Pharmaceutical composition containing polypeptide inhibitor and use of pharmaceutical composition

Abstract

The present invention relates to a pharmaceutical composition containing a polypeptide inhibitor and a use of the pharmaceutical composition. The composition has good stability and drug dissolution rate; the product has controllable quality; and a preparation method has simple process, strong operability, good reproducibility, and is suitable for large-scale industrial production.

Description

Pharmaceutical compositions of polypeptide inhibitors and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical formulations, in particular to a pharmaceutical composition comprising a polypeptide inhibitor and medical uses thereof. BACKGROUND

[0002] The cytokine IL23 plays an important role in innate and adaptive immunity in humans. IL-23 induces lymphocytes to express inflammatory cytokines, most notably helper T cells (TH17), innate lymphoid cells (ILC) and gamma delta T cells. The IL-23 heterodimeric receptor is composed of two subunits, IL-23R and IL-12Rβ1, with IL-23R being unique to the IL-23 pathway. IL-12Rβ1 is shared with the IL-12 receptor. Similarly, the IL-23 cytokine is composed of two subunits, p19 and p40, with the p19 subunit being unique to IL-23 and p40 being shared with IL-12.

[0003] IL-23 provides the necessary conditions for Th17 cell generation and survival. At the same time, a wealth of preclinical models and clinical evidence indicates that Th17 cells play a central role in the pathology of many autoimmune diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Evidence from preclinical models and clinical practice indicates that blocking the transduction of IL23 signals is effective in the treatment of autoimmune diseases, but the nature of the shared ligand and receptor subunits of the IL-23 and IL-12 pathways means that more complex biology and data on tumourigenesis, susceptibility to infection and autoimmune disorders suggest that IL-23 blockade appears to have therapeutic advantages over IL-12 blockade in terms of efficacy and safety.

[0004] Limitations of antibody therapies include high production costs, poorer stability, more stringent requirements for conditions of transport, storage, use and production, and often the need for infusion or injection for treatment, which is a challenge for patient compliance. Antibody immunosuppressive therapies are generally systemic, and patients receiving treatment are at risk of relapse and other serious infections. Therefore, a high proportion of patients with latent tuberculosis or hepatitis B (HBV) are excluded from anti-TNF or anti-IL23 therapy in many developing countries. Systemic antibody therapies have a long half-life, so that the development of anti-drug antibodies (ADA) neutralizing the antibody drug and leading to a decrease in efficacy. The intermittent dosing of anti-TNF antibodies greatly increases the likelihood of the development of ADAs, which increases the risk of treatment for patients.

[0005] WO2024114762 provides polypeptide molecules that inhibit IL-23R, which are used to treat various inflammatory, autoimmune diseases and cancers, and have stronger inhibitory effect on inflammation compared with PN-235. However, the chemical modification of polypeptide drugs has a complex structure, in order to make it more suitable for administration, and to maintain stability during storage and subsequent use, and to achieve better therapeutic effect, the formulation research of chemically modified polypeptide drugs is particularly important.

[0006] The oral administration of peptide drugs greatly improves the compliance of patients and reduces the risk of inflammation at the injection site. However, the physicochemical properties of peptide drugs and the complex physiological environment of the gastrointestinal tract make oral polypeptides face the problems of enzymatic hydrolysis, mucosal barrier and low permeability before entering the blood, resulting in low bioavailability of polypeptides, which significantly increases the development cost and difficulty of polypeptide drugs. Absorption enhancers can neutralize the acidic environment of the stomach, locally regulate the pH value of the gastrointestinal tract to inhibit the activity of proteases, enhance the stability of peptide drugs, open the tight junctions between epithelial cells, change the fluidity of the cell membrane, and improve the permeability of peptide drugs, or destroy the mucus layer to improve the mucus penetration ability, and promote the oral absorption of peptide drugs from multiple angles.

[0007] The present application aims to develop a new pharmaceutical composition to solve the difficulties of existing oral polypeptide delivery, effectively improve the bioavailability of oral polypeptide drugs, and provide therapeutic benefits for patients with inflammatory, autoimmune diseases and cancers. SUMMARY

[0008] A series of polypeptide structures are disclosed in the patent application of Shanghai Hansoh Biomedicine Co., Ltd. (WO2024114762), and in subsequent research and development, a pharmaceutical composition containing a polypeptide molecule suitable for drug use is developed. All contents related to WO2024114762 are incorporated by reference into the present application.

[0009] The present application aims to develop a new pharmaceutical composition to solve the difficulties of existing oral polypeptide delivery, effectively improve the bioavailability of oral polypeptide drugs, and provide therapeutic benefits for patients with inflammatory, autoimmune diseases and cancers.

[0010] In a preferred embodiment of the present application, the polypeptide in the pharmaceutical composition is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

[0011] wherein:

[0012] X 1 selected from amino acids;

[0013] X 2 selected from amino acids;

[0014] R 1 and R 2each independently selected from H, alkyl, or an amino acid;

[0015] R a selected from H, alkyl, or an amino acid;

[0016] R aa selected from alkyl, or an amino acid;

[0017] X1is selected from an amino acid;

[0018] X'1is selected from an amino acid;

[0019] R 3 selected from hydroxyl, alkyl, -NR 6 R 7 or an amino acid;

[0020] R 6 selected from H, alkyl, -CH2C(O)NH2, or an amino acid;

[0021] R 7 selected from H, alkyl, -CH2C(O)NH2, or an amino acid;

[0022] R c selected from H, alkyl, or an amino acid;

[0023] R cc selected from alkyl, or an amino acid;

[0024] X5is selected from an amino acid;

[0025] X'5is selected from an amino acid;

[0026] X6is selected from an amino acid;

[0027] X'6is selected from an amino acid;

[0028] X7is selected from an amino acid;

[0029] X'7is selected from an amino acid;

[0030] R 4 selected from H, alkyl, -CH2C(O)NH2, or an amino acid;

[0031] R 5 selected from H, alkyl, -CH2C(O)NH2, or an amino acid;

[0032] R b selected from H, alkyl, or an amino acid, which alkyl can be further substituted by hydroxy or alkoxy;

[0033] R bb selected from alkyl, or an amino acid;

[0034] X2is selected from an amino acid;

[0035] X'2is selected from an amino acid;

[0036] X3is selected from an amino acid;

[0037] X'3is selected from an amino acid;

[0038] X4is selected from an amino acid;

[0039] X'4is selected from an amino acid;

[0040] n ~ n2are each independently selected from an integer from 0 to 12;

[0041] t ~ t9are each independently selected from an integer from 0 to 12;

[0042] m ~ m21are each independently selected from an integer from 0 to 24;

[0043] m22is selected from an integer from 0 to 24.

