WO2024012589A1 - Polypeptide composition, pharmaceutical, pharmaceutical composition, and use thereof - Google Patents

Abstract

The present disclosure relates to a polypeptide composition, a pharmaceutical, a pharmaceutical composition, and a use thereof. The polypeptide composition comprises a polypeptide, a protease inhibitor, vegetable oil and an absorption promoter. The polypeptide composition provided by the present disclosure can markedly improve the in vitro stability of a polypeptide pharmaceutical, and oral administration of the polypeptide pharmaceutical can be achieved.

Description

A polypeptide composition, medicine, pharmaceutical composition and application thereof Technical field

The present disclosure belongs to the technical field of drug preparation, and specifically relates to a polypeptide composition for oral administration, a drug, a pharmaceutical composition and its application.

Background technique

In the process of disease treatment, peptide drugs are highly specific and effective, making them an ideal choice for the treatment of many human diseases. With the development of biotechnology, peptide drugs are increasingly used in clinical applications, such as calcitonin, insulin, and thymosin. However, peptide drugs have poor stability in vitro and low bioavailability in vivo, and can generally only be administered by injection. However, injection administration can easily lead to side effects such as infection and inflammation, and it is difficult for patients to overcome their fear of needles and poor compliance, which reduces patients' enthusiasm for taking medication on time.

Chinese Patent Publication No. CN103260608A, published on August 21, 2013, discloses an oral composition of semaglutide, which includes semaglutide and N-(8-(2-hydroxybenzoyl)amine ) sodium octanoate.

Oral drug delivery is the most widely used and accepted mode 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 this field to provide a polypeptide drug delivery system to achieve oral administration of polypeptide drugs.

Contents of the invention

In view of the shortcomings of the existing technology, the purpose of this disclosure is to provide a polypeptide composition and its application. The polypeptide composition can improve the stability of the polypeptide in vitro and enable oral administration of the polypeptide.

In a first aspect, the present disclosure provides a polypeptide composition comprising a polypeptide, a protease inhibitor, a vegetable oil, and at least one absorption enhancer.

In some embodiments, vegetable oils serve as stabilizers for polypeptides in the present disclosure, ensuring their stability in vitro.

In some embodiments, the polypeptides of the present disclosure include, but are not limited to: insulin, glucagon, glucagon-like peptide-1 (GLP-1) receptor agonist, glucagon Glucagon-like peptide-2 (GLP-2) receptor agonist, calcitonin (CT), growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, Any one or more of gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione, and thymosin species mixture.

In some embodiments, the polypeptides of the present disclosure include, but are not limited to: recombinant human insulin, insulin degludec, glucagon, exenatide, belaglutide, liraglutide, loxenatide, durglutide, Laglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, raw Long hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, leuprolide, prorelin, gonarelin, goserelin, buserelin, sermorelin , nafarelin, histrelin, triptorelin, timorelin, codorelin, lanreotide acetate, terlipressin, antiganide, teriparatide, abapa Peptides, nesiritide, eptifibatide, lixisenatide, sifuvirtide, atosiban, versicolor glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione, mannan Polyglycan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alamorelin, trypticin, polymyxin, serine Any one or a mixture of several of rapeptidase, thymosin α1, thymopentin and thymofaxin.

In some embodiments, the insulins described in this disclosure include human insulin, proinsulin, and insulin-like compounds, where the insulin-like compounds include insulin analogs, insulin derivatives, and the like.

In some embodiments, the insulins of the present disclosure include animal insulin and human insulin.

In some embodiments, the insulins of the present disclosure include rapid-acting insulins, short-acting insulins, intermediate-acting insulins, long-acting insulins, and ultra-long-acting insulins.

In some embodiments, an insulin analog as described in this disclosure refers to an insulin in which one or more amino acids are substituted while retaining some or all of one or more glucose-related activities of insulin.

In some embodiments, the insulins described in the present disclosure include: (1) rapid-acting insulin, such as insulin lispro, insulin aspart; (2) short-acting insulin, such as recombinant human insulin; (3) intermediate-acting insulin, such as low-acting insulin Protein zinc insulin (NPH); (4) long-acting insulin, such as protamine zinc insulin, insulin glargine, insulin detemir, insulin degludec, etc.; (5) ultra-long-acting insulin; (6) shifted insulin analogs ; (7) Insulin deletion analogs; (8) Derivatized insulins; (9) Derivatized insulin analogs; (10) Derivatized proinsulin; (11) Human insulin analog complexes (e.g., hexamer complexes) ; (12) Insulin mixture and (13) PEG insulin.

In some embodiments, glucagon-like peptide-1 described in this disclosure includes short-acting GLP-1 receptor agonists and long-acting GLP-1 receptor agonists.

In some embodiments, the glucagon-like peptide-1 of the present disclosure includes: Exenatide (trade name: Benaglutide), lixisenatide (Lixisenatide, trade name: Benaglutide) (Mingyi Shengtai), Liraglutide (Liraglutide, trade name Novoli), Taspoglutide (Taspoglutide), Loxenatide (Loxenatide, trade name Fulaimei), Semaglutide, Albiglutide and Dulaglutide (trade name: Dulaglutide), etc.

In some embodiments, the thymosin peptides described in this disclosure include; thymosin al, thymosin, thymosin beta4, or thymopentin.

In some embodiments, the polypeptides in the compositions described in the present disclosure can also be replaced with other active substances, such as other small molecule substances with poor oral bioavailability.

In some embodiments, the molecular weight of the polypeptides of the present disclosure is 100Da to 20000Da. In some embodiments, the molecular weight of the polypeptides of the present disclosure 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, 350 0Da, 3600Da, 3700Da, 3800Da, 3900Da, 4000Da, 4100Da, 4200Da, 4300Da, 4400Da, 4500Da, 4600Da, 4700Da, 4800Da, 4900Da, 5000Da, 5100Da, 5200Da, 5300Da, 5400Da, 5500Da, 5600Da, 5700Da, 5800Da, 5900Da, 600 0Da, 6100Da, 6200Da, 6300Da, 6400Da, 6500Da, 6600Da, 6700Da, 6800Da, 6900Da, 7000Da, 7100Da, 7200Da, 7300Da, 7400Da, 7500Da, 7600Da, 7700Da, 7800Da, 7900Da, 8000Da, 8100Da, 8200Da, 8300Da, 8400Da, 850 0Da, 8600Da, 8700Da, 8800Da, 8900Da, 9000Da, 9100Da, 9200Da, 9300Da, 9400Da, 9500Da, 9600Da, 9700Da, 9800Da, 9900Da, 10000Da, 11000Da, 12000Da, 13000Da, 14000Da, 15000Da, 16000Da, 17000Da, 18000Da, 19000Da, 20000Da; or any range between the above values .

In some embodiments, the molecular weight of the polypeptides described herein ranges from 1,000 Da to 20,000 Da. In some embodiments, the molecular weight of the polypeptides described herein ranges from 1,000 Da to 6,150 Da. In some embodiments, the molecular weight of the polypeptides described herein ranges from 1,209 Da. ~6104 Da. In some embodiments, the molecular weight of the polypeptides described in the present disclosure is 1000 Da ~ 6000 Da. In some embodiments, the molecular weight of the polypeptides described in the present disclosure is 2000 Da ~ 6000 Da.

In some embodiments, the polypeptides described in the present disclosure can be selected from the polypeptides described in Table 1 below:

Table 1

In some embodiments, the polypeptides described in the present disclosure may be naturally extracted polypeptides, chemically synthesized polypeptides, or polypeptides prepared through genetic engineering.

In some embodiments, the human insulin described in the present disclosure can be insulin prepared by chemical synthesis, or recombinant human insulin obtained by genetic engineering.

In some embodiments, the polypeptide compositions of the present disclosure are for oral administration; in some embodiments, the polypeptide compositions of the present disclosure for oral administration are prepared into the following dosage forms: tablets, pills, capsules, emulsions, Syrup or suspension.

Compared with the nanosystems prepared in the prior art, in the composition system provided by the present disclosure, the polypeptide exists in the form of a suspension, the system is uniform, and no burst release occurs, and there is no need to consider the encapsulation rate during the preparation process. problem, product quality is easy to control.

In some embodiments, the vegetable oil described in the present disclosure is selected from any one or a combination of castor oil, perilla oil, linseed oil, corn oil or soybean oil. In some embodiments, the vegetable oil described in the present disclosure is The vegetable oil is castor oil, perilla oil, or linseed oil. In some embodiments, the vegetable oil of the present disclosure is castor oil.

In some embodiments, the vegetable oils described in the present disclosure can be used in any combination. In some embodiments, the vegetable oils described in the present disclosure can be used in a combination of castor oil and linseed oil, a combination of castor oil and perilla oil, Combination of castor oil and corn oil, combination of castor oil and soybean oil, combination of perilla oil and linseed oil, combination of perilla oil and corn oil, combination of perilla oil and soybean oil, linseed oil and corn oil Combination of linseed oil and soybean oil, combination of corn oil and soybean oil, combination of castor oil, perilla oil and soybean oil, combination of castor oil, linseed oil and corn oil, castor oil, linseed oil combination with soybean oil, combination of castor oil, corn oil and soybean oil, combination of castor oil, perilla oil, linseed oil and corn oil, combination of castor oil, perilla oil, linseed oil and soybean oil, purple A combination of castor oil, linseed oil, corn oil and soybean oil, or a combination of castor oil, perilla oil, linseed oil, corn oil and soybean oil.

In some embodiments, the target protein of the protease inhibitor of the present disclosure is selected from any one or more of serine proteases, trypsin, chymotrypsin, carboxypeptidase, and aminopeptidase.

In some embodiments, the protease inhibitors of the present disclosure are selected from the group consisting of cysteine protease inhibitors, serine protease inhibitors, trypsin inhibitors, threonine protease inhibitors, aspartic protease inhibitors, and metalloprotease inhibitors any one or more inhibitors.

In some embodiments, the protease inhibitors of the present disclosure include naturally extracted protease inhibitors or protease inhibitors prepared using genetic engineering.

In some embodiments, the protease inhibitor of the present disclosure is selected from the group consisting of soybean trypsin inhibitor (SBTI), 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF-HCl, ), ε-aminocaproic acid, antiprotease, α1-antichymotrypsin, antithrombin, α1-antitrypsin, 4-amidophenyl-methanesulfonyl fluoride, aprotinin (sprotinin), benzamidine Hydrochloride, chymotrypsin, diisopropyl fluoride-phosphate, leupeptin, phenylmethylsulfonyl fluoride (PMSF), 1-chloro-3-toluenesulfonylamino-7-amino-2- Heptanone hydrochloride (TLCK), 1-chloro-3-toluenesulfonamido-4-phenyl-2-butanone (TPCK), pentamidine isethionate, egg white trypsin inhibitor (ovomycin Any one or more of protein), pepsin inhibitor, α2-macroglobulin, guanidium, iodoacetate, zinc and zinc chelators.

In some embodiments, the absorption enhancer of the present disclosure is selected from ethylenediaminetetraacetic acid or a salt thereof, ethylene glycol-bis(2-aminoethyl ether)-N,N,N′N′-tetraacetic acid or a salt thereof , N-(8-(2-hydroxybenzoyl)amino)octanoic acid or its salt, salicylic acid or its salt, citric acid or its salt, cholic acid or its salt, deoxycholic acid or its salt, glycine Cholic 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 Any one or more types of carnitines. In some embodiments, the absorption enhancer of the present disclosure is selected from the sodium salt of ethylenediaminetetraacetic acid.

In some embodiments, the polypeptide composition of the present disclosure includes, by mass parts:

Peptide: 0.1～100 parts by mass,

Vegetable oil: 0.1~1000 parts by mass,

Protease inhibitor: 1 to 300 parts by mass, and

Absorption enhancer: 1 to 500 parts by mass.

In some embodiments, the polypeptide composition of the present disclosure includes, by mass parts:

Peptide: 0.1～100 parts by mass,

Vegetable oil: 0.1~1000 parts by mass,

Protease inhibitor: 1 to 400 parts by mass, and

Absorption enhancer: 1 to 500 parts by mass.

In some embodiments, the polypeptide composition of the present disclosure includes, by mass parts:

Peptide: 2 to 50 parts by mass,

Vegetable oil: 90 to 532 parts by mass,

Protease inhibitor: 50 to 341 parts by mass, and

Absorption enhancer: 50 to 326 parts by mass.

In some embodiments, the mass fraction of the polypeptide described in the disclosure is 0.1 to 100 parts by mass. In some embodiments, the mass fraction of the polypeptide described in the disclosure can be 0.1 part, 0.2 part, 0.3 part, or 0.4 part. , 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 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 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 servings, 21 servings, 22 servings, 23 servings, 24 servings, 25 servings, 26 servings, 27 servings, 28 servings, 29 copies, 30 copies, 31 copies, 32 copies, 33 copies, 34 copies, 35 copies, 36 copies, 37 copies, 38 copies, 39 copies, 40 copies, 41 copies, 42 copies, 43 copies, 44 copies, 45 copies , 46 copies, 47 copies, 48 copies, 49 copies, 50 copies, 51 copies, 52 copies, 53 copies, 54 copies, 55 copies, 56 copies, 57 copies, 58 copies, 59 copies, 60 copies, 61 copies, 62 63 copies, 64 copies, 65 copies, 66 copies, 67 copies, 68 copies, 69 copies, 70 copies, 71 copies, 72 copies, 73 copies, 74 copies, 75 copies, 76 copies, 77 copies, 78 copies, 79 copies, 80 copies, 81 copies, 82 copies, 83 copies, 84 copies, 85 copies, 86 copies, 87 copies, 88 copies, 89 copies, 90 copies, 91 copies, 92 copies, 93 copies, 94 copies, 95 copies , 96 parts, 97 parts, 98 parts, 99 parts, 100 parts, etc. Other specific point values within this numerical range can be selected, and I will not go into details here.

In some embodiments, the mass fraction of the vegetable oil described in the present disclosure is 0.1 to 1000 mass parts. In some embodiments, the mass fraction of the vegetable oil described in the present disclosure can be 0.1 part, 0.2 part, 0.3 part, or 0.4 part. , 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 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 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 servings, 21 servings, 22 servings, 23 servings, 24 servings, 25 servings, 26 servings, 27 servings, 28 servings, 29 30 copies, 31 copies, 32 copies, 33 copies, 34 copies, 35 copies, 36 copies, 37 copies, 38 copies, 39 copies, 40 copies, 41 copies, 42 copies, 43 copies, 44 copies, 45 copies, 46 copies, 47 copies, 48 copies, 49 copies, 50 copies, 51 copies, 52 copies, 53 copies, 54 copies, 55 copies, 56 copies, 57 copies, 58 copies, 59 copies, 60 copies, 61 copies, 62 copies , 63 copies, 64 copies, 65 copies, 66 copies, 67 copies, 68 copies, 69 copies, 70 copies, 71 copies, 72 copies, 73 copies, 74 copies, 75 copies, 76 copies, 77 copies, 78 copies, 79 80 copies, 81 copies, 82 copies, 83 copies, 84 copies, 85 copies, 86 copies, 87 copies, 88 copies, 89 copies, 90 copies, 91 copies, 92 copies, 93 copies, 94 copies, 95 copies, 96 copies, 97 copies, 98 copies, 99 copies, 100 copies, 101 copies, 102 copies, 103 copies, 104 copies, 105 copies, 106 copies, 107 copies, 108 copies, 109 copies, 110 copies, 111 copies, 112 copies , 113 copies, 114 copies, 115 copies, 116 copies, 117 copies, 118 copies, 119 copies, 120 copies, 121 copies, 122 copies, 123 copies, 124 copies, 125 copies, 126 copies, 127 copies, 128 copies, 129 130 copies, 131 copies, 132 copies, 133 copies, 134 copies, 135 copies, 136 copies, 137 copies, 138 copies, 139 copies, 140 copies, 141 copies, 142 copies, 143 copies, 144 copies, 145 copies, 146 copies, 147 copies, 148 copies, 149 copies, 150 copies, 151 copies, 152 copies, 153 copies, 154 copies, 155 copies, 156 copies, 157 copies, 158 copies, 159 copies, 160 copies, 161 copies, 162 copies , 163 copies, 164 copies, 165 copies, 166 copies, 167 copies, 168 copies, 169 copies, 170 copies, 171 copies, 172 copies, 173 copies, 174 copies, 175 copies, 176 copies, 177 copies, 178 copies, 179 180 copies, 181 copies, 182 copies, 183 copies, 184 copies, 185 copies, 186 copies, 187 copies, 188 copies, 189 copies, 190 copies, 191 copies, 192 copies, 193 copies, 194 copies, 195 copies, 196 copies, 197 copies, 198 copies, 199 copies, 200 copies, 201 copies, 202 copies, 203 copies, 204 copies, 205 copies, 206 copies, 207 copies, 208 copies, 209 copies, 210 copies, 211 copies, 212 copies , 213 copies, 214 copies, 215 copies, 216 copies, 217 copies, 218 copies, 219 copies, 220 copies, 221 copies, 222 copies, 223 copies, 224 copies, 225 copies, 226 copies, 227 copies, 228 copies, 229 230 copies, 231 copies, 232 copies, 233 copies, 234 copies, 235 copies, 236 copies, 237 copies, 238 copies, 239 copies, 240 copies, 241 copies, 242 copies, 243 copies, 244 copies, 245 copies, 246 copies, 247 copies, 248 copies, 249 copies, 250 copies, 251 copies, 252 copies, 253 copies, 254 copies, 255 copies, 256 copies, 257 copies, 258 copies, 259 copies, 260 copies, 261 copies, 262 copies , 263 copies, 264 copies, 265 copies, 266 copies, 267 copies, 268 copies, 269 copies, 270 copies, 271 copies, 272 copies, 273 copies, 274 copies, 275 copies, 276 copies, 277 copies, 278 copies, 279 280 copies, 281 copies, 282 copies, 283 copies, 284 copies, 285 copies, 286 copies, 287 copies, 288 copies, 289 copies, 290 copies, 291 copies, 292 copies, 293 copies, 294 copies, 295 copies, 296 copies, 297 copies, 298 copies, 299 copies, 300 copies, 301 copies, 302 copies, 303 copies, 304 copies, 305 copies, 306 copies, 307 copies, 308 copies, 309 copies, 310 copies, 311 copies, 312 copies , 313 copies, 314 copies, 315 copies, 316 copies, 317 copies, 318 copies, 319 copies, 320 copies, 321 copies, 322 copies, 323 copies, 324 copies, 325 copies, 326 copies, 327 copies, 328 copies, 329 330 copies, 331 copies, 332 copies, 333 copies, 334 copies, 335 copies, 336 copies, 337 copies, 338 copies, 339 copies, 340 copies, 341 copies, 342 copies, 343 copies, 344 copies, 345 copies, 346 copies, 347 copies, 348 copies, 349 copies, 350 copies, 351 copies, 352 copies, 353 copies, 354 copies, 355 copies, 356 copies, 357 copies, 358 copies, 359 copies, 360 copies, 361 copies, 362 copies , 363 copies, 364 copies, 365 copies, 366 copies, 367 copies, 368 copies, 369 copies, 370 copies, 371 copies, 372 copies, 373 copies, 374 copies, 375 copies, 376 copies, 377 copies, 378 copies, 379 copies, 380 copies, 381 copies, 382 copies, 383 copies, 384 copies, 385 copies, 386 copies, 387 copies, 388 copies, 389 copies, 390 copies, 391 copies, 392 copies, 393 copies, 394 copies, 395 copies, 396 copies, 397 copies , 398 copies, 399 copies, 400 copies, 401 copies, 402 copies, 403 copies, 404 copies, 405 copies, 406 copies, 407 copies, 408 copies, 409 copies, 410 copies, 411 copies, 412 copies, 413 copies, 414 415 copies, 416 copies, 417 copies, 418 copies, 419 copies, 420 copies, 421 copies, 422 copies, 423 copies, 424 copies, 425 copies, 426 copies, 427 copies, 428 copies, 429 copies, 430 copies, 431 copies, 432 copies, 433 copies, 434 copies, 435 copies, 436 copies, 437 copies, 438 copies, 439 copies, 440 copies, 441 copies, 442 copies, 443 copies, 444 copies, 445 copies, 446 copies, 447 copies , 448 copies, 449 copies, 450 copies, 451 copies, 452 copies, 453 copies, 454 copies, 455 copies, 456 copies, 457 copies, 458 copies, 459 copies, 460 copies, 461 copies, 462 copies, 463 copies, 464 465 copies, 466 copies, 467 copies, 468 copies, 469 copies, 470 copies, 471 copies, 472 copies, 473 copies, 474 copies, 475 copies, 476 copies, 477 copies, 478 copies, 479 copies, 480 copies, 481 copies, 482 copies, 483 copies, 484 copies, 485 copies, 486 copies, 487 copies, 488 copies, 489 copies, 490 copies, 491 copies, 492 copies, 493 copies, 494 copies, 495 copies, 496 copies, 497 copies , 498 copies, 499 copies, 500 copies, 501 copies, 502 copies, 503 copies, 504 copies, 505 copies, 506 copies, 507 copies, 508 copies, 509 copies, 510 copies, 511 copies, 512 copies, 513 copies, 514 515 copies, 516 copies, 517 copies, 518 copies, 519 copies, 520 copies, 521 copies, 522 copies, 523 copies, 524 copies, 525 copies, 526 copies, 527 copies, 528 copies, 529 copies, 530 copies, 531 copies, 532 copies, 533 copies, 534 copies, 535 copies, 536 copies, 537 copies, 538 copies, 539 copies, 540 copies, 541 copies, 542 copies, 543 copies, 544 copies, 545 copies, 546 copies, 547 copies , 548 copies, 549 copies, 550 copies, 551 copies, 552 copies, 553 copies, 554 copies, 555 copies, 556 copies, 557 copies, 558 copies, 559 copies, 560 copies, 561 copies, 562 copies, 563 copies, 564 565 copies, 566 copies, 567 copies, 568 copies, 569 copies, 570 copies, 571 copies, 572 copies, 573 copies, 574 copies, 575 copies, 576 copies, 577 copies, 578 copies, 579 copies, 580 copies, 581 copies, 582 copies, 583 copies, 584 copies, 585 copies, 586 copies, 587 copies, 588 copies, 589 copies, 590 copies, 591 copies, 592 copies, 593 copies, 594 copies, 595 copies, 596 copies, 597 copies , 598 copies, 599 copies, 600 copies, 601 copies, 602 copies, 603 copies, 604 copies, 605 copies, 606 copies, 607 copies, 608 copies, 609 copies, 610 copies, 611 copies, 612 copies, 613 copies, 614 615 copies, 616 copies, 617 copies, 618 copies, 619 copies, 620 copies, 621 copies, 622 copies, 623 copies, 624 copies, 625 copies, 626 copies, 627 copies, 628 copies, 629 copies, 630 copies, 631 copies, 632 copies, 633 copies, 634 copies, 635 copies, 636 copies, 637 copies, 638 copies, 639 copies, 640 copies, 641 copies, 642 copies, 643 copies, 644 copies, 645 copies, 646 copies, 647 copies , 648 copies, 649 copies, 650 copies, 651 copies, 652 copies, 653 copies, 654 copies, 655 copies, 656 copies, 657 copies, 658 copies, 659 copies, 660 copies, 661 copies, 662 copies, 663 copies, 664 665 copies, 666 copies, 667 copies, 668 copies, 669 copies, 670 copies, 671 copies, 672 copies, 673 copies, 674 copies, 675 copies, 676 copies, 677 copies, 678 copies, 679 copies, 680 copies, 681 copies, 682 copies, 683 copies, 684 copies, 685 copies, 686 copies, 687 copies, 688 copies, 689 copies, 690 copies, 691 copies, 692 copies, 693 copies, 694 copies, 695 copies, 696 copies, 697 copies , 698 copies, 699 copies, 700 copies, 701 copies, 702 copies, 703 copies, 704 copies, 705 copies, 706 copies, 707 copies, 708 copies, 709 copies, 710 copies, 711 copies, 712 copies, 713 copies, 714 715 copies, 716 copies, 717 copies, 718 copies, 719 copies, 720 copies, 721 copies, 722 copies, 723 copies, 724 copies, 725 copies, 726 copies, 727 copies, 728 copies, 729 copies, 730 copies, 731 copies, 732 copies, 733 copies, 734 copies, 735 copies, 736 copies, 737 copies, 738 copies, 739 copies , 740 copies, 741 copies, 742 copies, 743 copies, 744 copies, 745 copies, 746 copies, 747 copies, 748 copies, 749 copies, 750 copies, 751 copies, 752 copies, 753 copies, 754 copies, 755 copies, 756 757 copies, 758 copies, 759 copies, 760 copies, 761 copies, 762 copies, 763 copies, 764 copies, 765 copies, 766 copies, 767 copies, 768 copies, 769 copies, 770 copies, 771 copies, 772 copies, 773 copies, 774 copies, 775 copies, 776 copies, 777 copies, 778 copies, 779 copies, 780 copies, 781 copies, 782 copies, 783 copies, 784 copies, 785 copies, 786 copies, 787 copies, 788 copies, 789 copies , 790 copies, 791 copies, 792 copies, 793 copies, 794 copies, 795 copies, 796 copies, 797 copies, 798 copies, 799 copies, 800 copies, 801 copies, 802 copies, 803 copies, 804 copies, 805 copies, 806 copies 807 copies, 808 copies, 809 copies, 810 copies, 811 copies, 812 copies, 813 copies, 814 copies, 815 copies, 816 copies, 817 copies, 818 copies, 819 copies, 820 copies, 821 copies, 822 copies, 823 copies, 824 copies, 825 copies, 826 copies, 827 copies, 828 copies, 829 copies, 830 copies, 831 copies, 832 copies, 833 copies, 834 copies, 835 copies, 836 copies, 837 copies, 838 copies, 839 copies , 840 copies, 841 copies, 842 copies, 843 copies, 844 copies, 845 copies, 846 copies, 847 copies, 848 copies, 849 copies, 850 copies, 851 copies, 852 copies, 853 copies, 854 copies, 855 copies, 856 857 copies, 858 copies, 859 copies, 860 copies, 861 copies, 862 copies, 863 copies, 864 copies, 865 copies, 866 copies, 867 copies, 868 copies, 869 copies, 870 copies, 871 copies, 872 copies, 873 copies, 874 copies, 875 copies, 876 copies, 877 copies, 878 copies, 879 copies, 880 copies, 881 copies, 882 copies, 883 copies, 884 copies, 885 copies, 886 copies, 887 copies, 888 copies, 889 copies , 890 copies, 891 copies, 892 copies, 893 copies, 894 copies, 895 copies, 896 copies, 897 copies, 898 copies, 899 copies, 900 copies, 901 copies, 902 copies, 903 copies, 904 copies, 905 copies, 906 907 copies, 908 copies, 909 copies, 910 copies, 911 copies, 912 copies, 913 copies, 914 copies, 915 copies, 916 copies, 917 copies, 918 copies, 919 copies, 920 copies, 921 copies, 922 copies, 923 copies, 924 copies, 925 copies, 926 copies, 927 copies, 928 copies, 929 copies, 930 copies, 931 copies, 932 copies, 933 copies, 934 copies, 935 copies, 936 copies, 937 copies, 938 copies, 939 copies , 940 copies, 941 copies, 942 copies, 943 copies, 944 copies, 945 copies, 946 copies, 947 copies, 948 copies, 949 copies, 950 copies, 951 copies, 952 copies, 953 copies, 954 copies, 955 copies, 956 957 copies, 958 copies, 959 copies, 960 copies, 961 copies, 962 copies, 963 copies, 964 copies, 965 copies, 966 copies, 967 copies, 968 copies, 969 copies, 970 copies, 971 copies, 972 copies, 973 copies, 974 copies, 975 copies, 976 copies, 977 copies, 978 copies, 979 copies, 980 copies, 981 copies, 982 copies, 983 copies, 984 copies, 985 copies, 986 copies, 987 copies, 988 copies, 989 copies , 990 copies, 991 copies, 992 copies, 993 copies, 994 copies, 995 copies, 996 copies, 997 copies, 998 copies, 999 copies, 1000 copies, etc. Other specific point values within this value range can be selected, here I won’t go into details one by one.

