and kept at room temperature. In vitro evaluation of peptide activity in whole blood from rats administered with a drug or vehicle. For this purpose, individual or pooled blood samples (containing glutamine and HEPES) The blood was diluted in a preheated RPMI-1640 in a ratio of 1 part blood to 4 parts culture medium. The blood was mixed by pipetting and kept at room temperature, and the peptide of SEQ ID NO: 1 and DMSO was dispensed into 96-well round-bottom plates using a Tecan D300e . Blood was mixed again and 240 μL per well was pipetted into the assay plates on which peptides were spotted. The assay plates were incubated at 37 °C in 5% CO2 for 30 - 60 minutes, followed by IL-23 and IL-1β stimulation as described below .

[0350] For determination of peptide concentration, an aliquot of blood from rats treated with peptides was collected into K2EDTA microtainer tubes and processed to plasma by centrifugation at 16,100 × g for 5 minutes . Plasma was collected into 5% volume protease inhibitor (one cocktail tablet dissolved in 2 mL PBS without Ca ++ and M g ++ ) and stored at -80 °C for LC MS-based bioanalysis of test articles. The remainder of each blood sample was diluted separately in pre-warmed RPMI-1640 (with glutamine and HEPES) at a ratio of 1 part blood to 4 parts medium . The diluted blood was mixed by pipetting and while holding at room temperature, working stocks of rat IL-23 and IL-1β were prepared in RPMI-16 40. Blood was mixed again and 240 μL per well was pipetted into 96-well round-bottom assay plates, followed by IL-23 and IL-1β stimulation as described below

[0351] IL-23 and IL-1β stimulation A total of 10 μL of medium supplemented with IL-23 and IL-1β or IL-1β only was added to each well of the diluted blood, resulting in a final concentration of IL-23 of 100, 20 ... The assay was performed at 4 ng / mL, and the final concentration of IL-1β was 4 ng / mL. The plates were incubated in 5% CO2 at 37°C. After approximately 24 hours, assay plates were prepared. The mixture was centrifuged at 1,300 rpm at room temperature for 6 minutes, and then cultured in at least 100 μL of cell culture medium. The supernatant was collected in a 96-well V-bottom plate. The plate containing the supernatant was sealed. For immediate measurement of L-17A, the samples were placed on ice or frozen at -80°C.

[0352] ELISA for measuring secreted IL-17A To measure IL-17A in cell culture supernatant, the thawed supernatant was subjected to 1,300 ml of water. The cells were centrifuged at rpm for 10 minutes at 4°C. A total of 20 μL of cell culture supernatant was used (rat IL). Mixed with 80 μL of NS buffer (provided in the -17A ELISA kit). Rat I Diluted L-17A samples, and newly prepared serial titration solutions (for standard curves). The quantity in a 96-well plate (provided in the rat IL-17A ELISA kit) It was combined with an affinity tag label capture and reporter conjugate detection antibody. After incubating at room temperature for 1 hour while condensing, wash each well with 350 μL / well. The plates were washed three times with a clean buffer. After the final wash, the plates were inverted and blotted to remove excess material. The liquid was removed. The plate was protected from light and shaken while developing color with TMB substrate for 10 minutes. After stopping the color reaction, the absorbance in each well was measured using SpectraMax. The readings were taken at 450nm using a 340PC plate reader.

[0353] Data Analysis Standard curves were replicated and generated for each ELISA plate. The standard curve data was then processed. Using SoftMax Pro software, 1 / y 2 A song with 4 parameters weighted together Linear fitting analysis was performed. The supernatant IL-17A level was analyzed in SoftMax Pro without any bleed. OD Ground subtraction optical density at 450nm 450) Use the values ​​to interpolate or extrapolate from the plate-specific standard curve, Microsof In Excel, correct the dilution factor used in the ELISA assay. did.

[0354] In an experiment in which blood was treated in vitro with the peptide of SEQ ID NO: 1 in a stepwise titration dose (Example 1) In 7), the diluted IL-17A level is compared to the logarithmically converted peptide concentration. Then plot, in vitro IC 50 The values ​​are obtained using nonlinear regression (curve fitting) - logarithmic [inhibitor] pair. Response (3 parameters) - Least squares regression used in GraphPad Prism The calculation was performed for the ex vivo IC5 of the orally administered peptide of SEQ ID NO: 1. 50 Estimate the value To determine this, the IL-17A levels were logarithmically transformed for each individual (administered) animal. The data was plotted against the plasma peptide levels obtained. Ex vivo IC5 50 The values ​​are regressed using nonlinear regression. Using curve fitting - log [inhibitor] vs. response (4 parameters) - robust regression, Gra Calculations were performed using phPad Prism. The upper part of each ex vivo exposure inhibition curve was used as the control. Median I detected in IL-23 / IL-1β stimulated blood from vehicles (administered via vehicle) It was limited to the L-17A level.

[0355] For comparative statistics, the arithmetic mean of the technical replicates is first logarithmically transformed, and then... We offset for equal variances and analyzed using one-way ANOVA. Post-hoc statistical studies were performed for each Dunnett multiple comparisons to compare the treatment group with the vehicle, or statistically significant results with p<0.05. Adjust using one of the Sidak multiple comparisons for selected comparisons with the p-value threshold. Ta.

[0356] Systemic activity results of orally administered peptide of SEQ ID NO: 1 in rats The systemic activity of the orally administered peptide of Sequence ID No. 1 is summarized in Table 12 above. Thus, it was tested in five independent experiments. Using these experiments, C max at The dose-exposure response relationship of the peptide of Sequence ID No. 1 in ex vivo whole blood was determined, and the sequence number Was there evidence of a sustained pharmacodynamic effect after the in vivo reduction of peptide exposure to sample 1? They evaluated that.

[0357] Dose response Two hours after administration, that is, when the orally administered peptide of SEQ ID NO: 1 was administered to rats... After the time it takes to reach the maximum plasma concentration, it is collected in 4, 20, or 100 ng / mL doses. Stimulation with L-23 plus 4 ng / mL IL-1β or 4 ng / mL IL-1β alone By using the collected blood and combining the data from all five experiments, The vivo dose-response profile was fully defined. Cell culture supernatant was analyzed by ELISA. The secreted IL-17A was collected approximately 24 hours later for measurement.

[0358] The peptide of SEQ ID NO: 1 (0.03-100 mg / kg, po) is found in whole blood. We demonstrated dose-dependent inhibition of L-23 and IL-1β-induced IL-17A secretion, and restricted The effect was achieved at a dose of 1 mg / kg or less, and complete or near-complete inhibition occurred at 30 and 10 Achieved at a dose of 0 mg / kg (Figures 2-5). Technical replicates were calculated using the arithmetic mean. Averaged by (100). Error bars have been omitted for clarity. Five different experiments (100 The data from three experiments on IL-23 conditions of ng / mL were combined (four Boxes represent the quantile range, and bars represent the minimum / maximum. Compare each procedure to the vehicle. One-way ANOVA in log-normalized values ​​in post-trial analysis (ns = not significant) * p<0.0 5. ** p<0.01, **** p<0.0001).

[0359] Diluted ex vivo IC5 for the orally administered peptide of SEQ ID NO: 1 50 value In blood challenged with 4 ng / mL of IL-23, the concentration was 0.032 nM. In blood samples challenged with 20 ng / mL of IL-23, the concentration was 0.27 nM. (Figure 5).

[0360] Therefore, exposure-dependent IL-17A production by orally administered peptide of SEQ ID NO: 1. Sexual ex vivo inhibition is more potent when whole blood is stimulated with lower concentrations of IL-23. This matched the peptide of SEQ ID NO: 1, which acts as a competitive antagonist of IL-23R.

[0361] Example 17. IC of the peptide of SEQ ID NO: 1 in in vitro treated rat blood. 50 The values ​​and ICs from rat blood collected ex vivo after oral administration. 50 Value comparison Orally administered peptide of SEQ ID NO: 1 showed dose-dependent systemic exposure in rat blood. If applicable, the inventors have measured the exposure-dependent values ​​in the blood of orally administered rats. Ex vivo IL-23 stimulating IL of the peptide of SEQ ID NO: 1, such as that generated from cellular inhibition. IC for inhibition of -17A 50 However, blood collected from rats that were not administered the drug ( The removed blood was then treated with the peptide of SEQ ID NO: 1. 50 This matches I predicted that he would become deaf.

[0362] Pooled blood samples from 6 naivet rats, or rats administered a vehicle. Individual blood samples were taken and, before stimulation with IL-23 and IL-1β, subjected to stepwise titration doses of peph The in vitro potency of the peptide of SEQ ID NO: 1 was determined by treatment with thiosulfate. The absolute amount of IL-17A produced from whole blood of animals was 20 ng / mL of IL- When stimulated with 23, the range was 536.0-2429 pg / mL, and 4 ng / mL When stimulated with IL-23, the levels ranged from 409.4 to 2196 pg / mL. In vitro IC for peptide in column number 1 50 Table 14 shows an overview of the values. Sequence ID In vitro IC for peptide 1 50 The values ​​are 4 ng / mL for IL-23 and 4 ng When stimulated with IL-1β at a concentration of / mL, the mean IC50 is 0.012~0.11nM. 50 0 The range is 0.054±0.034nM, and blood is stimulated with 20 ng / mL of IL-23. At that time, 0.16~0.34nM (average IC) 50 0.25±0.062nM, n=6 It was within the range of (a number of rats).