[0044] In preferred embodiments of the application, X 1 is selected from Thr,

[0045] In preferred embodiments of the application, X 2 is selected from

[0046] In preferred embodiments of the application, R 1 is selected from H, C 1-6 alkyl, or an amino acid;

[0047] R a is selected from H, C 1-6 alkyl, or an amino acid;

[0048] R aa selected from C 1-6 alkyl, or an amino acid;

[0049] X1is selected from an amino acid;

[0050] X'1is selected from an amino acid;

[0051] n is selected from an integer between 0 and 12;

[0052] t-t1are each independently selected from an integer between 0 and 12;

[0053] m-m3are each independently selected from an integer between 0 and 24.

[0054] In preferred embodiments of the application, R 2 is selected from H, C 1-6 alkyl, or an amino acid;

[0055] R a is selected from H, C 1-6 alkyl, or an amino acid;

[0056] R aa is selected from C 1-6 alkyl, or an amino acid;

[0057] X1is selected from an amino acid;

[0058] X'1is selected from an amino acid;

[0059] n is selected from an integer between 0 and 12;

[0060] t-t1are each independently selected from an integer between 0 and 12;

[0061] m-m3are each independently selected from an integer between 0 and 24.

[0062] In preferred embodiments of the application, R 3 is selected from hydroxyl, C 1-6 alkyl, -NR 6 R 7 or an amino acid;

[0063] R 6 is selected from H, C 1-6 alkyl, -CH2C(O)NH2, or an amino acid;

[0064] R 7 is selected from H, C1-6 alkyl, -CH2C(O)NH2, or an amino acid;

[0065] R c selected from H, C 1-6 alkyl, or an amino acid;

[0066] R cc selected from C 1-6 alkyl, or an amino acid;

[0067] X5is selected from an amino acid;

[0068] X'5is selected from an amino acid;

[0069] X6is selected from an amino acid;

[0070] X'6is selected from an amino acid;

[0071] X7is selected from an amino acid;

[0072] X'7is selected from an amino acid;

[0073] n2is selected from an integer between 0 and 12;

[0074] t6-t9are each independently selected from an integer between 0 and 12;

[0075] m13-m21are each independently selected from an integer between 0 and 24.

[0076] In preferred embodiments of the application, R 4 selected from H, C 1-6 alkyl, -CH2C(O)NH2, or an amino acid;

[0077] R b selected from H, C 1-6 alkyl, or an amino acid, which alkyl can be further substituted with a hydroxyl or alkoxy group;

[0078] R bb selected from C 1-6 alkyl, or an amino acid;

[0079] X2is selected from an amino acid;

[0080] X'2is selected from an amino acid;

[0081] X3is selected from an amino acid;

[0082] X'3 is selected from the group consisting of an amino acid;

[0083] X4 is selected from the group consisting of an amino acid;

[0084] X'4 is selected from the group consisting of an amino acid;

[0085] n1 is selected from the group consisting of an integer from 0 to 12;

[0086] t2 to t5 are each independently selected from the group consisting of an integer from 0 to 12;

[0087] m4 to m12 are each independently selected from the group consisting of an integer from 0 to 24;

[0088] m22 is selected from the group consisting of an integer from 0 to 24.

[0089] In a preferred embodiment of the application, R 5 is selected from the group consisting of H, C 1-6 alkyl, -CH2C(O)NH2, or an amino acid, further preferably, is selected from the group consisting of

[0090] R b is selected from the group consisting of H, C 1-6 alkyl, or an amino acid, which alkyl can be further substituted by hydroxy or alkoxy;

[0091] R bb is selected from the group consisting of C 1-6 alkyl, or an amino acid;

[0092] X2 is selected from the group consisting of an amino acid;

[0093] X'2 is selected from the group consisting of an amino acid;

[0094] X3 is selected from the group consisting of an amino acid;

[0095] X'3 is selected from the group consisting of an amino acid;

[0096] X4 is selected from the group consisting of an amino acid;

[0097] X'4 is selected from the group consisting of an amino acid;

[0098] n1 is selected from the group consisting of an integer from 0 to 12;

[0099] t2 to t5 are each independently selected from the group consisting of an integer from 0 to 12;

[0100] m4 to m12 are each independently selected from the group consisting of an integer from 0 to 24;

[0101] m22 is selected from the group consisting of an integer from 0 to 24.

[0102] In preferred embodiments of the application, selected from the group consisting of preferably selected from the group consisting of

[0103] In preferred embodiments of the application, selected from the group consisting of preferably selected from the group consisting of

[0104] In further embodiments of the application, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0105] n1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0106] n2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0107] t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0108] t1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0109] t2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0110] t3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0111] t4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0112] t5 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0113] t6 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0114] t7 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0115] t8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0116] t9 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0117] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0118] m1is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0119] m2is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0120] m3is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0121] m4is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0122] m5is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0123] m6is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0124] m7is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0125] m8is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0126] m9is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0127] m10 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0128] m11 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0129] m12 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0130] m13 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0131] m14 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0132] m15 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0133] m16 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0134] m17 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0135] m18 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0136] m19 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0137] m20 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

[0138] m21 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0139] m22 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0140] In preferred embodiments of the application, the amino acid is Gly, Ala, Val, Leu, He, Phe, Trp, Tyr, Asp, His, Asn, Glu, Lys, Gin, Met, Arg, Ser, Thr, Cys, Pro,

[0141] Preferably, the amino acid is Glu, Thr,

[0142] In preferred embodiments of the application, the polypeptide is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:

[0143] In preferred embodiments of the application, the absorption enhancer is one or more of a surfactant, a bile salt, a chelating agent, a pH modifier, or a protease inhibitor.