In some embodiments, the protease inhibitor described in the present disclosure is 1 to 300 parts by mass. In some embodiments, the protease inhibitor described in the present disclosure can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, or 6 parts. servings, 7 servings, 8 servings, 9 servings, 10 servings, 11 servings, 12 servings, 13 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 servings, 21 servings, 22 servings, 23 copies, 24 copies, 25 copies, 26 copies, 27 copies, 28 copies, 29 copies, 30 copies, 31 copies, 32 copies, 33 copies, 34 copies, 35 copies, 36 copies, 37 copies, 38 copies, 39 copies , 40 copies, 41 42 copies, 43 copies, 44 copies, 45 copies, 46 copies, 47 copies, 48 copies, 49 copies, 50 copies, 51 copies, 52 copies, 53 copies, 54 copies, 55 copies, 56 copies, 57 copies, 58 copies, 59 copies, 60 copies, 61 copies, 62 copies, 63 copies, 64 copies, 65 copies, 66 copies, 67 copies, 68 copies, 69 copies, 70 copies, 71 copies, 72 copies, 73 copies, 74 copies , 75 copies, 76 copies, 77 copies, 78 copies, 79 copies, 80 copies, 81 copies, 82 copies, 83 copies, 84 copies, 85 copies, 86 copies, 87 copies, 88 copies, 89 copies, 90 copies, 91 92 copies, 93 copies, 94 copies, 95 copies, 96 copies, 97 copies, 98 copies, 99 copies, 100 copies, 101 copies, 102 copies, 103 copies, 104 copies, 105 copies, 106 copies, 107 copies, 108 copies, 109 copies, 110 copies, 111 copies, 112 copies, 113 copies, 114 copies, 115 copies, 116 copies, 117 copies, 118 copies, 119 copies, 120 copies, 121 copies, 122 copies, 123 copies, 124 copies , 125 copies, 126 copies, 127 copies, 128 copies, 129 copies, 130 copies, 131 copies, 132 copies, 133 copies, 134 copies, 135 copies, 136 copies, 137 copies, 138 copies, 139 copies, 140 copies, 141 142 copies, 143 copies, 144 copies, 145 copies, 146 copies, 147 copies, 148 copies, 149 copies, 150 copies, 151 copies, 152 copies, 153 copies, 154 copies, 155 copies, 156 copies, 157 copies, 158 copies, 159 copies, 160 copies, 161 copies, 162 copies, 163 copies, 164 copies, 165 copies, 166 copies, 167 copies, 168 copies, 169 copies, 170 copies, 171 copies, 172 copies, 173 copies, 174 copies , 175 copies, 176 copies, 177 copies, 178 copies, 179 copies, 180 copies, 181 copies, 182 copies, 183 copies, 184 copies, 185 copies, 186 copies, 187 copies, 188 copies, 189 copies, 190 copies, 191 192 copies, 193 copies, 194 copies, 195 copies, 196 copies, 197 copies, 198 copies, 199 copies, 200 copies, 201 copies, 202 copies, 203 copies, 204 copies, 205 copies, 206 copies, 207 copies, 208 copies, 209 copies, 210 copies, 211 copies, 212 copies, 213 copies, 214 copies, 215 copies, 216 copies, 217 copies, 218 copies, 219 copies, 220 copies, 221 copies, 222 copies, 223 copies, 224 copies , 225 copies, 226 copies, 227 copies, 228 copies, 229 copies, 230 copies, 231 copies, 232 copies, 233 copies, 234 copies, 235 copies, 236 copies, 237 copies, 238 copies, 239 copies, 240 copies, 241 242 copies, 243 copies, 244 copies, 245 copies, 246 copies, 247 copies, 248 copies, 249 copies, 250 copies, 251 copies, 252 copies, 253 copies, 254 copies, 255 copies, 256 copies, 257 copies, 258 copies, 259 copies, 260 copies, 261 copies, 262 copies, 263 copies, 264 copies, 265 copies, 266 copies, 267 copies, 268 copies, 269 copies, 270 copies, 271 copies, 272 copies, 273 copies, 274 copies , 275 copies, 276 copies, 277 copies, 278 copies, 279 copies, 280 copies, 281 copies, 282 copies, 283 copies, 284 copies, 285 copies, 286 copies, 287 copies, 288 copies, 289 copies, 290 copies, 291 parts, 292 parts, 293 parts, 294 parts, 295 parts, 296 parts, 297 parts, 298 parts, 299 parts, 300 parts, etc. Other specific point values within this numerical range can be selected, and I will not go into details here. .

In some embodiments, the mass parts of the absorption enhancer described in the present disclosure are 1 to 500 parts by mass. In some embodiments, the mass parts of the absorption enhancer described in the present disclosure can be 1 part, 2 parts, 3 parts by mass. servings, 4 servings, 5 servings, 6 servings, 7 servings, 8 servings, 9 servings, 10 servings, 11 servings, 12 servings, 13 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 copies, 21 copies, 22 copies, 23 copies, 24 copies, 25 copies, 26 copies, 27 copies, 28 copies, 29 copies, 30 copies, 31 copies, 32 copies, 33 copies, 34 copies, 35 copies, 36 copies , 37 copies, 38 copies, 39 copies, 40 copies, 41 copies, 42 copies, 43 copies, 44 copies, 45 copies, 46 copies, 47 copies, 48 copies, 49 copies, 50 copies, 51 copies, 52 copies, 53 54 copies, 55 copies, 56 copies, 57 copies, 58 copies, 59 copies, 60 copies, 61 copies, 62 copies, 63 copies, 64 copies, 65 copies, 66 copies, 67 copies, 68 copies, 69 copies, 70 copies, 71 copies, 72 copies, 73 copies, 74 copies, 75 copies, 76 copies, 77 copies, 78 copies, 79 copies, 80 copies, 81 copies, 82 copies, 83 copies, 84 copies, 85 copies, 86 copies, 87 copies, 88 copies , 89 copies, 90 copies, 91 copies, 92 copies, 93 copies, 94 copies, 95 copies, 96 copies, 97 copies, 98 copies, 99 copies, 100 copies, 101 copies, 102 copies, 103 copies, 104 copies, 105 106 copies, 107 copies, 108 copies, 109 copies, 110 copies, 111 copies, 112 copies, 113 copies, 114 copies, 115 copies, 116 copies, 117 copies, 118 copies, 119 copies, 120 copies, 121 copies, 122 copies, 123 copies, 124 copies, 125 copies, 126 copies, 127 copies, 128 copies, 129 copies, 130 copies, 131 copies, 132 copies, 133 copies, 134 copies, 135 copies, 136 copies, 137 copies, 138 copies , 139 copies, 140 copies, 141 copies, 142 copies, 143 copies, 144 copies, 145 copies, 146 copies, 147 copies, 148 copies, 149 copies, 150 copies, 151 copies, 152 copies, 153 copies, 154 copies, 155 156 copies, 157 copies, 158 copies, 159 copies, 160 copies, 161 copies, 162 copies, 163 copies, 164 copies, 165 copies, 166 copies, 167 copies, 168 copies, 169 copies, 170 copies, 171 copies, 172 copies, 173 copies, 174 copies, 175 copies, 176 copies, 177 copies, 178 copies, 179 copies, 180 copies, 181 copies, 182 copies, 183 copies, 184 copies, 185 copies, 186 copies, 187 copies, 188 copies , 189 copies, 190 copies, 191 copies, 192 copies, 193 copies, 194 copies, 195 copies, 196 copies, 197 copies, 198 copies, 199 copies, 200 copies, 201 copies, 202 copies, 203 copies, 204 copies, 205 copies 206 copies, 207 copies, 208 copies, 209 copies, 210 copies, 211 copies, 212 copies, 213 copies, 214 copies, 215 copies, 216 copies, 217 copies, 218 copies, 219 copies, 220 copies, 221 copies, 222 copies, 223 copies, 224 copies, 225 copies, 226 copies, 227 copies, 228 copies, 229 copies, 230 copies, 231 copies, 232 copies, 233 copies, 234 copies, 235 copies, 236 copies, 237 copies, 238 copies , 239 copies, 240 copies, 241 copies, 242 copies, 243 copies, 244 copies, 245 copies, 246 copies, 247 copies, 248 copies, 249 copies, 250 copies, 251 copies, 252 copies, 253 copies, 254 copies, 255 256 copies, 257 copies, 258 copies, 259 copies, 260 copies, 261 copies, 262 copies, 263 copies, 264 copies, 265 copies, 266 copies, 267 copies, 268 copies, 269 copies, 270 copies, 271 copies, 272 copies, 273 copies, 274 copies, 275 copies, 276 copies, 277 copies, 278 copies, 279 copies, 280 copies, 281 copies, 282 copies, 283 copies, 284 copies, 285 copies, 286 copies, 287 copies, 288 copies , 289 copies, 290 copies, 291 copies, 292 copies, 293 copies, 294 copies, 295 copies, 296 copies, 297 copies, 298 copies, 299 copies, 300 copies, 301 copies, 302 copies, 303 copies, 304 copies, 305 copies 306 copies, 307 copies, 308 copies, 309 copies, 310 copies, 311 copies, 312 copies, 313 copies, 314 copies, 315 copies, 316 copies, 317 copies, 318 copies, 319 copies, 320 copies, 321 copies, 322 copies, 323 copies, 324 copies, 325 copies, 326 copies, 327 copies, 328 copies, 329 copies, 330 copies, 331 copies, 332 copies, 333 copies, 334 copies, 335 copies, 336 copies, 337 copies, 338 copies , 339 copies, 340 copies, 341 copies, 342 copies, 343 copies, 344 copies, 345 copies, 346 copies, 347 copies, 348 copies, 349 copies, 350 copies, 351 copies, 352 copies, 353 copies, 354 copies, 355 356 copies, 357 copies, 358 copies, 359 copies, 360 copies, 361 copies, 362 copies, 363 copies, 364 copies, 365 copies, 366 copies, 367 copies, 368 copies, 369 copies, 370 copies, 371 copies, 372 copies, 373 copies, 374 copies, 375 copies, 376 copies, 377 copies, 378 copies, 379 copies, 380 copies, 381 copies, 382 copies, 383 copies, 384 copies, 385 copies, 386 copies, 387 copies, 388 copies , 389 copies, 390 copies, 391 copies, 392 copies, 393 copies, 394 copies, 395 copies, 396 copies, 397 copies, 398 copies, 399 copies, 400 copies, 401 copies, 402 copies, 403 copies, 404 copies, 405 406 copies, 407 copies, 408 copies, 409 copies, 410 copies, 411 copies, 412 copies, 413 copies, 414 copies, 415 copies, 416 copies, 417 copies, 418 copies, 419 copies, 420 copies, 421 copies, 422 copies, 423 copies, 424 copies, 425 copies, 426 copies, 427 copies, 428 copies, 429 copies, 430 copies, 431 copies, 432 copies, 433 copies, 434 copies , 435 copies, 436 copies, 437 copies, 438 copies, 439 copies, 440 copies, 441 copies, 442 copies, 443 copies, 444 copies, 445 copies, 446 copies, 447 copies, 448 copies, 449 copies, 450 copies, 451 452 copies, 453 copies, 454 copies, 455 copies, 456 copies, 457 copies, 458 copies, 459 copies, 460 copies, 461 copies, 462 copies, 463 copies, 464 copies, 465 copies, 466 copies, 467 copies, 468 copies, 469 copies, 470 copies, 471 copies, 472 copies, 473 copies, 474 copies, 475 copies, 476 copies, 477 copies, 478 copies, 479 copies, 480 copies, 481 copies, 482 copies, 483 copies, 484 copies , 485 copies, 486 copies, 487 copies, 488 copies, 489 copies, 490 copies, 491 copies, 492 copies, 493 copies, 494 copies, 495 copies, 496 copies, 497 copies, 498 copies, 499 copies, 500 copies, etc., Other specific point values within this numerical range can be selected and will not be described one by one here.

In some embodiments, the polypeptide composition of the present disclosure includes, by mass parts:

Peptide: 1 to 80 parts by mass,

Vegetable oil: 10 to 850 parts by mass,

Protease inhibitor: 5 to 250 parts by mass, and

Absorption enhancer: 5 to 300 parts by mass.

In some embodiments, the polypeptide compositions of the present disclosure include, by mass parts;

Peptide: 1 to 50 parts by mass,

Vegetable oil: 50 to 850 parts by mass,

Protease inhibitor: 10 to 200 parts by mass, and

Absorption enhancer: 10 to 300 parts by mass.

In some embodiments, the polypeptide compositions of the present disclosure include, by mass parts;

Peptide: 2 to 50 parts by mass,

Vegetable oil: 90 to 532 parts by mass,

Protease inhibitor: 50 to 341 parts by mass, and

Absorption enhancer: 50 to 326 parts by mass.

In some embodiments, the polypeptide compositions of the present disclosure include, by mass parts;

Peptide: 1 to 50 parts by mass,

Vegetable oil: 50 to 500 parts by mass,

Protease inhibitor: 10 to 200 parts by mass, and

Absorption enhancer: 50 to 300 parts by mass.

In some embodiments, one or more absorption enhancers can be added to the polypeptide compositions of the present disclosure. In some embodiments, the absorption enhancers of the present disclosure include ethylenediaminetetraacetic acid or a salt thereof (such as ethylenediaminetetraacetic acid or a salt thereof). Disodium diamine tetraacetate), N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium salicylate, citric acid, cholic acid, deoxycholic acid, sodium deoxycholate, glycine Sodium cholate, taurocholate sodium salt, alkyl glycosides, sodium lauryl sulfate, sodium docusate, cyclodextrin or its derivatives, chitosan or its derivatives, caprylic acid, sodium caprylate, capric acid, Sodium caprate, lauric acid, sodium laurate, myristic acid, palmitic acid, stearic acid, fatty acid triglyceride, lecithin, bile Any one of alkali or carnitine or a combination of at least two.

In some embodiments, the polypeptide compositions of the present disclosure further comprise at least one emulsifier.

In some embodiments, the polypeptide composition of the present disclosure includes 0.1 to 1000 parts by mass of an emulsifier. In some embodiments, the emulsifier of the present disclosure is 10 to 850 parts by mass. In some embodiments, the emulsifier of the present disclosure is The emulsifier is 50 to 850 parts by mass. In some embodiments, the emulsifier of the present disclosure is 100 to 489 parts by mass.

