Oral polypeptide composition and application thereof

Abstract

An oral polypeptide composition comprising a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant and its use for the treatment of disease.

Description

Oral polypeptide composition and its use Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and in particular relates to a polypeptide composition for oral administration and its use. Background Art

[0002] In the treatment of diseases, peptide drugs, with their high specificity and effectiveness, are becoming an ideal choice for treating numerous human ailments. With the advancement of biotechnology, the clinical application of peptide drugs, such as calcitonin, insulin, and thymosin, is becoming increasingly widespread. However, peptide drugs have low in vivo bioavailability and are generally only administered via injection. However, injections are prone to side effects such as infection and inflammation, and patients struggle to overcome needle phobia and poor compliance, which reduces their motivation to take medication on time.

[0003] Oral administration is the most widely used and most acceptable method of drug delivery, but the harsh environment of the gastrointestinal tract limits the oral absorption of peptide drugs. Therefore, there is an urgent need in the art to provide a peptide drug delivery system to achieve oral administration of peptide drugs.

[0004] Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide a polypeptide composition for oral administration and its use. The oral polypeptide composition provided by the present invention can achieve oral administration of polypeptide drugs.

[0006] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide and fish oil;

[0007] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide and a protease inhibitor;

[0008] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide and an absorption enhancer;

[0009] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0010] The polypeptide is 0.1-100 parts by weight;

[0011] The fish oil is 0.01-800 parts by weight;

[0012] The protease inhibitor is 0.1-210 parts by weight;

[0013] The absorption promoter is 0.1-320 parts by weight; and

[0014] The surfactant is 1-800 parts by weight;

[0015] Preferably,

[0016] The polypeptide is 5-50 parts by weight;

[0017] The fish oil is 30-400 parts by weight;

[0018] The protease inhibitor is 40-210 parts by weight;

[0019] The absorption promoter is 60-320 parts by weight; and

[0020] The surfactant is 50-550 parts by weight;

[0021] Preferably,

[0022] The polypeptide is 8-32 parts by weight;

[0023] The fish oil is 0.01-320 parts by weight;

[0024] The protease inhibitor is 70-200 parts by weight;

[0025] The absorption promoter is 120-320 parts by weight; and

[0026] The surfactant is 105-450 parts by weight;

[0027] Preferably,

[0028] The polypeptide is 8-32 parts by weight;

[0029] The fish oil is 50-320 parts by weight;

[0030] The protease inhibitor is 70-200 parts by weight;

[0031] The absorption promoter is 120-320 parts by weight; and

[0032] The surfactant is 105-450 parts by weight;

[0033] Preferably,

[0034] The polypeptide is 8-32 parts by weight;

[0035] The fish oil is 105-320 parts by weight;

[0036] The protease inhibitor is 70-200 parts by weight;

[0037] The absorption promoter is 120-320 parts by weight; and

[0038] The surfactant is 105-320 parts by weight;

[0039] Preferably,

[0040] The polypeptide is 8-32 parts by weight;

[0041] The fish oil is 245-320 parts by weight;

[0042] The protease inhibitor is 70-160 parts by weight;

[0043] The absorption promoter is 120-250 parts by weight; and

[0044] The surfactant is 105-320 parts by weight;

[0045] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0046] The polypeptide is 8-16 parts by weight;

[0047] The fish oil is 105-320 parts by weight;

[0048] The protease inhibitor is 160-200 parts by weight;

[0049] The absorption promoter is 120-320 parts by weight; and

[0050] The surfactant is 245-320 parts by weight;

[0051] Or for,

[0052] The polypeptide is 16-32 parts by weight;

[0053] The fish oil is 105-245 parts by weight;

[0054] The protease inhibitor is 70-200 parts by weight;

[0055] The absorption promoter is 250-320 parts by weight; and

[0056] The surfactant is 105-245 parts by weight.

[0057] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0058] The polypeptide is 1 part by weight;

[0059] The fish oil is 0.01-800 parts by weight;

[0060] The protease inhibitor is 0.1-210 parts by weight;

[0061] The absorption promoter is 0.1-300 parts by weight; and

[0062] The surfactant is 1-800 parts by weight;

[0063] Preferably,

[0064] The polypeptide is 1 part by weight;

[0065] The fish oil is 3-50 parts by weight;

[0066] 1-30 parts by weight of the protease inhibitor;

[0067] The absorption promoter is 5-50 parts by weight; and

[0068] The surfactant is 3-65 parts by weight;

[0069] Preferably,

[0070] The polypeptide is 1 part by weight;

[0071] The fish oil is 8-40 parts by weight;

[0072] 3-20 parts by weight of the protease inhibitor;

[0073] The absorption promoter is 2-20 parts by weight; and

[0074] The surfactant is 8-40 parts by weight;

[0075] Preferably,

[0076] The polypeptide is 1 part by weight;

[0077] The fish oil is 8-40 parts by weight;

[0078] 3-10 parts by weight of the protease inhibitor;

[0079] The absorption promoter is 2-20 parts by weight; and

[0080] The surfactant is 8-40 parts by weight.

[0081] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0082] Preferably,

[0083] The polypeptide is 1 part by weight;

[0084] The fish oil is 6.3-40 parts by weight;

[0085] The protease inhibitor is 2.2-20 parts by weight;

[0086] The absorption promoter is 7.8-37.5 parts by weight; and

[0087] The surfactant is 3.3-56.3 parts by weight;

[0088] Preferably,

[0089] The polypeptide is 1 part by weight;

[0090] The fish oil is 6.6-40 parts by weight;

[0091] The protease inhibitor is 2.2-20 parts by weight;

[0092] The absorption promoter is 7.8-20 parts by weight; and

[0093] The surfactant is 3.3-40 parts by weight;

[0094] Preferably,

[0095] The polypeptide is 1 part by weight;

[0096] The fish oil is 7.7-40 parts by weight;

[0097] The protease inhibitor is 2.2-20 parts by weight;

[0098] The absorption promoter is 7.8-15 parts by weight; and

[0099] The surfactant is 3.3-40 parts by weight;

[0100] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0101] Or for,

[0102] The polypeptide is 1 part by weight;

[0103] The fish oil is 6.6-40 parts by weight;

[0104] The protease inhibitor is 12.5-20 parts by weight;

[0105] The absorption promoter is 15-20 parts by weight; and

[0106] The surfactant is 15.3-40 parts by weight;

[0107] Or for,

[0108] The polypeptide is 1 part by weight;

[0109] The fish oil is 6.6-7.7 parts by weight;

[0110] The protease inhibitor is 2.2-12.5 parts by weight;

[0111] The absorption promoter is 7.8-20 parts by weight; and

[0112] The surfactant is present in an amount of 3.3-15.3 parts by weight.

[0113] “Mass fraction” refers to the mass fraction of a component in the polypeptide composition, based on the sum of the weights of the polypeptide, fish oil, protease inhibitor, absorption enhancer and surfactant in the polypeptide composition.

[0114] For example, when the polypeptide composition includes 8 mg of recombinant human insulin, 320 mg of fish oil, 160 mg of soybean trypsin inhibitor, 120 mg of disodium edetate, and 320 mg of Tween 80, and the total weight of the polypeptide composition is 928 mg, the mass fraction of the recombinant human insulin is (8 mg / 928 mg)×100%=0.9%, and the mass fraction of the fish oil is (320 mg / 928 mg)×100%=34.5%.

[0115] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein,

[0116] The mass fraction of the polypeptide is 0.1% to 10.0%;

[0117] The mass fraction of the fish oil is 0.5% to 40.0%;

[0118] The mass fraction of the protease inhibitor is 5.0% to 28.0%;

[0119] The mass fraction of the absorption promoter is 8.0% to 42.0%; and

[0120] The mass fraction of the surfactant is 10.0% to 55.0%;

[0121] Preferably,

[0122] The mass fraction of the polypeptide is 0.9% to 4.6%;

[0123] The mass fraction of the fish oil is 5.5% to 34.9%;

[0124] The mass fraction of the protease inhibitor is 10.0% to 22.6%;

[0125] The mass fraction of the absorption promoter is 12.9% to 36.1%; and

[0126] The mass fraction of the surfactant is 15.0% to 49.6%;

[0127] Preferably,

[0128] The mass fraction of the polypeptide is 0.9% to 4.6%;

[0129] The mass fraction of the fish oil is 11.9% to 34.9%;

[0130] The mass fraction of the protease inhibitor is 10.0% to 22.6%;

[0131] The mass fraction of the absorption promoter is 12.9% to 36.1%; and

[0132] The mass fraction of the surfactant is 15.0% to 34.5%;

[0133] Preferably,

[0134] The mass fraction of the polypeptide is 0.9% to 4.6%;

[0135] The mass fraction of the fish oil is 20.0% to 34.9%;

[0136] The mass fraction of the protease inhibitor is 10.0% to 17.2%;

[0137] The mass fraction of the absorption promoter is 12.9% to 35.6%; and

[0138] The mass fraction of the surfactant is 15.0% to 34.5%;

[0139] Preferably,

[0140] The mass fraction of the polypeptide is 0.9% to 4.6%;

[0141] The mass fraction of the fish oil is 34.5% to 34.9%;

[0142] The mass fraction of the protease inhibitor is 10.0% to 17.2%;

[0143] The mass fraction of the absorption promoter is 12.9% to 35.6%; and

[0144] The mass fraction of the surfactant is 15.0% to 34.5%;

[0145] Preferably,

[0146] The mass fraction of the polypeptide is 0.9% to 1.8%;

[0147] The mass fraction of the fish oil is 11.9% to 34.5%;

[0148] The mass fraction of the protease inhibitor is 17.2% to 22.6%;

[0149] The mass fraction of the absorption promoter is 12.9% to 36.1%; and

[0150] The mass fraction of the surfactant is 27.7% to 34.5%;

[0151] Preferably,

[0152] The mass fraction of the polypeptide is 1.8% to 4.6%;

[0153] The mass fraction of the fish oil is 11.9% to 34.9%;

[0154] The mass fraction of the protease inhibitor is 10.0% to 22.6%;

[0155] The mass fraction of the absorption promoter is 35.6% to 36.1%; and

[0156] The mass fraction of the surfactant is 15.0% to 27.7%.