[0144] In preferred embodiments of the present application, the short chain fatty acid or salt thereof is selected from butyric acid and salts thereof, caproic acid and salts thereof, caprylic acid and salts thereof, capric acid and salts thereof, capuric acid and salts thereof, lauric acid and salts thereof, myristic acid and salts thereof, palmitic acid and salts thereof, stearic acid and salts thereof, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt (SNAC), N-(8-[2-hydroxy-5-chlorobenzoyl]-amino) caprylic acid (5-CNAC), N-(4-[2-hydroxy-4-chlorobenzoyl]-amino) butyric acid (4-CNAB), N-(10-[2-hydroxybenzoyl]-amino) capric acid (SNAD), N-(8-[2-hydroxy-4-methoxy] benzoyl) aminocaprylic acid (4-MOAC), sodium dodecyl sulfate, sodium dodecyl sulfonate, sodium diisooctyl sulfosuccinate (DSS) and derivatives thereof, dodecyl maltoside, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxyethylene glycerol ester, polysorbate or fatty acid glycerol triester, lecithin, choline, and carnitine.

[0145] In preferred embodiments of the present application, the bile acid salt is selected from sodium cholate, sodium deoxycholate, sodium taurocholate, sodium taurodeoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium chenodeoxycholate, or sodium taurodihydrofusidate.

[0146] In preferred embodiments of the present application, the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA) and salts thereof, diethylenetriaminepentaacetic acid (DTPA), ethyleneglycolbis(2-aminoethylether)tetraacetic acid (EGTA) and salts thereof, hydroxyethylethylenediaminetriacetic acid (HEDTA) and salts thereof, or dihydroxyethylglycine (DEG) and salts thereof.

[0147] In preferred embodiments of the present application, the pH adjusting agent is selected from anhydrous dibasic calcium phosphate, sodium hydroxide, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, sodium acetate, citric acid, tartaric acid, citric acid, fumaric acid, or acetic acid.

[0148] In preferred embodiments of the present application, the protease inhibitor is selected from gastrin A, camostat mesilate, bacitracin, soybean trypsin inhibitor, aprotinin, benzylsulfonyl fluoride, soybean trypsin-chymotrypsin inhibitor, colibactin, sunflower trypsin inhibitor, leupeptin, and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride.

[0149] In preferred embodiments of the present application, the absorption enhancer is selected from one or more of sodium (8-(2-hydroxybenzamido) caprylate (SNAC), sodium caprylate, sodium caprate, sodium taurocholate.

[0150] In preferred embodiments of the present application, the absorption enhancer is selected from any one of the following groups:

[0151] (1) Sodium (8-(2-hydroxybenzamido)octanoate (SNAC);

[0152] (2) Capric acid and its salts;

[0153] (3) Sodium (8-(2-hydroxybenzamido)octanoate (SNAC) and capric acid and its salts;

[0154] (4) Sodium taurocholate;

[0155] (5) Sodium octanoate and its salts;

[0156] (6) Acetylcarnitine;

[0157] In a preferred embodiment of the present application, the capric acid salt is sodium caprate.

[0158] In a preferred embodiment of the present application, the pharmaceutical composition further comprises one or more of a filler, a lubricant, a glidant, and a disintegrant.

[0159] In a preferred embodiment of the present application, the pharmaceutical composition further comprises a filler selected from one or more of microcrystalline cellulose, microcrystalline cellulose colloidal silicon dioxide co-treatment, mannitol, lactose, pregelatinized starch, dibasic calcium phosphate, or sorbitol; preferably microcrystalline cellulose, microcrystalline cellulose colloidal silicon dioxide co-treatment, or sorbitol.

[0160] In a preferred embodiment of the present application, the pharmaceutical composition further comprises a lubricant selected from one or more of magnesium stearate, glyceryl behenate, sodium stearyl fumarate, stearic acid, palmitic acid, calcium stearate, talc, or carnauba wax; preferably magnesium stearate.

[0161] In a preferred embodiment of the present application, the pharmaceutical composition further comprises a glidant selected from one or more of colloidal silicon dioxide or talc; preferably colloidal silicon dioxide.

[0162] In a preferred embodiment of the present application, the pharmaceutical composition further comprises a disintegrant selected from one or more of microcrystalline cellulose, alginic acid, alginic acid salts, polacrillin potassium, dibasic calcium phosphate, corn starch, pregelatinized starch, sodium carboxymethyl starch, sodium starch glycolate, cross-linked polyplasdone, cellulose powder, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or crosscarmellose sodium; preferably crosscarmellose sodium.

[0163] In preferred embodiments of the application, the absorption enhancer is present in an amount of 10% to 90%; preferably 40% to 80%; further preferably 50% to 80%; most preferably 50% to 55%, 65% to 70%, 60% to 65% or 70% to 75%.

[0164] In preferred embodiments of the application, the absorption enhancer is present in an amount of 10% to 90%; preferably 40% to 80%; further preferably 50% to 80%; most preferably 50% to 55%, 65% to 70%, 60% to 65% or 70% to 75%.

[0165] In preferred embodiments of the application, the absorption enhancer is SNAC, and the SNAC is present in an amount of 10% to 90%; preferably 20% to 80%; more preferably 50% to 70%; further preferably 60% to 65% or 70% to 75%.

[0166] In preferred embodiments of the application, the absorption enhancer is sodium caprate, and the sodium caprate is present in an amount of 10% to 90%; preferably 20% to 80%; more preferably 40% to 70%; further preferably 45% to 50%, 50% to 55% or 60% to 65%.