In some embodiments, one or more emulsifiers can be added to the polypeptide compositions of the present disclosure. In some embodiments, the mass parts of the emulsifiers of the present disclosure can be 0.1 to 1000 parts by mass. In some cases, In embodiments, the mass parts of the emulsifier described in the present disclosure may be 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, 1 part, 2 part, 3 part servings, 4 servings, 5 servings, 6 servings, 7 servings, 8 servings, 9 servings, 10 servings, 11 servings, 12 servings, 13 servings, 14 servings, 15 servings, 16 servings, 17 servings, 18 servings, 19 servings, 20 copies, 21 copies, 22 copies, 23 copies, 24 copies, 25 copies, 26 copies, 27 copies, 28 copies, 29 copies, 30 copies, 31 copies, 32 copies, 33 copies, 34 copies, 35 copies, 36 copies , 37 copies, 38 copies, 39 copies, 40 copies, 41 copies, 42 copies, 43 copies, 44 copies, 45 copies, 46 copies, 47 copies, 48 copies, 49 copies, 50 copies, 51 copies, 52 copies, 53 54 copies, 55 copies, 56 copies, 57 copies, 58 copies, 59 copies, 60 copies, 61 copies, 62 copies, 63 copies, 64 copies, 65 copies, 66 copies, 67 copies, 68 copies, 69 copies, 70 copies, 71 copies, 72 copies, 73 copies, 74 copies, 75 copies, 76 copies, 77 copies, 78 copies, 79 copies, 80 copies, 81 copies, 82 copies, 83 copies, 84 copies, 85 copies, 86 copies , 87 copies, 88 copies, 89 copies, 90 copies, 91 copies, 92 copies, 93 copies, 94 copies, 95 copies, 96 copies, 97 copies, 98 copies, 99 copies, 100 copies, 101 copies, 102 copies, 103 104 copies, 105 copies, 106 copies, 107 copies, 108 copies, 109 copies, 110 copies, 111 copies, 112 copies, 113 copies, 114 copies, 115 copies, 116 copies, 117 copies, 118 copies, 119 copies, 120 copies, 121 copies, 122 copies, 123 copies, 124 copies, 125 copies, 126 copies, 127 copies, 128 copies, 129 copies, 130 copies, 131 copies, 132 copies, 133 copies, 134 copies, 135 copies, 136 copies , 137 copies, 138 copies, 139 copies, 140 copies, 141 copies, 142 copies, 143 copies, 144 copies, 145 copies, 146 copies, 147 copies, 148 copies, 149 copies, 150 copies, 151 copies, 152 copies, 153 154 copies, 155 copies, 156 copies, 157 copies, 158 copies, 159 copies, 160 copies, 161 copies, 162 copies, 163 copies, 164 copies, 165 copies, 166 copies, 167 copies, 168 copies, 169 copies, 170 copies, 171 copies, 172 copies, 173 copies, 174 copies, 175 copies, 176 copies, 177 copies, 178 copies, 179 copies, 180 copies, 181 copies, 182 copies, 183 copies, 184 copies, 185 copies, 186 copies , 187 copies, 188 copies, 189 copies, 190 copies, 191 copies, 192 copies, 193 copies, 194 copies, 195 copies, 196 copies, 197 copies, 198 copies, 199 copies, 200 copies, 201 copies, 202 copies, 203 204 copies, 205 copies, 206 copies, 207 copies, 208 copies, 209 copies, 210 copies, 211 copies, 212 copies, 213 copies, 214 copies, 215 copies, 216 copies, 217 copies, 218 copies, 219 copies, 220 copies, 221 copies, 222 copies, 223 copies, 224 copies, 225 copies, 226 copies, 227 copies, 228 copies, 229 copies, 230 copies, 231 copies, 232 copies, 233 copies, 234 copies, 235 copies, 236 copies , 237 copies, 238 copies, 239 copies, 240 copies, 241 copies, 242 copies, 243 copies, 244 copies, 245 copies, 246 copies, 247 copies, 248 copies, 249 copies, 250 copies, 251 copies, 252 copies, 253 254 copies, 255 copies, 256 copies, 257 copies, 258 copies, 259 copies, 260 copies, 261 copies, 262 copies, 263 copies, 264 copies, 265 copies, 266 copies, 267 copies, 268 copies, 269 copies, 270 copies, 271 copies, 272 copies, 273 copies, 274 copies, 275 copies, 276 copies, 277 copies, 278 copies, 279 copies, 280 copies, 281 copies, 282 copies, 283 copies , 284 copies, 285 copies, 286 copies, 287 copies, 288 copies, 289 copies, 290 copies, 291 copies, 292 copies, 293 copies, 294 copies, 295 copies, 296 copies, 297 copies, 298 copies, 299 copies, 300 301 copies, 302 copies, 303 copies, 304 copies, 305 copies, 306 copies, 307 copies, 308 copies, 309 copies, 310 copies, 311 copies, 312 copies, 313 copies, 314 copies, 315 copies, 316 copies, 317 copies, 318 copies, 319 copies, 320 copies, 321 copies, 322 copies, 323 copies, 324 copies, 325 copies, 326 copies, 327 copies, 328 copies, 329 copies, 330 copies, 331 copies, 332 copies, 333 copies , 334 copies, 335 copies, 336 copies, 337 copies, 338 copies, 339 copies, 340 copies, 341 copies, 342 copies, 343 copies, 344 copies, 345 copies, 346 copies, 347 copies, 348 copies, 349 copies, 350 351 copies, 352 copies, 353 copies, 354 copies, 355 copies, 356 copies, 357 copies, 358 copies, 359 copies, 360 copies, 361 copies, 362 copies, 363 copies, 364 copies, 365 copies, 366 copies, 367 copies, 368 copies, 369 copies, 370 copies, 371 copies, 372 copies, 373 copies, 374 copies, 375 copies, 376 copies, 377 copies, 378 copies, 379 copies, 380 copies, 381 copies, 382 copies, 383 copies , 384 copies, 385 copies, 386 copies, 387 copies, 388 copies, 389 copies, 390 copies, 391 copies, 392 copies, 393 copies, 394 copies, 395 copies, 396 copies, 397 copies, 398 copies, 399 copies, 400 401 copies, 402 copies, 403 copies, 404 copies, 405 copies, 406 copies, 407 copies, 408 copies, 409 copies, 410 copies, 411 copies, 412 copies, 413 copies, 414 copies, 415 copies, 416 copies, 417 copies, 418 copies, 419 copies, 420 copies, 421 copies, 422 copies, 423 copies, 424 copies, 425 copies, 426 copies, 427 copies, 428 copies, 429 copies, 430 copies, 431 copies, 432 copies, 433 copies , 434 copies, 435 copies, 436 copies, 437 copies, 438 copies, 439 copies, 440 copies, 441 copies, 442 copies, 443 copies, 444 copies, 445 copies, 446 copies, 447 copies, 448 copies, 449 copies, 450 451 copies, 452 copies, 453 copies, 454 copies, 455 copies, 456 copies, 457 copies, 458 copies, 459 copies, 460 copies, 461 copies, 462 copies, 463 copies, 464 copies, 465 copies, 466 copies, 467 copies, 468 copies, 469 copies, 470 copies, 471 copies, 472 copies, 473 copies, 474 copies, 475 copies, 476 copies, 477 copies, 478 copies, 479 copies, 480 copies, 481 copies, 482 copies, 483 copies , 484 copies, 485 copies, 486 copies, 487 copies, 488 copies, 489 copies, 490 copies, 491 copies, 492 copies, 493 copies, 494 copies, 495 copies, 496 copies, 497 copies, 498 copies, 499 copies, 500 501 copies, 502 copies, 503 copies, 504 copies, 505 copies, 506 copies, 507 copies, 508 copies, 509 copies, 510 copies, 511 copies, 512 copies, 513 copies, 514 copies, 515 copies, 516 copies, 517 copies, 518 copies, 519 copies, 520 copies, 521 copies, 522 copies, 523 copies, 524 copies, 525 copies, 526 copies, 527 copies, 528 copies, 529 copies, 530 copies, 531 copies, 532 copies, 533 copies , 534 copies, 535 copies, 536 copies, 537 copies, 538 copies, 539 copies, 540 copies, 541 copies, 542 copies, 543 copies, 544 copies, 545 copies, 546 copies, 547 copies, 548 copies, 549 copies, 550 551 copies, 552 copies, 553 copies, 554 copies, 555 copies, 556 copies, 557 copies, 558 copies, 559 copies, 560 copies, 561 copies, 562 copies, 563 copies, 564 copies, 565 copies, 566 copies, 567 copies, 568 copies, 569 copies, 570 copies, 571 copies, 572 copies, 573 copies, 574 copies, 575 copies, 576 copies, 577 copies, 578 copies, 579 copies, 580 copies, 581 copies, 582 copies, 583 copies , 584 copies, 585 copies, 586 copies, 587 copies, 588 copies, 589 copies, 590 copies, 591 copies, 592 copies, 593 copies, 594 copies, 595 copies, 596 copies, 597 copies, 598 copies, 599 copies, 600 601 copies, 602 copies, 603 copies, 604 copies, 605 copies, 606 copies, 607 copies, 608 copies, 609 copies, 610 copies, 611 copies, 612 copies, 613 copies, 614 copies, 615 copies, 616 copies, 617 copies, 618 copies, 619 copies, 620 copies, 621 copies, 622 copies, 623 copies, 624 copies, 625 copies , 626 copies, 627 copies, 628 copies, 629 copies, 630 copies, 631 copies, 632 copies, 633 copies, 634 copies, 635 copies, 636 copies, 637 copies, 638 copies, 639 copies, 640 copies, 641 copies, 642 643 copies, 644 copies, 645 copies, 646 copies, 647 copies, 648 copies, 649 copies, 650 copies, 651 copies, 652 copies, 653 copies, 654 copies, 655 copies, 656 copies, 657 copies, 658 copies, 659 copies, 660 copies, 661 copies, 662 copies, 663 copies, 664 copies, 665 copies, 666 copies, 667 copies, 668 copies, 669 copies, 670 copies, 671 copies, 672 copies, 673 copies, 674 copies, 675 copies , 676 copies, 677 copies, 678 copies, 679 copies, 680 copies, 681 copies, 682 copies, 683 copies, 684 copies, 685 copies, 686 copies, 687 copies, 688 copies, 689 copies, 690 copies, 691 copies, 692 693 copies, 694 copies, 695 copies, 696 copies, 697 copies, 698 copies, 699 copies, 700 copies, 701 copies, 702 copies, 703 copies, 704 copies, 705 copies, 706 copies, 707 copies, 708 copies, 709 copies, 710 copies, 711 copies, 712 copies, 713 copies, 714 copies, 715 copies, 716 copies, 717 copies, 718 copies, 719 copies, 720 copies, 721 copies, 722 copies, 723 copies, 724 copies, 725 copies , 726 copies, 727 copies, 728 copies, 729 copies, 730 copies, 731 copies, 732 copies, 733 copies, 734 copies, 735 copies, 736 copies, 737 copies, 738 copies, 739 copies, 740 copies, 741 copies, 742 743 copies, 744 copies, 745 copies, 746 copies, 747 copies, 748 copies, 749 copies, 750 copies, 751 copies, 752 copies, 753 copies, 754 copies, 755 copies, 756 copies, 757 copies, 758 copies, 759 copies, 760 copies, 761 copies, 762 copies, 763 copies, 764 copies, 765 copies, 766 copies, 767 copies, 768 copies, 769 copies, 770 copies, 771 copies, 772 copies, 773 copies, 774 copies, 775 copies , 776 copies, 777 copies, 778 copies, 779 copies, 780 copies, 781 copies, 782 copies, 783 copies, 784 copies, 785 copies, 786 copies, 787 copies, 788 copies, 789 copies, 790 copies, 791 copies, 792 793 copies, 794 copies, 795 copies, 796 copies, 797 copies, 798 copies, 799 copies, 800 copies, 801 copies, 802 copies, 803 copies, 804 copies, 805 copies, 806 copies, 807 copies, 808 copies, 809 copies, 810 copies, 811 copies, 812 copies, 813 copies, 814 copies, 815 copies, 816 copies, 817 copies, 818 copies, 819 copies, 820 copies, 821 copies, 822 copies, 823 copies, 824 copies, 825 copies , 826 copies, 827 copies, 828 copies, 829 copies, 830 copies, 831 copies, 832 copies, 833 copies, 834 copies, 835 copies, 836 copies, 837 copies, 838 copies, 839 copies, 840 copies, 841 copies, 842 843 copies, 844 copies, 845 copies, 846 copies, 847 copies, 848 copies, 849 copies, 850 copies, 851 copies, 852 copies, 853 copies, 854 copies, 855 copies, 856 copies, 857 copies, 858 copies, 859 copies, 860 copies, 861 copies, 862 copies, 863 copies, 864 copies, 865 copies, 866 copies, 867 copies, 868 copies, 869 copies, 870 copies, 871 copies, 872 copies, 873 copies, 874 copies, 875 copies , 876 copies, 877 copies, 878 copies, 879 copies, 880 copies, 881 copies, 882 copies, 883 copies, 884 copies, 885 copies, 886 copies, 887 copies, 888 copies, 889 copies, 890 copies, 891 copies, 892 893 copies, 894 copies, 895 copies, 896 copies, 897 copies, 898 copies, 899 copies, 900 copies, 901 copies, 902 copies, 903 copies, 904 copies, 905 copies, 906 copies, 907 copies, 908 copies, 909 copies, 910 copies, 911 copies, 912 copies, 913 copies, 914 copies, 915 copies, 916 copies, 917 copies, 918 copies, 919 copies, 920 copies, 921 copies, 922 copies, 923 copies, 924 copies, 925 copies , 926 copies, 927 copies, 928 copies, 929 copies, 930 copies, 931 copies, 932 copies, 933 copies, 934 copies, 935 copies, 936 copies, 937 copies, 938 copies, 939 copies, 940 copies, 941 copies, 942 copies, 943 copies, 944 copies, 945 copies, 946 copies, 947 copies, 948 copies, 949 copies, 950 copies, 951 copies, 952 copies, 953 copies, 954 copies, 955 copies, 956 copies, 957 copies, 958 copies, 959 copies, 960 copies, 961 copies, 962 copies, 963 copies, 964 copies, 965 copies, 966 copies, 967 copies , 968 copies, 969 copies, 970 copies, 971 copies, 972 copies, 973 copies, 974 copies, 975 copies, 976 copies, 977 copies, 978 copies, 979 copies, 980 copies, 981 copies, 982 copies, 983 copies, 984 985 copies, 986 copies, 987 copies, 988 copies, 989 copies, 990 copies, 991 copies, 992 copies, 993 copies, 994 copies, 995 copies, 996 copies, 997 copies, 998 copies, 999 copies, 1000 copies, etc. , other specific point values within this numerical range can be selected, and will not be described one by one here.

In some embodiments, emulsifiers of the present disclosure include any one or a combination of at least two of ionic surfactants, nonionic surfactants, or zwitterionic surfactants.

In some embodiments, the emulsifiers described in the present disclosure are ionic surfactants. In some embodiments, the ionic surfactants described in the present disclosure include but are not limited to sulfates, sulfonates, and phosphates. Types, carboxylates, ammonium lauryl sulfate, sodium dodecyl sulfate (SDS), sodium polyoxyethylene alkyl sulfate, sodium laureth sulfate, sodium docusate (diisooctyl succinate sulfonate) Any one or at least two of sodium sulfate (DSS), perfluorooctane sulfonate (PFOS), perfluorobutane sulfonate, alkyl aryl ether phosphates and alkyl ether phosphates combination.

In some embodiments, the emulsifiers described in the present disclosure are non-ionic surfactants. In some embodiments, the non-ionic surfactants described in the present disclosure include, but are not limited to, Triton X-100, Poloxamers , Glyceryl monostearate, glyceryl monolaurate, sorbitan monolaurate, sorbitan anhydride monostearate, polyoxyethylene sorbitan fatty acid ester (Tween), Such as Tween 20, Tween 40, Tween 60 and Tween 80), any one or a combination of at least two of sorbitan fatty acid esters (Span).

The emulsifier described in this disclosure may also be 1,2-dipalmitoyl-sn-glyceryl-3-phosphatidylglycerol (DPPG), 1-palmitoyl-2-oleoyl-sn-glyceryl-3- Fatty ethanolamine (POPE), N-dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, cyclodextrin, and chitosan derivatives (e.g., protonated chitosan , trimethylchitosan chloride, etc.) or a combination of at least two.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 4 to 70 parts by mass,

Castor oil: 120 to 600 parts by mass,

Soybean trypsin inhibitor: 30 to 400 parts by mass,

Disodium ethylenediaminetetraacetate: 70 to 400 parts by mass, and

Tween 80: 50 to 500 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 1 to 100 parts by mass

Castor oil: 50 to 500 parts by mass,

Soybean trypsin inhibitor: 50 to 300 parts by mass, and

Disodium ethylenediaminetetraacetate: 50 to 350 parts by mass;

Tween 80: 50 to 500 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 to 50 parts by mass

Castor oil: 50 to 600 parts by mass,

Soybean trypsin inhibitor: 50 to 450 parts by mass,

Disodium ethylenediaminetetraacetate: 60 to 450 parts by mass, and

Tween 80: 50~450 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 to 50 parts by mass

Castor oil: 50 to 600 parts by mass,

Soybean trypsin inhibitor: 50 to 400 parts by mass,

Disodium ethylenediaminetetraacetate: 150 to 400 parts by mass, and

Tween 80: 50 to 450 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 to 100 parts by mass

Castor oil: 50 to 400 parts by mass,

Soybean trypsin inhibitor: 50 to 300 parts by mass,

Disodium ethylenediaminetetraacetate: 20 to 300 parts by mass, and

Tween 80: 100 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 to 50 parts by mass

Castor oil: 80 to 500 parts by mass,

Soybean trypsin inhibitor: 90 to 320 parts by mass,

Disodium ethylenediaminetetraacetate: 50 to 300 parts by mass, and

Tween 80: 100 to 500 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 8 to 50 parts by mass,

Castor oil: 150 to 500 parts by mass,

Soybean trypsin inhibitor: 50 to 250 parts by mass,

Disodium ethylenediaminetetraacetate: 70 to 300 parts by mass, and

Tween 80: 100 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 5 to 50 parts by mass

Castor oil: 100 to 400 parts by mass,

Soybean trypsin inhibitor: 75 to 250 parts by mass,

Disodium ethylenediaminetetraacetate: 75 to 300 parts by mass, and

Tween 80: 100 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 2 to 32 parts by mass

Castor oil: 93 to 532 parts by mass,

Soybean trypsin inhibitor: 80 to 341 parts by mass,

Disodium ethylenediaminetetraacetate: 100 to 326 parts by mass, and

Tween 80: 106~373 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 2 to 32 parts by mass

Castor oil: 93 to 532 parts by mass,

Soybean trypsin inhibitor: 80 to 341 parts by mass,

Disodium ethylenediaminetetraacetate: 197 to 326 parts by mass, and

Tween 80: 106~373 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 4 to 40 parts by mass

Castor oil: 90 to 377 parts by mass,

Soybean trypsin inhibitor: 70 to 230 parts by mass,

Disodium ethylenediaminetetraacetate: 50 to 282 parts by mass, and

Tween 80: 120 to 300 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 2 to 34 parts by mass

Castor oil: 110 to 443 parts by mass,

Soybean trypsin inhibitor: 111 to 291 parts by mass,

Disodium ethylenediaminetetraacetate: 83 to 220 parts by mass, and

Tween 80: 132 to 489 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 8 to 24 parts by mass,

Castor oil: 275 to 500 parts by mass,

Soybean trypsin inhibitor: 50 to 105 parts by mass,

Disodium ethylenediaminetetraacetate: 150 to 300 parts by mass, and

Tween 80: 100 to 275 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 5 to 25 parts by mass

Castor oil: 100 to 335 parts by mass,

Soybean trypsin inhibitor: 75 to 200 parts by mass,

Disodium ethylenediaminetetraacetate: 75 to 300 parts by mass, and

Tween 80: 290 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 8 to 32 parts by mass

Castor oil: 93 to 532 parts by mass,

Soybean trypsin inhibitor: 80 to 320 parts by mass,

Disodium ethylenediaminetetraacetate: 100 to 326 parts by mass, and

Tween 80: 106~373 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 2 to 16 parts by mass

Castor oil: 328 to 532 parts by mass,

Soybean trypsin inhibitor: 80 to 341 parts by mass,

Disodium ethylenediaminetetraacetate: 197 to 266 parts by mass, and

Tween 80: 106~131 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 4 to 20 parts by mass

Castor oil: 282 to 377 parts by mass,

Soybean trypsin inhibitor: 70 to 100 parts by mass,

Disodium ethylenediaminetetraacetate: 50 to 180 parts by mass, and

Tween 80: 120 to 300 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition Including by mass parts:

Insulin degludec: 2 to 15 parts by mass

Castor oil: 390 to 443 parts by mass,

Soybean trypsin inhibitor: 111 to 291 parts by mass,

Disodium ethylenediaminetetraacetate: 83 to 132 parts by mass, and

Tween 80: 132~401 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 24 to 50 parts by mass,

Castor oil: 150 to 500 parts by mass,

Soybean trypsin inhibitor: 50 to 250 parts by mass,

Disodium ethylenediaminetetraacetate: 70 to 300 parts by mass, and

Tween 80: 100 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 25 to 50 parts by mass

Castor oil: 100 to 400 parts by mass,

Soybean trypsin inhibitor: 75 to 250 parts by mass,

Disodium ethylenediaminetetraacetate: 150 to 300 parts by mass, and

Tween 80: 100 to 400 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 16 to 32 parts by mass

Castor oil: 93 to 532 parts by mass,

Soybean trypsin inhibitor: 80 to 175 parts by mass,

Disodium ethylenediaminetetraacetate: 266 to 326 parts by mass, and

Tween 80: 106~373 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 20 to 40 parts by mass

Castor oil: 90 to 282 parts by mass,

Soybean trypsin inhibitor: 100 to 230 parts by mass,

Disodium ethylenediaminetetraacetate: 50 to 282 parts by mass, and

Tween 80: 210~300 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 15 to 34 parts by mass

Castor oil: 110 to 390 parts by mass,

Soybean trypsin inhibitor: 111 to 147 parts by mass,

Disodium ethylenediaminetetraacetate: 83 to 220 parts by mass, and

Tween 80: 401～489 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Semaglutide: 4～70mg,

Castor oil: 120~600mg,

Soybean trypsin inhibitor: 30~400mg,

Disodium ethylenediaminetetraacetate: 70~400mg, and

Tween 80: 50～500mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Thymosin: 1～100mg

Castor oil: 50～500mg,

Soybean trypsin inhibitor: 50~300mg, and

Disodium ethylenediaminetetraacetate: 50~350mg;

Tween 80: 50～500mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Recombinant human insulin: 1～50mg

Castor oil: 50~600mg,

Soybean trypsin inhibitor: 50~400mg,

Disodium ethylenediaminetetraacetate: 150~400mg, and

Tween 80: 50～450mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Lupron: 1～100mg

Castor oil: 50～400mg,

Soybean trypsin inhibitor: 50～300mg,

Disodium ethylenediaminetetraacetate: 20~300mg, and

Tween 80: 100～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Insulin degludec: 1～50mg

Castor oil: 80～500mg,

Soybean trypsin inhibitor: 90～320mg,

Disodium ethylenediaminetetraacetate: 50~300mg, and

Tween 80: 100～500mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Semaglutide: 8～50mg,

Castor oil: 150～500mg,

Soybean trypsin inhibitor: 50～250mg,

Disodium ethylenediaminetetraacetate: 70~300mg, and

Tween 80: 100～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Thymosin: 5～50mg

Castor oil: 100～400mg,

Soybean trypsin inhibitor: 75～250mg,

Disodium ethylenediaminetetraacetate: 75~300mg, and

Tween 80: 100～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Recombinant human insulin: 2～32mg