[0363] [Table 15]

[0364] The ex vivo potency of the orally administered peptide of SEQ ID NO: 1 is equivalent to the ex vivo potency of the orally administered peptide of SEQ ID NO: 1 The in vitro activity was similar to that of the peptide measured in Example 17. In vitro rat whole blood IC for peptide 1 50 The values ​​are 4 and 20 ng / mL. Regarding stimulation at L-23, the values ​​were 0.054±0.034 nM and 0.25±0. The mass was 0.62 nM. In comparison, the orally administered sequence measured in Example 16 was different. Diluted and adjusted ex vivo IC for peptide number 1 50 The values ​​are blood samples 4 and 20 When stimulated with IL-23 at ng / mL, the levels were 0.032 nM and 0.27 nM, respectively. That was the case.

[0365] These data show that the dose of orally administered peptide SEQ ID NO: 1 in rat blood It was demonstrated that there is dose-dependent systemic exposure, and dose-dependent systemic exposure in rat blood is Regarding the exposure-dependent inhibition of ex vivo IL-23-stimulated IL-17A by the peptide of SEQ ID NO: Ten IC 50 By generating this, it is used to predict the level of systemic pharmacodynamic activity. It may be used to study the exposure dependence of ex vivo IL-23-stimulated IL-17A of the peptide of SEQ ID NO: 1. ICs regarding inhibition 50 This is blood taken from rats that have not been administered the drug (removed blood). The solution was then treated with the peptide of SEQ ID NO: 1. 50 This matches.

[0366] Example 18: Time course of ex vivo pharmacodynamic inhibition IL-23-induced IL-17A secretion at different time points after administration of the peptide of SEQ ID NO: 1 To determine ex vivo inhibition, rats were administered 10 mg / kg of peptide, and bilaterally... Blood samples were taken 6 hours later, followed by ex vivo stimulation with IL-23 and IL-1β. Two hours after administration, the median value in the blood of rats that received the peptide of SEQ ID NO: 1 IL-17A production is 100, 20, or 4 ng / mL of IL-23 and 4 ng / mL, respectively. After stimulation with IL-1β at a dose of / mL, it was significantly reduced (compared to the vehicle control sample) (Figure 6) The cell culture supernatant was used for approximately 2 minutes to measure secreted IL-17A by ELISA. Data was collected after 4 hours. Technical replicates were averaged by the arithmetic mean. Errors — has been omitted for clarity. Boxes represent the interquartile range, and bars represent the minimum / maximum. One-way ANO in log-normalized values ​​in the Sidac post-hoc trial comparing treatment with vehicle VA(ns = not significant) ** p<0.01, *** p<0.001, **** p<0. 0001).

[0367] Six hours after administration, the orally administered peptide of SEQ ID NO: 1 was found to be present in concentrations of 100 and 20 ng / m³. L did not have a significant effect on the ex vivo response to IL-23 and IL-1β, but 4n Median I in samples treated with g / mL IL-23 and 4 ng / mL IL-1β A significant decrease in L-17A levels was observed. The decrease was observed 6 hours after administration compared to 2 hours after administration. The inhibition observed was consistent with plasma peptide exposure at this point. Therefore, peptide exposure was There was no evidence of a sustained pharmacodynamic effect of ex vivo when the effect was reduced with nvivo.

[0368] Example 19. Rat skin activity - Under IL-23 by oral administration of the peptide of SEQ ID NO: 1 Inhibition of fluid gene expression. The objective of the experiment in Example 19 was to determine the effects on rat skin after oral administration of the peptide of SEQ ID NO: 1. Downstream gene expression of IL-23, specifically IL-17A, IL-17F, and IL-2 The goal was to measure tissue pharmacodynamics by measuring the inhibition of two genes.

[0369] Ear inflammation was recombined in Sprague-Dawley rats during days 0-3 of the study. Rat IL-23 was induced by daily intradermal injection. Treatment with the peptide of SEQ ID NO: 1. (Dose response via oral enteral nutrition: 1, 3, 10, 30, 100, and 300 mg / kg) (Twice a day) Start preventively, starting one day before inflammation is induced, and continue until the third day after inflammation is induced. This continued until the 4th day. All rats were humanely euthanized on the 4th day. (-1 day and The anti-IL-23 monoclonal antibody (administered intraperitoneally on day 3) was used as a positive control and comparator drug. Therefore, it was included in all studies.

[0370] Materials and methods Anti-IL-23p19 monoclonal antibody and IgG1 isotype monoclonal antibody It was supplied in PBS at a concentration of 2 mg / mL, ready for use. 10.11 g of Na2HPO4- Add 7H2O and 1.70g of NaH2PO4-H2O to 800mL of distilled water. By doing so, a vehicle (50 mM phosphate buffer (PB)) is prepared. The final pH was adjusted to 7.4 using HCl or NaOH. Then, the volume was distilled. The solution was diluted to a maximum of 1 liter using water and stored at 4°C.

[0371] The test material was dissolved in phosphate buffer at an appropriate concentration, aliquoted for each dose, and stored at 4°C. Stored in Eppend. Each dose formulation was kept after initial preparation and after the final dose on day 3. The samples were collected in a tube and stored at -80°C for bioanalysis of the test specimens by LC-MS.

[0372] Recombinant rat IL-23 was diluted to a concentration of 75 μg / mL in PBS, and 2.0 mL of it was added to the solution. The rats were divided into recoated portions and stored at -80°C. Every day from day 0 to day 3, the rats were treated with isoflurane. The patient was anesthetized with IL-23 and injected intradermally into the right ear. (1.5 μg in a volume of 20 μL). In the control group, 20 μL of PBS was injected. .

[0373] The rats were given a vehicle, starting in the morning before the IL-23 injection and continuing until the evening of the third day. Either (phosphate buffer) or the peptide compound of SEQ ID NO: 1 is administered via oral enteral nutrition (po .) Administer in a volume of 5 mL / kg twice a day (with approximately 10 hours between administrations). ) was administered. In one experiment, the peptide of SEQ ID NO: 1 was also administered in a volume of 5 mL / kg. It was administered subcutaneously (sc). In another experiment, 20m The peptide compound of Sequence ID No. 1 is administered in g / kg in the morning, and the vehicle (PB) is administered at night. This included the group that took the medication once a day.

[0374] Anti-IL-23p19 antibody or isotype antibody administered by intraperitoneal injection. The drug was administered via oneal (ip) at a volume of 5 mL / kg on days 1-1 and 3.

[0375] At the end of the study, four days after induction with IL-23 (approximately 16 hours after the evening dose on the third day) The animals were euthanized by CO2 asphyxiation. Ear tissue was weighed, flash-frozen, and inflammation was treated. For gene expression analysis of sex genes (IL-22, IL-17A, IL-17F, TNF) The sample was then stored at -80°C. Additional ear tissue was analyzed by LC-MS to determine the peptide of SEQ ID NO: 1. For anatomical analysis, the same procedure was used. Furthermore, ear tissue was treated with 10% neutral buffered formalin. The specimens were fixed in Neutral Buffered Formalin (NBF) for 24 hours, followed by histological treatment. For analysis, it was transferred to 70% ethanol.

[0376] Histopathological evaluation and scoring: Skin samples from the ear were processed as follows. 5 Micrometer sections were placed on a slide, stained with hematoxylin and eosin, and then exposed to light. Using a microscope, the procedure was evaluated by a certified veterinary pathologist who was unaware of the treatment conditions. Each ear sample was scored individually. Epidermal thickness (μm) was scored on a scale of 0 to 4 (0 :Within the normal range, thickness 30 μm or less, 1:Mainly less than 50 μm, 2:Mainly 50-8 Scoring is done based on 0μm, 3: mainly 80-110μm, 4: over 110μm), and other characteristics ( (Epidermal discharge, erosion / ulceration, epidermal thickening, and inflammation) are classified from 0 to 5 in increasing order of severity. The scores were assigned using this scale.

[0377] result The orally administered peptide of SEQ ID NO: 1 contains IL-17A, IL-17F, and IL-2 The IL-23-induced expression of compound 2 was attenuated in a dose-dependent manner (Figures 7, 8, and 9, respectively). (See reference).

[0378] Figure 7 shows the intradermal administration of naivet or recombinant rat IL-23, and The vehicle or the peptide compound of SEQ ID NO: 1 (1, 3, 10, 30, 100, 300 Oral administration of mg / kg bid (days 1-3), or anti-IL-23 or i- Skin in rats after intraperitoneal administration of sotype antibody (4 mg / kg on days -1 and 3) This shows changes in IL-17A gene expression. IL-23 is approximately 15% of the median IL-17A expression. It induced a doubling of IL-17A expression, and the median IL-17A expression was the same for all tested doses and 10 mg. Treatment with the peptide of SEQ ID NO: 1 at doses of 1 kg (bid) or more effectively inhibits IL-2 The levels were reduced to a level equivalent to that of the 3 antibodies.