[0167] In preferred embodiments of the application, the absorption enhancer is SNAC and sodium caprate, and the SNAC is present in an amount of 10% to 90%; preferably 10% to 80%; further preferably 15% to 50%; more preferably 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40% or 45% to 50%; the sodium caprate is present in an amount of 10% to 90%; preferably 10% to 80%; further preferably 20% to 60%; more preferably 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 45% to 50%, 50% to 55% or 55% to 60%; most preferably the SNAC is present in an amount of 15% to 50% and the sodium caprate is present in an amount of 20% to 60%.

[0168] In preferred embodiments of the application, the absorption enhancer is SNAC and sodium caprate, and the SNAC and sodium caprate are present in a mass ratio of 1:20 to 20:1; preferably 1:5 to 5:1; further preferably 1:3 to 2:1; more preferably 1:1, 2:1, 1:2 or 1:3.

[0169] In preferred embodiments of the application, the filler is present in an amount of 10% to 50%; preferably 10% to 15%, 15% to 20% or 20% to 25%.

[0170] In preferred embodiments of the application, the lubricant is present in an amount of 0.25% to 5%; preferably 0.5% to 1%.

[0171] In preferred embodiments of the application, the glidant is present in an amount of 0% to 2%.

[0172] In preferred embodiments of the application, the disintegrant is present in an amount of 0% to 20%.

[0173] In preferred embodiments of the application, the polypeptide is present in an amount of 0.5% to 50%; preferably 2% to 45%, further preferably 5% to 10%, 20% to 25%, 30% to 35%, or 40% to 45%.

[0174] In preferred embodiments of the application, the components of the composition are present in the following amounts:

[0175] (1) the absorption enhancer is present in an amount of 50% to 55%, and the polypeptide is present in an amount of 30% to 35%;

[0176] (2) the absorption enhancer is present in an amount of 60% to 65%, and the polypeptide is present in an amount of 20% to 25%;

[0177] (3) the absorption enhancer is present in an amount of 70% to 75%, and the polypeptide is present in an amount of 5% to 10%.

[0178] In preferred embodiments of the application, the components of the composition are present in the following amounts:

[0179] (1) the absorption enhancer is present in an amount of 50% to 55%, and the polypeptide is present in an amount of 30% to 35%; the mass ratio of absorption enhancer to polypeptide is 1.5: 1;

[0180] (2) the absorption enhancer is present in an amount of 60% to 65%, and the polypeptide is present in an amount of 20% to 25%; the mass ratio of absorption enhancer to polypeptide is 3: 1;

[0181] (3) the absorption enhancer is present in an amount of 70% to 75%, and the polypeptide is present in an amount of 5% to 10%; the mass ratio of absorption enhancer to polypeptide is 12: 1.

[0182] In preferred embodiments of the application, the absorption enhancer is SNAC and sodium caprate, and the components of the composition are present in the following amounts:

[0183] (1) the SNAC is present in an amount of 25% to 30%, the sodium caprate is present in an amount of 25% to 30%, and the polypeptide is present in an amount of 30% to 35%; the mass ratio of absorption enhancer to polypeptide is 1.5: 1;

[0184] (2) the content of SNAC is 30%-35%, the content of sodium caprate is 30%-35%, and the content of polypeptide is 20%-25%; the mass ratio of the absorption enhancer to the polypeptide is 3:1;

[0185] (3) the content of SNAC is 15%-20%, the content of sodium caprate is 45%-50%, and the content of polypeptide is 20%-25%; the mass ratio of the absorption enhancer to the polypeptide is 3:1;

[0186] (4) the content of SNAC is 20%-25%, the content of sodium caprate is 40%-45%, and the content of polypeptide is 20%-25%; the mass ratio of the absorption enhancer to the polypeptide is 3:1;

[0187] (5) the content of SNAC is 40%-45%, the content of sodium caprate is 20%-25%, and the content of polypeptide is 20%-25%; the mass ratio of the absorption enhancer to the polypeptide is 3:1;

[0188] (6) the content of SNAC is 35%-40%, the content of sodium caprate is 35%-40%, and the content of polypeptide is 5%-10%; the mass ratio of the absorption enhancer to the polypeptide is 12:1.

[0189] In a preferred embodiment of the present application, the pharmaceutical composition comprises the following components:

[0190] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, SNAC, magnesium stearate and microcrystalline cellulose;

[0191] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, SNAC, magnesium stearate, sodium stearyl fumarate and microcrystalline cellulose;

[0192] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, SNAC, colloidal silicon dioxide, sodium stearyl fumarate and microcrystalline cellulose;

[0193] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, sodium caprate, microcrystalline cellulose and magnesium stearate;

[0194] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, sodium caprate, microcrystalline cellulose, sorbitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate;

[0195] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, SNAC, sodium caprate, microcrystalline cellulose and magnesium stearate; or

[0196] the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, sodium taurine cholate and medium-chain triglyceride.

[0197] In a preferred embodiment of the present application, the content of the absorption enhancer is:

[0198] (1) SNAC content is 25%-30%, sodium caprate content is 25%-30%, and polypeptide content is 30%-35%;

[0199] (2) SNAC content is 30%-35%, sodium caprate content is 30%-35%, and polypeptide content is 20%-25%;

[0200] (3) SNAC content is 15%-20%, sodium caprate content is 45%-50%, and polypeptide content is 20%-25%;

[0201] (4) SNAC content is 20%-25%, sodium caprate content is 40%-45%, and polypeptide content is 20%-25%;

[0202] (5) SNAC content is 40%-45%, sodium caprate content is 20%-25%, and polypeptide content is 20%-25%;

[0203] (6) SNAC content is 35%-40%, sodium caprate content is 35%-40%, and polypeptide content is 5%-10%.