[0157] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, in a unit dosage form,

[0158] The polypeptide is 8-32 mg;

[0159] The fish oil is 0.01-320 mg;

[0160] The protease inhibitor is 70-200 mg;

[0161] The absorption enhancer is 120-320 mg; and

[0162] The surfactant is 105-450 mg;

[0163] Preferably,

[0164] The polypeptide is 8-32 mg;

[0165] The fish oil is 50-320 mg;

[0166] The protease inhibitor is 70-200 mg;

[0167] The absorption enhancer is 120-320 mg; and

[0168] The surfactant is 105-450 mg;

[0169] Preferably,

[0170] The polypeptide is 8-32 mg;

[0171] The fish oil is 105-320 mg;

[0172] The protease inhibitor is 70-200 mg;

[0173] The absorption enhancer is 120-320 mg; and

[0174] The surfactant is 105-320 mg;

[0175] Preferably,

[0176] The polypeptide is 8-32 mg;

[0177] The fish oil is 245-320 mg;

[0178] The protease inhibitor is 70-160 mg;

[0179] The absorption enhancer is 120-250 mg; and

[0180] The surfactant is 105-320 mg;

[0181] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, in a unit dosage form,

[0182] The polypeptide is 8-16 mg;

[0183] The fish oil is 105-320 mg;

[0184] The protease inhibitor is 160-200 mg;

[0185] The absorption enhancer is 120-320 mg; and

[0186] The surfactant is 245-320 mg;

[0187] or,

[0188] The polypeptide is 16-32 mg;

[0189] The fish oil is 105-245 mg;

[0190] The protease inhibitor is 70-200 mg;

[0191] The absorption enhancer is 250-320 mg; and

[0192] The surfactant is 105-245 mg;

[0193] In one embodiment, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, in a unit dosage form,

[0194] The polypeptide is 8 mg;

[0195] The fish oil is 320 mg;

[0196] The protease inhibitor is 160 mg;

[0197] The absorption enhancer is 120 mg; and

[0198] The surfactant is 320 mg;

[0199] or,

[0200] The polypeptide is 16 mg;

[0201] The fish oil is 105 mg;

[0202] The protease inhibitor is 200 mg;

[0203] The absorption enhancer is 320 mg; and

[0204] The surfactant is 245 mg;

[0205] or,

[0206] The polypeptide is 32 mg;

[0207] The fish oil is 245 mg;

[0208] The protease inhibitor is 70 mg;

[0209] The absorption enhancer is 250 mg; and

[0210] The surfactant is 105 mg;

[0211] or,

[0212] The polypeptide is 8 mg;

[0213] The fish oil is 50 mg;

[0214] The protease inhibitor is 100 mg;

[0215] The absorption enhancer is 300 mg; and

[0216] The surfactant is 450 mg.

[0217] In the present invention, the polypeptide, fish oil, protease inhibitor, absorption enhancer, and surfactant are present in specific ratios. The synergistic effect of these components results in a highly stable oral polypeptide composition. Under suitable storage conditions, the composition exhibits good stability and a long shelf life. The oral polypeptide composition of the present invention has high bioavailability.

[0218] In one embodiment, the present invention provides an oral polypeptide composition comprising a polypeptide, fish oil, a protease inhibitor, an absorption enhancer and a surfactant, wherein:

[0219] For example, the weight portion of the polypeptide is 0.1 to 100 parts by weight, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 200, 201

[0220] The weight portion of fish oil is 0.1 to 800, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 , 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 11, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208,209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408,409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517 7, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578 8, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608,609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633 , 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658 , 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683 , 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708 , 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733 , 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758 , 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, etc. Other specific point values ​​within this numerical range can be selected, or values ​​between any two points therein, which will not be repeated here.

[0221] Protease inhibitors 1 to 400 parts by weight, for example, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 7, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169 ,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253 , 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289 , 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325 , 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361 , 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, etc. Other specific point values ​​within this numerical range can be selected, or values ​​between any two points therein, which will not be repeated here.

[0222] The weight portion of the absorption promoter is 0.1 to 300, for example, it can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 55 parts, 56 parts, 57 parts, 58 parts, 59 parts, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 1, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217,218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256 6, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325 , 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356 6, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 3 87, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417,418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463 3, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, etc. Other specific point values ​​within this numerical range can be selected, or values ​​between any two points therein, which will not be repeated here.

[0223] The surfactant weight portion is 0.1 to 800, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 parts. , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 9, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 , 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 , 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 1 67, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208,209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408,409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 4 38, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467 , 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502 , 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 5 38, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573 , 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608,609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633 , 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658 , 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683 , 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708 , 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733 , 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758 , 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, etc. Other specific point values ​​within this numerical range can be selected, or values ​​between any two points therein, which will not be repeated here.

[0224] In one embodiment, the present invention provides an oral polypeptide composition comprising a polypeptide, fish oil, a protease inhibitor, an absorption promoter, and a surfactant, wherein when the weight portion of the polypeptide in the composition is 1,

[0225] The weight proportions of the fish oil in the composition are: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5 .0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 , 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510 , 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, or a value between any two points;

[0226] The weight proportion of the protease inhibitor in the composition is: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, or values ​​between any two points therein;

[0227] The weight proportions of the absorption promoter in the composition are: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, or any value between any two of them; and

[0228] The weight proportions of the surfactant in the composition are: 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 0, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, or any value between any two points.

[0229] In one embodiment, the present invention provides an oral polypeptide composition comprising a polypeptide, fish oil, a protease inhibitor, an absorption promoter and a surfactant, wherein when the weight portion of the polypeptide in the composition is 1,

[0230] The weight portion of the fish oil in the composition is 0.01-800, for example, preferably 0.02-790, 0.03-780, 0.04-770, 0.05-760, 0.06-750, 0.07-740, 0.08-730, 0.09-720, 0.1-710, 0.2-700, 0.3-690, 0.4-680, 0.5-670, 0.6- 660, 0.7-650, 0.8-640, 0.9-630, 1.0-620, 1.5-610, 2-600, 2.5-590, 3.0-580, 3.5-570, 4.0-560, 4.5-550, 5.0-540, 5.5-530, 6.0-520, 6.5-510, 7.0-500, 7.5-490, or 8.0-480;

[0231] The weight portion of the protease inhibitor in the composition is 0.1-210, for example, preferably 0.2-200, 0.3-190, 0.4-180, 0.5-170, 0.6-160, 0.7-150, 0.8-140, 0.9-130, 1.0-120, 1.5-110, 2-100, 2.5-90 or 3.0-80;

[0232] The absorption promoter is present in the composition in an amount of 0.1-300 parts by weight, for example, preferably 0.2-290, 0.3-280, 0.4-270, 0.5-260, 0.6-250, 0.7-240, 0.8-230, 0.9-220, 1.0-210, 1.5-200 or 2-190 parts by weight; and

[0233] The surfactant is present in the composition in an amount of 0.01-800 parts by weight, for example, preferably 0.02-790, 0.03-780, 0.04-770, 0.05-760, 0.06-750, 0.07-740, 0.08-730, 0.09-720, 0.1-710, 0.2-700, 0.3-690, 0.4-680, 0.5-670, 0.6 -660, 0.7-650, 0.8-640, 0.9-630, 1.0-620, 1.5-610, 2-600, 2.5-590, 3.0-580, 3.5-570, 4.0-560, 4.5-550, 5.0-540, 5.5-530, 6.0-520, 6.5-510, 7.0-500, 7.5-490 or 8.0-480.

[0234] In one embodiment of the present invention, after the oral polypeptide composition is stored under appropriate conditions for a period of time, the polypeptide content thereof is greater than 85%. For example, after the oral polypeptide composition is stored at 2°C to 8°C for 15 months, the polypeptide content thereof is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; after the oral polypeptide composition is stored at 2°C to 8°C for 18 months, the polypeptide content thereof is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; after the oral polypeptide composition is stored at 2°C to 8°C for 24 months, the polypeptide content thereof is >85%, >86%, >87%, >88%, >99%; After the oral polypeptide composition is stored at 2°C to 8°C for 30 months, the polypeptide content thereof is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; after the oral polypeptide composition is stored at 2°C to 8°C for 36 months, the polypeptide content thereof is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

[0235] In one embodiment of the present invention, after storage at 25°C for 5 days, the polypeptide content of the oral polypeptide composition is >85%, >90%, >91%, >95%, >98%; after storage at 25°C for 10 days, the polypeptide content is >70%, >75%, >80%, >85%, 90%; after storage at 25°C for 30 days, the polypeptide content is >80%; after storage for 60 days, the polypeptide content is >50%, >60%, >70%, >75%.

[0236] In one embodiment of the present invention, after the oral polypeptide composition is stored at 40°C for 5 days, the polypeptide content is >70%, >80%; after storage at 40°C for 10 days, the polypeptide content is >60%, >70%, >80%.

[0237] In one embodiment of the present invention, the cumulative dissolution rate of the polypeptide in the polypeptide composition is significantly higher than that in the prior art.

[0238] In one embodiment of the present invention, the cumulative dissolution rate of the soybean trypsin inhibitor in the polypeptide composition is significantly higher than that in the prior art.

[0239] In one embodiment of the present invention, the oral polypeptide composition uses phosphate buffer at pH 6.8 as the dissolution medium, and the cumulative dissolution rate of the polypeptide is >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90% at 2 minutes, and >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% at 5 minutes. At 10 min >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 20 min >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 30 min >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 45 min >90%, >95%, >96%, >97%, >98%. At 60 min >90%, >95%, >96%, >97%, >98%.

[0240] In one embodiment of the present invention, the oral polypeptide composition uses phosphate buffer at pH 6.8 as the dissolution medium, and the cumulative dissolution rate of the soybean trypsin inhibitor is >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90% at 2 minutes, and >15%, >20%, >30%, 35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% at 5 minutes. At 10 min >15%, >20%, >30%, 35%, 40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%.At 20 min >20%, >30%, 35%, 40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 30 min >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 45 min >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%. At 60 min >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98%.

[0241] The measurement of cumulative dissolution is affected by various factors, and it is inevitable that the data will have a certain deviation. The error range of the cumulative dissolution of the present invention can be within ±5%.

[0242] In the context of polypeptide stability, the "polypeptide content" used herein refers to the percentage of the actual content of the polypeptide to the labeled amount; for example, for liraglutide capsules, the liraglutide content in the capsule refers to For example, a capsule is labeled as containing 20mg of liraglutide. Samples are taken for testing and the test results show that each capsule actually contains 18mg of liraglutide. The liraglutide content is

[0243] In addition, the oral polypeptide composition increases the bioavailability of the polypeptide in a subject by at least 5%, at least 8%, at least 10%, at least 15%, at least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 200%, at least 300%, at least 400%, or at least 500%.

[0244] As a preferred technical solution of the present invention, the molecular weight of the polypeptide in the oral polypeptide composition is 100Da to 20000Da, for example, it can be 100Da, 200Da, 300Da, 400Da, 500Da, 600Da, 700Da, 800Da, 900Da, 1000Da, 1100Da, 1200Da, 1300Da, 1400Da, 1500Da, 1600Da, 1700Da, 1800Da, 1900Da, 2000Da, 2100Da, 2200Da, 2300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, 2900Da, 3000Da, 3100Da, 3200Da, 3300Da, 3400Da, 3500Da, 3600Da, 3700Da, 3800Da, 3900Da, 4000Da, 4100Da, 4200Da , 4300Da, 4400Da, 4500Da, 4600Da, 4700Da, 4800Da, 4900Da, 5000Da, 5100Da, 5200Da, 5300Da, 5400Da, 5500Da, 5600Da, 5700Da, 5800Da , 5900Da, 6000Da, 6100Da, 6200Da, 6300Da, 6400Da, 6500Da, 6600Da, 6700Da, 6800Da, 6900Da, 7000Da, 7100Da, 7200Da, 7300Da, 7400D a. 7500Da, 7600Da, 7700Da, 7800Da, 7900Da, 8000Da, 8100Da, 8200Da, 8300Da, 8400Da, 8500Da, 8600Da, 8700Da, 8800Da, 8900Da, 9000 or any range between the above values, preferably 1000Da to 20000Da, preferably 1000Da to 6000Da, and more preferably 2000Da to 6000Da.