[0379] Figure 8 shows the intradermal administration of naivet or recombinant rat IL-23, and Vehicle or peptide of Sequence ID No. 1 (1, 3, 10, 30, 100, 300 mg / k Oral administration of g BID, or intraperitoneal administration of anti-IL-23 or isotyped antibodies This shows changes in cutaneous interleukin-17F (IL-17F) gene expression in rats. vinegar.

[0380] Figure 9 shows the intradermal administration of naivet or recombinant rat IL-23, and Vehicle or peptide of Sequence ID No. 1 (1, 3, 10, 30, 100, 300 mg / k Oral administration of g BID, or intraperitoneal administration of anti-IL-23 or isotyped antibodies This shows changes in cutaneous interleukin-22 (IL-22) gene expression in rats.

[0381] Example 20. Rat skin activity - IL-23 induction by oral administration of the peptide of SEQ ID NO: 1 Inhibition of ostomatitis thickening Using a rat IL-23-induced skin inflammation model, the peptide of SEQ ID NO: 1 was used to study IL-2 The tissue pharmacodynamic activity of 3R peptide antagonists was evaluated. The purpose of the rat ear thickening experiment was to determine whether orally administered peptide SEQ ID NO: 1 was absorbed into the skin tissue. To determine whether there is sufficient systemic exposure to provide inhibition of IL-23R, Therefore, the goal is to model the efficacy of orally administered treatment in psoriatic skin tissue. The animals from Example 19 were also used for Example 20. On day 0, IL-23 injection was administered. Previously, the ipsilateral ear portion was approximately 0.4 mm on average. Rats injected with physiological saline solution As a result of repeated intradermal injections, the ear area swelled by an average of 0.053 mm by day 4. In comparison, IL-23 injections were used in vehicle-treated rats and isotype antibody-treated rats. The thickness of both ears of the rats subjected to this treatment gradually increased, respectively. By the fourth day, the average thickness reached approximately 0.240-0.242 mm. Anti-IL-23 monoclona Blocking IL-23 with antibody treatment reduced ear swelling to just 0.133 m by day 4. The reduction to m was statistically significant in all cases from day 2 to day 4. The treatment also demonstrated a reduction in IL-23-induced swelling, at 300 mg / kg, bid At the highest dose, swelling on day 4 was reduced to an average of 0.120 mm. Peptide of SEQ ID NO: 1 The reduction of hypertrophy by progressively decreasing the dose of thiocyanate is generally achieved at a minimum of 3 mg / kg. The dose-response was observed up to the bid dose: 1, 3, 10, 100, and 300 mg. The doses of / kg, po, and bid, compared to vehicle treatment, increase ear thickness by 3 and The dosage decreased to a statistically significant degree on the 4th day, and the dosage of 30 mg / kg, PO, BI was used. The dosage was statistically significant on days 2-4. 2 mg / kg, sc, and 20 mg / kg The reduction in ear thickness at doses of po and qd was not statistically significant (Figure 9 and Table 15).

[0382] result Orally administered peptide of SEQ ID NO: 1 prevented IL-23-induced ear thickening. 10 At doses of mg / kg(po,bid) or higher, the efficacy of the peptide of SEQ ID NO: 1 is The effectiveness was equal to or greater than that of anti-IL-23 antibody treatment.

[0383] Figure 10 shows the ear thickness (mm) of Naiveblatt or the skin of recombinant rat IL-23. Intravenous administration, and the vehicle or peptide compound of SEQ ID NO: 1 (1, 3, 10, 30, 10 0, 300 mg / kg bid, 20 mg / kg qd, -1 to 3 days) Oral administration, or anti-IL-23 or isotyped antibody (4 mg / kg on days 1 and 3). This shows the change in ear thickness (mm) in rats after intraperitoneal administration of IL-23. Compared to rats (median increase 0.05 mm), rats treated with isotype antibodies (median increase 0.05 mm) In rats treated with a vehicle (median increase of 0.25 mm) and in rats treated with a vehicle (median increase of 0.20 mm) This induced greater ear thickening. Peptide of SEQ ID NO: 1 (1, 3, 10, 30, 1 00, 300 mg / kg, po, bid, -1~3 days) are vehicle treatment and In comparison, a reduction in ear thickening was observed on day 4 (Table 15).

[0384] [Table 16] (ns = not significant) ** p<0.01, *** p<0.001, **** p<0.0 001)

[0385] Therefore, the orally administered peptide of SEQ ID NO: 1 was measured in the ear thickening experiment. This demonstrated dose-dependent inhibition of IL-23 in rat skin.

[0386] Example 21: Phase 1 First-in-Human Pharmacokinetics (PK) In healthy participants, the compound Ac-[Pen] * -NT-[W(7-Me)]-[Ly s(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal] -[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen Morphology Phase 1 First-in-Human (First I) (Lufide bond) (SEQ ID NO: 1) Human (FIH) over the tested dose range (10 mg to 1000 mg) This is currently being done to evaluate the safety and tolerance of the compound. All cohorts are This research is now complete.

[0387] Part 1 (Single dose escalation study): Administration as a single dose up to 1000 mg, Part 2 (Multiple dose-escalation studies) Doses up to 1000 mg, and Part 3 open-label relative BA / The results from studies on the effects of food were re-examined.

[0388] Systemic exposure to the drug (maximum observed serum concentration [C]) max ] and AUC) have been to date The dosage is approximately dose-proportional across the evaluated dose range. After once-daily administration, a steady state was achieved by day 7, which is approximately 10-12 hours of observation. This was consistent with the mean terminal phase half-life. After multiple once-daily doses, 13% of the AUC was observed. An average accumulation of approximately 50% was observed, which coincided with the half-life.

[0389] Ac-[Pen] from the ongoing FIH study * -NT-[W(7-Me)]-[Ly s(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal] -[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen Morphology Table 16 shows an overview of the preliminary single-dose PKs of the rufid bond (SEQ ID NO: 1).

[0390] Table 16.Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[ Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E -N-[3-Pal]-Sarc-NH2( * Pen-Pen morphological disulfide bond) Mean (%CV) single-dose pharmacokinetic parameters for SEQ ID NO: 1) Part 1: Administration as an oral solution under fasting conditions

[0391] [Table 17]

[0392] Food efficacy evaluation of enteric-coated tablets containing AbE is ongoing at FIH Research. This part of the research has been completed. Summary of the research design and top-line results from this study. The following is shown. The subject is Ac-[Pen], a single dose of 25 mg. * -NT-[W(7 -Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy) ]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pe n-Pen morphological disulfide bond) (SEQ ID NO: 1) should be used for at least 5 days between treatments. I received it four times, with a slush period in between.

[0393] Of the 12 participants enrolled in the study, 10 subjects participated in all phases of the crossover. The process has been completed. PK data from the 10 subjects is available, and the PK data Table 17 provides an overview of the details.

[0394] [Table 18]

[0395] The results from this study show that enteric-coated (pH-sensitive) coatings administered under fasting conditions are... Tablet formulations with a coating showed a median delay time of 3 hours and approximately when applied to oral solutions. This indicates an average oral bioavailability of 50%. In contrast, under fasting conditions... The enteric-coated tablet formulation containing AbE that was administered, when mixed with the oral solution, It had a median delay time of 1.5 hours and an average oral bioavailability of approximately 700%. When administered under feeding conditions, the absorption-enhancing enteric-coated tablet formulation absorbs 7 units of the oral solution. It had a median delay time and an average oral bioavailability of approximately 400%. The administration of the ant absorption-enhancing tablet formulation compared to the same formulation administered in a fasted state (CV approximately 57%) In comparison, it was associated with increased variability (coefficient of variation [CV] of approximately 90%).

[0396] In summary, the results of this relative study show that the absorption enhancer (AbE) sodium caprate is effective. A tablet formulation of a peptide containing (NaC10) minimizes the total daily dose requirement while ac -[Pen] *-NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -P he[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-P] al]-Sarc-NH2( * Pen-Pen morphological disulfide bond) (SEQ ID NO: 1) This demonstrates that oral bioavailability and systemic exposure can be significantly increased. The goal of using absorption-enhancing oral formulations is to increase the amount of peptide administered without increasing the amount of drug given. Because it increases systemic exposure to the virus, a relative increase of approximately five times the exposure is compared to existing pre-existing conditions. This is covered by the limits of clinical toxicology.