Castor oil: 93～532mg,

Soybean trypsin inhibitor: 80～341mg,

Disodium ethylenediaminetetraacetate: 197～326mg, and

Tween 80: 106~373 mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Lupron: 4～40mg

Castor oil: 90～377mg,

Soybean trypsin inhibitor: 70～230mg,

Disodium ethylenediaminetetraacetate: 50～282mg, and

Tween 80: 120~300mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Insulin degludec: 2～34mg

Castor oil: 110～443mg,

Soybean trypsin inhibitor: 111～291mg,

Disodium ethylenediaminetetraacetate: 83～220mg, and

Tween 80: 132～489mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Semaglutide: 8～24mg,

Castor oil: 275～500mg,

Soybean trypsin inhibitor: 50～105mg,

Disodium ethylenediaminetetraacetate: 150~300mg, and

Tween 80: 100～275mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Thymosin: 5～25mg

Castor oil: 100～335mg,

Soybean trypsin inhibitor: 75～200mg,

Disodium ethylenediaminetetraacetate: 75~300mg, and

Tween 80: 290～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Recombinant human insulin: 2～16mg

Castor oil: 328～532mg,

Soybean trypsin inhibitor: 80～341mg,

Disodium ethylenediaminetetraacetate: 197～266mg, and

Tween 80: 106～131mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Lupron: 4～20mg

Castor oil: 282～377mg,

Soybean trypsin inhibitor: 70～100mg,

Disodium ethylenediaminetetraacetate: 50～180mg, and

Tween 80: 120~300mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Insulin degludec: 2～15mg

Castor oil: 390～443mg,

Soybean trypsin inhibitor: 111～291mg,

Disodium ethylenediaminetetraacetate: 83～132mg, and

Tween 80: 132～401mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Semaglutide: 24～50mg,

Castor oil: 150～500mg,

Soybean trypsin inhibitor: 50～250mg,

Disodium ethylenediaminetetraacetate: 70~300mg, and

Tween 80: 100～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Thymosin: 25～50mg

Castor oil: 100～400mg,

Soybean trypsin inhibitor: 75～250mg,

Disodium ethylenediaminetetraacetate: 150~300mg, and

Tween 80: 100～400mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Recombinant human insulin: 16～32mg

Castor oil: 93～532mg,

Soybean trypsin inhibitor: 80～175mg,

Disodium ethylenediaminetetraacetate: 266~326mg, and

Tween 80: 106~373mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Lupron: 20～40mg

Castor oil: 90～282mg,

Soybean trypsin inhibitor: 100～230mg,

Disodium ethylenediaminetetraacetate: 50～282mg, and

Tween 80: 210～300mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition unit dose includes:

Insulin degludec: 15～34mg

Castor oil: 110～390mg,

Soybean trypsin inhibitor: 111～147mg,

Disodium ethylenediaminetetraacetate: 83～220mg, and

Tween 80: 401～489mg.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 1 part by mass,

Castor oil: 1 to 50 parts by mass,

Soybean trypsin inhibitor: 1 to 20 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 25 parts by mass;

Tween 80: 1 to 50 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 1 part by mass,

Castor oil: 3 to 35 parts by mass,

Soybean trypsin inhibitor: 2 to 14 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 19 parts by mass;

Tween 80: 4 to 35 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 1 part by mass,

Castor oil: 3 to 34.4 parts by mass,

Soybean trypsin inhibitor: 2.1 to 13.1 parts by mass, and

Disodium ethylenediaminetetraacetate: 1.4 to 18.8 parts by mass;

Tween 80: 4.2 to 34.4 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 1 part by mass,

Castor oil: 20.8~34.4 parts by mass,

Soybean trypsin inhibitor: 2.1 to 13.1 parts by mass, and

Disodium ethylenediaminetetraacetate: 12.5 to 18.8 parts by mass;

Tween 80: 4.2 to 34.4 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Semaglutide: 1 part by mass,

Castor oil: 3 to 20.8 parts by mass,

Soybean trypsin inhibitor: 2.1 to 5 parts by mass, and

Disodium ethylenediaminetetraacetate: 1.4 to 12.5 parts by mass;

Tween 80: 4.2 to 8 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 1 part by mass

Castor oil: 1 to 100 parts by mass,

Soybean trypsin inhibitor: 1 to 50 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 20 parts by mass;

Tween 80: 1 to 100 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 1 part by mass

Castor oil: 4 to 67 parts by mass,

Soybean trypsin inhibitor: 3 to 40 parts by mass, and

Disodium ethylenediaminetetraacetate: 3 to 15 parts by mass;

Tween 80: 2 to 58 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 1 part by mass

Castor oil: 4 to 67 parts by mass,

Soybean trypsin inhibitor: 3 to 40 parts by mass, and

Disodium ethylenediaminetetraacetate: 12 to 15 parts by mass;

Tween 80: 16 to 58 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Thymosin: 1 part by mass

Castor oil: 4 to 8 parts by mass,

Soybean trypsin inhibitor: 3 to 5 parts by mass, and

Disodium ethylenediaminetetraacetate: 3 to 12 parts by mass;

Tween 80: 2 to 16 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 part by mass

Castor oil: 1 to 200 parts by mass,

Soybean trypsin inhibitor: 1 to 200 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 100 parts by mass;

Tween 80: 1 to 100 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition Including by mass parts:

Recombinant human insulin: 1 part by mass

Castor oil: 2 to 164 parts by mass,

Soybean trypsin inhibitor: 5 to 171 parts by mass, and

Disodium ethylenediaminetetraacetate: 10 to 99 parts by mass;

Tween 80: 6 to 66 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 part by mass

Castor oil: 2.9 to 164 parts by mass,

Soybean trypsin inhibitor: 5.0 to 170.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 10.2 to 98.5 parts by mass;

Tween 80: 6.6 to 65.5 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 part by mass

Castor oil: 33.3 to 164 parts by mass,

Soybean trypsin inhibitor: 5.0 to 170.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 16.6 to 98.5 parts by mass;

Tween 80: 6.6 to 65.5 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 part by mass

Castor oil: 2.9 to 33.3 parts by mass,

Soybean trypsin inhibitor: 5.0 to 40 parts by mass, and

Disodium ethylenediaminetetraacetate: 10.2 to 16.6 parts by mass;

Tween 80: 6.6 to 31.3 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Recombinant human insulin: 1 part by mass

Castor oil: 2.9 to 33.3 parts by mass,

Soybean trypsin inhibitor: 5.0 to 5.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 10.2 to 16.6 parts by mass;

Tween 80: 6.6 to 11.7 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 part by mass

Castor oil: 1 to 120 parts by mass,

Soybean trypsin inhibitor: 1 to 30 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 70 parts by mass;

Tween 80: 1 to 50 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 part by mass

Castor oil: 2 to 95 parts by mass,

Soybean trypsin inhibitor: 5 to 18 parts by mass, and

Disodium ethylenediaminetetraacetate: 2 to 45 parts by mass;

Tween 80: 5 to 30 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 part by mass

Castor oil: 2.3~94.3 parts by mass,

Soybean trypsin inhibitor: 5 to 17.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 2.5 to 45 parts by mass;

Tween 80: 5.3 to 30 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 part by mass

Castor oil: 14.1～94.3 parts by mass,

Soybean trypsin inhibitor: 5 to 17.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 2.5 to 45 parts by mass;

Tween 80: 15 to 30 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Lupron: 1 part by mass

Castor oil: 2.3~14.1 parts by mass,

Soybean trypsin inhibitor: 5 to 5.8 parts by mass, and

Disodium ethylenediaminetetraacetate: 2.5 to 7.1 parts by mass;

Tween 80: 5.3 to 15 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 part by mass

Castor oil: 3 to 300 parts by mass,

Soybean trypsin inhibitor: 1 to 200 parts by mass, and

Disodium ethylenediaminetetraacetate: 1 to 100 parts by mass;

Tween 80: 5 to 100 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 part by mass

Castor oil: 3 to 222 parts by mass,

Soybean trypsin inhibitor: 4 to 146 parts by mass, and

Disodium ethylenediaminetetraacetate: 5 to 66.0 parts by mass;

Tween 80: 14 to 66.0 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 part by mass

Castor oil: 3.2 to 221.5 parts by mass,

Soybean trypsin inhibitor: 4.3 to 145.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 5.5 to 66.0 parts by mass;

Tween 80: 14.4～66.0 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 part by mass

Castor oil: 26 to 221.5 parts by mass,

Soybean trypsin inhibitor: 7.4 to 145.5 parts by mass, and

Disodium ethylenediaminetetraacetate: 5.5 to 66.0 parts by mass;

Tween 80: 26.7～66.0 parts by mass.

In some embodiments, the polypeptide composition of any one of the present disclosure, wherein the polypeptide composition includes, in parts by mass:

Insulin degludec: 1 part by mass

Castor oil: 3.2 to 26 parts by mass,

Soybean trypsin inhibitor: 4.3 to 7.4 parts by mass, and

Disodium ethylenediaminetetraacetate: 5.5 to 6.5 parts by mass;

Tween 80: 14.4～26.7 parts by mass.

On the other hand, in some embodiments, the present disclosure also provides a medicament, which includes the polypeptide composition as described in the first aspect; in some embodiments, the medicament of the present disclosure further includes a coating and/or or pharmaceutically acceptable excipients.

In some embodiments, the coatings of the present disclosure are selected from gastric coatings and/or enteric coatings.

In some embodiments, the coating materials of the present disclosure include: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin polyvinylpyrrolidone, cellulose acetate phthalate (CAP) ) Hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), etc.

It should be noted that in the present disclosure, the main function of the coating is to release the polypeptide in a specific part of the gastrointestinal tract. For example, enteric coating can make the polypeptide insoluble in gastric acid and soluble in intestinal juice. Those skilled in the art can select coating materials according to actual needs to achieve the release of the polypeptide in gastric juice or intestinal juice in the gastrointestinal tract.

In some embodiments, other pharmaceutically acceptable excipients described in the present disclosure are all pharmaceutically acceptable excipients except coating materials, such as: excipients, disintegrants, binders, and flavoring agents. or lubricant.

In some embodiments, the excipients of the present disclosure are selected from the group consisting of lactose, sorbitol, xylitol, mannitol, dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, lactose Any one or a combination of at least two of starch complexes, lactose-cellulose complexes or mannitol-starch complexes.

In some embodiments, the disintegrant of the present disclosure is selected from any one of croscarmellose sodium, crospolyvinylpyrrolidone, croscarmellose sodium or low-substituted hydroxypropyl cellulose Or at least a combination of two.

In some embodiments, the binder of the present disclosure is selected from colloidal microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, gelatin solution , starch slurry or sucrose solution, or a combination of at least two.

In some embodiments, the lubricant of the present disclosure is selected from any one or a combination of at least two of sodium stearyl fumarate, magnesium stearate, calcium stearate, micronized silica gel or talc.

In some embodiments, the flavoring agent described in the present disclosure is mannitol, sorbitol, aspartame, stevioside, sucralose, aspartame, neotame, stevia, hydroxyl sugar chloride or flavor. Any one or a combination of at least two.

In some embodiments, the present disclosure provides a polypeptide composition for oral administration comprising liraglutide, a vegetable oil, a protease inhibitor, and an absorption enhancer.

In some embodiments, the liraglutide of the present disclosure: 1 to 80 parts by mass,

Vegetable oil: 10 to 850 parts by mass,

The protease inhibitor: 5 to 250 parts by mass and

Absorption enhancer: 5 to 300 parts by mass.

In some embodiments, the vegetable oil of the present disclosure is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil.

In some embodiments, the absorption enhancer of the present disclosure may be disodium ethylenediaminetetraacetate.

In some embodiments, the polypeptide compositions of the present disclosure for oral administration further comprise at least one emulsifier;

In some embodiments, the emulsifier of the present disclosure: 0.1 to 1000 parts by mass. In some embodiments, the emulsifier of the present disclosure is 10 to 850 parts by mass. In some embodiments, the emulsifier of the present disclosure is 0.1 to 1000 parts by mass. 50 to 850 parts by mass.

In some embodiments, the emulsifier of the present disclosure is Tween.

In some embodiments, the present disclosure provides a polypeptide composition for oral administration comprising liraglutide, vegetable oil, a protease inhibitor, Tween 80, and disodium ethylenediaminetetraacetate.

In some embodiments, the liraglutide of the present disclosure is 1-80 parts by mass. In some embodiments, the liraglutide of the present disclosure is 1-75 parts by mass, 1-70 parts by mass, 1- 65 parts by mass, 1-60 parts by mass, 1-55 parts by mass, 1-50 parts by mass, 1-45 parts by mass, 1-40 parts by mass, 1-35 parts by mass, 1-30 parts by mass or 1-20 parts by mass parts, in some embodiments, the liraglutide of the present disclosure is about 20 parts by mass.

In some embodiments, the vegetable oil of the present disclosure is 10-850 parts by mass. In some embodiments, the vegetable oil of the present disclosure is 20-800 parts by mass, 30-750 parts by mass, 40-700 parts by mass, 50- 650 parts by mass, 60-600 parts by mass, 70-550 parts by mass, 80-500 parts by mass, 90-450 parts by mass, 100-400 parts by mass, 110-350 parts by mass, 150-300 parts by mass or 170-250 parts by mass parts, in some embodiments, the vegetable oil of the present disclosure is about 200 parts by mass.

In some embodiments, the protease inhibitor described in the present disclosure is 10-200 parts by mass. In some embodiments, the protease inhibitor described in the present disclosure is 15-190 parts by mass, 20-180 parts by mass, or 25-170 parts by mass. parts, 30-160 parts by mass, 35-150 parts by mass, 40-140 parts by mass, 45-130 parts by mass, 50-120 parts by mass, 55-110 parts by mass, 60-100 parts by mass or 65-90 parts by mass, In some embodiments, the protease inhibitor of the present disclosure is about 80 parts by mass.

In some embodiments, the Tween 80 of the present disclosure is 10-850 parts by mass. In some embodiments, the Tween 80 of the present disclosure is 20-800 parts by mass, 30-750 parts by mass, or 40-700 parts by mass. parts, 50-650 parts by mass, 60-600 parts by mass, 70-550 parts by mass, 80-500 parts by mass, 90-450 parts by mass, 100-400 parts by mass, 110-350 parts by mass, 150-300 parts by mass or 170-250 parts by mass. In some embodiments, the Tween 80 of the present disclosure is about 200 parts by mass.

In some embodiments, the disodium ethylenediaminetetraacetate of the present disclosure is 5 to 450 parts by mass. In some embodiments, the disodium ethylenediaminetetraacetate of the present disclosure is 10-425 parts by mass, 15- 400 parts by mass, 20-375 parts by mass, 25-350 parts by mass, 30-325 parts by mass, 35-300 parts by mass, 40-275 parts by mass, 45-250 parts by mass, 50-225 parts by mass, 55-200 parts by mass parts, 60-175 parts by mass or 65-150 parts by mass. In some embodiments, the disodium ethylenediaminetetraacetate of the present disclosure is about 100 parts by mass.

In some embodiments, the vegetable oil of the present disclosure is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil.

In addition, when the polypeptide composition containing liraglutide is made into a drug and administered orally, a better hypoglycemic effect can be achieved.

In some embodiments, the present disclosure provides a polypeptide composition for oral administration comprising semaglutide, a vegetable oil, a protease inhibitor, and an absorption enhancer.

In some embodiments, the semaglutide: 1 to 80 parts by mass,

Vegetable oil: 10 to 850 parts by mass,

The protease inhibitor: 5 to 250 parts by mass,

Described absorption enhancer: 5-300 parts by mass.

In some embodiments, the vegetable oil of the present disclosure is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil.

In some embodiments, the oral polypeptide compositions of the present disclosure further comprise an emulsifier.

In some embodiments, the emulsifiers of the present disclosure are selected from Tween.

In some embodiments, the present disclosure provides a polypeptide composition for oral administration comprising semaglutide, vegetable oil, a protease inhibitor, Tween 80, and disodium ethylenediaminetetraacetate.

In some embodiments, the semaglutide described in the present disclosure is 1-80 parts by mass. In some embodiments, the semaglutide described in the present disclosure is 1-75 parts by mass, 1-70 parts by mass, 1- 65 parts by mass, 1-60 parts by mass, 1-55 parts by mass, 1-50 parts by mass, 1-45 parts by mass, 1-40 parts by mass, 1-35 parts by mass, 1-30 parts by mass or 1-20 parts by mass share.

In some embodiments, the vegetable oil of the present disclosure is 10-850 parts by mass. In some embodiments, the vegetable oil of the present disclosure is 20-800 parts by mass, 30-750 parts by mass, 40-700 parts by mass, 50- 650 parts by mass, 60-600 parts by mass, 70-550 parts by mass, 80-500 parts by mass, 90-450 parts by mass, 100-400 parts by mass, 110-350 parts by mass, 150-300 parts by mass or 170-250 parts by mass share.

In some embodiments, the protease inhibitor described in the present disclosure is 10-200 parts by mass. In some embodiments, the protease inhibitor described in the present disclosure is 15-190 parts by mass, 20-180 parts by mass, or 25-170 parts by mass. parts, 30-160 parts by mass, 35-150 parts by mass, 40-140 parts by mass, 45-130 parts by mass, 50-120 parts by mass, 55-110 parts by mass, 60-100 parts by mass or 65-90 parts by mass.

In some embodiments, the disodium ethylenediaminetetraacetate of the present disclosure is 5 to 450 parts by mass. In some embodiments, the disodium ethylenediaminetetraacetate of the present disclosure is 10-425 parts by mass, 15- 400 parts by mass, 20-375 parts by mass, 25-350 parts by mass, 30-325 parts by mass, 35-300 parts by mass, 40-275 parts by mass, 45-250 parts by mass, 50-225 parts by mass, 55-200 parts by mass parts, 60-175 parts by mass or 65-150 parts by mass.

In some embodiments, the Tween 80 of the present disclosure is 10-850 parts by mass. In some embodiments, the Tween 80 of the present disclosure is 20-800 parts by mass, 30-750 parts by mass, or 40-700 parts by mass. parts, 50-650 parts by mass, 60-600 parts by mass, 70-550 parts by mass, 80-500 parts by mass, 90-450 parts by mass, 100-400 parts by mass, 110-350 parts by mass, 150-300 parts by mass or 170-250 parts by mass.

In some embodiments, the vegetable oil of the present disclosure is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil.

In addition, when the polypeptide composition containing semaglutide is made into a drug and administered orally, a better hypoglycemic effect can be achieved.

In some embodiments, the polypeptide composition of the present disclosure is an enteric-coated capsule. After oral administration, it passes through the stomach without being released in the stomach, and then enters the intestine, is released in the intestine, enters the blood, and is taken orally. The effect of diet on peptide absorption is greatly reduced compared to oral peptides absorbed through the stomach.

In some embodiments, the polypeptide composition of the present disclosure is an enteric-coated capsule, and the contents of the capsule The peptide is in a suspended state.

In some embodiments, the stability of the polypeptides in the polypeptide compositions of the present disclosure is significantly improved compared to the prior art.

In some embodiments, polypeptide compositions of the present disclosure are stable for storage at 2-40°C.

In some embodiments, polypeptide compositions of the present disclosure are stable for storage at 8-40°C.

In some embodiments, polypeptide compositions of the present disclosure are stable for storage at 25-40°C.

In some embodiments, the polypeptide content of the oral polypeptide composition of the present disclosure is >85% after storage under appropriate conditions for a period of time. For example, after the oral polypeptide composition is stored at 2°C to 8°C for 6 months, its polypeptide content is >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; the oral polypeptide composition is stored at 2°C to 8°C for 9 months After one month, its polypeptide content was >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 12 months, its polypeptide content is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; in some In embodiments, after the oral polypeptide composition of the present disclosure is stored at 2°C to 8°C for 15 months, its polypeptide content is >85%, >86%, >87%, >88%, >89%, >90 %, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; in some embodiments, the oral polypeptides of the present disclosure After the composition is stored at 2°C to 8°C for 18 months, its polypeptide content is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%; in some embodiments, the oral polypeptide compositions of the present disclosure are stored at 2°C to 8°C After 24 months, the peptide content was >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, > 95%, >96%, >97%, >98%, >99%; in some embodiments, the polypeptide content of the oral polypeptide composition of the present disclosure after being stored at 2°C to 8°C for 30 months >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97 %, >98%, >99%; in some embodiments, after the oral polypeptide composition of the present disclosure is stored at 2°C to 8°C for 36 months, its polypeptide content is >85%, >86%, > 87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% .

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >85%, >86%, >87%, >88%, >89%, >90%, after being placed at 25°C for 15 days. >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >85%, >86%, >87%, >88%, >89%, >90%, after being placed at 25°C for 30 days. >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >85%, >86%, >87%, >88%, >89%, >90%, after being placed at 25°C for 60 days. ＞91%, ＞92%, ＞ 93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 25°C for 90 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 25°C for 180 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 25°C for 20 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 30 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 30 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 60 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 90 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 180 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the oral polypeptide composition of the present disclosure has a polypeptide content of >70%, >75%, >80%, >85%, >86%, >87%, after being placed at 40°C for 360 days. >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In the context of polypeptide stability, the "content of a polypeptide" used herein refers to the actual content of the polypeptide as a percentage of the labeled amount; for example, for a capsule of liraglutide, the liraglutide content in the capsule refers to yes For example, if the prescription of a capsule is labeled as containing 20 mg of liraglutide, and a sample is taken for testing, and the test results show that each capsule actually contains 18 mg of liraglutide, then it will be beneficial. The content of lalutide is

In addition, compared to a polypeptide composition not containing vegetable oil, the oral polypeptide composition increases the bioavailability of the polypeptide in the subject by at least 5%, at least 6%, at least 7%, at least 8%, at least 9% %, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, At least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34 %, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, At least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59 %, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, At least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84 %, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, At least 97%, at least 98%, at least 99%, at least 100%.

In some embodiments, the present disclosure also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a first polypeptide, a second polypeptide, a protease inhibitor, a vegetable oil, and at least one absorption enhancer.

In some embodiments, pharmaceutical compositions of the present disclosure comprise the following combinations:

a first polypeptide composition, the first polypeptide composition comprising a first polypeptide, a protease inhibitor, a vegetable oil, and at least one absorption enhancer;

A second polypeptide composition comprising a second polypeptide, a protease inhibitor, a vegetable oil, and at least one absorption enhancer.

