CN119454605A

CN119454605A - A composition for achieving oral absorption of polypeptides

Info

Publication number: CN119454605A
Application number: CN202311625950.9A
Authority: CN
Inventors: 窦浏; 麦扬; 袁邦皓; 随宇声
Original assignee: Shenzhen Aoli Biotechnology Co ltd
Current assignee: Shenzhen Aoli Biotechnology Co ltd
Priority date: 2023-11-30
Filing date: 2023-11-30
Publication date: 2025-02-18
Also published as: WO2025112258A1

Abstract

本发明属于生物医药领域，具体涉及在胃肠道稳定吸收的口服多肽类组合物体系，具体公开了一种口服多肽组合物，所述组合物包含多肽分子(A)、表面活性剂(B)、氨基酸单分子或双分子组合(C)；所述口服多肽组合物中用于作为药物使用的肽类药物分子量为0.1kDa～20kDa范围。所述组合物体系作用部位为小肠或大肠；本发明的多肽类组合物在胃肠道中，其稳定性与吸收性具有明显改善和提高。The present invention belongs to the field of biomedicine, and specifically relates to an oral polypeptide composition system that is stably absorbed in the gastrointestinal tract, and specifically discloses an oral polypeptide composition, the composition comprising a polypeptide molecule (A), a surfactant (B), and an amino acid monomolecule or bimolecule combination (C); the molecular weight of the peptide drug used as a drug in the oral polypeptide composition is in the range of 0.1kDa to 20kDa. The composition system acts on the small intestine or the large intestine; the polypeptide composition of the present invention has significantly improved and enhanced stability and absorbability in the gastrointestinal tract.

Description

Composition for realizing oral absorption of polypeptide

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to an oral polypeptide composition.

Background

The polypeptide is a compound formed by connecting a plurality of amino acids through peptide bonds, generally consists of 10-100 amino acid molecules, is commonly found in organisms, has tens of thousands of polypeptides which are widely involved in and regulate the functional activities of various systems, organs, tissues and cells in the organisms so far, and plays an important role in life activities. The polypeptide clinical therapeutic drug has the advantages of high efficiency, selectivity and low toxicity, is widely applied to a plurality of diseases including diabetes, cancer and metabolic diseases, has the characteristics of high efficiency, low toxicity and strong specificity compared with the micromolecular drug compared with the (Fosgerau K,Hoffmann T Peptide therapeutics:current status and future directions.Drug Discov Today.2015;20(1):122–128.). polypeptide drug which is more attractive than the micromolecular drug, and has been approved by the FDA in the United states to be on the market. The polypeptide is a macromolecule with good hydrophilicity, has extremely poor permeability, and is rich in protease for degrading the polypeptide in the gastrointestinal tract, so that most of polypeptide medicines on the market are injection. The polypeptide is also easy to be degraded by plasma, liver and kidney peptidases, has short half-life and poor injection administration compliance, which causes challenges to the drug compliance of patients, and especially causes long-term pain, injection aversion and other problems (ZizzariAT,et al.New perspectives in oral peptide delivery.Drug Discov Today.2021;26(4):1097–1105.). aiming at the pain point problems existing clinically in the polypeptide drug under the condition of long-term administration of chronic patients, and the mode of administration is changed, so that the development of the oral polypeptide drug becomes a promising solution. In addition, from the aspect of production, compared with the production of injection medicines, the oral polypeptide medicine has larger production scale and lower production cost.

The gastrointestinal tract is a major obstacle to the oral administration of polypeptide drugs, and has the effect of digesting carbohydrates, proteins and other nutrients into amino acids and monosaccharides, while protecting the body from pathogen invasion. The pH value of gastric juice is 1-2 under the condition of empty stomach, and the strong acid environment can induce the polypeptide to undergo the reactions of hydrolysis, deamination, oxidation and the like so as to inactivate the passivation. In addition, enzymes that cleave polypeptides, including pepsin secreted by the gastric glands, pancreatic proteases, chymotrypsin, carboxypeptidase and elastase, aminopeptidase, endopeptidase and beta-glutamine transpeptidase secreted by the intestinal cells, and the like, are distributed throughout the gastrointestinal tract. Guo et al use bacitracin and leupeptin as protease inhibitors to enhance the oral absorption of angiotensin 1 converting enzyme inhibitory peptides. An ideal polypeptide drug oral delivery system should be able to keep the polypeptide molecule intact and release the drug at the target absorption site before reaching the absorption site, and preferably have some interaction with the release site, and should also be able to stay at the polypeptide release site providing sufficient time and concentration gradient for the transport of the polypeptide drug across the membrane.