[0397] Example 22: The peptide of SEQ ID NO: 1 reduces intestinal inflammation in an animal model of IBD. The in vivo anti-inflammatory activity of the peptide of SEQ ID NO: 1 was demonstrated in rat trinitrobenzenes in IBD. Evaluation in a trinitrobenzenesulfonic acid (TNBS)-induced colitis model. Intracolonic TNBS infusion in Sprague-Dawley rats was performed. Induces colon inflammation partially driven by IL-23R signaling (Ch eng X, Taranath R, Mattheakis L, Bhandari A ,Liu D.The biomarker profile of PTG-200, an oral peptide antagonist of IL-23 rece ptor,tracks with efficacy in a preclinic al model of IBD.J Crohns Colitis.AGA Abs (tracts, 2017). Therefore, the TNBS rat model is IL-23 / IL- This provides a measure of the local GI effect of SEQ ID NO: 1 on 23R signaling. These results are Furthermore, it supported the human dose prediction for the peptide of SEQ ID NO: 1.

[0398] Research design Take the peptide of SEQ ID NO: 1 three times a day (0.03, 0.1, 0.3, 1, 3, 10 mg). In a rat TNBS model administered orally only ( / kg / day), three independent rat T1 The peptide was evaluated in the NBS experiment. In all studies, the peptide of Sequence ID No. 1 was used in the TNBS experiment. The drug was administered starting two days before induction and continued until the sixth day, with euthanasia scheduled for the seventh day. .

[0399] result Following TNBS administration and induction of colitis, the rats showed a rapid decrease in body weight (Figure 11). In contrast, the naive animals continued to gain weight throughout the experimental timeframe. These differences Furthermore, the difference between the naive group and the TNBS group up to day 7 was 91.9g (95% CI: 80). A net loss of 8,103g occurred as a result of TNBS infusion. This reflected an overall decline in health. Peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, Initiation of treatment at doses 1, 3, and 10 mg / kg / day was consistent across all three studies. It prevented and reversed NBS-induced weight loss. The peptide of SEQ ID NO: 1 reduced weight loss. The weak dose ranged from 0.03 to 1 mg / kg / day and was dose-dependent. 3 and 10 mg / kg / The effect observed was equivalent to that seen with 1 mg / kg / day. (3 sets of TNBS experiments) Based on the combined analysis, as early as 5 days after TNBS, peptide (1) of sequence number 1 was detected. mg / kg / day, po) showed a significant reduction in weight loss (p=0.022), and 7 days Up to day 1, doses of 0.3, 1, 3, and 10 mg / kg / day were used to treat weight loss in a significant manner. The effects were provided (for p<0.0001, p<0.0001, p<0.0001, respectively). (and p=0.002). Based on day 7 as the study endpoint, 0.3 mg / k The peptide of Sequence ID No. 1, administered in g / day, was considered the minimum effective dose (Figure 11).

[0400] Figure 11 shows weight gain in Naivet, or intracolonic administration of TNBS, and water (- Days 2-6) or peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, 1, 3, and weight loss in rats after oral administration of 10 mg / kg / day (days 2-6) The data shows the change over time. The data represents the average weight (n=10-29 rats, across 3 studies). (Combined together). Error bars have been omitted for clarity. Sequence ID 1 (0.3 Body weight in rats treated with 1, 3, and 10 mg / kg / day increased by day 7. , significantly different from the vehicle group (ns = not significant) ** p<0.001, **** p< 0.0001).

[0401] TNBS-induced colitis manifests as colonic shortening, increased edema, and colonic thickening. Compared to naivet rats, the total colon weight / length ratio in rats treated with TNBS A physical increase results from this. The colon weight / length ratio in Naivet is approximately 0. The level was 1 g / cm³, which increased to approximately 0.5 g / cm³ in rats treated with TNBS. Estimated absolute difference of 0.422 g / cm³, 95% CI: 0.335, 0.508 g / cm³). Peptides in column 1 (0.03, 0.1, 0.3, and 1 mg / kg / day) are measured by colon weight. Regarding the attenuation of the change in length ratio, a dose-related trend was observed, and a similar magnitude of effect was observed. The results were shown at 3, and 10 mg / kg / day (Figure 12). Compared to the TNBS group, the results were 0.1, 0 The peptide of SEQ ID NO: 1 at doses of 0.3, 1, 3, and 10 mg / kg / day corresponds to colon weight / length. Significant therapeutic effect in reducing the ratio (p=0.0019, p<0.0001, p< (0.0001, p<0.0001, and p=0.0073), and 0.1 mg / kg / The minimum effective dose was considered to be [number] days (Figure 12).

[0402] Figure 12 shows the intracolonic administration of Naivet or TNBS, and water (- Day 2~). Day 6) or peptide of SEQ ID NO: 1 (0.03, 0.1, 0.3, 1, 3, and 10 The colon weight / length ratio in rats after oral administration of mg / kg / day (days 2-6) It shows a change. Data from three different studies were combined (at each dose level, as follows): Represented by the shape of the symbols. Study 1 (Δ), Study 2 (□), Study 3 (〇), Interquartiles Range in boxes, minimum / maximum in bars. 0.1, 0.3, 1, 3, and 10 mg / kg / day The peptide of SEQ ID NO: 1 at this dose showed a significant therapeutic effect in reducing the colon weight / length ratio. (ns = not significant) ** p<0.01, **** p<0.0001).

[0403] The resulting disease severity from TNBS can be categorized as follows: formation of stenosis, adhesions, and ulcers. It can be evaluated by qualitative scoring of changes and increases in wall thickness. Total colon score Compared to NaiveBlatt, the TNBS group had a median of 11 (10-12 quarters). It increases significantly within the interorder range (Figure 13). The lowest dose (0.03 mg / kg / day) The colon score for the peptide in SEQ ID NO: 1 is similar to the colon score observed only in TNBS. The colon score was as follows: Reduced by treatment with the peptide of SEQ ID NO: 1 (p=0.0187, p= 0.0002, p<0.0001, p<0.0001, and p<0.0001), colitis Overlapping inhibition levels of the symptoms were observed within this dose range. Based on this qualitative scoring... The peptide of sequence number 1 at 0.1 mg / kg / day showed the minimum effective dose for the colon score. This was considered to be the dosage (Figure 13).

[0404] Figure 13 shows the intracolonic administration of Naivet or TNBS, and water or array. Peptide No. 1 (0.03, 0.1, 0.3, 1, 3, and 10 mg / kg / day, -2 This shows the changes in the colon inflammation score in rats after oral administration from day 1 to day 6. The data from the studies were combined (represented by the shape of the following symbols at each dose level). Study 1 (Δ), Study 2 (□), Study 3 (〇), box in the interquartile range, minimum / (Maximum bar). The colon is assessed using the following parameters: adhesions (0-2), strictures (0-3), ulcers (0 (5) and wall thickness (0-2) are scored for the total component score range of 0-12. The colon score was determined by SEQ ID NO: 1 for doses of 3, 10, 30, and 100 mg / kg / day. Reduced by peptide treatment (ns = not significant) * p<0.05, *** p< 0.001, **** p<0.0001).

[0405] At the end of each study, colon contents and colon tissue samples were collected from each animal and subjected to LC-MS / Massaging. Drug concentrations were analyzed by S. High concentrations of SEQ ID NO: 1 were found in the colonic contents and colon. Observed in tissues, levels increased with increasing dose (Table 18).

[0406] [Table 19] Note: Three independent experiments were conducted on TNBS-induced colitis in male Sprague Dawley. The experiments were conducted in a laboratory setting. The results for each experiment are presented below. a If more than half of the samples have a BQL value, the BQL is set to 0, and the average is... This is calculated. "-" = Not applicable, BID = Twice a day, BQL = Below the limit of quantification, N = Number, QD = 1 TID = 3 times a day, TNBS = trinitrobenzenesulfonic acid.

[0407] In summary, in vivo studies in a rat model of TNBS-induced colitis are... The dose-related and GI exposure-related attenuation of disease parameters is shown, and the minimum effective dose is given by SEQ ID NO: 1. The peptide level was 0.3 mg / kg / day. Correlations were found in colon tissue, fecal concentration, and This was observed between the pharmacological activity / efficacy endpoints.

[0408] Example 23: First-in-Human clinical study, orally administered SEQ ID NO: 1 Evidence of systemic IL-23 pathway involvement with ptide Ex vivo whole blood IL-23-inducible IFNγ production assay Using an ex vivo whole blood IL-23-inducible IFNγ assay, first-in-one testing was performed. In the Human study, the systemic pharmacodynamic activity of the orally administered peptide of Sequence ID No. 1 was evaluated. The assay was evaluated across all multiple ascending dose (MAD) cohorts. In the study, the program was conducted at multiple time points on day 1 and day 10, and healthy volunteers were given a placebo. , or the dosage of the peptide of SEQ ID NO: 1 (10 mg, 25 mg, 100 mg, 300 mg, 1 One of the 000mg doses was administered orally once daily for 10 consecutive days. On days 1 and 10... When the assay was performed, the subjects received the target dose after fasting overnight for approximately 10 hours. Participants received either sevofibrillator (SEQ ID NO: 1) or the peptide and remained fasted for approximately 4 hours after administration. After oral administration on days 1 and 10, whole blood from the subjects was taken for IFNγ stimulation using TruC ulture(TM) Tube (Rules Based Medicine,Q 2 solution IL-2 (10 ng / mL) and IL-18 (20 ng / mL) within ions company / mL), or IL-2 (10 ng / mL), IL-18 (20 ng / mL), and IL Stimulation was ex vivo at either -23 (0.5 ng / mL). IFNγ production was: If IL-23R signaling is inhibited, suppression is expected. However, Therefore, lower IFNγ production in the assay is due to orally administered peptide of SEQ ID NO: 1. Sufficient exposure and associated systemic pharmacodynamic (PD) activity are required to achieve the associated .