In some embodiments, the active ingredients in the pharmaceutical compositions of the present disclosure are in the same dosage form or in separate dosage forms. In the case of separate dosage forms, both may be administered simultaneously or 30 minutes apart from each other.

In some embodiments, the dosage form containing the second component of the present disclosure can be administered 2-10 minutes after the dosage form containing the first component; in other embodiments, 10-20 minutes after the dosage form containing the first component Administration; in other embodiments, 20-30 minutes after the dosage form containing the first component; and in other embodiments, 30-60 minutes after the dosage form containing the first component.

In some embodiments, the first polypeptide and the second polypeptide of the present disclosure are each selected from the group consisting of insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 Receptor agonists, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon , any one of vasopressin, vancomycin, erythropoietin, glutathione and thymosin.

In some embodiments, the first polypeptide of the disclosure is selected from the group consisting of insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lisenatide Natide, semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, special Riparatide, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, leuprorelin, triptorelin, temorelin Relin, codorelin, lanreotide acetate, terlipressin, antigantide, teriparatide, abalapatide, nesiritide, eptifibatide, lixisenatide, Fuvirtide, atosiban, Yunzhi glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, that Any one of cerebropeptides, hirudin, glatiramer acetate, aprotinin, alamorelin, trypsinogenase, polymyxin, serratiopeptidase, thymosin α1, thymopentin, and thymofacin kind.

In some embodiments, the second polypeptide of the disclosure is selected from the group consisting of insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, glucagon-like peptide-2 receptor agonist, Calcium, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, vasopressin, Any one or more of vancomycin, erythropoietin, glutathione, and thymosin; in some embodiments, the polypeptides of the present disclosure are selected from the group consisting of insulin, glucagon, exenatide, bela Lutide, liraglutide, loxenatide, dulaglutide, lixenatide, semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin hormone, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, leuprolide, prorelin, gonadorelin, goserelin, buserelin, sermox Relin, nafarelin, histrelin, triptorelin, timorelin, codorelin, lanreotide acetate, terlipressin, antiganide, teriparatide, alfa Balpatide, nesiritide, eptifibatide, lixisenatide, sifuvirtide, atosiban, versicolor glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione , mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin, glatiramer acetate, aprotinin, alamorelin, trypticin, polymyxin , serratiopeptidase, thymosin α1, thymopentin and thymofaxin, and is different from the first polypeptide.

In some embodiments, the combination of the first polypeptide and the second polypeptide of the present disclosure is selected from the group consisting of insulin and a glucagon-like peptide-1 receptor agonist, insulin and glucagon-like peptide-2 A combination of receptor agonists, a combination of insulin and parathyroid hormone, or a combination of insulin and thymosin; in some embodiments, the combination of the first polypeptide and the second polypeptide of the present disclosure is insulin and liraglutide , insulin and semaglutide, insulin and dulaglutide, insulin and albiglutide, insulin and dulaglutide, or insulin and teduglutide combinations.

In another aspect, the present disclosure provides the use of a polypeptide composition, a medicament or a pharmaceutical composition in the preparation of an oral medicament for the treatment of a disease selected from the group consisting of hyperglycemia, type 1 diabetes, type 2 diabetes, non-insulin dependence diabetes, maturity-onset diabetes of the young, gestational diabetes, obesity, non-alcoholic fatty liver disease, liver steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer, Alzheimer's disease, Parkinson's disease and impaired glucose tolerance disease.

In another aspect, the present disclosure provides use of a polypeptide composition, a medicament or a pharmaceutical composition in the preparation of a medicament for enhancing immune response.

In another aspect, the present disclosure provides a method of treating or preventing a disease selected from the group consisting of orally administering to a subject in need thereof a therapeutically effective amount of a polypeptide composition, medicament or pharmaceutical composition of the present disclosure. Hyperglycemia, type 1 diabetes, type 2 diabetes, non-insulin-dependent diabetes mellitus, mature-onset diabetes of youth, gestational diabetes, obesity, non-alcoholic fatty liver disease, hepatic steatosis, hepatitis, hepatic fibrosis, cirrhosis, liver cancer , Alzheimer's disease, Parkinson's disease, and disorders of impaired glucose tolerance.

In another aspect, the present disclosure also provides a method of enhancing an immune response, comprising orally administering a therapeutically effective amount of a polypeptide composition, medicament, or pharmaceutical composition of the present disclosure to a subject in need thereof.

On the other hand, the present disclosure also provides a method for improving the storage stability of polypeptides. The method includes mixing the polypeptide and vegetable oil to obtain a mixture; in some embodiments, the mass ratio of the polypeptide to vegetable oil is 1:1~ 1:10000.

In some embodiments, after the polypeptide is stored under appropriate conditions for a period of time, the content of the polypeptide is >85%, specifically, the content of the polypeptide is >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%.

In some embodiments, the mass ratio of the polypeptide to vegetable oil can be 1:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:45, 1: 50, 1:60, 1:80, 1:90, 1:100, 1:120, 1:150, 1:180, 1:200, 1:500, 1:800, 1:1000, 1:1500, 1:2000, 1:2500, 1:3000, 1:4000, 1:5000, 1:6000, 1:7000, 1:8000, 1:9000, 1:10000, etc.

Wherein, the polypeptide is selected from the group consisting of insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, and somatostatin , thyroid-stimulating hormone-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, vasopressin, vancomycin, erythropoietin, glutathione Any one or more of thione and thymosin.

In some embodiments, the polypeptide is selected from the group consisting of insulin, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide, soma Lutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teriparatide, leukotide Prorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, triptorelin, temorelin, cortisol Relin, lanreotide acetate, terlipressin, antigantide, teriparatide, abalapatide, nesiritide, eptifibatide, lixisenatide, sifuvirtide, alfa Tosiban, Yunzhi glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide, hirudin , glatiramer acetate, aprotinin, alamorelin, trypsin, polymyxin, serratiopeptidase, thymosin α1, thymopentin and thymofaxin any one or more.

In some embodiments, the vegetable oil is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil. In some embodiments, the vegetable oil is selected from castor oil or Linseed oil, In some embodiments, the vegetable oil is selected from castor oil.

Compared with the existing technology, the beneficial effects of the present disclosure are:

The present disclosure provides a polypeptide composition that can improve the stability of the polypeptide in vitro. In some embodiments, castor oil, perilla oil, linseed oil, corn oil or soybean oil is used as a stabilizer. , after being placed at 25°C for 15 days, the polypeptide content in the polypeptide composition is still greater than 80%; in some embodiments, castor oil and linseed oil are used as stabilizers to obtain a polypeptide composition containing protease inhibitors, emulsifiers and surfactants. The polypeptide composition, after the polypeptide composition is stored at 25°C for 15 days, the polypeptide content in the polypeptide composition is still greater than 95%; it can be stored at 4°C for at least 18 months. The polypeptide compositions of the present disclosure enable oral administration.

Description of drawings

Figure 1 shows the change curve of average blood drug concentration over time in beagle dogs after intravenous injection or oral administration;

Figure 2 shows the blood drug concentration change curve over time of each experimental animal in the intravenous administration group G1;

Figure 3 shows the blood drug concentration change curve over time of each experimental animal in the oral administration G1 group;

Figure 4 shows the blood drug concentration change curve over time of each experimental animal in the oral administration G2 group.

Detailed ways

The technical solutions of the present disclosure will be further explained below through specific implementations. However, the following examples are only simple examples of the present disclosure and do not represent or limit the scope of protection of the present disclosure. The scope of protection of the present disclosure shall be subject to the claims. .

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

Example 1

This embodiment provides a polypeptide composition. 20 mg of liraglutide and 200 mg of flaxseed oil are mixed and put into a capsule to obtain the polypeptide composition.

Example 2

This embodiment provides a polypeptide composition. 20 mg of liraglutide and 200 mg of castor oil are mixed and put into a capsule to obtain the polypeptide composition.

Example 3

This embodiment provides a polypeptide composition. 20 mg of liraglutide, 200 mg of castor oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, castor oil and Tween 80 is 1:10:10. capsule to obtain the polypeptide composition.

Example 4

This embodiment provides a polypeptide composition in which 20 mg of liraglutide, 200 mg of flaxseed oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, flaxseed oil and Tween 80 is 1:10:10. Put it into a capsule to obtain the polypeptide composition.

Example 5

This embodiment provides a polypeptide composition. 20 mg of liraglutide, 200 mg of perilla oil and 200 mg of Tween 80 are mixed and put into a capsule. The mass ratio of liraglutide, perilla oil and Tween 80 is 1: 10:10, the polypeptide composition is obtained.

Example 6

This embodiment provides a polypeptide composition. 20 mg of liraglutide, 200 mg of corn oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, corn oil and Tween 80 is 1:10:10. capsule to obtain the polypeptide composition.

Example 7

This embodiment provides a polypeptide composition. 20 mg of liraglutide, 200 mg of soybean oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, soybean oil and Tween 80 is 1:10:10. capsule to obtain the polypeptide composition.

Example 8

This embodiment provides a polypeptide composition. 2 mg of recombinant human insulin and 328 mg of castor oil are mixed and put into a capsule to obtain the polypeptide composition.

Example 9

This embodiment provides a polypeptide composition. 16 mg of recombinant human insulin and 532 mg of castor oil are mixed and put into a capsule to obtain the polypeptide composition.

Example 10

This embodiment provides a polypeptide composition. 32 mg of recombinant human insulin and 93 mg of castor oil are mixed and put into a capsule to obtain the polypeptide composition.

Comparative example 1

This comparative example provides a polypeptide composition. 20 mg of liraglutide and 200 mg of fish oil are mixed and put into capsules to obtain the polypeptide composition.

Comparative example 2

This embodiment provides a polypeptide composition. 20 mg of liraglutide and 200 mg of algal oil are mixed and put into a capsule to obtain the polypeptide composition.

Comparative example 3

This comparative example provides a polypeptide composition. 20 mg of liraglutide, 200 mg of fish oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, fish oil and Tween 80 is 1:10:10, and put into a capsule. The polypeptide composition is obtained.

Comparative example 4

This comparative example provides a polypeptide composition in which 20 mg of liraglutide, 200 mg of polyene fish oil and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, polyene fish oil and Tween is 1:10:10. Put it into a capsule to obtain the polypeptide composition.

Comparative example 5

This comparative example provides a polypeptide composition, which mixes 20 mg liraglutide, 200 mg DHA and 200 mg Tween 80. The mass ratio of liraglutide, DHA and Tween 80 is 1:10:10, and puts it into a capsule. The polypeptide composition is obtained.

Comparative example 6

This comparative example provides a polypeptide composition in which 20 mg of liraglutide, 200 mg of alpha-linolenic acid and 200 mg of Tween 80 are mixed. The mass ratio of liraglutide, alpha-linolenic acid and Tween 80 is 1:10:10. Put it into a capsule to obtain the polypeptide composition.

Comparative example 7

This comparative example provides a polypeptide composition, which mixes 20 mg of liraglutide, 200 mg of algal oil and 200 mg of Tween 80. The mass ratio of liraglutide, algal oil and Tween 80 is 1:10:10. Put it into a capsule to obtain the polypeptide composition.

Comparative example 8

This comparative example provides a polypeptide composition, which mixes 20 mg liraglutide, 200 mg oleic acid and 200 mg Tween 80. The mass ratio of liraglutide, oleic acid and Tween 80 is 1:10:10, and is loaded into capsule to obtain the polypeptide composition.

In order to provide a polypeptide composition that reduces the degradation rate of the polypeptide and improves the stability of the polypeptide, the present disclosure studies the effects of various components in the polypeptide composition on the stability of the polypeptide. The research shows that the oil in the polypeptide composition Phase components can significantly affect the stability of polypeptides.

Therefore, in Examples 1 and 2 and Comparative Examples 1 and 2, only the polypeptide and the oil phase as the stabilizer were used as the composition to study the change of liraglutide in the polypeptide composition at 25°C with time.

The specific components of the above embodiments and comparative examples are shown in Table 2:

Table 2

HPLC was used to detect the content of liraglutide in the peptide compositions placed at 25°C on days 0, 1, 5, 10, and 15. Each polypeptide composition was tested for 3 times at each time point. samples, and the results are shown in Table 3. The content in Table 3 is the average of three samples at each time point.

table 3

The "content of liraglutide" in Table 3 above refers to the actual content of liraglutide as a percentage of the labeled amount; for example, in Comparative Example 7, the labeled amount of liraglutide in the polypeptide composition is 20 mg. ℃ for 15 days, take 3 samples, HPLC detection, calculated to actually contain liraglutide (average) is 12.04 mg, then the polypeptide composition is left at 25 ℃ for 15 days, the content of liraglutide is

In Comparative Example 5, the liraglutide content on day 0 was 74.0%. The applicant retested several times and the content was basically the same. It is speculated that it was caused by the reaction between the excipients and liraglutide.

It should be noted that the content >100% stated in the table is the error generated during the measurement process, and the measurement error of ±10% is within the valid range.

"/" indicates that the content was not detected at this time point.

According to the above table, it can be seen that the vegetable oils used in the present disclosure as components of the polypeptide composition, namely, linseed oil, castor oil, perilla oil, corn oil and soybean oil, can significantly improve the stability of the polypeptide in the polypeptide composition. .

Use HPLC to detect the content of recombinant human insulin in the polypeptide composition of Examples 8-10 when placed at 25°C on the 0th day, the 5th day, the 10th day, the 30th day, the 60th day, and the 90th day. Three samples of each polypeptide composition were tested at each time point, and the results are shown in Table 4. The content in Table 4 is the average of the three samples at each time point.

Table 4

in conclusion:

After being placed at 25°C for 90 days, the content of recombinant human insulin in the polypeptide composition of Examples 8-10 is >50%. For example, the content of recombinant human insulin in the polypeptide composition of Example 8 is 60.5%. It can be seen that castor oil significantly improves the stability of recombinant human insulin.

Application Example 1 (Stability of liraglutide + flaxseed oil)

This embodiment provides a polypeptide composition, which includes 20 mg liraglutide, 200 mg flaxseed oil, 200 mg Tween 80, 80 mg soybean trypsin inhibitor, and 100 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 20mg liraglutide, 80mg soybean trypsin inhibitor, 100mg disodium edetate, 200mg flaxseed oil and 200mg Tween 80 respectively;

Then mix the weighed liraglutide, soybean trypsin inhibitor, and disodium ethylenediaminetetraacetate, add the weighed flaxseed oil and Tween 80, mix, and put it into a gelatin capsule to obtain an oral solution. Peptide compositions.

Application Example 2 (Stability of liraglutide + castor oil)

This embodiment provides a polypeptide composition, which includes 20 mg liraglutide, 200 mg castor oil, 200 mg Tween 80, 80 mg soybean trypsin inhibitor, and 100 mg disodium ethylenediaminetetraacetate;

The preparation method of the polypeptide composition is:

Weigh 20mg liraglutide, 80mg soybean trypsin inhibitor, 100mg disodium edetate, 200mg castor oil and 200mg Tween 80 respectively;

Then mix the weighed liraglutide, soybean trypsin inhibitor, and disodium ethylenediaminetetraacetate, add the weighed castor oil and Tween 80, mix, and put it into a gelatin capsule to obtain an oral polypeptide. combination.

Application Example 3 (Stability of Semaglutide + Castor Oil)

This embodiment provides a polypeptide composition, which includes 8 mg semaglutide, 275 mg castor oil, 275 mg Tween 80, 105 mg soybean trypsin inhibitor, and 150 mg disodium ethylenediaminetetraacetate;

The preparation method of the polypeptide composition is:

Weigh 8mg semaglutide, 105mg soybean trypsin inhibitor, 150mg disodium edetate, 275mg castor oil and 275mg Tween 80 respectively;

Then mix the weighed semaglutide, soybean trypsin inhibitor, and disodium ethylenediaminetetraacetate, add the weighed castor oil and Tween 80, mix, and put it into a gelatin capsule to obtain an oral polypeptide. combination.

Application Example 4 (Stability of Semaglutide + Castor Oil)

This embodiment provides a polypeptide composition, which includes 24 mg semaglutide, 500 mg castor oil, 100 mg Tween 80, 50 mg soybean trypsin inhibitor, and 300 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 24 mg semaglutide, 500 mg castor oil, 100 mg Tween 80, 50 mg soybean trypsin inhibitor and 300 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule. A polypeptide composition is obtained.

Application Example 5 (Stability of Semaglutide + Castor Oil)

This embodiment provides a polypeptide composition, which includes 50 mg semaglutide, 150 mg castor oil, 400 mg Tween 80, 250 mg soybean trypsin inhibitor, and 70 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 50 mg semaglutide, 150 mg castor oil, 400 mg Tween 80, 250 mg soybean trypsin inhibitor and 70 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule. A polypeptide composition is obtained.

Application Example 6 (Stability of thymosin + castor oil)

This embodiment provides a polypeptide composition, which includes 5 mg of thymomethasin, 335 mg of castor oil, 290 mg of Tween 80, 200 mg of soybean trypsin inhibitor, and 75 mg of disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 5 mg of thymus law, 335 mg of castor oil, 290 mg of Tween 80, 200 mg of soybean trypsin inhibitor and 75 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to get Peptide compositions.

Application Example 7 (Stability of thymosin + castor oil)

This embodiment provides a polypeptide composition, which includes 25 mg of thymomethasone, 100 mg of castor oil, 400 mg of Tween 80, 75 mg of soybean trypsin inhibitor, and 300 mg of disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 25 mg of thymus law, 100 mg of castor oil, 400 mg of Tween 80, 75 mg of soybean trypsin inhibitor and 300 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule to obtain the polypeptide. combination.

Application Example 8 (Stability of thymosin + castor oil)

This embodiment provides a polypeptide composition, which includes 50 mg thymomethasin, 400 mg castor oil, 100 mg Tween 80, 250 mg soybean trypsin inhibitor, and 150 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 50 mg of thymus law, 400 mg of castor oil, 100 mg of Tween 80, 250 mg of soybean trypsin inhibitor and 150 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule to obtain the polypeptide. combination.

Application Example 9 (Stability of recombinant human insulin + castor oil)

This embodiment provides a polypeptide composition, which includes 2 mg of recombinant human insulin, 328 mg of castor oil, 131 mg of Tween 80, 341 mg of soybean trypsin inhibitor, and 197 mg of disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 2 mg of recombinant human insulin, 328 mg of castor oil, 131 mg of Tween 80, 341 mg of soybean trypsin inhibitor, and 197 mg of disodium ethylenediaminetetraacetate respectively; then add the weighed recombinant human insulin, soybean trypsin inhibitor, and Mix disodium ethylenediaminetetraacetate, add weighed castor oil and Tween 80, mix evenly, and put into a gelatin capsule to obtain a polypeptide composition.

Application Example 10 (Stability of recombinant human insulin + castor oil)

This embodiment provides a polypeptide composition, which includes 16 mg of recombinant human insulin, 532 mg of castor oil, 106 mg of Tween 80, 80 mg of soybean trypsin inhibitor, and 266 mg of disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 16 mg of recombinant human insulin, 532 mg of castor oil, 106 mg of Tween 80, 80 mg of soybean trypsin inhibitor, and 266 mg of disodium ethylenediaminetetraacetate, and then add the weighed recombinant human insulin, soybean trypsin inhibitor, and Mix disodium ethylenediaminetetraacetate, add weighed castor oil and Tween 80, mix evenly, and put into a gelatin capsule to obtain a polypeptide composition.

Application Example 11 (Stability of recombinant human insulin + castor oil)

This embodiment provides a polypeptide composition, which includes 32 mg of recombinant human insulin, 93 mg of castor oil, 373 mg of Tween 80, 175 mg of soybean trypsin inhibitor, and 326 mg of disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 32 mg of recombinant human insulin, 93 mg of castor oil, 373 mg of Tween 80, 175 mg of soybean trypsin inhibitor, and 326 mg of disodium ethylenediaminetetraacetate, and then add the weighed recombinant human insulin, soybean trypsin inhibitor, and Mix disodium ethylenediaminetetraacetate, add weighed castor oil and Tween 80, mix evenly, and put into a gelatin capsule to obtain a polypeptide composition.

Application Example 12 (Stability of Lupron + Castor Oil)

This embodiment provides a polypeptide composition, which includes 4 mg leuprolide, 377 mg castor oil, 120 mg Tween 80, 70 mg soybean trypsin inhibitor, and 180 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 4mg leuprolide, 377mg castor oil, 120mg Tween 80, 70mg soybean trypsin inhibitor and 180mg disodium ethylenediaminetetraacetate respectively, then add the weighed leuprolide and soybean trypsin inhibitor Mix the agent and disodium ethylenediaminetetraacetate, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to obtain a polypeptide composition.

Application Example 13 (Stability of Lupron + Castor Oil)

This embodiment provides a polypeptide composition, which includes 20 mg leuprolide, 282 mg castor oil, 300 mg Tween 80, 100 mg soybean trypsin inhibitor, and 50 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 20mg leuprolide, 282mg castor oil, 300mg Tween 80, 100mg soybean trypsin inhibitor and 50mg disodium ethylenediaminetetraacetate respectively, then add the weighed leuprolide and soybean trypsin inhibitor Mix the agent and disodium ethylenediaminetetraacetate, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to obtain a polypeptide composition.

Application Example 14 (Stability of Lupron + Castor Oil)

This embodiment provides a polypeptide composition, which includes 40 mg leuprolide, 90 mg castor oil, 210 mg Tween 80, 230 mg soybean trypsin inhibitor, and 282 mg disodium ethylenediaminetetraacetate.

The preparation method of the polypeptide composition is:

Weigh 40mg leuprolide, 90mg castor oil, 210mg Tween 80, 230mg soybean trypsin inhibitor and 282mg disodium ethylenediaminetetraacetate respectively, then add the weighed leuprolide and soybean trypsin inhibitor Mix the agent and disodium ethylenediaminetetraacetate, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to obtain a polypeptide composition.

Application Example 15 (Stability of insulin degludec + castor oil)

Weigh 2 mg of insulin degludec, 443 mg of castor oil, 132 mg of Tween 80, 291 mg of soybean trypsin inhibitor, and 132 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to get Peptide compositions.