[0245] In one embodiment of the oral polypeptide composition of the present invention, the polypeptide is selected from any one or more of insulin, or a derivative or analog thereof, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione and thymosin;

[0246] Preferably, the polypeptide is selected from animal insulin, human insulin, recombinant human insulin, insulin derivatives, insulin analogs, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protolol, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histidine, triptorelin, tesmorelin, cortirelin, heparin, granulocyte colony stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, Any one or more of erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteotide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, prokinase, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

[0247] Preferably, the polypeptide is selected from porcine insulin, bovine insulin, human insulin, recombinant human insulin, lispro insulin, aspart insulin, protamine zinc insulin, protamine zinc insulin, glargine insulin, detemir insulin, degludec insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, recombinant growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protamine zinc insulin, gonadorelin, goserelin, buserelin, sermorelin, nafa Any one or more of oxazolidinone, histidine, triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, recombinant human interferon α2b, recombinant human interferon b, recombinant human interferon γ, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-angitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteopeptide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

[0248] The insulin described in the present invention includes animal insulin, human insulin, recombinant human insulin, proinsulin and insulin-like compounds, and insulin-like compounds include insulin analogs and insulin derivatives. The insulin described in the present invention includes fast-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin and ultra-long-acting insulin.

[0249] The insulin analogs described in the present invention refer to insulin in which one or more amino acids are substituted while retaining some or all of one or more glucose-related activities of insulin.

[0250] The insulin derivatives mentioned in the present invention generally refer to compounds that can be prepared from natural peptides or their analogs by chemical modification, in particular by covalent linkage of one or more substituents.

[0251] The insulin, proinsulin, insulin analogs and insulin derivatives described in the present invention include: (1) rapid-acting insulin (sometimes also called "monomeric insulin analogs"), such as lispro insulin and aspart insulin; (2) short-acting insulin (sometimes also called "regular" insulin); (3) intermediate-acting insulin, such as protamine zinc insulin (NPH) and recombinant human insulin; (4) long-acting (so-called "basal insulin"), protamine zinc insulin, glargine insulin, detemir insulin, etc.; (5) ultra-long-acting insulin; (6) translocation insulin analogs; (7) insulin loss analogs; (8) derivatized insulin; (9) derivatized insulin analogs; (10) derivatized proinsulin; (11) human insulin analog complexes (e.g., hexameric complexes), (12) insulin mixtures, and (13) PEG insulin.

[0252] The glucagon-like peptide-1 described in the present invention includes short-acting and long-acting GLP-1 receptor agonists.

[0253] The glucagon-like peptide-1 includes: Exenatide, Lixisenatide, Benaglutide, Liraglutide, Taspoglutid, Loxenatide, Semaglutide, Albiglutide and Dulaglutide, etc.

[0254] The thymosin peptides of the present invention include thymosin α1, thymosin α-sin, thymosin β4 or thymopentin. It should be noted that the polypeptides in the composition of the present invention can also be replaced by other active substances, such as other small molecules with poor oral bioavailability.

[0255] As a preferred technical solution of the present invention, the target protein of the protease inhibitor is selected from any one or more of serine protease, trypsin, chymotrypsin, carboxypeptidase and aminopeptidase;

[0256] Preferably, the protease inhibitor is selected from any one or more of cysteine ​​protease inhibitors, serine protease inhibitors, trypsin inhibitors, threonine protease inhibitors, aspartic acid protease inhibitors and metalloproteinase inhibitors;

[0257] Preferably, the protease inhibitor is selected from soybean trypsin inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, ε-aminocaproic acid, antiprotease, α1-antichymotrypsin, antithrombin, α1-antitrypsin, 4-amidinophenyl-methanesulfonyl fluoride, aprotinin, benzamidine-HCl, chymostatin, diisopropyl fluoride-phosphate, leupeptin, phenylmethylsulfonyl fluoride, 1-chloro-3-sulfonylamino-7-amino-2-heptanone HCl, 1-chloro-3-sulfonylamino-4-phenyl-2-butanone, pentamidine isethionate, egg white trypsin inhibitor, pepsin inhibitor, α2-macroglobulin, guanidinium, iodoacetic acid, zinc and any one or more of a zinc chelator.

[0258] In one embodiment of the present invention, the soybean trypsin inhibitor is selected from Kunitz trypsin inhibitor and / or Bowman-Birk trypsin inhibitor.

[0259] In one embodiment of the present invention, the at least one absorption promoter is selected from any one or more of ethylenediaminetetraacetic acid or its salts, N-(8-(2-hydroxybenzoyl)amino)octanoic acid or its salts, salicylic acid or its salts, citric acid or its salts, bile acid or its salts, deoxycholic acid or its salts, glycocholic acid or its salts, taurocholic acid or its salts, alkyl glycosides, sodium lauryl sulfate, docusate sodium, cyclodextrin or its derivatives, chitosan or its derivatives, caprylic acid or its salts, capric acid or its salts, lauric acid or its salts, myristic acid, palmitic acid, stearic acid, fatty acid triglycerides, lecithin, choline and carnitine. Preferably, the ethylenediaminetetraacetic acid salt is selected from disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, trisodium ethylenediaminetetraacetic acid or tetrasodium ethylenediaminetetraacetic acid.

[0260] In one embodiment of the present invention, the at least one surfactant is selected from any one or more of an ionic surfactant, a nonionic surfactant, and a zwitterionic surfactant;

[0261] Preferably, the at least one absorption promoter is selected from ammonium lauryl sulfate, N-dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sodium lauryl sulfate, sodium docusate, cyclodextrin or its derivatives, chitosan or its derivatives, polyoxyethylene alkyl sodium sulfate, sodium lauryl ether sulfate, dioctyl sodium sulfosuccinate, poloxamer, glyceryl monostearate, glyceryl monolaurate, sorbitan monolaurate, sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene monopalmitate, polyoxyethylene hydrogenated castor oil, C6-C 12 Fatty acid triglycerides and C8-C 10 Any one or more of fatty acid triglycerides.

[0262] Preferably, the at least one surfactant is selected from Tween, preferably, the at least one surfactant is selected from any one or more of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 and Tween 85.

[0263] In one embodiment of the present invention, by controlling the weight ratio of fish oil to surfactant in the oral polypeptide composition, the cumulative dissolution rate of the polypeptide in the oral polypeptide composition is significantly improved.

[0264] In one embodiment of the present invention, by controlling the weight ratio of fish oil to surfactant in the oral polypeptide composition, the cumulative dissolution rate of the soybean trypsin inhibitor in the oral polypeptide composition is significantly improved.

[0265] In one embodiment of the present invention, the weight ratio of the fish oil to the surfactant is 1:(0.2-15), preferably 1:(0.43-9), preferably 1:(0.43-5), preferably 1:(0.43-3), preferably 1:(0.43-2.33), preferably 1:(0.43-1), preferably 1:0.5-1:2, preferably 1:0.8-1:1.2, or any value between any two of the above ratios; preferably 1:0.8-1:1.2.

[0266] In one embodiment, the present invention provides an oral polypeptide composition, wherein the weight ratio of the fish oil to the surfactant is 1:1, or 1:2.33, or 1:0.43, or 1:9.

[0267] In one embodiment, the present invention provides an oral polypeptide composition, wherein the polypeptide is selected from human insulin, the protease inhibitor is selected from soybean trypsin inhibitor, the absorption promoter is selected from ethylenediaminetetraacetic acid or its salt, and the surfactant is selected from Tween.

[0268] In one embodiment, the present invention provides an oral polypeptide composition, wherein the polypeptide is selected from recombinant human insulin, the protease inhibitor is selected from soybean trypsin inhibitor, the absorption promoter is selected from ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid, and the surfactant is selected from Tween 80.

[0269] In one embodiment of the present invention, the stability and bioavailability of the oral polypeptide composition are improved by adjusting the weight ratio of fish oil to surfactant.

[0270] As used herein, the term "fish oil," also known as omega-3 triglycerides, is a type of oil extracted from fatty fish. It is rich in n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fatty fish species from which fish oil can be extracted include, but are not limited to, mackerel, tuna, salmon, sturgeon, anchovies, sardines, herring, and trout.

[0271] In one embodiment of the present invention, the present invention further provides a medicine comprising the oral polypeptide composition as described above.

[0272] In one embodiment of the present invention, the drug further comprises a pharmaceutically acceptable excipient.

[0273] Preferably, the pharmaceutically acceptable excipients further include a coating, and the coating is selected from any one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic resin, polyvinyl pyrrolidone, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; preferably, the pharmaceutically acceptable excipients further include any one or more of an excipient, a disintegrant, a binder, a flavoring agent and a lubricant.

[0274] It should be noted that the primary function of coatings in the present disclosure is to release polypeptides in specific locations within the gastrointestinal tract. For example, enteric coatings can render polypeptides insoluble in gastric acid but soluble in intestinal fluid. Those skilled in the art can select coating materials based on actual needs to achieve polypeptide release in gastric or intestinal fluid within the gastrointestinal tract.

[0275] Preferably, the excipient is selected from any one or more of lactose, sorbitol, xylitol, mannitol, calcium sulfate, calcium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose starch complex, lactose cellulose complex and mannitol starch complex;

[0276] Preferably, the disintegrant is selected from any one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose;

[0277] Preferably, the binder is selected from any one or more of starch slurry, gelatin solution, sucrose solution, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone;

[0278] Preferably, the lubricant is selected from any one or more of sodium stearyl fumarate, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium stearate, calcium stearate, micropowder silica gel and talc;

[0279] Preferably, the flavoring agent is selected from any one or more of mannitol, sorbitol, aspartame, stevioside, sucralose, aspartame, neotame, stevioside, hydroxystearic acid chloride and essence.

[0280] In one embodiment of the present invention, the dosage form of the drug is selected from any one or more of tablets, pills, capsules, emulsions, syrups or suspensions.

[0281] In one embodiment of the present invention, the oral polypeptide composition or medicament is anhydrous.

[0282] In one embodiment of the present invention, the oral polypeptide composition comprises a capsule containing recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA, and Tween 80. The capsule contents are an anhydrous suspension. "Anhydrous" means that no water is intentionally added to the capsule contents during the preparation of the oral polypeptide composition of the present invention, but does not preclude the absorption of water from the air by the components in the capsule contents.

[0283] In one embodiment of the present invention, the system consisting of polypeptide, fish oil, protease inhibitor, absorption promoter and surfactant is a suspension.