[0204] In a preferred embodiment of the present application, the content of each component in the composition is as follows:

[0205] (1) SNAC content is 25%-30%, sodium caprate content is 25%-30%, polypeptide content is 30%-35%, microcrystalline cellulose content is 10%-15%, and magnesium stearate content is 0.5%-1%;

[0206] (2) SNAC content is 30%-35%, sodium caprate content is 30%-35%, polypeptide content is 20%-25%, microcrystalline cellulose content is 15%-20%, and magnesium stearate content is 0.5%-1%;

[0207] (3) SNAC content is 15%-20%, sodium caprate content is 45%-50%, polypeptide content is 20%-25%, microcrystalline cellulose content is 15%-20%, and magnesium stearate content is 0.5%-1%;

[0208] (4) SNAC content is 20%-25%, sodium caprate content is 40%-45%, polypeptide content is 20%-25%, microcrystalline cellulose content is 15%-20%, and magnesium stearate content is 0.5%-1%;

[0209] (5) SNAC content is 40%-45%, sodium caprate content is 20%-25%, polypeptide content is 20%-25%, microcrystalline cellulose content is 15%-20%, and magnesium stearate content is 0.5%-1%;

[0210] (6) SNAC content is 35%-40%, sodium caprate content is 35%-40%, polypeptide content is 5%-10%; microcrystalline cellulose content is 20%-25%; magnesium stearate content is 0.5%-1%.

[0211] In a preferred embodiment of the present application, the pharmaceutical composition is an oral preparation.

[0212] In a preferred embodiment of the present application, the pharmaceutical composition is a powder, granules, tablets, capsules or lyophilized preparation.

[0213] In a preferred embodiment of the present application, the pharmaceutical composition is a tablet.

[0214] In some embodiments, the pharmaceutical composition is an immediate release preparation.

[0215] In some embodiments, the pharmaceutical composition is a modified release preparation.

[0216] In some embodiments, the pharmaceutical composition is a coated tablet.

[0217] In some embodiments, the tablet further comprises an enteric coating.

[0218] Another object of the present application is to provide a method for preparing the above-mentioned pharmaceutical composition, and the preparation method uses granulation and compression or powder direct compression; the granulation method comprises wet granulation and dry granulation.

[0219] Another object of the present application is to provide a method for preparing the above-mentioned pharmaceutical composition, and the preparation method is specifically as follows:

[0220] (1) powder direct compression

[0221] In addition to the lubricant, the prescription amount of raw materials and excipients are mixed, and the lubricant is added and mixed uniformly before tabletting.

[0222] (2) granulation and compression

[0223] The prescription amount of internal additive materials is granulated and mixed with external additive materials, and then tabletted after mixing.

[0224] Optionally, the following steps are performed:

[0225] (3) isolation layer coating

[0226] The raw tablets are added to the coating pot, the coating spray gun height is adjusted according to the tablet bed thickness, and the tablet bed temperature is controlled for coating until the coating weight gain is 2.0%-4.0%.

[0227] (4) enteric coating

[0228] The bottom-coated tablets are added to the coating pan, the height of the coating spray gun is adjusted according to the thickness of the tablet bed, the temperature of the tablet bed is controlled for coating, and the coating is performed until the coating weight is increased to 10.0% to 12.0% based on the weight of the tablet core.

[0229] In certain embodiments of the application, the pharmaceutical composition can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration.

[0230] The present application further relates to the use of the pharmaceutical composition for the preparation of an IL-23R inhibitor medicament. The present application further relates to the use of the pharmaceutical composition for the preparation of a medicament for the treatment of inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douin syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes.

[0231] The present application further relates to the use of the pharmaceutical composition for the preparation of a method for the treatment of inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douin syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes.

[0232] The present application further relates to a method of treating, preventing and / or treating prophylactically inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douglas syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes, comprising administering to the patient a therapeutically effective dose of the pharmaceutical composition.

[0233] The present application further relates to a method of treating, preventing and / or treating prophylactically inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douglas syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes, comprising administering to the patient a therapeutically effective dose of the pharmaceutical composition.

[0234] In some embodiments, the present methods are directed to inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douin syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE), or diabetes;

[0235] Preferably, the inflammatory bowel disease, arthritis or psoriasis.

[0236] Detailed description of the invention

[0237] Unless otherwise defined herein, scientific and technical terms used in this patent application shall have the meanings that are commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the techniques described herein follow those set forth in the art of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry.

[0238] The term "polypeptide" refers broadly to a sequence of two or more amino acids joined together by peptide bonds. It is to be understood that this term does not connote a particular length of the amino acid polymer, nor is it intended to connote or distinguish between polypeptides produced using recombinant techniques, chemical or enzymatic synthesis, or naturally occurring polypeptides. The term polypeptide includes cyclic peptides.

[0239] The term "amino acid" refers to any and all amino acids and residues thereof, including naturally occurring amino acids (e.g., a-amino acids), non-natural amino acids, modified amino acids, synthetic amino acids, or rare amino acids, which include both D- and L-amino acids. Natural amino acids include the 23 amino acids found in nature, such as the building blocks that combine into peptide chains to form the vast array of proteins. These stereoisomers are predominantly L stereoisomers, but some D-amino acids are found in bacterial envelopes and some antibiotics. The 20 "standard" natural amino acids are alanine (Ala); arginine (Arg); asparagine (Asn); aspartic acid (Asp); cysteine (Cys); glutamine (Gin); glutamic acid (Glu); glycine (Gly); histidine (His); isoleucine (lie); leucine (Leu); lysine (Lys); methionine (Met); phenylalanine (Phe); proline (Pro); serine (Ser); threonine (Thr); tryptophan (Trp); tyrosine (Tyr); and valine (Val). "Nonstandard" natural amino acids are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (found in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the initiation codon AUG in bacteria, chloroplasts, and chloroplasts). "Non-natural" or "non-natural amino acids" are non-proteinogenic amino acids that are either naturally occurring or chemically synthesized (i.e., not naturally encoded or found in the genetic code). Over 140 non-natural amino acids are known and there can be thousands of combinations. Examples of "non-natural" amino acids include beta-amino acids (beta 3 and beta 2 ), homoamino acids, proline derivatives and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, cyclically substituted phenylalanine and tyrosine derivatives, linear nucleic amino acids, di-amino acids, D-di-amino acids, alpha-methyl amino acids, and N-methyl amino acids. Non-natural or non-natural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include groups or chemical moieties that do not naturally occur on amino acids. Preferably, the non-natural amino acids described herein include, but are not limited to,

[0240] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0241] Any hydrogen atom described herein can be replaced by its isotope deuterium. Any hydrogen atom in the compounds of the embodiments described herein can be replaced by deuterium.