Application Example 16 (Stability of insulin degludec + castor oil)

Weigh 15 mg of insulin degludec, 390 mg of castor oil, 401 mg of Tween 80, 111 mg of soybean trypsin inhibitor, and 83 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to get Peptide compositions.

Application Example 17 (Stability of insulin degludec + castor oil)

Weigh 34 mg of insulin degludec, 110 mg of castor oil, 489 mg of Tween 80, 147 mg of soybean trypsin inhibitor, and 220 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a gelatin capsule to get Peptide compositions.

Application Example 18 (Stability of recombinant human insulin + castor oil)

Weigh 8 mg of recombinant human insulin, 320 mg of castor oil, 250 mg of Tween 80, 320 mg of soybean trypsin inhibitor and 100 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain a polypeptide composition.

Application Comparative Example 1 (stability of liraglutide + fish oil)

This embodiment provides a polypeptide composition, which includes 20 mg liraglutide, 200 mg fish oil, 200 mg Tween 80, 80 mg soybean trypsin inhibitor, and 100 mg disodium ethylenediaminetetraacetate;

The preparation method of the polypeptide composition is:

Weigh 20 mg of liraglutide, 80 mg of soybean trypsin inhibitor, and 100 mg of ethylenediaminetetraethylene respectively. Disodium acidate, 200mg fish oil and 200mg Tween 80;

Then mix the weighed liraglutide, soybean trypsin inhibitor, and disodium ethylenediaminetetraacetate, add the weighed fish oil and Tween 80, mix, and put it into a gelatin capsule to obtain an oral polypeptide combination. things.

Use HPLC to detect the content of liraglutide or semaglutide on days 0, 5, 10, 15, 30, and 60 when the polypeptide composition is placed at 25°C. Each polypeptide composition Three samples were detected at each time point, and the results are shown in Table 5. The content in Table 5 is the average value of the polypeptides in the three samples at each time point.

table 5

"/" indicates that the content was not detected at this time point.

According to Table 5 above, after the obtained polypeptide composition was placed at 25°C for 15 days, the liraglutide content in Application Example 1 and Application Example 2 remained basically unchanged, that is, the polypeptide composition used flaxseed. Oil and castor oil can prevent the degradation of peptides and improve their stability.

After being placed at 25°C for 60 days, compared with day 0, the liraglutide content in the polypeptide composition remained basically unchanged. For example, the liraglutide content in the polypeptide composition of Example 2 is 98.6%, while the polypeptide of Comparative Example 1 is used. The liraglutide content in the composition is 48.6%.

After being placed at 25°C for 30 days, compared with day 0, the semaglutide content in the polypeptide composition remained basically unchanged. For example, the content of semaglutide in the polypeptide composition of Application Examples 3-5 remains essentially unchanged.

It can be seen that castor oil can significantly improve the stability of liraglutide and semaglutide in polypeptide compositions.

The polypeptide compositions of Application Examples 6-8, Application Examples 12-14, and Application Examples 15-17 were respectively placed at 40°C on the 0th day, the 5th day, the 10th day, the 20th day, and the 30th day. , take samples on the 60th day, the 90th day, the 120th day, the 180th day, and the 365th day, and use HPLC to detect the peptide content in the polypeptide composition. Three samples of each polypeptide composition were tested at each time point, and the results are shown in Table 6. The content in Table 6 is the average of the thymosin or leuprolide content in the three samples at each time point. .

Table 6

Note: “/” indicates that the content was not detected at this time point. "d" is the abbreviation of "day", 0d means day 0, and the rest are the same.

It can be seen from Table 6 that after being placed at 40° C. for 180 days, the thymosin content in the polypeptide compositions of Application Examples 6-8 is ≥87.0%. For example, the thymusfaxin content in the polypeptide composition of Application Example 6 is 87.0%.

It can be seen from Table 6 that after being placed at 40°C for 180 days, the leuprolide content in the polypeptide composition of Application Examples 12-14 is >88.0%. For example, the leuprolide content in the polypeptide composition of Application Example 12 is 89.8%. .

It can be seen from Table 6 that after being placed at 40°C for 30 days, the insulin degludec content in the polypeptide composition of Application Examples 15-17 is >85.0%. For example, the insulin degludec content in the polypeptide composition of Application Example 15 is 89.3%.

It can be seen from Table 6 that compared with the prior art, castor oil can significantly improve the stability of thymosin, insulin degludec and leuprolide in the polypeptide composition.

The polypeptide compounds of Examples 9-11 were placed at 25°C, and samples were taken on the 0th day, the 5th day, the 10th day, the 30th day, the 60th day, the 90th day, the 180th day, and the 365th day. Use HPLC to detect the polypeptide content in the polypeptide composition. Three samples of each polypeptide composition were tested at each time point, and the results are shown in Table 7. The content in Table 7 is the average of the recombinant human insulin content in the three samples at each time point.

Table 7

Note: “/” indicates that the content was not detected at this time point. "d" is the abbreviation of "day", 0d means day 0, and the rest are the same.

Conclusion: It can be seen from Table 7 that after being placed at 25°C for 365 days, the content of recombinant human insulin in the polypeptide compositions of Application Examples 9-11 and Application Example 18 is >90.0%. For example, the recombinant human insulin content in the polypeptide composition of Application Example 9 is Insulin content is 91.5%.

It can be seen that compared with the prior art, castor oil can significantly improve the stability of recombinant human insulin in the polypeptide composition.

Based on Table 4-7, it can be seen that compared with the existing technology, vegetable oil can significantly improve the stability of the polypeptide in the polypeptide composition and effectively prevent the degradation of the polypeptide. The vegetable oil may be selected from linseed oil, castor oil, perilla oil, corn oil or soybean oil. The polypeptide may be selected from semaglutide, recombinant human insulin, thymusfasin, insulin degludec or leuprolide.

Animal experiment 1

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide compositions for animal experiments:

Preparation of polypeptide composition 1 for animal experiments:

Weigh 8mg semaglutide, 275mg fish oil, 275mg Tween 80, 105mg soybean trypsin inhibitor and 150mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed fish oil and Tween 80, mix evenly, and put it into a capsule. Coating, the coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to On the surface of the capsule, polypeptide composition 1 was obtained.

Preparation of polypeptide composition 2 for animal experiments:

Weigh 8mg semaglutide, 275mg castor oil, 275mg Tween 80, 105mg soybean trypsin inhibitor and 150mg disodium ethylenediaminetetraacetate in sequence. First, weigh the weighed semaglutide and soybean trypsin Mix the inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, put it into a capsule, and coat the capsule. The coating materials include 40mg Eudragit L-100, 40mg Talcum powder and 5 mg polyethylene glycol 6000, dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid, and spray the coating liquid onto the capsule surface to obtain polypeptide composition 2.

(2) Experimental animals: 15 male beagle dogs, 0.5 to 1 year old, weighing 9 to 11kg.

(3) Dosing schedule: The experimental animals were randomly divided into 3 groups, with 5 animals in each group. The animals were fasted for ≥12 hours before administration, and the animals were fasted for 4 hours after administration.

Intravenous administration group G1:

Single administration, intravenous injection of semaglutide injection, dosage 0.015mg/kg, beagle number Dog#01, Dog#02, Dog#03, Dog#04, Dog#05.

Oral administration group:

There are 2 oral administration groups, namely oral administration group G1 and oral administration group G2.

Oral administration group G1: Beagle numbers Dog#06, Dog#07, Dog#08, Dog#09, Dog#10.

Orally feed capsules of polypeptide composition 1, once a day, one capsule each time, for 5 days.

Oral administration group G2: Beagle numbers Dog#11, Dog#12, Dog#13, Dog#14, Dog#15.

Orally feed capsules of polypeptide composition 2, once a day, one capsule each time, for 5 days.

(4)Plasma collection and processing:

Intravenous administration group G1:

Blood samples were collected at 0h (0h is before intravenous administration), 5min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 10h, 24h, 48h, 96h, and 144h after administration. The sampling site was the peripheral veins of the limbs. , use anticoagulant tubes containing EDTA-K ₂ to collect 800 μl of whole blood at each time point, centrifuge, separate, and store the plasma at -80°C until detection.

Oral administration group:

Continue administration for 5 days, and collect blood on the fifth day. The blood collection time points are: 0h (0h before the fifth oral administration), 5min, 30min, 1h, 1.5h, 2h, 3h after the fifth oral administration. , 4h, 6h, 10h, 24h, 48h, 96h, 144h; the sampling site is the peripheral veins of the limbs. Use anticoagulant tubes containing EDTA-K ₂ to collect 800 microliters of whole blood at each time point, centrifuge, separate, and place the plasma in Store at -80°C until detection.

(5) Detection method: LC/MS/MS is used for detection, using diclofenac sodium as the internal standard, and the chromatographic column Protein BEH C4, gradient elution, mobile phase A: water (containing 1% trifluoroacetic acid), mobile phase B: acetonitrile: methanol: water = 85:15:5:1, flow rate 0.5ml/min, column temperature 40°C , the injection volume is 10 μL, and the lower detection limit LLOQ=1ng/mL.

Table 8. Gradient elution table

The time-varying curves of drug concentration in plasma of each experimental group are shown in Figures 1 to 4;

The calculation results of pharmacokinetic parameters for intravenous administration are shown in Table 9 below, and the calculation results of pharmacokinetic parameters for oral administration are shown in Table 10 below:

Table 9

Table 10

In the table: t _1/2 is the half-life, C _max is the peak concentration, C _ss is the steady-state concentration, CL is the clearance rate, and F is the absolute bioavailability.

AUC _last (hr*ng/mL) represents the area under the plasma concentration-time curve from 0 to the quantitative time point;

AUC _Inf (hr*ng/mL) represents the area under the blood drug concentration-time curve from 0 to infinity time point;

It can be seen from the data in the table that after oral administration of the polypeptide composition provided by the present disclosure, semaglutide can be detected in the plasma of beagle dogs, and the bioavailability of the oral administration group G2 is significantly higher than that of the oral administration group G1. That is, using castor oil as a stabilizer can improve the bioavailability of the drug, indicating that the polypeptide composition provided by the present disclosure can promote the absorption of the polypeptide in the gastrointestinal tract, thereby achieving the purpose of oral administration.

Animal experiment 2

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 3 for animal experiments:

Weigh 24 mg of semaglutide, 500 mg of castor oil, 100 mg of Tween 80, and 50 mg of trypsin soybean in sequence. Platinase inhibitor and 300mg disodium edetate. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating. The coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to the capsule surface to obtain polypeptide composition 3.

(2) Preparation of polypeptide composition 4 for animal experiments:

Weigh 50 mg semaglutide, 150 mg castor oil, 400 mg Tween 80, 250 mg soybean trypsin inhibitor and 70 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating. The coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to the capsule surface to obtain polypeptide composition 4.

(3) Experimental animals:

There are 18 beagles, half male and half female, the female is not pregnant, 6 to 7 months old, and weighs 7 to 9kg;

Animal grouping

There are 3 dose groups in this experiment, and the number of animals in each group is 6, half male and half female. Grouping method: Random grouping by gender and weight. See Table 11 for specific groupings.

Table 11. Grouping situation table

Note: The first digit of the animal number represents the group (3, 4, and 5 represent the G3 oral group, G4 oral group, and Ozempic injection group respectively). The second letter represents the gender (M is male, F is female), and the three, four, and five digits represent the individual animal number.

(4)Dosing regimen:

G3 oral group: 24mg/animal, administered orally. The drug used in the G3 oral group was the polypeptide composition 3 prepared in this example.

G4 oral group: 50mg/animal, administered orally. The drug used in the G4 oral group was the polypeptide composition 4 prepared in this example.

Ozempic injection group: 0.015mg/kg, administered by abdominal subcutaneous injection. The drug used in the Ozempic injection group is Novo Nordisk Semaglutide Injection.

Dosing frequency:

G3 oral group: Orally feed the polypeptide composition 3 prepared in this example, one pill at a time, for a total of once.

G4 oral group: Orally feed the polypeptide composition 4 prepared in this example, one pill at a time, for a total of once.

Ozempic injection group: subcutaneous injection into the abdomen on the first day of the experiment, once in total.

illustrate:

The oral administration group and the subcutaneous injection group were fasted for 12 hours overnight before administration, and were administered on an empty stomach the next day. They were fed 5 mL/kg drinking water at the same time as the administration, and they were free to eat 4 hours after administration. The first day of administration was defined as day 1 of the trial (Day 1).

In the Ozempic injection group, the injection dosage of each animal was calculated based on the latest body weight.

(5) Blood collection time point

Oral administration group: before administration, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 204, 240h after administration.

Subcutaneous injection group: before administration, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 204, 240h after administration.

Collect animals: all surviving animals in each group;

Collection method: blood collection from forelimb veins;

Blood collection volume: about 1mL/bird/time;

Anticoagulation method: EDTA anticoagulation.

(6)Sample processing and testing

Store the whole blood (anticoagulation) temporarily in an ice box before centrifugation, and leave it for no more than 2 hours. Centrifuge it at 2-8°C and a centrifugal force of about 2000g for 10 minutes to separate the plasma. The plasma is divided into 2 tubes, each tube is 100 μL, and placed at -85~-70 Store at ℃ for inspection. After the sample processing at the last time point is completed, 20 mL each of female and male Beagle dog blank plasma will be sent together with the samples for testing. Detected using the detection method of Animal Experiment 1.

The calculation results of the absolute bioavailability F of the oral administration group are shown in Table 12 below:

Table 12. Absolute bioavailability F for oral administration

It can be seen from the data in the table that after oral administration of the polypeptide composition provided by the present disclosure, semaglutide can be detected in the plasma of beagle dogs, achieving oral administration of semaglutide.

Animal experiment 3

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 5 for animal experiments:

Weigh 8mg semaglutide, 275mg castor oil, 275mg Tween 80, 105mg soybean trypsin inhibitor and 150mg disodium ethylenediaminetetraacetate in sequence. First, weigh the weighed semaglutide and soybean trypsin Mix the inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 5.

(2) Preparation of polypeptide composition 6 for animal experiments:

Weigh 24 mg semaglutide, 500 mg castor oil, 100 mg Tween 80, 50 mg soybean trypsin inhibitor and 300 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed semaglutide, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 6.

(3) Preparation of placebo for animal experiments:

Weigh 500 mg castor oil, 100 mg Tween 80, 50 mg soybean trypsin inhibitor and 300 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and obtain a placebo.

(4) Experimental animals

Species: ZDF model rat, type 2 diabetes model rat; Grade: SPF grade;

16 animals, gender: male; age: about 28 to 29 weeks old; weight: about 400 to 500g. The individual weight should be within ±20% of the average body weight. They are randomly divided into four groups. See Table 13 for group details.

Duodenal intubation administration method: After the rat is anesthetized with isoflurane, the rat is fixed in a supine position; a transverse incision is made below the xiphoid process, and the opening is as small as possible; the position of the stomach is determined, the pylorus is found, and a solution infiltrated with normal saline is used Hold the duodenum with a cotton swab, poke a small hole about 2cm away from the pylorus, insert the cannula that has been drained of air with saline in advance through the small hole, and intubate down the duodenum to the length of 3cm, fix the gastrointestinal intubation and intestinal wall with two needles in a part with few blood vessels; suture the muscle and skin separately, sew the muscle layer and bury the heparin cap of the indwelling needle under the abdominal skin, disinfect the skin, and directly pass the heparin every day Insert the cap into the needle and repeat the dose.

Table 13 Experimental grouping and dose design table

Remarks: [1] Qd: once a day, Qd×14: once a day, a total of 14 doses;

[2] The first digit of the animal number represents the group, the first digit represents the group, the second letter represents the gender (M is female), and the 3rd, 4th and 5th digits represent the individual animal number;

[3] Note: The day of the first dose is defined as the first day of the trial, recorded as D1, followed by D2, D3..., and so on.

(5)Dosing regimen:

model control group

Route of administration: administration via duodenal intubation; repeated administration, once a day, for 14 consecutive days, for a total of 14 administrations, using the placebo prepared in this example.

Dosing volume: 100ul/box

Semaglutide duodenal administration group

Route of administration: administration via duodenal intubation; repeated administration, once a day, for 14 consecutive days, a total of 14 times.

Oral semaglutide group G1: a single dose of 2.86 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 5 prepared in this example;

Semaglutide oral G2 group: 8.20 mg/kg was administered via duodenal intubation in a single dose, and the drug used was polypeptide composition 6 prepared in this example.

The oral dosage of semaglutide in the G1 group is 2.86 mg/kg, which refers to the administration of 2.86 mg of semaglutide per kg of rats through duodenal intubation. Assuming that the weight of a rat is 400mg, the weight of each component of the polypeptide composition given to the rat is: semaglutide: 2.86mg/kg*0.4kg=1.14mg, castor oil: (1.14/8)*275mg , Tween 80: (1.14/8)*275mg, soybean trypsin inhibitor: (1.14/8)*105mg, disodium edetate: (1.14/8)*150mg, which is equivalent to the polypeptide composition Weigh (1.14/8)*100%=14.25% in 5, and then administer it through duodenal intubation.

The dosage of semaglutide oral G2 group was calculated in the same way.

(6) Blood collection time and blood glucose measurement

Measurement time:

Rats were fasted overnight, and fasting blood glucose levels were measured before administration; after the first administration, fasting blood glucose levels at 2 hours, 4 hours, 6 hours, and 8 hours and random blood glucose levels at 10 hours and 24 hours were measured;

Fast overnight before the last dose, and measure fasting blood glucose and random blood glucose at 10 and 24 hours before and 2 hours, 4 hours, 6 hours, and 8 hours after administration;

During the dosing period, fast overnight before each blood glucose measurement, and measure fasting blood glucose 2 hours after dosing, twice a week for a total of 2 weeks.

Test animals: all surviving rats in each group;

Measurement method: Prick the tip of the tail and wait for the blood to seep out. The blood glucose meter is equipped with a blood glucose test paper to absorb a trace amount of blood and read the blood glucose value.

(7)Weight measurement

Measurement time: 2 times/week after group administration, for a total of 2 weeks;

Measuring animals: rats in each group.

(8) Increase blood sugar after administration:

The formula for calculating the blood sugar reduction rate is (blood sugar value of the model control group - blood sugar value of the drug administration group)/blood sugar value of the model control group * 100%; where, the blood sugar value of the model control group represents the blood sugar value of the rats in the model control group at time t. The blood glucose value of the drug group represents the blood glucose value of the rats in the drug group at time t.

Before the first and last administration of duodenal intubation and 0 to 24 hours after administration, the blood glucose levels of animals in each group showed a steady increase after starting to eat, but the overall increase in blood glucose of animals in the oral administration group of semaglutide was slower.

After the first administration, compared with the model control group, the semaglutide oral G1 group achieved the maximum hypoglycemic effect in 2 to 6 hours, and the hypoglycemic rate of the four rats ranged from 23.42 to 38.30%, P < 0.05, with statistical significance. significance. After the first administration, compared with the model control group, the blood glucose level of the semaglutide oral G2 group was significantly reduced at 4 to 8 hours, and the blood sugar reduction rate of the four rats ranged from 26.43 to 37.53%, P<0.05, with statistical significance. .

After the last administration, the blood glucose values of the semaglutide oral G1 group and the semaglutide oral G2 group were always lower than the model control group within 24 hours. After the last dose, compared with the model control group, the semaglutide oral G1 group had the best blood sugar control at 4 to 6 hours, and the blood sugar reduction rate of the four rats ranged from 23.95 to 35.52%, P<0.05, with statistical significance. . After the last dose, compared with the model control group, the semaglutide oral G2 group had the best blood sugar control at 2 to 6 hours, and the blood sugar reduction rate of the four rats ranged from 26.43 to 35.52%, P<0.05, with statistical significance. .

(9)Weight

Compared with the model control group, after 14 days of continuous administration, the average body weight of rats in the semaglutide oral G1 group decreased by 25.28%, P<0.05, which was statistically significant.

Compared with the model control group, after 14 days of continuous administration, the average body weight of rats in the semaglutide oral G2 group decreased by 30.78%, P<0.05, which was statistically significant.

Animal experiment 4

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 7 for animal experiments:

Weigh 5 mg of thymus law, 335 mg of castor oil, 290 mg of Tween 80, 200 mg of soybean trypsin inhibitor and 75 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating, the coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to On the surface of the capsule, polypeptide composition 7 was obtained.

(2) Preparation of polypeptide composition 8 for animal experiments:

Weigh 25 mg of thymus law, 100 mg of castor oil, 400 mg of Tween 80, 75 mg of soybean trypsin inhibitor and 300 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating, the coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to On the surface of the capsule, polypeptide composition 8 was obtained.

(3) Preparation of polypeptide composition 9 for animal experiments:

Weigh 50 mg of thymus law, 400 mg of castor oil, 100 mg of Tween 80, 250 mg of soybean trypsin inhibitor and 150 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed thymus law, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, and mix well. Evenly, put into a capsule, and coat the capsule. The coating materials include 40 mg Eudragit L-100, 40 mg talc powder, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol. The coating liquid is obtained, and the coating liquid is sprayed onto the capsule surface to obtain polypeptide composition 9.

(4) Experimental animals:

Group design: thymusfaxin injection group, thymusfaxin oral group G1, thymusfaxin oral group G2, thymusfaxin oral group G3;

Number of animals: Beagle dogs, 3 in each group, 12 in total; Beagle dogs weigh about 7 to 10kg;

Sex ratio: half male and half female;

Grouping method: Randomly group Beagle dogs according to their weight;

See Table 14 for specific grouping information.

Table 14. Test group conditions

Note: The first digit of the animal number represents the group. The second letter represents the gender (F for female, M for male), and the last three digits represent the animal serial number.

(5)Dosing regimen:

Thymusfaxin oral group

Route of administration: Oral administration; single dose.