[0284] In one embodiment of the present invention, the system composed of polypeptide, fish oil, protease inhibitor, absorption promoter, surfactant and other pharmaceutically acceptable excipients is a suspension.

[0285] In one embodiment of the present invention, the system consisting of polypeptide, fish oil, protease inhibitor, absorption promoter and surfactant is a non-nano system.

[0286] In one embodiment of the present invention, the system consisting of polypeptide, fish oil, protease inhibitor, absorption promoter, surfactant and other pharmaceutically acceptable excipients is a non-nano system.

[0287] In one embodiment of the present invention, the system consisting of the polypeptide, fish oil, protease inhibitor, absorption promoter and surfactant is an emulsion such as non-water-in-oil or oil-in-water.

[0288] In one embodiment of the present invention, the system composed of polypeptide, fish oil, protease inhibitor, absorption promoter, surfactant and other pharmaceutically acceptable excipients is an emulsion such as non-water-in-oil or oil-in-water.

[0289] In one embodiment of the present invention, the system consisting of the polypeptide, fish oil, protease inhibitor, absorption promoter and surfactant is a composite emulsion such as non-water-in-oil-in-water or oil-in-water-in-oil.

[0290] In one embodiment of the present invention, the system composed of polypeptide, fish oil, protease inhibitor, absorption promoter, surfactant and other pharmaceutically acceptable excipients is a composite emulsion such as non-water-in-oil-in-water or oil-in-water-in-oil.

[0291] In one embodiment of the present invention, the oral polypeptide composition is absorbed from the intestine.

[0292] In one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising two or more different polypeptides, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein

[0293] The total weight of the two or more different polypeptides is 0.1-100;

[0294] The weight portion of the fish oil is 0.01-800;

[0295] The weight portion of the protease inhibitor is 0.1-210;

[0296] The weight portion of the absorption promoter is 0.1-300; and

[0297] The weight portion of the surfactant is 1-800;

[0298] Preferably,

[0299] The total weight of the two or more different polypeptides is 1;

[0300] The weight portion of the fish oil is 0.01-800;

[0301] The weight portion of the protease inhibitor is 0.1-210;

[0302] The weight portion of the absorption promoter is 0.1-300; and

[0303] The weight portion of the surfactant is 1-800;

[0304] Preferably,

[0305] The two or more different polypeptides are present in the same preparation, or are independently present in different preparations;

[0306] Preferably, the two or more different polypeptides are selected from any two or more of insulin, or a derivative or analog thereof, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione and thymosin;

[0307] Preferably, the two or more different polypeptides are selected from animal insulin, human insulin, recombinant human insulin, insulin derivatives, insulin analogs, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abaloparatide, leuprorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, group Any two or more of aminorelin, triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteotide, myosinidine, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin, and thymofasin

[0308] Preferably, the polypeptide is selected from porcine insulin, bovine insulin, human insulin, recombinant human insulin, lispro insulin, aspart insulin, protamine zinc insulin, protamine zinc insulin, glargine insulin, detemir insulin, degludec insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, recombinant growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protamine zinc insulin, gonadorelin, goserelin, buserelin, sermorelin, nafa Any two or more of oxazolidinone, histrelin, triptorelin, tesmorelin, cortirelin, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, recombinant human interferon α2b, recombinant human interferon b, recombinant human interferon γ, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteopeptide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alaninerelin, trypsinogenase, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

[0309] In one embodiment, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises two or more different polypeptides, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein

[0310] The total mass fraction of the two or more different polypeptides is 0.1% to 10.0%;

[0311] The mass fraction of the fish oil is 0.5% to 40.0%;

[0312] The mass fraction of the protease inhibitor is 5.0% to 28.0%;

[0313] The mass fraction of the absorption promoter is 8.0% to 42.0%; and

[0314] The mass fraction of the surfactant is 10.0% to 55.0%;

[0315] Preferably,

[0316] The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%;

[0317] The mass fraction of the fish oil is 5.5% to 34.9%;

[0318] The mass fraction of the protease inhibitor is 10.0% to 22.6%;

[0319] The mass fraction of the absorption promoter is 12.9% to 36.1%; and

[0320] The mass fraction of the surfactant is 15.0% to 49.6%;

[0321] Preferably,

[0322] The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%;

[0323] The mass fraction of the fish oil is 11.9% to 34.9%;

[0324] The mass fraction of the protease inhibitor is 10.0% to 22.6%;

[0325] The mass fraction of the absorption promoter is 12.9% to 36.1%; and

[0326] The mass fraction of the surfactant is 15.0% to 34.5%;

[0327] Preferably,

[0328] The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%;

[0329] The mass fraction of the fish oil is 20.0% to 34.9%;

[0330] The mass fraction of the protease inhibitor is 10.0% to 17.2%;

[0331] The mass fraction of the absorption promoter is 12.9% to 35.6%; and

[0332] The mass fraction of the surfactant is 15.0% to 34.5%;

[0333] Preferably,

[0334] The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%;

[0335] The mass fraction of the fish oil is 34.5% to 34.9%;

[0336] The mass fraction of the protease inhibitor is 10.0% to 17.2%;

[0337] The mass fraction of the absorption promoter is 12.9% to 35.6%; and

[0338] The mass fraction of the surfactant is 15.0% to 34.5%.

[0339] In one embodiment, the present invention provides a pharmaceutical composition, wherein the weight ratio of fish oil to surfactant is 1:(0.2-15), preferably 1:(0.43-9), preferably 1:(0.43-5), preferably 1:(0.43-3), preferably 1:(0.43-2.33), preferably 1:(0.43-1), preferably 1:0.5-1:2, preferably 1:0.8-1:1.2.

[0340] In one embodiment, the present invention provides a pharmaceutical composition, wherein the weight ratio of the fish oil to the surfactant is 1:1, or 1:2.33, or 1:0.43, or 1:9.

[0341] In one embodiment of the present invention, the present invention provides the use of the oral polypeptide composition, the medicine and the pharmaceutical composition in the preparation of a medicine for preventing or treating diabetes, obesity, impaired glucose tolerance, liver steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer and improving immunity.

[0342] In one embodiment of the present invention, the present invention provides the oral polypeptide composition, the drug and the use of the pharmaceutical composition in the preparation of a drug for preventing or treating non-alcoholic fatty liver disease, wherein the non-alcoholic fatty liver disease is selected from simple fatty liver and non-alcoholic steatohepatitis.

[0343] In one embodiment of the present invention, the present invention provides the use of the oral polypeptide composition, the medicine and the pharmaceutical composition in the preparation of a medicine for preventing or treating non-alcoholic fatty liver disease combined with diabetes, non-alcoholic fatty liver disease combined with kidney disease, non-alcoholic fatty liver disease combined with cardiovascular disease, non-alcoholic fatty liver disease combined with obesity and non-alcoholic fatty liver disease combined with hyperlipidemia.

[0344] In one embodiment of the present invention, the present invention provides a method for treating or preventing a disease, wherein the method comprises orally administering a therapeutically effective amount of the oral polypeptide composition, the drug or the pharmaceutical composition to a subject in need thereof, wherein the disease is selected from diabetes, obesity, impaired glucose tolerance, hepatic steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer and immune diseases.

[0345] In one embodiment of the present invention, the present invention provides a method for treating or preventing a disease, comprising orally administering to a subject a single dose of 8-32 mg of the polypeptide in the oral polypeptide composition, 1-3 times a day, 1-3 capsules each time; or orally administering to a subject a single dose of 8-32 mg of the polypeptide in the drug, 1-3 times a day, 1-3 capsules each time; or orally administering to a subject a single dose of 8-32 mg of the polypeptide in the pharmaceutical composition, 1-3 times a day, 1-3 capsules each time.

[0346] In one embodiment of the present invention, the present invention provides a method for treating or preventing a disease, comprising orally administering to a subject a single dose of 8 mg, 16 mg or 32 mg of the polypeptide in the oral polypeptide composition, 1, 2 or 3 times a day, 1, 2 or 3 capsules each time; or orally administering to a subject a single dose of 8 mg, 16 mg or 32 mg of the polypeptide in the drug, 1, 2 or 3 times a day, 1, 2 or 3 capsules each time; or or orally administering to a subject a single dose of 8 mg, 16 mg or 32 mg of the polypeptide in the pharmaceutical composition, 1, 2 or 3 times a day, 1, 2 or 3 capsules each time.

[0347] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil and at least one surfactant, and the cumulative solubility of the polypeptide can reach 20%-95%, or 39%-95%, or 48%-95%, or 83%-95% in 2 minutes using a pH 6.8 phosphate buffer as the dissolution medium.

[0348] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the oral polypeptide composition further comprises a protease inhibitor and at least one absorption enhancer, and the cumulative solubility of the polypeptide, using a pH 6.8 phosphate buffer as the dissolution medium, can reach 20%-95%, or 39%-95%, or 48%-95%, or 83%-95% in 2 minutes.

[0349] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 45%-101.0%, or 57%-101.0%, or 93%-101.0% in 5 minutes using pH 6.8 phosphate buffer as the dissolution medium.

[0350] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 57%-99.0%, or 73%-99.0%, or 96.0%-99.0% in 10 minutes using pH 6.8 phosphate buffer as the dissolution medium.

[0351] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 75%-99%, or 94%-99% in 20 minutes using pH 6.8 phosphate buffer as the dissolution medium.

[0352] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 91%-100%, or 96%-100% in 30 minutes using pH 6.8 phosphate buffer as the dissolution medium.

[0353] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 96%-100% in 45 minutes using a phosphate buffer solution at pH 6.8 as a dissolution medium.

[0354] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the cumulative dissolution rate of the polypeptide can reach 96%-100% in 60 minutes using a phosphate buffer solution at pH 6.8 as a dissolution medium.