[0242] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption, resulting in the active ingredient exerting a biological effect.

[0243] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present application which is safe and effective for use in a mammal, and possesses the desirable biological activity. DETAILED DESCRIPTION

[0244] The present application is further described in connection with the following examples, which are not intended to limit the scope of the present application. The compounds of the present disclosure were prepared according to the methods described in WO2024114762, and the polypeptide compound structure is as follows:

[0245] I. Preparation of pharmaceutical compositions

[0246] (1) Materials and methods

[0247] Materials: Compound 1, absorption enhancer: 8-(2-hydroxybenzamido) sodium octanoate (SNAC), sodium caprate, sodium octanoate, acetylcarnitine, one or a combination thereof, and common excipients.

[0248] (2) Tablet preparation method:

[0249] Method 1, direct compression of powder

[0250] Mix the raw materials and excipients in the prescription amount, add the lubricant, mix uniformly, and then compress the tablets.

[0251] Method 2, granulation and compression

[0252] Granulate the internal additive materials in the prescription amount, mix with the external additive materials, and then compress the tablets after mixing.

[0253] Optional isolation layer coating

[0254] Add the tablets to the coating pan, adjust the height of the coating spray gun according to the thickness of the tablet bed, control the temperature of the tablet bed, and coat until the coating weight increases to 2.0% to 4.0%.

[0255] Optional enteric coating

[0256] Add the bottom-coated tablets to the coating pan, adjust the height of the coating spray gun according to the thickness of the tablet bed, control the temperature of the tablet bed, and coat until the coating weight increases to 10.0% to 12.0% based on the weight of the tablet core.

[0257] According to the following table, take the corresponding dose of Compound 1, absorption enhancer (including 8-(2-hydroxybenzamido) sodium octanoate (SNAC), sodium caprate, sodium octanoate, acetylcarnitine, one or a combination thereof), and common excipients, mix them, and then compress the tablets according to the tablet compression methods of Method 1 or Method 2 after uniform mixing.

[0258] SNAC formulation examples I-1 to I-2 were used alone, as shown in Table 1 below.

[0259] Table 1

[0260] Sodium caprate formulation examples II-1 to II-3 were used alone, as shown in Table 2 below.

[0261] Table 2

[0262] SNAC and / or sodium caprate formulation examples III-A, III-B, III-1 to III-11 were used, as shown in Tables 3-4 below.

[0263] Table 3

[0264] Table 4

[0265] Sodium caprylate or acetyl carnitine formulation examples III-12, III-13 were used, as shown in Table 5 below.

[0266] Table 5

[0267] Compound 1, sodium taurocholate, and medium chain triglycerides (MCT) were weighed and ground together. Sodium taurocholate formulation example IV-1 was used, as shown in Table 6 below.

[0268] Table 6

[0269] II. Dissolution Test

[0270] The dissolution test was performed according to the second method paddle method of the Chinese Pharmacopoeia 0931. The 0.1 N HC1 medium was prepared using hydrochloric acid, and the pH 6.8 medium was prepared using potassium dihydrogen phosphate and sodium hydroxide. The dissolution experiment was performed at 37°C, and samples were taken at appropriate intervals for testing. Compound 1, SNAC, and sodium caprate were simultaneously detected using HPLC to determine the release amount, and the release amounts of Compound 1, SNAC, and sodium caprate were calculated as a percentage of the labeled content of the tablets. The API in the table is Compound 1.

[0271] Table 7 Dissolution results of formulations I-1, I-2, II-3 in 0.1 N HC1 medium

[0272] Table 8 Dissolution of formulations II-1 to II-3 in pH 6.8 medium

[0273] Table 9 Dissolution of SNAC, sodium caprate formulation tablets in pH 6.8 medium

[0274] The results show that the above pharmaceutical composition using SNAC and sodium caprate as absorption enhancers, the cumulative dissolution of Compound 1 in pH 6.8 buffer salt medium is all more than 80% at 20 min, and the cumulative dissolution is all more than 90% at 30 min, showing a rapid dissolution behavior.

[0275] III. Stability test

[0276] The stable pharmaceutical preparation has no significant change observed under the following conditions: storage at refrigeration temperature (2-8°C) for at least 3 months, at least 6 months, at least 1 year, and up to 2 years. In addition, the stable pharmaceutical preparation includes a preparation that exhibits desired characteristics after storage at 25°C for a period of time including 1 month, 3 months, 6 months, or at 40°C for 1 month. A typical acceptable standard of stability is that the degradation of the compound is generally no more than 10%, for example, no more than 5% as measured by HPLC. The pharmaceutical composition has completed the stability test under the conditions of refrigeration, room temperature and acceleration for 6 months, and the results are shown in Table 10.

[0277] Table 10

[0278] The results show that the pharmaceutical composition of the present application has excellent stability, and the degradation of the compound is less than 5% under the conditions of refrigeration (2-8°C), 25°C, 30°C, and 40°C for 6 months.

[0279] The results of the influence of Compound 1 on the finished product of the preparation are shown in Table 11.

[0280] Table 11

[0281] The results show that the pharmaceutical composition of the present application can significantly improve the stability of the active substance, and the increase in total impurities is reduced by 80%-95% under light conditions.