[0409] method Collect whole blood in a TruCulture® tube according to the manufacturer's instructions for use. The tubes were incubated in a block thermostat at 37°C for 24 hours (±1 hour). After incubation at 37°C, the supernatant is collected by TruCultube® tube manufacturer. Instructions for use (Rules Based Medicine, Q 2 solutions c The sample was collected according to the company's guidelines. An ELISA assay was used to analyze the IF in the supernatant. The level of Ng was quantified.

[0410] result Mean whole body weight for the 25mg, 100mg, 300mg, and 1000mg cohorts. Sexual PD activity reached near 100% maximum inhibition, and inhibition of over 50% was maintained for at least approximately 8 hours. The inventors also demonstrated that the peptide of SEQ ID NO: 1 reaches a steady state level on day 10. When this level was reached, a dose-dependent effect on IFNγ inhibition was observed (Figure 14). Therefore, the orally administered peptide of SEQ ID NO: 1 was found to affect IL-23 in human whole blood. Dose-dependent inhibition of vigorous IFNγ production was demonstrated. In the assay, blood was diluted threefold. Therefore, the measured level of IFNγ inhibition is the peptide of SEQ ID NO: 1 in the blood. The in vivo pharmacodynamic activity is underestimated.

[0411] Regarding the 10, 25, 100, 300, and 1000 mg cohorts compared to placebo: The first-in-human systemic IFNγ pharmacodynamic dataset is shown in Figure 14. As shown, IL-23 induction from multiple indicated time points on days 1 and 10 of the MAD cohort. Percentage inhibition (mean ± SE) of conductive IFNγ production data is shown relative to baseline. One person with an abnormal value was excluded from the placebo (PBO) and 10 mg cohorts. Removed. IFNγ = Interferon Gamma, Time (h) = Time (hours).

[0412] STAT3 ex vivo whole blood phosphorylation assay Furthermore, using the ex vivo whole blood IL-23-inducible STAT3 phosphorylation assay, In a first-in-human study, the systemic effects of orally administered peptide SEQ ID NO: 1 were observed. Pharmacodynamic activity was evaluated. This proximal IL-23R signaling assay was performed using flow site By using a meter to analyze IL-23-induced phosphorylation of STAT3, The assay was performed in a 25 mg MAD cohort, with multiple assays conducted on days 1 and 10. At that point, healthy volunteers were given either a placebo or 25 mg of the peptide of Sequence ID No. 1. It was administered orally once a day for 10 consecutive days. When the assay was performed on days 1 and 10... The subjects received either a placebo or peptide of SEQ ID NO: 1 after fasting for approximately 10 hours overnight. After receiving the drug and administering it, the patient remained fasting for approximately 4 hours. (After oral administration on days 1 and 10) In addition, whole blood from subjects was used to evaluate STAT3 phosphorylation in specific immune cell subsets. Therefore, IL-23 was incubated ex vivo with or without STAT3 I L-23-induced phosphorylation occurs when IL-23R signaling is inhibited in immune cells. It is expected to be suppressed in a subset. Therefore, it will be read out by the assay. Lower STAT3 phosphorylation, such as that which affects the systemic effects of orally administered SEQ ID NO: 1 peptide It is associated with sufficient exposure to achieve pharmacodynamic activity. Without the required blood dilution, The release point is proximal to IFNγ production, and the response is characteristic of immune cells that respond to IL-23. Because it measures in a specific subset, the pSTAT3 assay is more sensitive than IFNγ. This is a highly pharmacodynamic interpretation.

[0413] method Whole blood samples were collected using standard clinical trial procedures and vaccinated with lithium heparin. The sample was collected in a uette tube. The sample was ali-coated onto a preheated plate and heated at 37°C. The sample was incubated in a block for 30 minutes. After incubation, the sample was 1 The sample was stimulated with IL-23 at 00 ng / mL for 30 minutes at 37°C. Then, the sample was preheated... The samples were fixed at 37°C for 15 minutes using BD Phosflow® dissolution / fixation buffer. Afterward, the sample was permeabilized in 100% methanol at 4°C for 15 minutes, and flow cytometry was performed. Before analysis with the ter, pSTAT3 (phosphorylation site, PY705 / clone, 4 / P-ST AT3), CD45 (clone, HI30), CD3 (clone, UCHT1), CD5 6 (clone, HCD56), CD4 (clone, RPA-T4), CD8 (clone, RPA-T8), CD45RA (clone, H1100), and CD26 (clone, M The sample was stained with an antibody against -A261) at room temperature for 60 minutes.

[0414] result In all three subjects who received 25 mg of the peptide of SEQ ID NO: 1, STAT3 Nearly complete inhibition of phosphorylation was observed in all analyzed immune cell subsets (memory CD26). h igh CD4 + T cells, memory CD26 high CD8 + T cells and CD26 high Inhibition was observed in NKT cells, but not in the two placebo-controlled subjects. (Figure 15). These datasets are sequences in the blood of 25 mg cohort subjects. The level of peptide number 1 is sufficient to inhibit IL-23R signaling in the blood. This demonstrates the systemic pharmacodynamic activity of the peptide of Sequence ID No. 1, further supporting its efficacy.

[0415] In summary, these datasets were obtained by the inventors at doses of 25 mg or more, orally. We are observing robust systemic pharmacodynamic activity with the administered peptide of Sequence ID No. 1. I will prove it definitively.

[0416] First-in-Human study on a 25mg cohort compared to placebo. The phase study systemic pSTAT3 pharmacodynamic dataset is shown in Figure 15, which represents the 25 mg IL-23-induced p from multiple indicated time points on days 1 and 10 of the MAD cohort Percentage inhibition (mean ± SEM) of STAT3 data is shown. The peptide of SEQ ID NO: 1 was administered. The four subjects were in a 25mg cohort, but data for the 0-hour mark is unavailable. Due to the nature of the task, it was not possible to include one subject in the analysis. CD26Hi = Surface Antigen classification 26 high, mCD4 = memory surface antigen classification 4, mCD8 = memory surface antigen classification 8. NKT = Natural Killer T cell, pSTAT3 = Phosphorylation signaling and transcriptional activator Child 3.

[0417] In addition, U.S. patents, published U.S. patent applications, U.S. patent applications, and foreign patents referenced herein. All references, including foreign patent applications and non-patent publications, are consistent with this specification. These are incorporated herein by reference to the extent that they contradict each other. In the event of any conflict between this application and the provided references, this application shall take precedence.

[0418] The present invention described above is further described in some detail, for the purpose of clarity of understanding, as examples and illustrations. However, it is a person skilled in the art that certain changes and modifications may be made within the scope of the attached claims. This should be understood.

[0419] The present invention is not limited to the embodiments described above as exemplifies herein, and the rights are not limited to the exemplify embodiments. Please understand that this is reserved for all modifications included in the described manner and claims.

[0420] In addition, U.S. patents, published U.S. patent applications, U.S. patent applications, and foreign patents referenced herein. All references, including foreign patent applications and non-patent publications, are consistent with this specification. These are incorporated herein by reference to the extent that they contradict each other. In the event of any conflict between this application and the provided references, this application shall take precedence.

[0421] The present invention described above is further described in some detail, for the purpose of clarity of understanding, as examples and illustrations. However, it is a person skilled in the art that certain changes and modifications may be made within the scope of the attached claims. This should be understood.