[0355] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein:

[0356] The polypeptide is 0.1-100 parts by weight;

[0357] The fish oil is 0.01-800 parts by weight;

[0358] The protease inhibitor is 0.1-400 parts by weight;

[0359] The absorption promoter is 0.1-500 parts by weight; and

[0360] The surfactant is 1-800 parts by weight;

[0361] or,

[0362] The polypeptide is 0.1-100 parts by weight;

[0363] The fish oil is 0.01-800 parts by weight;

[0364] The protease inhibitor is 0.1-210 parts by weight;

[0365] The absorption promoter is 0.1-300 parts by weight; and

[0366] The surfactant is 1-800 parts by weight;

[0367] or,

[0368] The polypeptide is 0.1-50 parts by weight;

[0369] The fish oil is 0.01-600 parts by weight;

[0370] The protease inhibitor is 40-300 parts by weight;

[0371] The absorption promoter is 80-400 parts by weight; and

[0372] The surfactant is 50-600 parts by weight;

[0373] or,

[0374] The polypeptide is 5-50 parts by weight;

[0375] The fish oil is 0.01-600 parts by weight;

[0376] The protease inhibitor is 40-300 parts by weight;

[0377] The absorption promoter is 120-400 parts by weight; and

[0378] The surfactant is 105-450 parts by weight;

[0379] or,

[0380] The polypeptide is 8-32 parts by weight;

[0381] The fish oil is 0.01-320 parts by weight;

[0382] The protease inhibitor is 70-200 parts by weight;

[0383] The absorption promoter is 120-320 parts by weight; and

[0384] The surfactant is 105-450 parts by weight;

[0385] or,

[0386] The polypeptide is 8-32 parts by weight;

[0387] The fish oil is 50-320 parts by weight;

[0388] The protease inhibitor is 70-200 parts by weight;

[0389] The absorption promoter is 120-320 parts by weight; and

[0390] The surfactant is 105-450 parts by weight;

[0391] or,

[0392] The polypeptide is 8-32 parts by weight;

[0393] The fish oil is 105-320 parts by weight;

[0394] The protease inhibitor is 70-200 parts by weight;

[0395] The absorption promoter is 120-320 parts by weight; and

[0396] The surfactant is 105-320 parts by weight;

[0397] or,

[0398] The polypeptide is 8-32 parts by weight;

[0399] The fish oil is 245-320 parts by weight;

[0400] The protease inhibitor is 70-160 parts by weight;

[0401] The absorption promoter is 120-250 parts by weight; and

[0402] The surfactant is 105-320 parts by weight;

[0403] or,

[0404] The polypeptide is 8-16 parts by weight;

[0405] The fish oil is 105-320 parts by weight;

[0406] The protease inhibitor is 160-200 parts by weight;

[0407] The absorption promoter is 120-320 parts by weight; and

[0408] The surfactant is 245-320 parts by weight;

[0409] or,

[0410] The polypeptide is 16-32 parts by weight;

[0411] The fish oil is 105-245 parts by weight;

[0412] The protease inhibitor is 70-200 parts by weight;

[0413] The absorption promoter is 250-320 parts by weight; and

[0414] The surfactant is 105-245 parts by weight.

[0415] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the polypeptide is selected from any one or more of insulin, or a derivative or analog thereof, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione and thymosin;

[0416] Preferably, the polypeptide is selected from animal insulin, human insulin, recombinant human insulin, insulin derivatives, insulin analogs, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, qu Any one or more of prarelin, tesmorelin, cortirelin, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteotide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

[0417] Preferably, the polypeptide is selected from porcine insulin, bovine insulin, human insulin, recombinant human insulin, lispro insulin, aspart insulin, protamine zinc insulin, protamine zinc insulin, glargine insulin, detemir insulin, degludec insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, recombinant growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protamine zinc insulin, gonadorelin, goserelin, buserelin, sermorelin, nafa Any one or more of oxazolidinone, histidine, triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, recombinant human interferon α2b, recombinant human interferon b, recombinant human interferon γ, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-angitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteopeptide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

[0418] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the target protein of the protease inhibitor is selected from any one or more of serine proteases, trypsin, chymotrypsin, carboxypeptidase and aminopeptidase;

[0419] Preferably, the protease inhibitor is selected from any one or more of cysteine ​​protease inhibitors, serine protease inhibitors, trypsin inhibitors, threonine protease inhibitors, aspartic acid protease inhibitors and metalloproteinase inhibitors;

[0420] Preferably, the protease inhibitor is selected from soybean trypsin inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, ε-aminocaproic acid, antiprotease, α1-antichymotrypsin, antithrombin, α1-antitrypsin, 4-amidinophenyl-methanesulfonyl fluoride, aprotinin, benzamidine-HCl, chymostatin, diisopropyl fluoride-phosphate, leupeptin, phenylmethylsulfonyl fluoride, 1-chloro-3-sulfonylamino-7-amino-2-heptanone HCl, 1-chloro-3-sulfonylamino-4-phenyl-2-butanone, pentamidine isethionate, egg white trypsin inhibitor, pepsin inhibitor, α2-macroglobulin, guanidinium, iodoacetic acid, zinc and any one or more of a zinc chelator.

[0421] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the at least one absorption enhancer is selected from any one or more of ethylenediaminetetraacetic acid or a salt thereof, N-(8-(2-hydroxybenzoyl)amino)octanoic acid or a salt thereof, salicylic acid or a salt thereof, citric acid or a salt thereof, bile acid or a salt thereof, deoxycholic acid or a salt thereof, glycocholic acid or a salt thereof, taurocholic acid or a salt thereof, alkyl glycosides, sodium lauryl sulfate, docusate sodium, cyclodextrin or a derivative thereof, chitosan or a derivative thereof, caprylic acid or a salt thereof, capric acid or a salt thereof, lauric acid or a salt thereof, myristic acid, palmitic acid, stearic acid, fatty acid triglycerides, lecithin, choline and carnitine.

[0422] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the at least one surfactant is selected from any one or more of an ionic surfactant, a nonionic surfactant, and a zwitterionic surfactant;

[0423] Preferably, the at least one surfactant is selected from ammonium lauryl sulfate, N-dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sodium lauryl sulfate, sodium docusate, cyclodextrin or its derivatives, chitosan or its derivatives, polyoxyethylene alkyl sodium sulfate, sodium lauryl ether sulfate, dioctyl sodium sulfosuccinate, poloxamer, glyceryl monostearate, glyceryl monolaurate, sorbitan monolaurate, sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene monopalmitate, polyoxyethylene hydrogenated castor oil, C6-C 12 Fatty acid triglycerides and C8-C 10 Any one or more of fatty acid triglycerides;

[0424] Preferably, the at least one surfactant is selected from Tween, preferably, the at least one surfactant is selected from any one or more of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 and Tween 85.

[0425] In one embodiment of the present invention, the present invention provides an oral polypeptide composition, wherein the weight ratio of fish oil to surfactant is 1:(0.2-15), preferably 1:(0.43-9), preferably 1:(0.43-5), preferably 1:(0.43-3), preferably 1:(0.43-2.33), preferably 1:(0.43-1).

[0426] In one embodiment of the present invention, the present invention provides a method for treating or preventing a disease, wherein the method comprises orally administering a therapeutically effective amount of the oral polypeptide composition, the drug or the pharmaceutical composition to a subject in need thereof, wherein the disease is selected from non-alcoholic fatty liver disease.

[0427] In one embodiment of the present invention, the present invention provides a method for treating or preventing a disease, wherein the method comprises orally administering a therapeutically effective amount of the oral polypeptide composition, the drug or the pharmaceutical composition to a subject in need thereof, wherein the disease is selected from non-alcoholic fatty liver disease combined with diabetes, non-alcoholic fatty liver disease combined with kidney disease, non-alcoholic fatty liver disease combined with cardiovascular disease, non-alcoholic fatty liver disease combined with obesity and non-alcoholic fatty liver disease combined with hyperlipidemia.

[0428] Compared with the prior art, the present invention has the following beneficial effects:

[0429] The present invention provides an oral polypeptide composition, which can improve the in vitro stability and bioavailability of polypeptide drugs and realize oral administration.

[0430] The present invention provides an oral polypeptide composition, which can significantly improve the cumulative dissolution rate of the polypeptide. DETAILED DESCRIPTION

[0431] The technical solution of the present invention is further illustrated below with reference to the accompanying drawings and through specific implementation methods. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0432] In the following examples, unless otherwise specified, all reagents and consumables used were purchased from conventional reagent manufacturers in the field; unless otherwise specified, all experimental methods and technical means used were conventional methods and means in the field.

[0433] For example, recombinant human insulin can be purchased from Hefei Tianmai Biotechnology Development Co., Ltd., fish oil can be purchased that meets the quality standards of omega-3 fatty acid triglycerides in the European Pharmacopoeia EP10.8, soybean trypsin inhibitor can be purchased from Sigma-Aldrich, disodium ethylenediaminetetraacetic acid can be purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., and Tween 80 can be purchased from Sigma-Aldrich.

[0434] Example 1

[0435] This embodiment provides an oral polypeptide composition, wherein the mass ratio of recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA and Tween 80 contained in the oral polypeptide composition is 1:40:20:15:40, wherein the mass of the recombinant human insulin is 8 mg.

[0436] Preparation method: 8 mg of recombinant human insulin, 320 mg of fish oil, 160 mg of soybean trypsin inhibitor, 120 mg of ethylenediaminetetraacetic acid disodium and 320 mg of Tween 80 are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor and ethylenediaminetetraacetic acid disodium are mixed, the weighed fish oil and Tween 80 are added, mixed evenly, and filled into a gelatin capsule. The capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 40 mg of talc and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, and the coating solution is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0437] The oral polypeptide composition prepared in this example contains capsules containing recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA, and Tween 80. The capsule contents are an anhydrous suspension. "Anhydrous" means that no water was intentionally added to the capsule contents during the preparation of the oral polypeptide composition in this example, but this does not preclude the absorption of water from the air by the various components in the capsule contents.

[0438] Calculation shows that the oral polypeptide composition obtained in this embodiment has a mass fraction of 0.9% recombinant human insulin, a mass fraction of 34.5% fish oil, a mass fraction of 17.2% soybean trypsin inhibitor, a mass fraction of 12.9% disodium edetate, and a mass fraction of 34.5% Tween 80.

[0439] Example 2

[0440] This embodiment provides an oral polypeptide composition, which contains recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium edetate and Tween 80, wherein the mass of the recombinant human insulin is 16 mg.

[0441] Preparation method: 16 mg of recombinant human insulin, 105 mg of fish oil, 200 mg of soybean trypsin inhibitor, 320 mg of ethylenediaminetetraacetic acid disodium and 245 mg of Tween 80 are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor and ethylenediaminetetraacetic acid disodium are mixed, the weighed fish oil and Tween 80 are added, mixed evenly, and filled into a gelatin capsule. The capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 30 mg of talc and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, and the coating solution is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0442] The oral polypeptide composition prepared in this example contains capsules containing recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA, and Tween 80. The capsule contents are an anhydrous suspension. "Anhydrous" means that no water was intentionally added to the capsule contents during the preparation of the oral polypeptide composition in this example, but this does not preclude the absorption of water from the air by the various components in the capsule contents.

[0443] Calculation shows that the oral polypeptide composition obtained in this embodiment has a mass fraction of recombinant human insulin of 1.8%, a mass fraction of fish oil of 11.9%, a mass fraction of soybean trypsin inhibitor of 22.6%, a mass fraction of disodium edetate of 36.1%, and a mass fraction of Tween 80 of 27.7%.

[0444] Example 3

[0445] This embodiment provides an oral polypeptide composition, which contains recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium edetate and Tween 80, wherein the mass of the recombinant human insulin is 32 mg.

[0446] Preparation method: 32 mg of recombinant human insulin, 245 mg of fish oil, 70 mg of soybean trypsin inhibitor, 250 mg of ethylenediaminetetraacetic acid disodium and 105 mg of Tween 80 are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor and ethylenediaminetetraacetic acid disodium are mixed, the weighed fish oil and Tween 80 are added, mixed evenly, and filled into a gelatin capsule. The capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 30 mg of talc and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, and the coating solution is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0447] The oral polypeptide composition prepared in this example contains capsules containing recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA, and Tween 80. The capsule contents are an anhydrous suspension. "Anhydrous" means that no water was intentionally added to the capsule contents during the preparation of the oral polypeptide composition in this example, but this does not preclude the absorption of water from the air by the various components in the capsule contents.