Thymosin oral group G1: A single oral feeding of the polypeptide composition 7 prepared in this example, 1 capsule/animal, in the upper cross (before washout); A single oral feeding of this embodiment in the lower cross (after washout) Polypeptide composition 7 prepared in Example 7, 1 capsule/bird;

Thymusfasin oral group G2: A single oral feeding of the polypeptide composition 8 prepared in this example in the upper cross (before washout), 1 capsule/animal; A single oral feeding of the polypeptide composition 8 prepared in this example in the lower cross (after washout) Polypeptide composition 8 prepared in the example, 1 capsule/bird;

Thymusfasin oral group G3: the upper cross (before washout) was given a single oral feeding of the polypeptide composition 9 prepared in this example, 1 capsule/animal; the lower cross (after washout) was orally fed and prepared in this example Polypeptide composition 9, 1 capsule/piece;

Note: All Beagle dogs should fast for ≥12 hours before administration and within 8 hours after administration.

Thymus method injection group

Route of administration: subcutaneous injection; single dose.

Subcutaneous injection volume: 1mg/mL, the dosage of each animal is calculated based on the most recent body weight measurement;

Subcutaneous injection group: upper cross (before washout) single subcutaneous injection of the marketed Thymus Faxin Injection, 0.05 mg/kg; lower cross (after washout) single subcutaneous injection of the marketed Thymus Faxin Injection, 0.05 mg/kg. Note: All Beagle dogs should fast for ≥12 hours before administration and within 8 hours after administration.

See Table 15 for specific dosing.

Table 15. Dosing design

Note:

1. The elution cycle is one week;

2. The drug administration adopts a crossover design: the thymusfaxin oral group G1 is crossed with the thymusfaxin oral group G2; the thymusfaxin oral group G3 is crossed with the thymusfaxin injection group.

(6) Blood collection and processing:

Sampling time of thymofaxin oral group: 30 minutes, 45 minutes, 1 hour, 75 minutes, 90 minutes, 105 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours after the end of administration;

Sampling time of thymusfaxin injection group: 15 minutes, 30 minutes, 45 minutes, 1 hour, 75 minutes, 90 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours after the end of administration;

Sampling site: saphenous vein of lower limbs or other suitable veins;

Sampling sites: all surviving Beagle dogs;

Sampling volume: about 0.6mL;

Anticoagulant: EDTA-K ₂ ;

Blood sample processing: Temporarily store whole blood samples in an ice box (no more than 2 hours) before centrifugation. Centrifuge at 2-8°C at about 10,000 rpm for 5 minutes. The plasma of each group is divided into 2 tubes (the first tube is 50 μL, and the remaining plasma is placed in another tube). Medium), store below -66℃ and submit for inspection.

Table 16. Absolute bioavailability F of thymosin administered orally

Animal experiment 5

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 10 for animal experiments:

Weigh 2 mg of recombinant human insulin, 328 mg of castor oil, 131 mg of Tween 80, 341 mg of soybean trypsin inhibitor and 197 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain the polypeptide composition 10.

(2) Preparation of polypeptide composition 11 for animal experiments:

Weigh 16 mg of recombinant human insulin, 532 mg of castor oil, 106 mg of Tween 80, 80 mg of soybean trypsin inhibitor and 266 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain the polypeptide composition 11.

(3) Preparation of polypeptide composition 12 for animal experiments:

Weigh 32 mg of recombinant human insulin, 93 mg of castor oil, 373 mg of Tween 80, 175 mg of soybean trypsin inhibitor, and 326 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain the polypeptide composition 12.

(4) Preparation of polypeptide composition 13 for animal experiments:

Weigh 8 mg of recombinant human insulin, 320 mg of castor oil, 250 mg of Tween 80, 320 mg of soybean trypsin inhibitor and 100 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 13.

(5) Placebo preparation for animal experiments:

Weigh 532 mg castor oil, 106 mg Tween 80, 80 mg soybean trypsin inhibitor and 266 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed recombinant human insulin, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and obtain a placebo.

(6) Experimental animals

Group design: normal control group, model control group, insulin injection group, insulin duodenal administration group G1, insulin duodenal administration group G2, insulin duodenal administration group G3, insulin duodenal administration group Enteral administration group G4;

Number of animals: The normal control group used 12 normal rats without modeling, and the remaining groups used STZ model rats. Rats, 12 in each group, 84 in total, each rat weighs about 300-380g;

Reasons for animal strain selection: The STZ model rat was established by intraperitoneal injection of streptozotocin in SD rats, damaging the rat islets, and feeding with high-fat and high-sugar feed to induce type 2 diabetes model. Therefore, this research system selected STZ rats as the research object to observe the hypoglycemic effect of the test substance on the type 2 diabetes rat model.

Sex ratio: half male and half female;

Grouping method: Rats with blood sugar ≥16.7mmol/L were included in the drug administration group, and rats were randomly divided into groups according to their blood sugar and body weight;

Duodenal intubation administration method: After the rat is anesthetized with isoflurane, the rat is fixed in a supine position; a transverse incision is made below the xiphoid process, and the opening is as small as possible; the position of the stomach is determined, the pylorus is found, and a solution infiltrated with normal saline is used Hold the duodenum with a cotton swab, poke a small hole about 2cm away from the pylorus, insert the cannula that has been drained of air with saline in advance through the small hole, and intubate down the duodenum to the length of 3cm, fix the gastrointestinal intubation and intestinal wall with two needles in a part with few blood vessels; suture the muscle and skin separately, sew the muscle layer and bury the heparin cap of the indwelling needle under the abdominal skin, disinfect the skin, and directly pass the heparin every day Insert the cap into the needle and repeat the dose.

Methods of sham surgery for the insulin injection group: After the rats were anesthetized with isoflurane, they were fixed in a supine position; a transverse incision was made under the xiphoid process, with the opening as small as possible; the position of the stomach was determined, the pylorus was found, and a cotton swab soaked in normal saline was used to hold it Hold the duodenum, poke a small hole about 2cm away from the pylorus, then sew the small hole with a needle, and then sew the abdominal wall muscles and skin layer by layer to close the abdomen.

The normal control group did not undergo surgery.

See Table 17 for specific grouping information.

Table 17. Test group conditions

Note: The first digit of the animal number represents the group. The second letter indicates gender (F for female, M for male), and the last three digits represent the animal's serial number.

(7)Dosing regimen:

normal control group

No medication required

model control group

Route of administration: administration via duodenal intubation; repeated administration, three times a day, for 14 consecutive days, using the placebo prepared in this example.

Dosing volume: 100ul/box

Insulin injection group

Route of administration: subcutaneous injection; repeated administration, three times a day, for 14 consecutive days

Subcutaneous injection dosage: 0.0347mg/kg

Insulin duodenal administration group

Route of administration: administration via duodenal intubation; repeated administration, three times a day, for 14 consecutive days

Insulin duodenal administration group G1: a single administration of 0.5 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 10 prepared in this example;

Insulin duodenal administration group G2: a single dose of 2 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 11 prepared in this example;

Insulin duodenal administration group G3: a single administration of 10 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 12 prepared in this example.

Insulin duodenal administration group G4: a single administration of 4 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 13 prepared in this example.

The G1 dosage of insulin duodenal administration group 0.5 mg/kg refers to the administration of 0.5 mg recombinant human insulin per kg of rats through duodenal intubation. Assuming that a rat weighs 300 mg, the weight of each component of the polypeptide composition administered to the rat is: recombinant human insulin: 0.5*0.3mg=0.15mg, castor oil: (0.15/2)*328mg, Tween 80 (0.15/2)*131mg, soybean trypsin inhibitor: (0.15/2)*341mg, disodium edetate: (0.15/2)*197mg, which is equivalent to giving (0.15/2)*100 % = 7.5% of polypeptide composition 10.

The dosage of insulin duodenal administration group G2, insulin duodenal administration group G3 and insulin duodenal administration group G4 is calculated in the same way.

See Table 18 for specific dosing.

Table 18 Dosing Design

(8) Blood collection and processing:

Blood glucose measurement time of the normal control group: 0 o'clock on D1, 0, 5 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours on D14 hours, 24 hours;

Blood glucose measurement time in the model control group: 0:00 on day D1, 5 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours before and after administration on day D14. 6 hours, 12 hours, 24 hours;

Blood glucose measurement time in the insulin injection group: 0:00 on day D1, 5 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours before and after administration on day D14. 6 hours, 12 hours, 24 hours;

Blood glucose measurement time in the duodenal administration group of insulin: 0 o'clock on day D1, 5 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 before and after administration on day D14 Hours, 4 hours, 6 hours, 12 hours, 24 hours.

(9) Blood glucose measurement method: Prick the tip of the tail and wait for the blood to seep out. The blood glucose meter is equipped with a blood glucose test paper to absorb a trace amount of blood and read the blood glucose value.

(10)Blood sugar

Before and 0 to 24 hours after administration:

Duodenostomy surgery was performed, and the patient recovered for 3 days after the operation. The blood glucose was measured before administration, that is, the blood glucose value at 0:00 on day D1. The administration was then continued for 14 days. The blood glucose at each point was measured after the last administration.

On D1 day 0h before administration, the average blood glucose level of the rats in the model control group, insulin injection group, and insulin duodenal administration group was significantly higher than that of the normal control group. The P value was less than 0.05, which was statistically significant, indicating that the modeling was successful. . There was no significant difference in the blood glucose of rats in the model control group, insulin injection group and insulin duodenal administration group, and the P value was greater than 0.05, indicating that there was no significant difference in the basal blood glucose levels of rats in these groups.

Comprehensive blood glucose values at each stage showed that there was no significant change in the blood glucose of rats in the model control group before and after administration, and it was significantly greater than that of the normal control group, with a P value of less than 0.05, indicating that the diabetes model continues to be effective.

The blood glucose values of rats in the duodenal administration group of insulin and the insulin injection group showed a trend of first decreasing and then increasing within 1 to 6 hours. The overall value was lower than that of the model control group. The P value was less than 0.05, which was statistically significant. .

The formula for calculating the blood sugar reduction rate is (blood sugar value of the model control group - blood sugar value of the drug administration group)/blood sugar value of the model control group * 100%; where, the blood sugar value of the model control group represents the blood sugar value of the rats in the model control group at time t. The blood glucose value of the drug group represents the blood glucose value of the rats in the drug group at time t.

The blood glucose in the insulin injection group began to decrease significantly at 45 minutes and reached the lowest level at 1 hour, with 12 rats falling. The sugar rate ranged from 42.69 to 58.36%. Compared with the model control group, the P value was less than 0.01, which was statistically significant.

As for the rats in the duodenal administration group of insulin, the duodenal administration group G1 had the greatest blood sugar reduction at 2 hours, and the blood sugar reduction rate of the 12 rats ranged from 16.33 to 26.56%, which was the same as the model control group. Compared with the model control group, the P value is less than 0.05; the insulin duodenal administration group G2 has the largest blood sugar reduction at 2 hours, and the blood sugar reduction rate of 12 rats ranges from 24.36 to 33.78%. Compared with the model control group, the P value is less than 0.05; Insulin duodenal administration group G3 had the largest blood sugar reduction at 3 hours. Compared with the model control group, the blood sugar reduction rate was 46.89-55.76%, and the P value was less than 0.01. Compared with the insulin injection group, the P value Greater than 0.05, indicating that there is no significant difference in blood glucose lowering levels between the insulin duodenal administration group G3 and the insulin injection group.

Insulin duodenal administration group G4 had the greatest blood sugar reduction at 2 hours, and the blood sugar reduction rate of 12 rats ranged from 19.77 to 30.52%. Compared with the model control group, the P value was less than 0.05.

The blood glucose levels of the four insulin duodenal administration groups were always lower than the model control group within 6 hours after administration. Compared with the model control group, blood glucose control was best between 1 and 4 hours, and the overall blood glucose lowering rate was 13.21 to 55.76. %,has statistical significane.

Animal experiments 6

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 14 for animal experiments:

Weigh 4 mg leuprolide, 377 mg castor oil, 120 mg Tween 80, 70 mg soybean trypsin inhibitor and 180 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed leuprolide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating. The coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to the capsule surface to obtain polypeptide composition 14.

(2) Preparation of polypeptide composition 15 for animal experiments:

Weigh 20 mg leuprolide, 282 mg castor oil, 300 mg Tween 80, 100 mg soybean trypsin inhibitor and 50 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed leuprolide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating. The coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to the capsule surface to obtain polypeptide composition 15.

(3) Preparation of polypeptide composition 16 for animal experiments:

Weigh 40 mg leuprolide, 90 mg castor oil, 210 mg Tween 80, 230 mg soybean trypsin inhibitor and 282 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed leuprolide, soybean trypsin inhibitor and disodium edetate evenly, add the weighed castor oil and Tween 80, mix evenly, and put it into a capsule. Coating. The coating materials include 40 mg Eudragit L-100, 40 mg talc, and 5 mg polyethylene glycol 6000. Dissolve the above coating materials with an appropriate amount of methylene chloride and isopropyl alcohol to obtain a coating liquid. Spray the coating liquid to the capsule surface to obtain polypeptide composition 16.

(4) Experimental animals:

Group design: leuprolide injection group, leuprolide oral group G1, leuprolide oral group G2, leuprolide oral group G3;

Number of animals: Beagle dogs, 3 in each group, 12 in total; Beagle dogs weigh approximately 9 to 11 kg;

Sex ratio: half male and half female;

Grouping method: Randomly group Beagle dogs according to their weight;

See Table 19 for specific grouping information.

Table 19. Test group conditions

Note: The first digit of the animal number represents the group. The second letter represents the gender (F for female, M for male), and the last three digits represent the animal serial number.

(5)Dosing regimen:

Lupron oral group

Route of administration: Oral administration; single dose.

Leuprorelin oral group G1: A single oral feeding of the polypeptide composition 14 prepared in this example in the upper cross (before washout), 1 capsule/animal; A single oral feeding of the polypeptide composition 14 prepared in this example in the lower cross (after washout) Polypeptide composition 14 prepared in Example, 1 capsule/animal;

Leuprorelin oral group G2: a single oral feeding of the polypeptide composition 15 prepared in this example, 1 capsule/animal, in the upper cross (before washout); a single oral feeding of the polypeptide composition 15 prepared in this example in the lower cross (after washout) Polypeptide composition 15 prepared in Example, 1 capsule/bird;

Leuprorelin oral group G3: A single oral feeding of the polypeptide composition 16 prepared in this example, 1 capsule/animal, in the upper cross (before washout); A single oral feeding of this example in the lower cross (after washout) Prepared polypeptide composition 16, 1 capsule/bird;

Note: All Beagle dogs should fast for ≥12 hours before administration and within 8 hours after administration.

Lupron injection group

Route of administration: subcutaneous injection; single dose.

Subcutaneous injection volume: 1mg/mL, the dosage of each animal is calculated based on the most recent body weight measurement;

Subcutaneous injection group: upper cross (before washout) single subcutaneous injection of the marketed leuprorelin injection, 0.1mg/kg; lower cross (after washout) single subcutaneous injection of the marketed leuprorelin injection ,0.1mg/kg. Note: All Beagle dogs should fast for ≥12 hours before administration and within 8 hours after administration.

See Table 20 for specific dosing.

Table 20. Dosing Design

Note:

1. The elution cycle is one week;

2. The drug administration adopts a crossover design: the leuprorelin oral group G1 is crossed with the leuprorelin oral group G2; the leuprorelin oral group G3 is crossed with the leuprorelin injection group.

(6) Blood collection and processing:

Sampling time for leuprolide oral group: before administration and 30 minutes, 45 minutes, 1 hour, 75 minutes, 90 minutes, 105 minutes, 2 hours, 4 hours, 8 hours, 12 hours after administration;

Sampling time for the leuprolide injection group: 5 minutes, 15 minutes, 30 minutes, 1 hour, 75 minutes, 90 minutes, 2 hours, 4 hours, 8 hours, and 12 hours before and after administration;

Sampling site: saphenous vein of lower limbs or other suitable veins;

Sampling sites: all surviving Beagle dogs;

Sampling volume: about 0.6mL;

Anticoagulant: EDTA-K2;

Blood sample processing: Temporarily store whole blood samples in an ice box (no more than 2 hours) before centrifugation. Centrifuge at 2-8°C at about 10,000 rpm for 5 minutes. The plasma of each group is divided into 2 tubes (the first tube is 50 μL, and the remaining plasma is placed in another tube). Medium), store below -66℃ and submit for inspection.

Table 21. Absolute bioavailability F of leuprolide after oral administration

Animal experiments 7

This example uses the polypeptide composition to conduct animal experiments.

(1) Preparation of polypeptide composition 17 for animal experiments:

Weigh 2 mg of insulin degludec, 443 mg of castor oil, 132 mg of Tween 80, 291 mg of soybean trypsin inhibitor, and 132 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 17.

(2) Preparation of polypeptide composition 18 for animal experiments:

Weigh 15 mg of insulin degludec, 390 mg of castor oil, 401 mg of Tween 80, 111 mg of soybean trypsin inhibitor, and 83 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 18.

(3) Preparation of polypeptide composition 19 for animal experiments:

Weigh 34 mg of insulin degludec, 110 mg of castor oil, 489 mg of Tween 80, 147 mg of soybean trypsin inhibitor, and 220 mg of disodium ethylenediaminetetraacetate in sequence. First, mix the weighed insulin degludec, soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, and mix evenly to obtain polypeptide composition 19.

(4) Placebo preparation for animal experiments:

Weigh 390 mg castor oil, 401 mg Tween 80, 111 mg soybean trypsin inhibitor and 83 mg disodium ethylenediaminetetraacetate in sequence. First, mix the weighed soybean trypsin inhibitor and disodium ethylenediaminetetraacetate evenly, add the weighed castor oil and Tween 80, mix evenly, and obtain the placebo.

(5) Experimental animals

Group design: normal control group, model control group, insulin degludec injection group, insulin degludec oral group G1, insulin degludec oral group G2, and insulin degludec oral group G3.

Number of animals: SD rats, male. Each rat weighs approximately 250-300g. The normal control group used 12 normal rats without modeling, and the remaining groups used STZ model rats, with 12 rats in each group.

Establishment of diabetes model: The STZ rat model was established by intraperitoneal injection of streptozotocin in SD rats, damaging rat pancreatic islets, and supplemented by feeding with high-fat and high-sugar feed to induce type 2 diabetes model. Four days later, blood was collected through tail incision to measure fasting blood glucose. Animals with fasting blood glucose higher than 16.7mmol/L were included in the group, and a total of 60 rats were selected for the experiment.

Grouping method: Randomly group the rats according to their blood sugar and body weight;

Duodenal intubation administration method: After the rat is anesthetized with isoflurane, the rat is fixed in a supine position; a transverse incision is made below the xiphoid process, and the opening is as small as possible; the position of the stomach is determined, the pylorus is found, and a solution infiltrated with normal saline is used Hold the duodenum with a cotton swab, poke a small hole about 2cm away from the pylorus, insert the cannula that has been drained of air with saline in advance through the small hole, and intubate down the duodenum to the length of 3cm, fix the gastrointestinal intubation and intestinal wall with two needles in a part with few blood vessels; suture the muscle and skin separately, sew the muscle layer and bury the heparin cap of the indwelling needle under the abdominal skin, disinfect the skin, and directly pass the heparin every day Insert the cap into the needle and repeat the dose.

No surgery was performed in the insulin degludec injection group.

See Table 22 for specific grouping information.

Table 22 Test group status

Note: The first digit of the animal number represents the group. The second letter indicates gender (M is male), and the last three digits represent the animal's serial number.

(6)Dosing regimen:

Normal control group: no medication required.

Model control group: The placebo prepared in this example was administered via the duodenum once a day for 14 consecutive days. Dosing volume: 100ul/animal.

Insulin degludec injection group: Insulin degludec injection Subcutaneous injection; once daily. Administer continuously for 14 days. Subcutaneous injection dosage: 0.1mg/kg.

Insulin degludec oral group:

Insulin degludec oral group G1, insulin degludec oral group G2, and insulin degludec oral group G3: administration via duodenal intubation, once a day, for 14 consecutive days.

Insulin degludec oral group G1: a single administration of 0.5 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 17 prepared in this example;

Insulin degludec oral group G2: a single administration of 2 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 18 prepared in this example;

Insulin degludec oral group G3: a single administration of 10 mg/kg via duodenal intubation, and the drug used was the polypeptide composition 19 prepared in this example;

The G1 dosage of insulin degludec duodenal administration group 0.5 mg/kg refers to the administration of 0.5 mg insulin degludec per kg of rats through duodenal intubation. Assuming that a rat weighs 300 mg, the weight of each component of the polypeptide composition administered to the rat is: insulin degludec: 0.5mg/kg*0.3kg=0.15mg, castor oil: (0.15/2)*443mg, Tween 80: (0.15/2)*132mg, soybean trypsin inhibitor: (0.15/2)*291mg, disodium edetate: (0.15/2)*132mg, which is equivalent to giving (0.15/2 )*100%=7.5% of polypeptide composition 16.

The dosage of insulin degludec oral group G2 and insulin degludec oral group G3 are calculated in the same way.

Note: All rats fasted for 2 hours before administration and had a meal 1 hour after administration.

See Table 23 for specific dosing.

Table 23 Dosing Design

Note: The first digit of the animal number represents the group. The second letter expresses gender, M is male, and the last three digits represent the animal serial number.

(7) Blood glucose collection time:

Blood glucose measurement time: before the first dose (0:00 before dosing on Day 1); before the last dose (0:00 before dosing on Day 14) and after dosing (after dosing on Day 14) 0.5, 1, 1.5, 2, 3, 4 ,6,8,12,24h,48h;

(8) Measurement method: Prick the tip of the tail and wait for the blood to seep out. The blood glucose meter is equipped with a blood glucose test paper to absorb a trace amount of blood and read the blood glucose value.

(9)Blood sugar

Diabetes model evaluation: After 4 days of administration of streptozotocin to rats in the model control group, insulin degludec injection group, and insulin degludec oral administration group, individual blood glucose levels were significantly higher than those in the normal control group (p<0.05), suggesting that the diabetes model created The model was successful.

The formula for calculating the blood sugar reduction rate is (blood sugar value of the model control group - blood sugar value of the drug administration group)/blood sugar value of the model control group * 100%; where, the blood sugar value of the model control group represents the blood sugar value of the rats in the model control group at time t. The blood glucose value of the drug group represents the blood glucose value of the rats in the drug group at time t.