In combination with research progress of polypeptide drugs, polypeptide drug oral administration is currently mainly faced with two technical challenges, one is the problem of stability of polypeptide drugs in the gastrointestinal tract. Because of the protease present in the gastrointestinal tract, polypeptide drugs are typically broken down into amino acids by proteases soon after oral administration and lose their pharmacological activity (Wang J,et al.Toward oral delivery of biophar-maceuticals:an assessment of the gastrointestinal stability of 17peptide drugs.Mol Pharm.2015;12(3):966–973.). are typically spread throughout the gastrointestinal tract with different types and concentrations of proteases near the front end, e.g., the stomach and duodenum, and the higher the concentration and activity of proteases, the more rapidly they are broken down and deactivated after oral administration. In addition, the second challenge of oral administration of polypeptide drugs is the problem of gastrointestinal absorption efficiency. Generally, drugs permeate from the inner layer of the gastrointestinal tract into local vein vessels through oral administration to complete the gastrointestinal tract absorption process, enter the systemic circulation and exert curative effects. However, due to the structural characteristics of large molecular weight and the like of the polypeptide medicament, the polypeptide medicament is difficult to permeate through physiological structures such as mucus layers, epithelial cells and the like of the gastrointestinal tract, so that the gastrointestinal tract absorptivity of the polypeptide medicament is extremely low (Verma S,Goand UK,HusainA,et al.Challenges ofpeptide andprotein drug delivery by oral route:current strategies to improve the bioavailability.Drug Dev Res.2021;82(7):927–944.).

Common polypeptide drug oral delivery techniques include:

(1) The polypeptide is easy to be degraded by various enzymes in vivo, but the enzyme stability of the polypeptide, including the stability in a whole body system, can be improved by PEGylation, lipidation and glycosylation of the polypeptide through cyclization or covalent bonds, and the half life period is prolonged. Cyclosporin (cyclosporineA, csA) is a cyclic lipophilic 11 peptide, its capsule Approved by the FDA in the United states in 1990, the oral bioavailability is up to 25% -30%, and the trans isomer analogue of CsA, voclosporinThe pharmaceutical composition is commercially available in 1 st 2021 for treating lupus nephritis, and has an oral bioavailability of about 8% (HEO YA. Voclosporin: first approval [ J ]. Drug, 2021,81 (5): 605-610 ]) desmopressin acetateThe 9 peptide with certain hydrophilicity is natural arginin analogue, which is obtained by amino acid 1 to remove amino and D-arginine at 8 th position to replace L-arginine, although the oral bioavailability is only 0.08% -0.16%, the synthetic cost is low and the potency is high, so that the polyethylene glycol insulin analogue Tregopil insulin (IN-105) which is developed by (KOTTKE D,BURCKHARDT BB,KNAAB TC,et al.Development and evaluation of a composite dosage form containing desmopressin acetate for buccal administration[J].Int J Pharm X,2021.3:100082.). Indian Biocon biological company can be orally taken, the phase III clinical study is completed, the ghrelin receptor agonist TZP-102[18] which is developed by Ocera medical company IN the United states and the SCY635 which is developed by Scynexis company IN the United states have both phase II clinical study. Although cyclization can improve stability, the large polar surface formed by a large number of amide bonds also limits the oral absorption of the cyclic peptide, nielsen et al detected the physicochemical parameters and oral absorption of 125 cyclic peptides, most of which had poor bioavailability, and how to improve the oral bioavailability of the cyclic peptide was yet to be studied intensively.