[0448] Calculation shows that the oral polypeptide composition obtained in this embodiment has a mass fraction of 4.6% recombinant human insulin, a mass fraction of 34.9% fish oil, a mass fraction of 10.0% soybean trypsin inhibitor, a mass fraction of 35.6% disodium edetate, and a mass fraction of 15.0% Tween 80.

[0449] Example 4

[0450] This embodiment provides an oral polypeptide composition, which contains recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium edetate and Tween 80, wherein the mass of the recombinant human insulin is 8 mg.

[0451] Preparation method: 8 mg of recombinant human insulin, 50 mg of fish oil, 100 mg of soybean trypsin inhibitor, 300 mg of disodium edetate, and 450 mg of Tween 80 are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor, and disodium edetate are mixed, and the weighed fish oil and Tween 80 are added and mixed evenly, and the mixture is put into a gelatin capsule, and the capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 30 mg of talc, and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, and the coating solution is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0452] The oral polypeptide composition prepared in this example contains capsules containing recombinant human insulin, fish oil, soybean trypsin inhibitor, disodium EDTA, and Tween 80. The capsule contents are an anhydrous suspension. "Anhydrous" means that no water was intentionally added to the capsule contents during the preparation of the oral polypeptide composition in this example, but this does not preclude the absorption of water from the air by the various components in the capsule contents.

[0453] Calculation shows that the oral polypeptide composition obtained in this embodiment has a mass fraction of 0.9% recombinant human insulin, 5.5% fish oil, 11.0% soybean trypsin inhibitor, 33.0% disodium edetate, and 49.6% Tween 80.

[0454] Example 5-Comparative Example

[0455] This embodiment provides an oral polypeptide composition, which contains recombinant human insulin, soybean trypsin inhibitor, disodium edetate and Tween 80, wherein the mass of the recombinant human insulin is 16 mg.

[0456] Preparation method: 16 mg of recombinant human insulin, 200 mg of soybean trypsin inhibitor, 320 mg of ethylenediaminetetraacetic acid disodium and 350 mg of Tween 80 are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor and ethylenediaminetetraacetic acid disodium are mixed, and weighed Tween 80 is added and mixed evenly, and the mixture is put into a gelatin capsule, and the capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 30 mg of talc and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, and the coating solution is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0457] Example 6 - Comparative Example

[0458] This embodiment provides an oral polypeptide composition, which contains recombinant human insulin, fish oil, soybean trypsin inhibitor and disodium edetate, wherein the mass of the recombinant human insulin is 16 mg.

[0459] Preparation method: 16 mg of recombinant human insulin, 350 mg of fish oil, 200 mg of soybean trypsin inhibitor and 320 mg of EDTA disodium are weighed respectively; the weighed recombinant human insulin, soybean trypsin inhibitor and EDTA disodium are mixed, the weighed fish oil is added, mixed evenly, and placed in a gelatin capsule. The capsule is coated with a coating material comprising 40 mg of Eudragit L-100, 30 mg of talc and 5 mg of polyethylene glycol 6000. The coating material is dissolved in appropriate amounts of dichloromethane and isopropyl alcohol to obtain a coating solution, which is sprayed onto the capsule surface to obtain an oral polypeptide composition.

[0460] Example 7

[0461] Stability test

[0462] The content of recombinant human insulin in the oral polypeptide compositions of Example 1, Example 2, Example 3 and Example 4 was detected by HPLC at 25° C. on day 0, day 5, day 10, day 30 and day 60, respectively. Three samples of each oral polypeptide composition were tested at each time point. The results are shown in Table 1. The content in Table 1 is the average of the three samples at each time point.

[0463] Table 1 Stability data of recombinant human insulin at 25℃

[0464] "Recombinant human insulin content" refers to the percentage of the actual content of recombinant human insulin to the labeled amount. For example, the labeled amount of recombinant human insulin in an oral polypeptide composition is 8 mg. After standing, three samples are taken and tested by HPLC. The actual amount of recombinant human insulin (average value) is calculated to be 4.8 mg. The content of recombinant human insulin in the oral polypeptide composition is

[0465] HPLC conditions for the content of recombinant human insulin:

[0466] Chromatographic column: octadecylsilane bonded silica gel;

[0467] Mobile phase A: 600 mL of 0.1 M sodium sulfate buffer (pH 4.8), 100 mL of acetonitrile, and 300 mL of water;

[0468] Mobile phase B: 100 mL of 0.1 M sodium sulfate buffer (pH 4.8), 600 mL of acetonitrile, and 300 mL of water;

[0469] Flow rate: 1.0 ml / min; column temperature 35°C; detection wavelength UV 214 nm; injection volume 20 μl.

[0470] The gradient elution table is as follows:

[0471] Table 1.1 Gradient elution table

[0472] As shown in Table 1, the content of recombinant human insulin in the oral polypeptide composition at 25°C remains essentially unchanged after 5 days; the content of recombinant human insulin is greater than 95% after 10 days; the content of recombinant human insulin is greater than 83% after 30 days; and the content of recombinant human insulin is greater than 62% after 60 days.

[0473] HPLC was used to detect the content of recombinant human insulin in the oral polypeptide compositions of Example 1, Example 2, Example 3 and Example 4 at 40°C on day 0, day 5 and day 10, respectively. Three samples of each oral polypeptide composition were tested at each time point. The results are shown in Table 2. The content in Table 2 is the average of the three samples at each time point.

[0474] Table 2 Stability data of recombinant human insulin at 40℃

[0475] As shown in Table 2, when the oral polypeptide composition is placed at 40° C. for 5 days, the content of recombinant human insulin is greater than 84%; when placed for 10 days, the content of recombinant human insulin is greater than 75%.

[0476] Example 8

[0477] Dissolution test

[0478] According to the dissolution test method specified in the second method of Part 4 of the Chinese Pharmacopoeia 2020, using pH 6.8 phosphate buffer as the dissolution medium, the contents of the oral polypeptide compositions prepared in Examples 1, 2, 3, 4, 5, and 6 were poured into different dissolution cups and dissolved in the above dissolution medium at a speed of 50 revolutions per minute and a constant temperature of 37°C ± 0.5°C. Dissolution tests were performed. Samples were taken at 0 min, 2 min, 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min, and the recombinant human insulin content was measured by HPLC. The cumulative dissolution data are shown in Table 3.

[0479] Table 3 Cumulative dissolution data of recombinant human insulin

[0480] HPLC conditions for the content of recombinant human insulin:

[0481] Chromatographic column: octadecylsilane bonded silica gel;

[0482] Mobile phase A: 600 mL of 0.1 M sodium sulfate buffer (pH 4.8), 100 mL of acetonitrile, and 300 mL of water;

[0483] Mobile phase B: 100 mL of 0.1 M sodium sulfate buffer (pH 4.8), 600 mL of acetonitrile, and 300 mL of water;

[0484] Flow rate: 1.0 ml / min; column temperature 35°C; detection wavelength UV 214 nm; injection volume 20 μl.

[0485] The gradient elution table is as follows:

[0486] Table 3.1 Gradient elution table

[0487] From Table 3, we can see that

[0488] The oral polypeptide composition of Example 4 has a cumulative dissolution rate of more than 90% in 30 minutes, and is substantially completely dissolved in 45 minutes.

[0489] The oral polypeptide composition of Example 2 has a cumulative dissolution rate of more than 90% in 20 minutes and is substantially completely dissolved in 30 minutes.

[0490] The oral polypeptide compositions of Example 1 and Example 3 have a cumulative dissolution rate of greater than 80% in 2 minutes, a cumulative dissolution rate of greater than 90% in 5 minutes, and are substantially completely dissolved in 10 minutes.

[0491] Dissolution test

[0492] According to the dissolution test method specified in the second method of Part 0931 of the General Rules of the Fourth Volume of the 2020 Chinese Pharmacopoeia, using pH 6.8 phosphate buffer as the dissolution medium, the contents of the oral polypeptide compositions prepared in Examples 1, 2, 3, and 4 were poured into different dissolution cups and dissolved in the above dissolution medium at a speed of 50 rpm and a constant temperature of 37°C ± 0.5°C. Dissolution tests were performed. Samples were taken at 0 min, 2 min, 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min, and the soybean trypsin inhibitor content was measured by HPLC. Cumulative dissolution data are shown in Table 4.

[0493] Table 4 Cumulative dissolution data of soybean trypsin inhibitor

[0494] HPLC conditions for soybean trypsin inhibitor content:

[0495] Mobile phase A: water-acetonitrile-trifluoroacetic acid (95 ml: 5 ml: 0.05 ml);

[0496] Mobile phase B: water-acetonitrile-trifluoroacetic acid (10 ml: 90 ml: 0.05 ml);

[0497] Column: C18;

[0498] Flow rate: 1 mL / min;

[0499] Column temperature: 40°C;

[0500] Detector: UV 214 nm;

[0501] Injection volume: 20 μL;

[0502] The gradient elution table is as follows:

[0503] Table 4.1 Gradient elution table

[0504] Example 9

[0505] Animal testing

[0506] The oral polypeptide compositions prepared in Examples 1-4 were subjected to animal testing.

[0507] (1) Experimental animals

[0508] Beagle, male, 8-10kg.

[0509] (2) Animal grouping and drug administration design

[0510] Group design: The experiment set up 4 groups, namely low-dose group 1, medium-dose group, high-dose group, and low-dose group 2;

[0511] Number of animals: 8 males in each dosing group;

[0512] Experimental methods: Two rounds of experiments were conducted, with four groups of four mice in each round; the washout period was set at 48 hours;

[0513] Grouping method: Randomized groups were performed based on body weight. Specific grouping information is shown in Table 5.

[0514] Table 5 Dosage and group information

[0515] Note: [1] The first digit of the animal number represents the group, and the second letter represents the sex (M is male).

[0516] 4 or 5 digits represent the individual animal number;

[0517] [2] After the first round of the test, the second round of the test was conducted after 48 hours of washout and random grouping;

[0518] [3] Do not eat for more than 12 hours before administration.

[0519] (3) Method of administration

[0520] Low-dose group 1, medium-dose group, high-dose group, and low-dose group 2

[0521] Route of administration: Oral;

[0522] Dosing frequency: 1 dose;

[0523] Dosage quantity: 1 tablet;

[0524] (4) Blood glucose testing

[0525] Before and after administration, blood samples were collected from the forelimb vein and blood glucose was measured using a blood glucose meter.

[0526] in conclusion:

[0527] In the low-dose group 1, the blood sugar level began to decrease at 0.667 h, returned to normal at 2.5 h, and reached the maximum blood sugar-lowering effect at 1.33 h, with a maximum blood sugar-lowering rate of 49.72%.