[0422] The present invention is not limited to the embodiments described above as illustrated herein, and it should be understood that rights are reserved to all modifications included in the illustrated embodiments and claims. Various embodiments of the present invention are shown below. 1. A composition, The composition comprises approximately 0.1% to approximately 15% (w / w) of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, One or more pharmaceutically acceptable excipients, A composition containing the following: 2. The composition according to item 1, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof has the following chemical structure. [ka] 3. The composition according to 1 or 2 above, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is in acetate form. 4. The composition according to 3 above, wherein the acetate form of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is in an amorphous form. 5. The composition according to any one of 1 to 4 above, wherein the amount of the peptide of Sequence ID No. 1 or its pharmaceutically acceptable salt or solvate form is about 1 mg to about 1000 mg. 6. The composition according to any one of 1 to 5 above, wherein the amount of the peptide of Sequence ID No. 1 or its pharmaceutically acceptable salt or solvate form is about 10 mg to about 300 mg. 7. The composition according to any one of 1 to 6 above, wherein the amount of the peptide of Sequence ID No. 1 or its pharmaceutically acceptable salt or solvate form is about 25 mg to about 150 mg. 8. The composition according to any one of 1 to 7 above, wherein the amount of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is about 25 mg to about 100 mg. 9. The composition according to any one of 1 to 7 above, wherein the amount of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is about 25 mg. 10. The composition according to any one of 1 to 7 above, wherein the amount of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is about 100 mg. 11. The composition according to any one of 1 to 7 above, wherein the amount of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is about 150 mg. 12. The composition according to any one of 1 to 11 above, wherein the composition further comprises microcrystalline cellulose. 13. The composition according to 12, wherein the microcrystalline cellulose is present in an amount of about 1% to about 25% (w / w) of the composition. 14. The composition according to any one of 1 to 13 above, wherein the composition further comprises silicified microcrystalline cellulose. 15. The composition according to 14, wherein the silicified microcrystalline cellulose is present in an amount of about 25% to about 60% (w / w) of the composition. 16. The composition according to any one of 1 to 15 above, wherein the composition further comprises one or more of alphacellulose, betacellulose, gammacellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, calcium diphosphate, calcium triphosphate, or calcium carbonate. 17. The composition according to any one of 1 to 16 above, wherein the composition further comprises sorbitol. 18. The composition according to 17, wherein the sorbitol is present in an amount of about 5% to about 15% (w / w) of the composition. 19. The composition according to any one of 1 to 18 above, wherein the composition further comprises an absorption enhancer. 20. A composition, The composition comprises approximately 0.1% to approximately 15% (w / w) of the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, Approximately 10% to 60% (w / w) of absorption enhancers, One or more pharmaceutically acceptable excipients, A composition containing the following: 21. The composition according to 19 or 20 above, wherein the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium-chain fatty acid triglycerides of capric acid and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC). 22. The composition according to 21, wherein the absorption enhancer is sodium caprate. 23. The composition according to 21, wherein the absorption enhancer is sodium salcaprozate. 24. The composition according to 21, wherein the absorption enhancer is a polyethylene glycol (PEG)-modified medium-chain fatty acid triglyceride of capric acid and caprylic acid. 25. Minister of the Interior, Approximately 0.1% to approximately 15% (w / w) of the aforementioned composition, the peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate thereof, Sodium caprate in an amount of approximately 20% to approximately 45% (w / w) of the above composition, The interior, including, An outer phase disposed on top of the inner phase, The outer phase contains microcrystalline cellulose, A composition according to any one of items 19 to 22 above, including the above. 26. The composition according to 25, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 1% to about 5% (w / w). 27. The composition according to 25 or 26, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 1.8% (w / w). 28. The composition according to any one of 25 to 27 above, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 10 mg to about 50 mg. 29. The composition according to any one of the above 25 to 28, wherein the sodium caprate is present in an amount of about 30% to about 40% (w / w). 30. The composition according to any one of the above 25 to 29, wherein the sodium caprate is present in an amount of about 35.7% (w / w). 31. The composition according to any one of 25 to 30 above, wherein the sodium caprate has a purity of at least 98%. 32. The composition according to any one of 25 to 31 above, wherein the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof, and the sodium caprate form a granular mixture. 33. The composition according to any one of 25 to 32 above, wherein the composition further comprises a disintegrant. 34. The composition according to 33, wherein the disintegrant is present in an amount of about 1% to about 10% (w / w) of the composition. 35. The composition according to any one of 25 to 34 above, wherein the composition further comprises hydrophilic silica. 36. The composition according to 35, wherein the hydrophilic silica is present in an amount of about 0.1% to about 1.5% (w / w) of the composition. 37. The aforementioned internal phase, A disintegrant in an amount of approximately 1% to approximately 10% (w / w) of the aforementioned composition, Approximately 1% to approximately 10% (w / w) of the above composition is microcrystalline cellulose. The aforementioned composition contains approximately 0.1% to approximately 1.5% (w / w) of hydrophilic silica, or Sorbitol in an amount of approximately 5% to approximately 15% (w / w) of the above composition A composition according to any one of the above 25 to 36, further comprising at least one of the above. 38. The composition according to any one of 25 to 37 above, wherein the microcrystalline cellulose of the outer phase includes silicified microcrystalline cellulose (SMCC). 39. The composition according to 38, wherein the microcrystalline cellulose of the outer phase is silicified microcrystalline cellulose (SMCC). 40. The composition according to 38 or 39, wherein the silicified microcrystalline cellulose is SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. 41. The composition according to any one of the above 38 to 40, wherein the silicified microcrystalline cellulose is present in an amount of about 25% to about 45% (w / w) of the composition. 42. The aforementioned Foreign Minister, A lubricant in an amount of approximately 0.1% to approximately 0.5% (w / w) of the aforementioned composition, A disintegrant in an amount of about 1% to about 10% (w / w) of the aforementioned composition, or Hydrophilic silica in an amount of approximately 0.1% to approximately 1.5% (w / w) of the above composition A composition according to any one of items 25 to 41 above, further comprising at least one of the above. 43. The composition according to any one of items 1 to 42 above, wherein the composition is a tablet or capsule composition. 44. The composition according to any one of items 1 to 43 above, wherein the composition is a tablet composition. 45. The composition according to 43 or 44, wherein the tablet composition contains a unit dose size of approximately 500 mg to approximately 2000 mg. 46. ​​The composition according to 44 or 45, wherein the tablet composition contains a unit dose size of approximately 1400 mg. 47. The aforementioned internal phase, The acetate form of the peptide of Sequence ID No. 1 in an amount of approximately 1.8% (w / w), and Approximately 35.7% (w / w) of sodium caprate Includes, The aforementioned foreign minister, Approximately 36.6% (w / w) of silicified microcrystalline cellulose HD90 including, The composition described in item 25 above. 48. The aforementioned internal phase is A granular mixture of approximately 1.8% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of a disintegrant, and Approximately 0.5% (w / w) of hydrophilic silica Includes, The aforementioned foreign minister, Approximately 36.6% (w / w) of silicified microcrystalline cellulose, Approximately 5.0% (w / w) of disintegrant, Approximately 0.5% (w / w) of hydrophilic silica, and Lubricant in an amount of approximately 0.25% (w / w) including, The composition described in item 47 above. 49. The aforementioned internal phase, A granular mixture of approximately 1.8% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of croscarmellose sodium, and Approximately 0.5% (w / w) of colloidal anhydrous silica Includes, The aforementioned foreign minister, Approximately 36.6% (w / w) of silicified microcrystalline cellulose, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of colloidal anhydrous silica, and Approximately 0.25% (w / w) of magnesium stearate including, The composition described in item 48 above. 50. The aforementioned internal phase, A granular mixture of approximately 1.8% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of Avicel PH101, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of croscarmellose sodium, and Approximately 0.5% (w / w) of Aerosil 200 Includes, The aforementioned foreign minister, Approximately 36.6% (w / w) of SMCC HD90, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of Aerosil 200, and Approximately 0.25% (w / w) of magnesium stearate including, The composition described in item 48 above. 51. The aforementioned internal phase, The acetate form of the peptide of Sequence ID No. 1 in an amount of approximately 7.1% (w / w), and Approximately 35.7% (w / w) of sodium caprate Includes, The aforementioned foreign minister, Approximately 30.75% (w / w) of silicified microcrystalline cellulose HD90 including, The composition described in item 25 above. 52. The aforementioned internal phase, A granular mixture of approximately 7.1% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of disintegrant, Approximately 0.5% (w / w) of hydrophilic silica, and Lubricant in an amount of approximately 0.25% (w / w) Includes, The aforementioned foreign minister, Approximately 30.75% (w / w) of silicified microcrystalline cellulose, Approximately 5.0% (w / w) of disintegrant, Approximately 0.5% (w / w) of hydrophilic silica, and Lubricant in an amount of approximately 0.5% (w / w) including, The composition described in item 25 above. 53. The aforementioned internal phase, A granular mixture of approximately 7.1% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of Avicel PH101, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of Aerosil 200, and Approximately 0.25% (w / w) of magnesium stearate Includes, The aforementioned foreign minister, Approximately 30.75% (w / w) of SMCC HD90, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of Aerosil, and Approximately 0.5% (w / w) of magnesium stearate including, The composition described in item 52 above. 54. The aforementioned internal phase is A granular mixture of approximately 7.1% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of colloidal anhydrous silica, and Approximately 0.25% (w / w) of magnesium stearate Includes, The aforementioned foreign minister, Approximately 31.0% (w / w) of silicified microcrystalline cellulose, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of colloidal anhydrous silica, and Approximately 0.25% (w / w) of magnesium stearate including, The composition described in item 25 above. 55. The aforementioned internal phase, A granular mixture of approximately 10.7% (w / w) of the acetate form of the peptide of Sequence ID No. 1 and approximately 35.7% (w / w) of sodium caprate. Approximately 3.9% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 5.0% (w / w) of croscarmellose sodium, and Approximately 0.5% (w / w) of colloidal anhydrous silica Includes, The aforementioned foreign minister, Approximately 27.7% (w / w) of silicified microcrystalline cellulose, Approximately 5.0% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of colloidal anhydrous silica, and Approximately 0.25% (w / w) of magnesium stearate including, The composition described in item 25 above. 56. The composition is The acetate form of the peptide of Sequence ID No. 1 in an amount of approximately 16.3% (w / w), Approximately 50.0% (w / w) of sodium caprate, The composition described in item 1 above, including the above. 57. Approximately 6.0% (w / w) of poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), Approximately 15.2% (w / w) of mannitol, Approximately 10.0% (w / w) of disintegrant, Approximately 1.0% (w / w) of hydrophilic silica, Approximately 1.5% (w / w) of lubricant, The composition according to 56 above, further comprising: 58. Approximately 6.0% (w / w) of Kolliphor P188, Approximately 15.2% (w / w) of mannitol, Approximately 10.0% (w / w) of croscarmellose sodium, Approximately 1.0% (w / w) of Aerosil 200, Approximately 1.5% (w / w) of magnesium stearate, The composition according to 57 above, further comprising: 59. The aforementioned internal phase, The acetate form of the peptide of Sequence ID No. 1 in an amount of approximately 1.8% (w / w), and Approximately 21.3% (w / w) of microcrystalline cellulose, Approximately 10.7% (w / w) of sorbitol, Approximately 2.5% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of hydrophilic silica, and Approximately 0.25% (w / w) of magnesium stearate Includes, The aforementioned foreign minister, Approximately 59.6% (w / w) of silicified microcrystalline cellulose HD90, Approximately 2.5% (w / w) of croscarmellose sodium, Approximately 0.5% (w / w) of hydrophilic silica, and Approximately 0.25% (w / w) of magnesium stearate including, The composition described in item 1 above. 60. The composition according to any one of 1 to 59 above, further comprising a subcoating of PVA-PEG graft copolymer disposed on the composition. 61. The composition according to 60, wherein the sub-coating is present in an amount of about 1% to about 10% (w / w). 62. The composition according to 60 or 61, further comprising an enteric coating disposed on the sub-coating. 63. The composition according to 62, wherein the enteric coating is present in an amount of about 1% to about 15% (w / w). 64. The composition according to any one of items 1 to 63 above, wherein the composition has a bioavailability of at least about 1 to about 10% (w / w). 65. The composition according to any one of items 1 to 63 above, wherein the composition has a bioavailability in the range of about 10% to about 50% (w / w). 66. A composition, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, A 50 mM pH 7.4 phosphate buffer solution and A composition containing the following: 67. It is a tablet, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, Sodium caprate and, A process of granulating a mixture, including To the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and The process of adding hydrophilic silica to form the internal phase, A process of compressing an outer phase onto an inner phase, wherein the outer phase includes silicified microcrystalline cellulose. A process of applying a sub-coating onto the outer phase, A process of forming a tablet by applying an enteric coating on the sub-coating, A tablet manufactured by [a specific method / company]. 