Permeation-promoting techniques intestinal permeation enhancers (permeation enhancers, PEs) can transiently increase epithelial cell permeability, and are one of the most widely used delivery strategies currently in clinical use for improving oral absorption of polypeptides.Is the 1 st marketed oral glucagon-like peptide-1 (glucon-LIKE PEPTIDE-1, GLP-1) analog developed by using Emissphere IncThe technology for achieving oral absorption uses a range of medium chain fatty acid based penetration enhancers including sodium N-2 hydroxybenzoyl-hexanoate (SNAC), sodium 8- [ N- (2-hydroxy-5-chlorobenzoyl) amino ] octanoate (5-CNAC), and N- (4-salicyloyl chloride) -4-aminobutyrate (4-CNAB), etc., with SNAC being most widely used, approved by the us FDA as a food additive, but the technology selects the stomach as the absorption site for solving the stability problem, and thus sacrifices the absorption efficiency of the drug. Buckley et al determined that oral cord Ma Lutai was absorbed in the stomach by intragastric imaging, food effect on absorption, pyloric ligation, and distribution of cord Ma Lutai in the splenic and portal veins 30min post-administration. SNAC (pKa 1=4.5, pka2=8.6) has a strong buffer effect in the stomach, and can improve the enzyme stability of the cord Ma Lutai by adjusting the pH, and can also promote permeation of the cord Ma Lutai by promoting depolymerization of the cord Ma Lutai into monomers and interaction with lipid membranes. Since the stomach is not a major absorption organ compared to the intestine and SNAC promoters have limited effect in the stomach, the overall technology has a problem of low drug absorption rate. In the preclinical research stage of early beagle dogs and cynomolgus monkeys, the relative bioavailability of the oral preparation of the technology is in the range of 0.04-4.04%, and in the subsequent human body experimental research, the oral preparation only shows 0.4-1% of bioavailability. Oral octreotide is the only oral delivery achieved by TPE ^TM technology developed by Chiasma company, and is the only oral somatostatin analogue used for treating acromegaly. The TPE ^TM technology is to form a suspension of polypeptide, medium chain fatty acid salt and polyvinylpyrrolidone (PVP) plus a hydrophobic medium and deliver with an enteric capsule. This technique has limited scope of application because it does not address the technical challenges of stability, and is only useful for polypeptide drugs with very good stability, and is not a general-purpose delivery technique. In addition, the technology only realizes the effect of instant permeation promotion, the whole absorption rate is not high, and the absolute bioavailability is only that according to the result of human body experiments 0.7％(Tuvia S,Atsmon J,Teichman SL,et al.Oral octreotide absorption in human subjects:comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.J Clin Endocrinol Metab.2012;97(7):2362–2369.).The sodium octoate used in the method can transiently and reversibly open cell bypass tight connection, and the phase III clinical research result shows that the sodium octoate has good effectiveness and safety, and the blood level is equivalent to that of octreotide injection. Although the promotion of oral absorption of polypeptides by PEs is well documented, the spatiotemporal effects of polypeptides on PEs are often neglected. After oral administration of cord Ma Lutai, high concentrations of cord Ma Lutai and SNAC were only observed directly under or in the surface area of the tablet, and absorption of cord Ma Lutai was also only in the localized area where the tablet was located. The formulation of patent WO2013189988A1 issued by norand nod corporation, which releases SNAC faster than chordae Ma Lutai, has a higher bioavailability, probably because SNAC first dissolves to form a buffer environment and enhance cell membrane permeability, reducing unnecessary losses of chordae Ma Lutai. Thus, the effects of gastrointestinal motility on co-delivery of polypeptides and PEs also affect the oral absorption of polypeptides, and the movement of the fasting stomach exhibits periodic transitional complex movement characteristics, with the peristaltic capacity of the duodenum and proximal jejunum being significantly higher than that of the ileum. Sladek et al encapsulate PEs with insulin-related anionic polyelectrolyte nanoparticle complexes and achieve co-delivery using enteric techniques. Furthermore, for PEs of the intercellular route, it may be necessary to appropriately increase the formulation diffusion range to open more tight junctions. In addition to the marketed technology, merrion company developedThe technology utilizes sodium caprate as PE, and shows good blood glucose control capability and low risk of hypoglycemia in phase II clinical study of delivering long-acting oral basal insulin 'I338'. Oramed company POD technology, israel Oramed Pharma, developed a polypeptide oral delivery technology Peptide Oral Delivery (POD) using EDTA as a pro-absorber, and oral insulin developed using this technology failed in clinical trial phase III. The technology selects intestinal tract part for absorption, overcomes the problem of stability by adding protease inhibitor auxiliary materials (BBI or KTI), and overcomes the problem of low absorption by using EDTA as an absorption promoting agent. According to preclinical studies, this technique achieved a relative bioavailability (Li W-dwY-Z,Zeng R,Greenberg-ShushlavY,et al.Pharmacokinetic and pharmacodynamic profiles of orally,duodenally and subcuta-neously delivered insulin in beagle canines.Paper presented at:American Diabetes Association(ADA);June 10-14,2016;New Orleans,LA.2016.)..41±2.26% in beagle experiments but this technique had safety risks during long-term dosing with the proportion of use and chronic disease due to the addition of protease inhibitors, which also partially explained the failure of oral insulin developed by virtue of this technique in clinical phase III. Enteris Biopharma to PEPTELLIGENCE. The technique selects intestinal tract as absorption site, and inhibits protease activity of local environment of intestinal tract by adding large amount of organic acid (such as citric acid), thereby overcoming stability problem. In addition, the technology can promote intestinal tract permeation and absorption of polypeptide by adding surfactant, L-lauroyl carnitine, and solve the absorption problem. The oral leuprorelin developed by the technology shows 1.1+/-0.18% absolute bioavailability in the study of preclinical beagle dogs, and the clinical phase II is finished at present. However, the large amount of acid used in this technique to inhibit proteases in the intestinal tract (not less than 50 mg) presents a safety risk for long-term use. Furthermore, the overall absorption effect of this technique does not achieve a high bioavailability.