[0528] The animals in the medium-dose group began to experience a decrease in blood sugar at 1.00 h, which returned to normal at 2.75 h, and reached the maximum blood sugar-lowering effect at 1.33 h, with a maximum blood sugar-lowering rate of 53.41%;

[0529] The blood sugar level of the animals in the high-dose group began to decrease at 0.667 hours, returned to normal at 3.5 hours, and reached the maximum blood sugar-lowering effect at 1.75 hours, with a maximum blood sugar-lowering rate of 61.18%;

[0530] The blood sugar level of animals in low-dose group 2 began to decrease at 0.667 h, returned to normal at 2.5 h, and reached the maximum blood sugar-lowering effect at 1.33 h, with a maximum blood sugar-lowering rate of 50.23%.

[0531] Calculation of blood sugar lowering rate: (average blood sugar value at each time point - blood sugar value at 0h) / blood sugar value at 0h.

[0532] The applicant declares that the above description is merely a preferred embodiment of the present invention and is intended only to illustrate the technical solution of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are included within the scope of protection of the present invention.

Claims

1. An oral polypeptide composition, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, The polypeptide is 0.1-100 parts by weight; The fish oil is 0.01-800 parts by weight; The protease inhibitor is 0.1-210 parts by weight; The absorption promoter is 0.1-320 parts by weight; and The surfactant is 1-800 parts by weight; Preferably, The polypeptide is 5-50 parts by weight; The fish oil is 30-400 parts by weight; The protease inhibitor is 40-210 parts by weight; The absorption promoter is 60-320 parts by weight; and The surfactant is 50-550 parts by weight; Preferably, The polypeptide is 8-32 parts by weight; The fish oil is 50-320 parts by weight; The protease inhibitor is 70-200 parts by weight; The absorption promoter is 120-320 parts by weight; and The surfactant is 105-450 parts by weight; Preferably, The polypeptide is 8-32 parts by weight; The fish oil is 105-320 parts by weight; The protease inhibitor is 70-200 parts by weight; The absorption promoter is 120-320 parts by weight; and The surfactant is 105-320 parts by weight; Preferably, The polypeptide is 8-32 parts by weight; The fish oil is 245-320 parts by weight; The protease inhibitor is 70-160 parts by weight; The absorption promoter is 120-250 parts by weight; and The surfactant is 105-320 parts by weight.

2. An oral polypeptide composition according to claim 1, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, The polypeptide is 1 part by weight; The fish oil is 0.01-800 parts by weight; The protease inhibitor is 0.1-210 parts by weight; The absorption promoter is 0.1-300 parts by weight; and The surfactant is 1-800 parts by weight; Preferably, The polypeptide is 1 part by weight; The fish oil is 3-50 parts by weight; 1-30 parts by weight of the protease inhibitor; The absorption promoter is 5-50 parts by weight; and The surfactant is 3-65 parts by weight; Preferably, The polypeptide is 1 part by weight; The fish oil is 6.3-40 parts by weight; The protease inhibitor is 2.2-20 parts by weight; The absorption promoter is 7.8-37.5 parts by weight; and The surfactant is 3.3-56.3 parts by weight; Preferably, The polypeptide is 1 part by weight; The fish oil is 6.6-40 parts by weight; The protease inhibitor is 2.2-20 parts by weight; The absorption promoter is 7.8-20 parts by weight; and The surfactant is 3.3-40 parts by weight; Preferably, The polypeptide is 1 part by weight; The fish oil is 7.7-40 parts by weight; The protease inhibitor is 2.2-20 parts by weight; The absorption promoter is 7.8-15 parts by weight; and The surfactant is 3.3-40 parts by weight.

3. An oral polypeptide composition according to claim 1, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, The mass fraction of the polypeptide is 0.1% to 10.0%; The mass fraction of the fish oil is 0.5% to 40.0%; The mass fraction of the protease inhibitor is 5.0% to 28.0%; The mass fraction of the absorption promoter is 8.0% to 42.0%; and The mass fraction of the surfactant is 10.0% to 55.0%; Preferably, The mass fraction of the polypeptide is 0.9% to 4.6%; The mass fraction of the fish oil is 5.5% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 22.6%; The mass fraction of the absorption promoter is 12.9% to 36.1%; and The mass fraction of the surfactant is 15.0% to 49.6%; Preferably, The mass fraction of the polypeptide is 0.9% to 4.6%; The mass fraction of the fish oil is 11.9% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 22.6%; The mass fraction of the absorption promoter is 12.9% to 36.1%; and The mass fraction of the surfactant is 15.0% to 34.5%; Preferably, The mass fraction of the polypeptide is 0.9% to 4.6%; The mass fraction of the fish oil is 20.0% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 17.2%; The mass fraction of the absorption promoter is 12.9% to 35.6%; and The mass fraction of the surfactant is 15.0% to 34.5%; Preferably, The mass fraction of the polypeptide is 0.9% to 4.6%; The mass fraction of the fish oil is 34.5% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 17.2%; The mass fraction of the absorption promoter is 12.9% to 35.6%; and The mass fraction of the surfactant is 15.0% to 34.5%; Preferably, The mass fraction of the polypeptide is 0.9% to 1.8%; The mass fraction of the fish oil is 11.9% to 34.5%; The mass fraction of the protease inhibitor is 17.2% to 22.6%; The mass fraction of the absorption promoter is 12.9% to 36.1%; and The mass fraction of the surfactant is 27.7% to 34.5%; Preferably, The mass fraction of the polypeptide is 1.8% to 4.6%; The mass fraction of the fish oil is 11.9% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 22.6%; The mass fraction of the absorption promoter is 35.6% to 36.1%; and The mass fraction of the surfactant is 15.0% to 27.7%.

4. An oral polypeptide composition according to claim 1, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, In unit dosage form, The polypeptide is 8-32 mg; The fish oil is 50-320 mg; The protease inhibitor is 70-200 mg; The absorption enhancer is 120-320 mg; and The surfactant is 105-450 mg; Preferably, The polypeptide is 8-32 mg; The fish oil is 105-320 mg; The protease inhibitor is 70-200 mg; The absorption enhancer is 120-320 mg; and The surfactant is 105-320 mg; Preferably, The polypeptide is 8-32 mg; The fish oil is 245-320 mg; The protease inhibitor is 70-160 mg; The absorption enhancer is 120-250 mg; and The surfactant is 105-320 mg.

5. An oral polypeptide composition according to claim 1, wherein the oral polypeptide composition comprises a polypeptide, fish oil, a protease inhibitor, at least one absorption enhancer and at least one surfactant; wherein, In unit dosage form, The polypeptide is 8 mg; The fish oil is 320 mg; The protease inhibitor is 160 mg; The absorption enhancer is 120 mg; and The surfactant is 320 mg; or, The polypeptide is 16 mg; The fish oil is 105 mg; The protease inhibitor is 200 mg; The absorption enhancer is 320 mg; and The surfactant is 245 mg; or, The polypeptide is 32 mg; The fish oil is 245 mg; The protease inhibitor is 70 mg; The absorption enhancer is 250 mg; and The surfactant is 105 mg; or, The polypeptide is 8 mg; The fish oil is 50 mg; The protease inhibitor is 100 mg; The absorption enhancer is 300 mg; and The surfactant is 450 mg.

6. The oral polypeptide composition according to claim 1, wherein the molecular weight of the polypeptide is 100Da to 20,000Da, preferably 1,000Da to 20,000Da, more preferably 1,000Da to 6,000Da, and further preferably 2,000Da to 6,000Da.

7. The oral polypeptide composition according to claim 1, wherein the polypeptide is selected from any one or more of insulin, or a derivative or analog thereof, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione and thymosin; Preferably, the polypeptide is selected from animal insulin, human insulin, recombinant human insulin, insulin derivatives, insulin analogs, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, Any one or more of triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteotide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, prokinase, polymyxin, serrapeptase, thymosin α1, thymopentin, and thymofasin kind; Preferably, the polypeptide is selected from porcine insulin, bovine insulin, human insulin, recombinant human insulin, lispro insulin, aspart insulin, protamine zinc insulin, protamine zinc insulin, glargine insulin, detemir insulin, degludec insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, recombinant growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protamine zinc insulin, gonadorelin, goserelin, buserelin, sermorelin, nafa Any one or more of oxazolidinone, histidine, triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, recombinant human interferon α2b, recombinant human interferon b, recombinant human interferon γ, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-angitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteopeptide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

8. The oral polypeptide composition according to claim 1, wherein the target protein of the protease inhibitor is selected from any one or more of serine proteases, trypsin, chymotrypsin, carboxypeptidase and aminopeptidase; Preferably, the protease inhibitor is selected from any one or more of cysteine ​​protease inhibitors, serine protease inhibitors, trypsin inhibitors, threonine protease inhibitors, aspartic acid protease inhibitors and metalloproteinase inhibitors; Preferably, the protease inhibitor is selected from soybean trypsin inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, ε-aminocaproic acid, antiprotease, α1-antichymotrypsin, antithrombin, α1-antitrypsin, 4-amidinophenyl-methanesulfonyl fluoride, aprotinin, benzamidine-HCl, chymostatin, diisopropyl fluoride-phosphate, leupeptin, phenylmethylsulfonyl fluoride, 1-chloro-3-sulfonylamino-7-amino-2-heptanone HCl, 1-chloro-3-sulfonylamino-4-phenyl-2-butanone, pentamidine isethionate, egg white trypsin inhibitor, pepsin inhibitor, α2-macroglobulin, guanidinium, iodoacetic acid, zinc and any one or more of a zinc chelator.

9. The oral polypeptide composition according to claim 1, wherein the at least one absorption promoter is selected from any one or more of ethylenediaminetetraacetic acid or a salt thereof, N-(8-(2-hydroxybenzoyl)amino)octanoic acid or a salt thereof, salicylic acid or a salt thereof, citric acid or a salt thereof, cholic acid or a salt thereof, deoxycholic acid or a salt thereof, glycocholic acid or a salt thereof, taurocholic acid or a salt thereof, alkyl glycoside, sodium lauryl sulfate, docusate sodium, cyclodextrin or a derivative thereof, chitosan or a derivative thereof, caprylic acid or a salt thereof, capric acid or a salt thereof, lauric acid or a salt thereof, myristic acid, palmitic acid, stearic acid, fatty acid triglyceride, lecithin, choline and carnitine, preferably, the ethylenediaminetetraacetic acid salt is selected from disodium edetate, dipotassium edetate, trisodium edetate or tetrasodium edetate.

10. The oral polypeptide composition according to claim 1, wherein the at least one surfactant is selected from any one or more of an ionic surfactant, a nonionic surfactant, and a zwitterionic surfactant; Preferably, the at least one surfactant is selected from ammonium lauryl sulfate, N-dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sodium lauryl sulfate, sodium docusate, cyclodextrin or its derivatives, chitosan or its derivatives, polyoxyethylene alkyl sodium sulfate, sodium lauryl ether sulfate, dioctyl sodium sulfosuccinate, poloxamer, glyceryl monostearate, glyceryl monolaurate, sorbitan monolaurate, sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene monopalmitate, polyoxyethylene hydrogenated castor oil, C6-C 12 Fatty acid triglycerides and C8-C 10 Any one or more of fatty acid triglycerides; Preferably, the at least one surfactant is selected from Tween, preferably, the at least one surfactant is selected from any one or more of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 and Tween 85.