68. A method, The peptide of SEQ ID NO: 1 or its pharmaceutically acceptable salt or solvate form, Sodium caprate and, Granulating a mixture containing, To the granulated mixture, Microcrystalline cellulose, Sorbitol, Disintegrant, and Adding hydrophilic silica to form the internal phase, Compressing an outer phase onto the inner phase, wherein the outer phase contains silicified microcrystalline cellulose, Applying a sub-coating on the outer phase, The enteric coating is applied on top of the sub-coating to form a tablet, Methods that include... 69. A method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of any of the compositions described in 1 to 66 above or the tablets described in 67 above. 70. The method according to 69 above, wherein the inflammatory disease is inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, psoriasis, or psoriatic arthritis. 71. A method for treating inflammatory bowel disease (IBD) in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of any of the compositions described in 1 to 66 above or the tablets described in 67 above. 72. The method according to 71 above, wherein the IBD is Crohn's disease or ulcerative colitis. 73. Use of any of the compositions described in items 1 to 66 above or the tablets described in item 67 above in the manufacture of a pharmaceutical product for the treatment of inflammatory bowel disease (IBD). 74. A method for treating psoriasis or psoriatic arthritis in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of any of the compositions described in 1 to 66 above or the tablets described in 67 above. 75. Use of any of the compositions described in 1 to 66 above or the tablets described in 67 above in the manufacture of a medicament for the treatment of psoriasis or psoriatic arthritis. 76. A method for IL-23 receptor inhibition for the treatment of an inflammatory disease or disorder, comprising administering a systemically active peptide Ac-[Pen] to a patient in need thereof. * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method that involves delivering the pharmaceutically acceptable salt or solvate form thereof. 77. A method for inhibiting IL-23 receptors for the treatment of inflammatory diseases or disorders, For those who need this, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, with or without an absorption enhancer. [c] at least one pharmaceutically acceptable excipient, A method that is carried out by delivering a pharmaceutical composition containing [a certain substance]. 78. A method for IL-23 receptor inhibition for treating an inflammatory disease or disorder as described in 76 or 77, wherein the systemically active peptide or a pharmaceutically acceptable salt thereof or pharmaceutical composition is administered orally. 79. A method for IL-23 receptor inhibition for treating an inflammatory disease or disorder as described in 76 or 77, wherein the systemically active peptide compound or a pharmaceutically acceptable salt thereof or a corresponding pharmaceutical composition thereof is delivered directly to the blood, blood circulation, tissues, skin, or joints, or via the blood, blood circulation, tissues, skin, or joints, for the treatment of an inflammatory disease or disorder. 80. For the treatment of inflammatory diseases or disorders, ● IL-23 receptor, ● IL-23 signaling via the IL-23 receptor, or ● IL-23 route A method for systemically inhibiting or pharmacologically blocking, For patients who need this, a therapeutically effective dose of the systemically active peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising orally administering a pharmaceutically acceptable salt or solvate form thereof. 81. For the treatment of inflammatory diseases or disorders, ● IL-23 receptor, ● IL-23 signaling via the IL-23 receptor, or ● IL-23 route A method for systemically inhibiting or pharmacologically blocking, For patients who need this, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, with or without an absorption enhancer. [c] at least one pharmaceutically acceptable excipient, A method comprising orally administering a pharmaceutical composition containing [a specific compound]. 82. The method for systemically inhibiting or pharmacologically blocking the inflammatory disease or disorder according to 80 or 81 above, wherein the inflammatory disease or disorder is psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. 83. The method for systemically inhibiting or pharmacologically blocking the inflammatory disease or disorder described in 82 above, characterized in a moderate to severe degree. 84. A method for systemically inhibiting or pharmacologically blocking a drug according to 80 or 81, comprising administering the therapeutically effective amount of the systemically active peptide in a dose range of approximately 1 mg to approximately 1000 mg. 85. A method for systemic inhibition or pharmacological blockade according to 84 above, comprising administering the systemically active peptide in an amount in the dose range of approximately 25 mg to approximately 100 mg. 86. A method for systemically inhibiting or pharmacologically blocking a substance according to any one of 83 to 85, comprising administering, if necessary, a specific dose of the systemically active peptide of 10 mg, 25 mg, or 50 mg once or twice daily. A method for systemic inhibition or pharmacological blockade according to any one of the above 83 to 86, comprising administering 87.10 mg once daily. A method for systemic inhibition or pharmacological blockade according to any one of the above 83 to 86, comprising administering 88.10 mg twice daily. A method for systemic inhibition or pharmacological blockade according to any one of the above 83 to 86, comprising administering 89.25 mg once daily. A method for systemic inhibition or pharmacological blockade according to any one of items 83 to 86 above, comprising administering 90.25 mg twice daily. A method for systemic inhibition or pharmacological blockade according to any one of the above 83 to 86, comprising administering 91.50 mg once daily. A method for systemic inhibition or pharmacological blockade according to any one of items 83 to 86 above, comprising administering 92.50 mg twice daily. A method for systemically inhibiting or pharmacologically blocking a substance according to any one of items 80 to 92 above, wherein more than 50% inhibition over a 24-hour period is observed after administration of 93.50 mg of the systemically active peptide once or twice daily. 94. Methods for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of inflammatory diseases or disorders, Oral dose therapeutically effective amount of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] The pharmaceutically acceptable salt or solvate form A method including administering [a substance]. 95. Methods for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of inflammatory diseases or disorders, For patients who need this, [a] A therapeutically effective dose of systemically active peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] Its pharmaceutically acceptable salt or solvate form, [b]Optionally, with or without an absorption enhancer. [c] at least one pharmaceutically acceptable excipient, A method comprising administering an orally administered therapeutically effective amount of a pharmaceutical composition containing [a specific compound]. 96. A method for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of an inflammatory disease or disorder as described in 94 or 95 above, wherein the inhibition or blockade of IL-23 receptors (IL23R) occurs in tissues including and beyond the gastrointestinal tract. 97. Methods for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of an inflammatory disease or disorder as described in 94 or 95 above, wherein the inflammatory disease or disorder is selected from psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. 98. Methods for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of an inflammatory disease or disorder as described in 97 above, wherein the inflammatory disease or disorder is of moderate to severe degree. 99. A method for inhibiting or blocking IL-23 receptors in blood, blood circulation, tissue, skin, or joints for the treatment of an inflammatory disease or disorder as described in any of 94 to 98 above, wherein the systemic pharmacodynamic activity in the blood is directly proportional to systemic exposure in a human subject. 100. A method for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissue, skin, or joints for the treatment of any of the inflammatory diseases or disorders described in any of 94-98 above, wherein the level of targeted blockade is predicted by the IC50 value. 101. A sufficient exposure level to the systemically active peptide is observed for at least 24 hours. 50 A method for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissue, skin, or joints for the treatment of any of the inflammatory diseases or disorders described in any of the above paragraphs 94 to 98. 102. The target blockade level is in the picomolar range of IC 50 A method for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissues, skin, or joints for the treatment of any of the inflammatory diseases or disorders described in any of the above 94 to 98, as determined by a value. 103. A method for inhibiting or blocking IL-23 receptors in the blood, blood circulation, tissue, skin, or joints for the treatment of any of the inflammatory diseases or disorders described in any of 94 to 98 above, wherein systemic exposure is required for inhibitory activity in the blood. 104. A method for inhibiting IL-23 receptors in a tissue selected from blood, skin, cartilage, or synovial membrane, wherein the inhibitory inhibitor is administered to a patient in need of such inhibition by an oral dose of a therapeutically effective amount of peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate form thereof. 105. The method according to 104 above, wherein the tissue is blood. 106. The method according to 104 above, wherein the tissue is skin. 107. The method according to 104 above, wherein the tissue is cartilage. 108. The method according to 104 above, wherein the tissue is synovial membrane. 109. A method for inhibiting IL-23 receptors in gastrointestinal tissue, comprising administering an oral dose of a therapeutically effective amount of peptide Ac-[Pen] to a patient in need of inhibition. * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate form thereof. 110. The method according to 109, wherein the tissue is selected from the group consisting of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. 111. The method according to 109 above, wherein the tissue is a mouth. 112. The method according to 109 above, wherein the tissue is the esophagus. 113. The method according to 109 above, wherein the tissue is the stomach. 114. The method according to 109 above, wherein the tissue is the small intestine. 115. The method according to 109 above, wherein the tissue is the large intestine. 116. The method according to 109 above, wherein the tissue is the duodenum. 117. The method according to 109 above, wherein the tissue is the anus. 118. A method for inhibiting the production of IL-17A in a tissue selected from blood, skin, cartilage, or synovial membrane, wherein the inhibition is administered to a patient in need of such inhibition by an oral dose of a therapeutically effective amount of the peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 119. The method according to 118 above, wherein the tissue is blood. 120. The method according to 118 above, wherein the tissue is skin. 121. The method according to 118 above, wherein the tissue is cartilage. 122. The method according to 118, wherein the tissue is synovial membrane. 123. A method for inhibiting IL-17A production in gastrointestinal tissue, comprising administering an oral dose of a therapeutically effective amount of peptide Ac-[Pen] to a patient requiring such inhibition. * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 124. The method according to 123, wherein the tissue is selected from the group consisting of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. 125. The method according to 123 above, wherein the tissue is a mouth. 126. The method according to 123 above, wherein the tissue is the esophagus. 127. The method according to 123 above, wherein the tissue is the stomach. 128. The method according to 123 above, wherein the tissue is the small intestine. 129. The method according to 123 above, wherein the tissue is the large intestine. 130. The method according to 123 above, wherein the tissue is the duodenum. 131. The method according to 123 above, wherein the tissue is the anus. 132. A method for inhibiting the production of IL-17F in a tissue selected from blood, skin, cartilage, or synovial membrane, wherein the inhibition is administered to a patient in need of such inhibition by an oral dose of a therapeutically effective amount of the peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 133. The method according to 132 above, wherein the tissue is blood. 134. The method according to 132 above, wherein the tissue is skin. 135. The method according to 132 above, wherein the tissue is cartilage. 136. The method according to claim 132, wherein the tissue is synovial membrane. 137. A method for inhibiting IL-17F production in gastrointestinal tissue, comprising administering an oral dose of a therapeutically effective amount of the peptide Ac-[Pen] to a patient requiring such inhibition. * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 138. The method according to claim 137, wherein the tissue is selected from the group consisting of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. 139. The method according to claim 137, wherein the tissue is a mouth. 140. The method according to claim 137, wherein the tissue is the esophagus. 141. The method according to claim 137, wherein the tissue is the stomach. 142. The method according to claim 137, wherein the tissue is the small intestine. 143. The method according to claim 137, wherein the tissue is the large intestine. 144. The method according to claim 137, wherein the tissue is the duodenum. 145. The method according to claim 137, wherein the tissue is the anus. 146. A method for inhibiting the production of IL-22 in a tissue selected from blood, skin, cartilage, or synovial membrane, wherein the inhibition is administered to a patient in need of such inhibition by an oral dose of a therapeutically effective amount of the peptide Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 147. The method according to claim 146, wherein the tissue is blood. 148. The method according to claim 146, wherein the tissue is skin. 149. The method according to claim 146, wherein the tissue is cartilage. 150. The method according to claim 146, wherein the tissue is synovial membrane. 151. A method for inhibiting IL-22 production in gastrointestinal tissue, comprising administering an oral dose of a therapeutically effective amount of peptide Ac-[Pen] to a patient requiring such inhibition. * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( * Pen-Pen morphology (disulfide bond) (SEQ ID NO: 1) [ka] A method comprising administering a pharmaceutically acceptable salt or solvate thereof. 152. The method according to claim 151, wherein the tissue is selected from the group consisting of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. 153. The method according to claim 151, wherein the tissue is a mouth. 154. The method according to claim 151, wherein the tissue is the esophagus. 155. The method according to claim 151, wherein the tissue is the stomach. 156. The method according to claim 151, wherein the tissue is the small intestine. 157. The method according to claim 151, wherein the tissue is the large intestine. 158. The method according to claim 151, wherein the tissue is the duodenum. 159. The method according to claim 151, wherein the tissue is the anus. 160. The method according to any one of claims 104-108, 118-122, 132-136, or 146-150, wherein the oral dose is 10 mg to 25 mg. 161. The method according to any one of claims 109 to 117, 123 to 131, 137 to 145, or 151 to 159, wherein the oral dose is 25 mg to 50 mg. 162. The method according to claim 160, wherein the oral dose is 10 mg. 163. The method according to claim 160, wherein the oral dose is 25 mg. 164. The method according to claim 161, wherein the oral dose is 25 mg. 165. The method according to claim 161, wherein the oral dose is 50 mg.