After 14 days of continuous administration, the model control group continued to maintain a state of hyperglycemia, with no significant difference from before administration (before administration on Day 1) (P>0.05). Compared with the rats in the normal control group, the blood glucose level was statistically different (P< 0.05).

In the insulin degludec injection group, the blood glucose levels of rats showed a trend of first decreasing and then increasing within 48 hours. The overall blood glucose AUC _0-48 value was lower than that of the model control group, and reached the lowest level 3 hours after administration on Day 14. Overall, The blood glucose AUC _0-48 values were lower than those of the model control group. Compared with the model control group, the blood glucose lowering rate of the 12 rats ranged from 35.58% to 51.64%, which was statistically significant (P<0.01).

The blood glucose level of the insulin degludec oral group G1 began to decrease 2 hours after administration on Day 14, and reached the lowest level 6 hours after administration. Compared with the model control group, the blood glucose lowering rate of the 12 rats ranged from 5.67% to 8.49%.

In the insulin degludec oral group G2, the blood glucose level began to decrease 2 hours after administration on Day 14, and reached the lowest level 6 hours after administration; the AUC _{0 to 48} values were lower than those of the model control group rats; compared with the model control group, 12 The hypoglycemic rate of rats ranged from 13.24% to 21.97%, with statistical differences (P<0.05).

The blood glucose of G3 rats in the insulin degludec oral group began to decrease 1.5 hours after administration on Day 14, and reached the lowest level 6 hours after administration. The AUC _0-48 value of blood glucose in rats was lower than that of rats in the model control group, and was comparable to that of the model control group. Ratio, the hypoglycemic rate of 12 rats ranged from 31.18% to 43.55%, with statistical difference (P<0.01). Compared with the insulin degludec oral group G3 group and the insulin degludec injection group, the mean AUC _{0 to 48} values were relatively close, and there was no statistical difference in the blood glucose values of AUC _{0 to 48} (P>0.05).

The applicant declares that the above are only specific implementation modes of the present disclosure, but the protection scope of the present disclosure is not limited thereto. Those skilled in the technical field should understand that any person skilled in the technical field will not use the disclosure disclosed in the present disclosure. Within the technical scope, changes or substitutions that can be easily imagined fall within the protection scope and disclosure scope of the present disclosure.

Claims (29)

A polypeptide composition, wherein the polypeptide composition includes a polypeptide, a protease inhibitor, a vegetable oil, and at least one absorption enhancer. The polypeptide composition according to claim 1, wherein the molecular weight of the polypeptide is 100Da～20000Da, preferably 1000Da～20000Da, preferably 1000Da～6150Da, preferably 1209Da～6104Da, preferably 1000Da～6000Da, further preferably 2000Da ~6000Da; Preferably, the vegetable oil is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil, preferably castor oil or linseed oil, and further preferably castor oil. The polypeptide composition according to claim 1 or 2, wherein the polypeptide is selected from the group consisting of insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist agents, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, vasopressin Any one or more of vasopressin, vancomycin, erythropoietin, glutathione and thymosin; Preferably, the polypeptide is selected from recombinant human insulin, insulin degludec, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide , semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teripa Peptide, leuprolide, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, triptorelin, temorelin , codorelin, lanreotide acetate, terlipressin, antigantide, teriparatide, abalapatide, nesiritide, eptifibatide, lixisenatide, safevir Peptide, atosiban, versicolor glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide or Various. The polypeptide composition according to any one of claims 1 to 3, wherein the target protein of the protease inhibitor is selected from any one of serine protease, trypsin, chymotrypsin, carboxypeptidase and aminopeptidase species or species; Preferably, the protease inhibitor is selected from any of cysteine protease inhibitors, serine protease inhibitors, trypsin inhibitors, threonine protease inhibitors, aspartic protease inhibitors and metalloprotease inhibitors. one or more; Preferably, the protease inhibitor includes a naturally extracted protease inhibitor or a protease inhibitor prepared using genetic engineering; Preferably, the protease inhibitor is selected from the group consisting of soybean trypsin inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, ε-aminocaproic acid, anti-protease, α1-antichymotrypsin, Antithrombin, α1-antitrypsin, 4-amidophenyl-methanesulfonyl fluoride, aprotinin, benzamidine-HCl, chymotrypsin, diisopropyl fluoride-phosphate, leupeptin, Phenylmethylsulfonyl fluoride, 1-chloro-3-sulfonylamino-7-amino-2-heptanone HCl, 1-chloro-3-sulfonylamino-4-phenyl-2-butanone, isethyl sulfonate Any one or more of acid pentamidine, egg white trypsin inhibitor, pepsin inhibitor, α2-macroglobulin, guanidium, iodoacetic acid, zinc and zinc chelators. The polypeptide composition according to any one of claims 1 to 4, wherein the absorption enhancer is selected from the group consisting of ethylenediaminetetraacetic acid or a salt thereof, N-(8-(2-hydroxybenzoyl)amine) Caprylic acid or its salt, salicylic acid or its salt, citric acid or its salt, cholic acid or its salt, deoxycholic acid or its salt, glycocholic acid or its salt, taurocholic acid or its salt, alkyl glycoside, Sodium lauryl sulfate, sodium docusate, cyclodextrin or its derivatives, chitosan or its derivatives, caprylic acid or its salt, capric acid or its salt, lauric acid or its salt, myristic acid, palmitic acid Any one or more of acid, stearic acid, fatty acid triglycerides, lecithin, choline and carnitine. The polypeptide composition according to any one of claims 1 to 5, wherein the polypeptide composition includes in parts by mass: Peptide: 0.1～100 parts by mass, Vegetable oil: 0.1~1000 parts by mass, Protease inhibitor: 1 to 400 parts by mass, and Absorption enhancer: 1 to 500 parts by mass; Preferably, the polypeptide composition includes in parts by mass: Peptide: 1 to 80 parts by mass, Vegetable oil: 10 to 850 parts by mass, Protease inhibitor: 5 to 250 parts by mass, and Absorption enhancer: 5 to 300 parts by mass; Preferably, the polypeptide composition includes in parts by mass: Peptide: 2 to 50 parts by mass, Vegetable oil: 90 to 532 parts by mass, Protease inhibitor: 50 to 341 parts by mass, and Absorption enhancer: 50 to 326 parts by mass. The polypeptide composition according to claim 6, wherein the polypeptide composition includes in parts by mass: Peptide: 1 to 50 parts by mass, Vegetable oil: 50 to 500 parts by mass, Protease inhibitor: 10 to 200 parts by mass, and Absorption enhancer: 50 to 300 parts by mass. The polypeptide composition according to any one of claims 1-7, wherein the polypeptide composition further comprises at least one emulsifier; Preferably, the polypeptide composition includes 0.1-1000 parts by mass of emulsifier, preferably 10-850 parts by mass, further preferably 50-850 parts by mass, and preferably 100-489 parts by mass. The polypeptide composition according to claim 8, wherein the emulsifier is selected from any one or more of ionic surfactants, nonionic surfactants and zwitterionic surfactants; Preferably, the emulsifier is selected from the group consisting of ammonium lauryl sulfate, N-dodecyl-β-D-maltoside, tridecyl-β-D-maltoside, sodium lauryl sulfate, polyglucoside, Sodium custate, cyclodextrin or its derivatives, chitosan or its derivatives, sodium polyoxyethylene alkyl sulfate, sodium laureth sulfate, dioctyl sodium sulfosuccinate, poloxamer, monohard Glyceryl fatty acid ester, glyceryl monolaurate, sorbitan monolaurate, sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene Any one or more of ethylene monopalmitate, polyoxyethylene hydrogenated castor oil, C ₆ -C ₁₂ fatty acid triglycerides and C ₈ -C ₁₀ fatty acid triglycerides. The polypeptide composition according to any one of claims 1-9, wherein the polypeptide composition includes in parts by mass: Semaglutide: 4 to 70 parts by mass, Castor oil: 120 to 600 parts by mass, Soybean trypsin inhibitor: 30 to 400 parts by mass, Disodium ethylenediaminetetraacetate: 70 to 400 parts by mass, and Tween 80: 50 to 500 parts by mass; or Thymosin: 1 to 100 parts by mass Castor oil: 50 to 500 parts by mass, Soybean trypsin inhibitor: 50 to 300 parts by mass, and Disodium ethylenediaminetetraacetate: 50 to 350 parts by mass; Tween 80: 50 to 500 parts by mass; or Recombinant human insulin: 1 to 50 parts by mass Castor oil: 50 to 600 parts by mass, Soybean trypsin inhibitor: 50 to 450 parts by mass, Disodium ethylenediaminetetraacetate: 60 to 450 parts by mass, and Tween 80: 50~450 parts by mass; or Lupron: 1 to 100 parts by mass Castor oil: 50 to 400 parts by mass, Soybean trypsin inhibitor: 50 to 300 parts by mass, Disodium ethylenediaminetetraacetate: 20 to 300 parts by mass, and Tween 80: 100~400 parts by mass; or Insulin degludec: 1 to 50 parts by mass Castor oil: 80 to 500 parts by mass, Soybean trypsin inhibitor: 90 to 320 parts by mass, Disodium ethylenediaminetetraacetate: 50 to 300 parts by mass, and Tween 80: 100 to 500 parts by mass. The polypeptide composition according to any one of claims 1-9, wherein the polypeptide composition includes in parts by mass: Semaglutide: 8 to 50 parts by mass, Castor oil: 150 to 500 parts by mass, Soybean trypsin inhibitor: 50 to 250 parts by mass, Disodium ethylenediaminetetraacetate: 70 to 300 parts by mass, and Tween 80: 100~400 parts by mass; or Thymosin: 5 to 50 parts by mass Castor oil: 100 to 400 parts by mass, Soybean trypsin inhibitor: 75 to 250 parts by mass, Disodium ethylenediaminetetraacetate: 75 to 300 parts by mass, and Tween 80: 100~400 parts by mass; or Recombinant human insulin: 2 to 32 parts by mass Castor oil: 93 to 532 parts by mass, Soybean trypsin inhibitor: 80 to 341 parts by mass, Disodium ethylenediaminetetraacetate: 100 to 326 parts by mass, and Tween 80: 106~373 parts by mass; or Lupron: 4 to 40 parts by mass Castor oil: 90 to 377 parts by mass, Soybean trypsin inhibitor: 70 to 230 parts by mass, Disodium ethylenediaminetetraacetate: 50 to 282 parts by mass, and Tween 80: 120~300 parts by mass; or Insulin degludec: 2 to 34 parts by mass Castor oil: 110 to 443 parts by mass, Soybean trypsin inhibitor: 111 to 291 parts by mass, Disodium ethylenediaminetetraacetate: 83 to 220 parts by mass, and Tween 80: 132 to 489 parts by mass. The polypeptide composition according to any one of claims 1-9, wherein the polypeptide composition includes in parts by mass: Semaglutide: 8 to 24 parts by mass, Castor oil: 275 to 500 parts by mass, Soybean trypsin inhibitor: 50 to 105 parts by mass, Disodium ethylenediaminetetraacetate: 150 to 300 parts by mass, and Tween 80: 100~275 parts by mass; or Thymosin: 5 to 25 parts by mass Castor oil: 100 to 335 parts by mass, Soybean trypsin inhibitor: 75 to 200 parts by mass, Disodium ethylenediaminetetraacetate: 75 to 300 parts by mass, and Tween 80: 290~400 parts by mass; or Recombinant human insulin: 8 to 32 parts by mass Castor oil: 93 to 532 parts by mass, Soybean trypsin inhibitor: 80 to 320 parts by mass, Disodium ethylenediaminetetraacetate: 100 to 326 parts by mass, and Tween 80: 106~373 parts by mass; or Lupron: 4 to 20 parts by mass Castor oil: 282 to 377 parts by mass, Soybean trypsin inhibitor: 70 to 100 parts by mass, Disodium ethylenediaminetetraacetate: 50 to 180 parts by mass, and Tween 80: 120~300 parts by mass; or Insulin degludec: 2 to 15 parts by mass Castor oil: 390 to 443 parts by mass, Soybean trypsin inhibitor: 111 to 291 parts by mass, Disodium ethylenediaminetetraacetate: 83 to 132 parts by mass, and Tween 80: 132~401 parts by mass. The polypeptide composition according to any one of claims 1-9, wherein the polypeptide composition includes in parts by mass: Semaglutide: 24 to 50 parts by mass, Castor oil: 150 to 500 parts by mass, Soybean trypsin inhibitor: 50 to 250 parts by mass, Disodium ethylenediaminetetraacetate: 70 to 300 parts by mass, and Tween 80: 100~400 parts by mass; or Thymosin: 25 to 50 parts by mass Castor oil: 100 to 400 parts by mass, Soybean trypsin inhibitor: 75 to 250 parts by mass, Disodium ethylenediaminetetraacetate: 150 to 300 parts by mass, and Tween 80: 100~400 parts by mass; or Recombinant human insulin: 16 to 32 parts by mass Castor oil: 93 to 532 parts by mass, Soybean trypsin inhibitor: 80 to 175 parts by mass, Disodium ethylenediaminetetraacetate: 266 to 326 parts by mass, and Tween 80: 106~373 parts by mass; or Lupron: 20 to 40 parts by mass Castor oil: 90 to 282 parts by mass, Soybean trypsin inhibitor: 100 to 230 parts by mass, Disodium ethylenediaminetetraacetate: 50 to 282 parts by mass, and Tween 80: 210~300 parts by mass; or Insulin degludec: 15 to 34 parts by mass Castor oil: 110 to 390 parts by mass, Soybean trypsin inhibitor: 111 to 147 parts by mass, Disodium ethylenediaminetetraacetate: 83 to 220 parts by mass, and Tween 80: 401～489 parts by mass. A medicament, wherein the medicament includes the polypeptide composition according to any one of claims 1-13; The medicine also includes coatings and/or other pharmaceutically acceptable excipients. The drug according to claim 14, wherein the coating is selected from the group consisting of gastric coating and/or enteric coating; Preferably, the coating is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, acrylic resin, polyvinylpyrrolidone, cellulose acetate phthalate, hypromellose phthalate and hypromellose acetate. Any one or more of cellulose succinates; Preferably, the other pharmaceutically acceptable excipients are selected from any one or more of excipients, disintegrants, binders, glidants, flavoring agents and lubricants; Preferably, the excipient is selected from the group consisting of lactose, sorbitol, xylitol, mannitol, calcium sulfate, calcium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, Any one or more of lactose starch complex, lactose cellulose complex and mannitol starch complex; Preferably, the disintegrant is selected from any one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose. species or species; Preferably, the binder is selected from starch slurry, gelatin solution, sucrose solution, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and Any one or more of polyvinylpyrrolidone; Preferably, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium stearate, calcium stearate, Any one or more of micronized silica gel and talc; Preferably, the flavoring agent is selected from any one of mannitol, sorbitol, aspartame, stevioside, sucralose, aspartame, neotame, stevia, hydroxyl sugar chloride and flavor, or Various. A pharmaceutical composition, wherein the pharmaceutical composition contains two or more different polypeptides, a protease inhibitor, a vegetable oil, and at least one absorption enhancer; Preferably, the two or more different polypeptides are simultaneously contained in a formulation containing a protease inhibitor, vegetable oil and at least one absorption enhancer, or the two or more different polypeptides are contained separately in a formulation containing In a preparation of protease inhibitors, vegetable oil and at least one absorption enhancer; Preferably, the two or more different polypeptides are each independent of different formulations. The pharmaceutical composition according to claim 16, wherein said two or more different polypeptides Selected from insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor agonist, calcitonin, growth hormone, somatostatin, thyroid-stimulating hormone releasing hormone Hormones, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferons, vasopressin, vancomycin, erythropoietin, glutathione, and thymosin any two or more of; Preferably, the two or more different polypeptides are selected from the group consisting of recombinant human insulin, insulin degludec, glucagon, exenatide, belaglutide, liraglutide, loxenatide, and durglutide. Laglutide, lixisenatide, semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, thyroid Parathyroid hormone fragment, teriparatide, leuprorelin, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, trelin Prelin, timorelin, codorelin, lanreotide acetate, terlipressin, antigantide, teriparatide, abalapatide, nesiritide, eptifibatide, Lixisenatide, sifuvirtide, atosiban, versicolor glycopeptide, ginseng glycopeptide, bone peptide, carosinate, glutathione, mannan peptide, enfuvirtide, bradykinin , enkephalins, nosiheptide, hirudin, glatiramer acetate, aprotinin, alamorelin, trypsin, polymyxin, serratiopeptidase, thymosin α1, thymopentin and thymus Any two or more of the following: Preferably, the two different polypeptides are insulin and a glucagon-like peptide-1 receptor agonist, or insulin and a glucagon-like peptide-2 receptor agonist, or insulin and parathyroid hormone, Or insulin and thymosin; further preferably, the two different polypeptides are insulin and liraglutide, or insulin and semaglutide, or insulin and dulaglutide, or insulin and albiglutide, or insulin and diglutide. laglutide, or insulin and teduglutide. The dosage forms of the polypeptide composition according to any one of claims 1 to 13, the medicine according to claims 14 or 15, or the pharmaceutical composition according to claims 16 or 17 include tablets, pills, capsules, emulsions, and syrups. formulation or suspension. Preferably, the polypeptide in the capsule content is in a suspended state. The polypeptide composition according to any one of claims 1 to 13, the medicine according to claims 14 or 15, or the pharmaceutical composition according to claims 16 or 17 is used in the preparation of oral administration for the treatment or prevention of diseases. Use in medicine, the disease being selected from the group consisting of hyperglycemia, type 1 diabetes, type 2 diabetes, non-insulin-dependent diabetes, mature-onset diabetes of the young, gestational diabetes, obesity, non-alcoholic fatty liver disease, hepatic steatosis, Hepatitis, liver fibrosis, cirrhosis, liver cancer, Alzheimer's disease, Parkinson's disease and impaired glucose tolerance. The polypeptide composition according to any one of claims 1 to 13, the medicine according to claims 14 or 15, or the pharmaceutical composition according to claims 16 or 17 in the preparation of medicines for enhancing immune response Applications. A method for improving the storage stability of a polypeptide, the method comprising mixing the polypeptide and vegetable oil to obtain a mixture; Preferably, the mass ratio of the polypeptide to vegetable oil is 1:1 to 1:10000, and more preferably, the mass ratio of the polypeptide to vegetable oil is 1:1, 1:2, 1:5, 1:10, 1 :20, 1:30, 1:40, 1:45, 1:50, 1:60, 1:80, 1:90, 1:100, 1:120, 1:150, 1:180, 1:200 , 1:500, 1:800, 1:1000, 1:1500, 1:2000, 1:2500, 1:3000, 1:4000, 1:5000, 1:6000, 1:7000, 1:8000, 1 :9000, 1:10000, or any value in between. A method for improving the storage stability of a polypeptide, the method comprising mixing the polypeptide, vegetable oil and an emulsifier to obtain a mixture; Preferably, the mass ratio of the polypeptide to vegetable oil is 1:1 to 1:10000. A method for improving the oral bioavailability of a polypeptide, the method comprising mixing the polypeptide with vegetable oil, protease inhibitors and absorption enhancers to obtain a mixture; Preferably, the mass ratio of the polypeptide to vegetable oil is 1:1 to 1:10000. A method for improving the storage stability of a polypeptide and increasing its oral bioavailability, the method comprising mixing the polypeptide with vegetable oil, protease inhibitors, absorption enhancers and emulsifiers to obtain a mixture; Preferably, the mass ratio of the polypeptide to vegetable oil is 1:1 to 1:10000. The method according to any one of claims 21-24, wherein the polypeptide is selected from the group consisting of insulin, glucagon, glucagon-like peptide-1 receptor agonist, glucagon-like peptide-2 receptor Body agonists, calcitonin, growth hormone, somatostatin, thyrotropin-releasing hormone, parathyroid hormone, gonadotropin-releasing hormone, heparin, granulocyte colony-stimulating factor, prostaglandins, cyclosporine, interferon, Any one or more of vasopressin, vancomycin, erythropoietin, glutathione, and thymosin; Preferably, the polypeptide is selected from recombinant human insulin, insulin degludec, glucagon, exenatide, belaglutide, liraglutide, loxenatide, dulaglutide, lixisenatide , semaglutide, albiglutide, dulaglutide, teduglutide, calcitonin, salmon calcitonin, growth hormone, octreotide, thyrotropin-releasing hormone, parathyroid hormone fragment, teripa Peptide, leuprolide, prorelin, gonadorelin, goserelin, buserelin, sermorelin, nafarelin, histrelin, triptorelin, temorelin , codorelin, lanreotide acetate, terlipressin, antigantide, teriparatide, abalapatide, nesiritide, eptifibatide, lixisenatide, safevir Peptide, atosiban, versicolor glycopeptide, ginseng glycopeptide, bone peptide, carnosine glycoside, glutathione, mannan peptide, enfuvirtide, bradykinin, enkephalin, nosiheptide or Various. The method according to any one of claims 21-24, wherein the vegetable oil is selected from any one or more of castor oil, linseed oil, perilla oil, corn oil and soybean oil, preferably castor oil Or linseed oil, more preferably castor oil. The method according to claim 21 or 22, wherein the storage temperature is -10°C to 40°C, the storage temperature is preferably 0°C to 40°C, the storage temperature is preferably 0°C to 25°C, and the storage temperature is preferably 0°C to 20°C. ℃, the storage temperature is preferably 0°C to 10°C, and the storage temperature is preferably 2°C to 8°C. A method of treating or preventing disease, the method comprising orally administering to a subject in need a therapeutically effective amount of the polypeptide composition of any one of claims 1-13, 14 or 15 The medicament or the pharmaceutical composition of claim 16 or 17, wherein the disease is selected from the group consisting of hyperglycemia, type 1 diabetes, type 2 diabetes, non-insulin-dependent diabetes, mature-onset diabetes of young age, gestational diabetes, obesity, Non-alcoholic fatty liver disease, hepatic steatosis, hepatitis, liver fibrosis, cirrhosis, liver cancer, Alzheimer's disease, Parkinson's disease and impaired glucose tolerance. A method of enhancing an immune response, wherein the method comprises orally administering to a subject in need a therapeutically effective amount of the polypeptide composition of any one of claims 1-13, 14 or 15 A medicament or a pharmaceutical composition according to claim 16 or 17.