11. The oral polypeptide composition according to any one of claims 1 to 10, wherein the weight ratio of fish oil to surfactant is 1:(0.2-15), preferably 1:(0.43-9), preferably 1:(0.43-5), preferably 1:(0.43-3), preferably 1:(0.43-2.33), preferably 1:(0.43-1).

12. The oral polypeptide composition according to any one of claims 1-10, wherein the weight ratio of the fish oil to the surfactant is 1:1, or 1:2.33, or 1:0.43, or 1:

9.

13. The oral polypeptide composition according to any one of claims 1-10, wherein the polypeptide is selected from human insulin, the protease inhibitor is selected from soybean trypsin inhibitor, the absorption promoter is selected from ethylenediaminetetraacetic acid or its salt, and the surfactant is selected from Tween.

14. The oral polypeptide composition according to any one of claims 1-10, wherein the polypeptide is selected from recombinant human insulin, the protease inhibitor is selected from soybean trypsin inhibitor, the absorption promoter is selected from ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid, and the surfactant is selected from Tween 80.

15. A medicine, wherein the medicine comprises the oral polypeptide composition according to claims 1-14; preferably, the medicine further comprises a pharmaceutically acceptable excipient.

16. The drug according to claim 15, wherein the pharmaceutically acceptable excipient comprises a coating selected from a gastric-soluble coating and / or an enteric-soluble coating; Preferably, the coating is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic resin, polyvinyl pyrrolidone, cellulose acetate phthalate, hypromellose phthalate and hypromellose acetate succinate. Any one or more of amber esters.

17. The drug according to claim 16, wherein the pharmaceutically acceptable excipients further comprise any one or more of an excipient, a disintegrant, a binder, a flavoring agent, and a lubricant; Preferably, the excipient is selected from any one or more of lactose, sorbitol, xylitol, mannitol, calcium sulfate, calcium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose starch complex, lactose cellulose complex and mannitol starch complex; Preferably, the disintegrant is selected from any one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; Preferably, the binder is selected from any one or more of starch slurry, gelatin solution, sucrose solution, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone; Preferably, the lubricant is selected from any one or more of sodium stearyl fumarate, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium stearate, calcium stearate, micropowder silica gel and talc; Preferably, the flavoring agent is selected from any one or more of mannitol, sorbitol, aspartame, stevioside, sucralose, aspartame, neotame, stevioside, hydroxystearic acid chloride and essence.

18. The drug according to any one of claims 15 to 17, wherein the drug is prepared into any one or more dosage forms selected from tablets, pills, capsules, emulsions, syrups or suspensions.

19. The medicament according to any one of claims 15 to 17, wherein the medicament is anhydrous.

20. A pharmaceutical composition comprising two or more different polypeptides, fish oil, a protease inhibitor, at least one absorption enhancer, and at least one surfactant; The total weight of the two or more different polypeptides is 0.1-100; The weight portion of the fish oil is 0.01-800; The weight portion of the protease inhibitor is 0.1-210; The weight portion of the absorption promoter is 0.1-300; and The weight portion of the surfactant is 1-800; Preferably, The total weight of the two or more different polypeptides is 1; The weight portion of the fish oil is 0.01-800; The weight portion of the protease inhibitor is 0.1-210; The weight portion of the absorption promoter is 0.1-300; and The weight portion of the surfactant is 1-800; Preferably, The two or more different polypeptides are present in the same preparation, or are independently present in different preparations; Preferably, the two or more different polypeptides are selected from any two or more of insulin, or a derivative or analog thereof, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione and thymosin; More preferably, the two or more different polypeptides are selected from animal insulin, human insulin, recombinant human insulin, insulin derivatives, insulin analogs, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, group Any two or more of aminorelin, triptorelin, tesmorelin, cortisone, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-agitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteotide, myosinidine, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alaninerelin, protrypsin, polymyxin, serrapeptase, thymosin α1, thymopentin, and thymofasin; Preferably, the two or more different polypeptides are selected from porcine insulin, bovine insulin, human insulin, recombinant human insulin, lispro insulin, aspart insulin, protamine zinc insulin, protamine zinc insulin, glargine insulin, detemir insulin, degludec insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, lixisenatide, calcitonin, salmon calcitonin, recombinant growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, abalaparatide, leuprorelin, protamine zinc insulin, gonadorelin, goserelin, buserelin, sermorelin, Any two or more of lin, nafarelin, histrelin, triptorelin, tesmorelin, cortirelin, heparin, granulocyte colony-stimulating factor, prostaglandin, cyclosporine, recombinant human interferon α2b, recombinant human interferon b, recombinant human interferon γ, vasopressin, vancomycin, erythropoietin, lanreotide acetate, terlipressin, anti-angitide, nesiritide, eptifibatide, sifuvirtide, atosiban, osteopeptide, myosin, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alanine, trypsinogenase, polymyxin, serrapeptase, thymosin α1, thymopentin and thymofasin.

21. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition comprises two or more different polypeptides, fish oil, a protease inhibitor, at least one absorption enhancer, and at least one surfactant; in The total mass fraction of the two or more different polypeptides is 0.1% to 10.0%; The mass fraction of the fish oil is 0.5% to 40.0%; The mass fraction of the protease inhibitor is 5.0% to 28.0%; The mass fraction of the absorption promoter is 8.0% to 42.0%; and The mass fraction of the surfactant is 10.0% to 55.0%; Preferably, The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%; The mass fraction of the fish oil is 5.5% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 22.6%; The mass fraction of the absorption promoter is 12.9% to 36.1%; and The mass fraction of the surfactant is 15.0% to 49.6%; Preferably, The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%; The mass fraction of the fish oil is 11.9% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 22.6%; The mass fraction of the absorption promoter is 12.9% to 36.1%; and The mass fraction of the surfactant is 15.0% to 34.5%; Preferably, The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%; The mass fraction of the fish oil is 20.0% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 17.2%; The mass fraction of the absorption promoter is 12.9% to 35.6%; and The mass fraction of the surfactant is 15.0% to 34.5%; Preferably, The total mass fraction of the two or more different polypeptides is 0.9% to 4.6%; The mass fraction of the fish oil is 34.5% to 34.9%; The mass fraction of the protease inhibitor is 10.0% to 17.2%; The mass fraction of the absorption promoter is 12.9% to 35.6%; and The mass fraction of the surfactant is 15.0% to 34.5%.

22. The pharmaceutical composition according to claim 21, wherein the weight ratio of fish oil to surfactant is 1:(0.2-15), preferably 1:(0.43-9), preferably 1:(0.43-5), preferably 1:(0.43-3), preferably 1:(0.43-2.33), preferably 1:(0.43-1).

23. The pharmaceutical composition according to claim 21, wherein the weight ratio of the fish oil to the surfactant is 1:1, or 1:2.33, or 1:0.43, or 1:

9.

24. Use of the oral polypeptide composition according to any one of claims 1-14, the medicine according to any one of claims 15-19, or the pharmaceutical composition according to any one of claims 20-23 in the preparation of a medicament for preventing or treating diabetes, obesity, impaired glucose tolerance, hepatic steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer, and improving immunity.

25. Use of the oral polypeptide composition according to any one of claims 1-14, the medicament according to any one of claims 15-19, and the pharmaceutical composition according to any one of claims 20-23 in the preparation of a medicament for preventing or treating non-alcoholic fatty liver disease, wherein the non-alcoholic fatty liver disease is selected from simple fatty liver and / or non-alcoholic steatohepatitis.

26. Use of the oral polypeptide composition according to any one of claims 1-14, the medicine according to any one of claims 15-19, and the pharmaceutical composition according to any one of claims 20-23 in the preparation of a medicament for preventing or treating non-alcoholic fatty liver disease combined with diabetes, non-alcoholic fatty liver disease combined with kidney disease, non-alcoholic fatty liver disease combined with cardiovascular disease, non-alcoholic fatty liver disease combined with obesity, and non-alcoholic fatty liver disease combined with hyperlipidemia.

27. A method for treating or preventing a disease, wherein the method comprises orally administering to a subject in need thereof a therapeutically effective amount of the oral polypeptide composition of any one of claims 1-14, the medicament of any one of claims 15-19, or the pharmaceutical composition of any one of claims 20-23, wherein the disease is selected from diabetes, obesity, impaired glucose tolerance, hepatic steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer, and immune diseases.

28. A method for treating or preventing a disease, wherein the method comprises orally administering to a subject in need thereof a therapeutically effective amount of the oral polypeptide composition of any one of claims 1-14, the medicament of any one of claims 15-19, or the pharmaceutical composition of any one of claims 20-23, wherein the disease is selected from non-alcoholic fatty liver disease.

29. A method for treating or preventing a disease, wherein the method comprises orally administering to a subject in need thereof a therapeutically effective amount of the oral polypeptide composition of any one of claims 1-14, the medicament of any one of claims 15-19, or the pharmaceutical composition of any one of claims 20-23, wherein the disease is selected from non-alcoholic fatty liver disease combined with diabetes, non-alcoholic fatty liver disease combined with kidney disease, non-alcoholic fatty liver disease combined with cardiovascular disease, non-alcoholic fatty liver disease combined with obesity, and non-alcoholic fatty liver disease combined with hyperlipidemia.

30. A method for treating or preventing a disease according to any one of claims 27 to 29, comprising orally administering to a subject a single dose of 8-32 mg of the polypeptide in the oral polypeptide composition according to any one of claims 1 to 14, 1 to 3 times a day, 1 to 3 capsules each time; or orally administering to a subject a single dose of 8-32 mg of the polypeptide in the medicament according to any one of claims 15 to 19, 1 to 3 times a day, 1 to 3 capsules each time; or orally administering to a subject a single dose of 8-32 mg of the polypeptide in the pharmaceutical composition according to any one of claims 20 to 23, 1 to 3 times a day, 1 to 3 capsules each time.

31. A method for treating or preventing a disease according to any one of claims 27 to 29, comprising orally administering to a subject a single dose of 8 mg, 16 mg, or 32 mg of the polypeptide in the oral polypeptide composition of any one of claims 1 to 14, 1, 2, or 3 times a day, 1, 2, or 3 times a day; or orally administering to a subject a single dose of 8 mg, 16 mg, or 32 mg of the polypeptide in the medicament of any one of claims 15 to 19, 1, 2, or 3 times a day, 1, 2, or 3 times a day; or orally administering to a subject a single dose of 8 mg, 16 mg, or 32 mg of the polypeptide in the pharmaceutical composition of any one of claims 20 to 23, 1, 2, or 3 times a day, 1, 2, or 3 times a day.