Claims

1. A pharmaceutical composition, Approximately 1 mg to approximately 1000 mg of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof, One or more pharmaceutically acceptable excipients, A pharmaceutical composition containing the above.

2. The peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is A pharmaceutical composition according to claim 1, having the following chemical structure: 【Chemistry 1】 A pharmaceutical composition in which the peptide of Sequence ID No. 1 or its pharmaceutically acceptable salt or solvate form is in the form of a pharmaceutically acceptable salt.

3. The pharmaceutical composition according to claim 1, wherein the amount of the peptide of Sequence ID No. 1 or a pharmaceutically acceptable salt or solvate thereof is about 10 mg to about 300 mg.

4. The pharmaceutical composition according to claim 1, wherein the composition comprises a filler, a binder, and a disintegrant.

5. The pharmaceutical composition according to claim 4, wherein the filler is microcrystalline cellulose.

6. The pharmaceutical composition according to claim 5, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

7. The pharmaceutical composition according to claim 1, wherein the composition further comprises one or more of alphacellulose, betacellulose, gammacellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, calcium diphosphate, calcium triphosphate, or calcium carbonate.

8. The pharmaceutical composition according to claim 1, wherein the composition further comprises an absorption enhancer.

9. The pharmaceutical composition according to claim 4, wherein the disintegrant is selected from one or more of the following: agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums, and low-substituted hydroxypropyl cellulose.

10. The pharmaceutical composition according to claim 7, wherein the composition further comprises a lubricant.

11. The pharmaceutical composition according to claim 1 for treating an inflammatory disease in a subject.

12. The inflammatory disease is inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, psoriasis, or The pharmaceutical composition according to claim 11, which is for psoriatic arthritis.

13. The pharmaceutical composition according to claim 12, wherein the inflammatory disease is inflammatory bowel disease (IBD).

14. The pharmaceutical composition according to claim 12, wherein the inflammatory disease is Crohn's disease.

15. The pharmaceutical composition according to claim 12, wherein the inflammatory disease is ulcerative colitis.

16. The pharmaceutical composition according to claim 12, wherein the inflammatory disease is psoriasis.

17. The pharmaceutical composition according to claim 12, wherein the inflammatory disease is psoriatic arthritis.

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