[0282] IV. Pharmacokinetics in beagle dogs

[0283] Beagle dogs were chosen as model animals to study the pharmacokinetics of different tablets after oral administration. Male beagle dogs with similar body weights were selected, 3 in each group. The animals were fasted overnight before the test, and fed 4 hours after administration. The dogs were subjected to gastric acid stimulation before the experiment. That is, 30 min before administration, atropine sulfate solution (10 μg / 0.1 mL / kg) was injected intravenously and pentagastrin solution (10 μg / 0.1 mL / kg) was injected intramuscularly, and a small amount of gastric juice was taken to measure the pH value before administration. If the pH is 1-2, continue to orally administer the preparation, if the pH>2, replace the dog or supplement the atropine sulfate solution (IV, 10 μg / 0.1 mL / kg) and the pentagastrin solution (IM, 10 μg / 0.1 mL / kg). 45 minutes after intravenous injection of atropine sulfate solution, a small amount of gastric juice was taken to measure the pH value, and the pentagastrin solution (10 μg / 0.1 mL / kg) was injected intramuscularly for the second time. 60 min after administration, a small amount of gastric juice was taken to measure the pH value, and the pentagastrin solution (10 μg / 0.1 mL / kg) was injected intramuscularly for the third time.

[0284] The examples were administered orally, and samples were taken at predetermined time points. After blood sample collection, the samples were placed on ice and immediately centrifuged to separate the plasma (2-8°C). The samples were analyzed by LC-MS / MS, and the pharmacokinetic parameters were calculated from the blood concentration data at different time points.

[0285] Table 12

[0286] Note: The last sampling time point is 168 hr after administration.

[0287] The results show that Examples I-1 and I-2 achieve good exposure in animals, and show a certain linearity in the 20-100 mg dose range.

[0288] Table 13

[0289] Note: The last sampling time point is 168 hr after administration.

[0290] The results show that the data in the table compared with I-1 can be known that the use of absorption enhancers compared to not adding absorption enhancers can significantly improve the PK.

[0291] Table 14

[0292] The results show that the combination of sodium caprate and SNAC as absorption enhancers has a synergistic effect compared with the use of sodium caprate or SNAC alone as absorption enhancers, which can significantly improve the exposure.

[0293] The above formulations use Compound 1 as the API, but one of skill in the art will recognize that pharmaceutical compositions of other compounds, such as Compounds 2-11, will have similar properties.

Claims

A pharmaceutical composition comprising an absorption enhancer and a polypeptide, characterized in that, The polypeptide is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: The pharmaceutical composition according to claim 1, characterized in that, The absorption enhancer is selected from one or more of sodium (8-(2-hydroxybenzamido)octanoate (SNAC), sodium octanoate, sodium decanoate, sodium taurocholate. The pharmaceutical composition according to any one of claims 1-2, characterized in that, The absorption enhancer is selected from any one of the following groups: (1) sodium (8-(2-hydroxybenzamido)octanoate (SNAC); (2) decanoic acid and its salts; (3) sodium (8-(2-hydroxybenzamido)octanoate (SNAC) and decanoic acid and its salts; (4) sodium taurocholate; Preferably, the decanoate salt is sodium decanoate. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that Further comprising a filler selected from one or more of microcrystalline cellulose, microcrystalline cellulose colloidal silicon dioxide co-processed, mannitol, lactose, pregelatinized starch, dibasic calcium phosphate, or sorbitol; preferably microcrystalline cellulose, microcrystalline cellulose colloidal silicon dioxide co-processed, or sorbitol. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that Further comprising a lubricant selected from one or more of magnesium stearate, glyceryl behenate, sodium stearyl fumarate, stearic acid, palmitic acid, calcium stearate, talc, or carnauba wax; preferably magnesium stearate. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that Further comprising a glidant selected from one or more of colloidal silicon dioxide or talc; preferably colloidal silicon dioxide. and / or, Further comprising a disintegrant selected from one or more of microcrystalline cellulose, alginic acid, alginic acid salts, polacrilin potassium, dibasic calcium phosphate, corn starch, pregelatinized starch, sodium carboxymethyl starch, sodium starch glycolate, crosscarmellose sodium, cellulose powder, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or crosscarmellose sodium; preferably crosscarmellose sodium. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The absorption enhancer is present in an amount of 10% to 90%; preferably 40% to 80%, further preferably 50% to 80%; most preferably 50% to 55%, 60% to 65%, 65% to 70%, or 70% to 75%. and / or, the polypeptide is present in an amount of 0.5% to 50%; preferably 2% to 45%; further preferably 5% to 10%, 10% to 15%, 20% to 25%, 30% to 35%, or 40% to 45%. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that The absorption enhancer and the polypeptide are present in a mass ratio of 0.5:1 to 275:1; preferably 1:1 to 30:1; further preferably 1:1 to 5:1 or 10:1 to 15:1; most preferably 1:1, 1.5:1, 3:1, 12:1, or 15:

1. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The absorption enhancer is SNAC and is present in an amount of 10% to 90%; preferably 20% to 80%; more preferably 50% to 70%; further preferably 60% to 65% or 70% to 75%. The absorption enhancer is sodium decanoate and is present in an amount of 10% to 90%; preferably 20% to 80%; more preferably 40% to 70%; further preferably 45% to 50%, 50% to 55%, 60% to 65%; The absorption enhancer is SNAC and sodium caprate, and the content of SNAC is 10% to 90%; preferably 10% to 80%; further preferably 15% to 50%; more preferably 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, or 45% to 50%; the content of sodium caprate is 10% to 90%; preferably 10% to 80%; further preferably 20% to 60%; more preferably 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 45% to 50%, or 50% to 55%; Most preferably, the content of SNAC is 15% to 50%, and the content of sodium caprate is 20% to 60%. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that The absorption enhancer is SNAC and sodium caprate, and the mass ratio of SNAC and sodium caprate is 1:20 to 20:1; preferably 1:5 to 5:1; further preferably 1:3 to 2:1; more preferably 1:1, 2:1, 1:2, or 1:

3. The pharmaceutical composition according to any one of claims 1-10, characterized in that, The content of the filler is 10% to 50%; preferably 10% to 15%, 15% to 20%, or 20% to 25%; And / or, the content of the lubricant is 0.25% to 5%; preferably 0.5% to 1%; And / or, the content of the glidant is 0% to 2%; And / or, the content of the disintegrant is 0% to 20%. The pharmaceutical composition according to any one of claims 1-11, characterized in that, The content of the following components in the composition is: (1) the content of the absorption enhancer is 50% to 55%, and the content of the polypeptide is 30% to 35%; (2) the content of the absorption enhancer is 60% to 65%, and the content of the polypeptide is 20% to 25%; (3) the content of the absorption enhancer is 70% to 75%, and the content of the polypeptide is 5% to 10%. The pharmaceutical composition according to any one of claims 1-12, characterized in that, The content of each component in the composition is: (1) the content of the absorption enhancer is 50% to 55%, and the content of the polypeptide is 30% to 35%; the mass ratio of the absorption enhancer to the polypeptide is 1.5:1; (2) the content of the absorption enhancer is 60% to 65%, and the content of the polypeptide is 20% to 25%; the mass ratio of the absorption enhancer to the polypeptide is 3:1; (3) the content of the absorption enhancer is 70% to 75%, and the content of the polypeptide is 5% to 10%; the mass ratio of the absorption enhancer to the polypeptide is 12:

1. The pharmaceutical composition according to any one of claims 1 to 13, characterized in that Comprise the following components: 1) polypeptide, SNAC, magnesium stearate, and microcrystalline cellulose; 2) polypeptide, SNAC, magnesium stearate, sodium stearyl fumarate, and microcrystalline cellulose; 3) polypeptide, SNAC, colloidal silicon dioxide, sodium stearyl fumarate, and microcrystalline cellulose; 4) polypeptide, sodium caprate, microcrystalline cellulose, and magnesium stearate; 5) polypeptide, sodium caprate, microcrystalline cellulose, sorbitol, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate; 6) polypeptide, SNAC, sodium caprate, microcrystalline cellulose, and magnesium stearate; or 7) polypeptide, sodium taurocholate, and medium-chain triglyceride. The pharmaceutical composition according to any one of claims 1-14, characterized in that, The content of the absorption enhancer is: (1) the content of SNAC is 25% to 30%, the content of sodium caprate is 25% to 30%, and the content of the polypeptide is 30% to 35%; (2) SNAC content is 30%-35%, sodium caprate content is 30%-35%, polypeptide content is 20%-25%; (3) SNAC content is 15%-20%, sodium caprate content is 45%-50%, polypeptide content is 20%-25%; (4) SNAC content is 20%-25%, sodium caprate content is 40%-45%, polypeptide content is 20%-25%; (5) SNAC content is 40%-45%, sodium caprate content is 20%-25%, polypeptide content is 20%-25%; (6) SNAC content is 35%-40%, sodium caprate content is 35%-40%, polypeptide content is 5%-10%. The pharmaceutical composition according to any one of claims 1-15, characterized in that, The content of each component in the composition is: (1) SNAC content is 25%-30%, sodium caprate content is 25%-30%, polypeptide content is 30%-35%; microcrystalline cellulose content is 10%-15%; magnesium stearate content is 0.5%-1%; (2) SNAC content is 30%-35%, sodium caprate content is 30%-35%, polypeptide content is 20%-25%; microcrystalline cellulose content is 15%-20%; magnesium stearate content is 0.5%-1%; (3) SNAC content is 15%-20%, sodium caprate content is 45%-50%, polypeptide content is 20%-25%; microcrystalline cellulose content is 15%-20%; magnesium stearate content is 0.5%-1%; (4) SNAC content is 20%-25%, sodium caprate content is 40%-45%, polypeptide content is 20%-25%; microcrystalline cellulose content is 15%-20%; magnesium stearate content is 0.5%-1%; (5) SNAC content is 40%-45%, sodium caprate content is 20%-25%, polypeptide content is 20%-25%; microcrystalline cellulose content is 15%-20%; magnesium stearate content is 0.5%-1%; (6) SNAC content is 35%-40%, sodium caprate content is 35%-40%, polypeptide content is 5%-10%; microcrystalline cellulose content is 20%-25%; magnesium stearate content is 0.5%-1%. The pharmaceutical composition according to any one of claims 1-16, characterized in that, The pharmaceutical composition is an oral preparation, preferably a powder, granules, tablets, capsules or lyophilized preparation; the pharmaceutical composition is a fast-release preparation or a modified-release preparation. A method of preparing a pharmaceutical composition according to any one of claims 1 to 17, characterized in that, The preparation method adopts tabletting or powder direct compression; The specific operation is as follows: (1) powder direct compression Mix the prescription amount of raw materials and auxiliary materials, add the lubricant, mix uniformly, and then tablet; (2) granulation tabletting Granulate the prescription amount of internal additive materials, mix with external additive materials, and then tablet after mixing; Optionally, the following steps are included: (3) isolation layer coating Add the base tablet to the coating pan, adjust the height of the coating spray gun according to the tablet bed thickness, control the tablet bed temperature for coating, and coat until the coating weight increases to 2.0%-4.0%; (4) enteric coating Add the base-coated tablet to the coating pan, adjust the height of the coating spray gun according to the tablet bed thickness, control the tablet bed temperature for coating, and coat until the coating weight increases to 10.0%-12.0% based on the weight of the tablet core. The pharmaceutical composition according to any one of claims 1-18 for use in the treatment of inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, celiac disease, enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schödi-Drach syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus or diabetes; preferably in the treatment of inflammatory bowel disease, rheumatoid arthritis or psoriasis. The pharmaceutical composition according to any one of claims 1-18 for use in the treatment of inflammatory, autoimmune diseases and cancer, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, celiac disease, enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schödi-Drach syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus or diabetes; preferably in the treatment of inflammatory bowel disease, rheumatoid arthritis or psoriasis.

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