(3) The nano-technology is that Nano Particles (NPs) are solid particles with the particle size of 1-100 nm, so that polypeptide can be protected from being degraded by enzymes in gastrointestinal tracts, transmembrane absorption of intestinal epithelium can be increased, and a targeting treatment effect can be realized through ligand modification. Oshadi Icp is an NPs delivery system developed by Oshadi company for delivering compositions of insulin, proinsulin and C-peptide insulin using physiologically inert hydrophobic silica nanoparticles as carriers and capable of producing tight non-covalent binding with polypeptides and polysaccharides. The nanoparticle can protect polypeptide from gastrointestinal tract and brush border peptidase, and promote polypeptide absorption. The published phase II clinical study results show that Oshadi Icp has good safety, tolerability and hypoglycemic effects in type 1 diabetics. Liver-directed insulin vesicles developed by Diasome (HEPATICDIRECTED VESICLE insulin, HDV-I) can deliver insulin directly to the liver with a particle size <150nm via surface modification. After being taken orally, the HDV-I is taken in the intestinal tract and passes through the hepatic portal vein, so that normal insulin physiological response can be realized, and the completed phase II clinical research results show that the HDV-I has remarkable blood glucose reducing effect in an oral glucose tolerance test and a diabetes meal, and a phase III clinical research is in progress. With the continuous progress of physical and chemical characterization technology and imaging technology of nanostructures, the biocompatibility, reproducibility and scalability of NPs remain the difficulties of current research, and core technology is yet to be updated.

(4) Pharmaceutical combinations the pharmaceutical combinations are novel directions for oral delivery of polypeptides, which are suitable for delivery of a variety of different peptides with lower requirements on polypeptide molecule size, stability, hydrophobicity, etc. Pharmaceutical-mechanical combinations include microneedles, intestinal patches, micro-containers, etc., with microneedles being the most promising technique. The pain sensor is not caused in the intestinal tract, the painless administration can be realized, the combination of the medicine and the machinery can protect the polypeptide from being degraded by enzymes in the intestinal tract on one hand, and the unidirectional co-delivery of the polypeptide and the PEs in time and space can be realized on the other hand. A self-orienting micro applicator (SOMA) commonly developed by the institute of technology of the ma and the norand nod corporation is an administration system designed to automatically reset and adhere to the gastric mucosa according to the turning over of the leopard tortoise, and the internal spring can insert the insulin needle into the gastric wall without piercing the outer layer of the gastric wall. In vivo studies of SOMA in rats and pigs were performed with insulin as a model drug, with blood levels comparable to subcutaneous injections. The robotic pill developed by Rani Therapeutics (RaniPill) consisted of compartments filled with citric acid and sodium bicarbonate, which when entered the intestine, the barrier eroded, and mixed to produce CO ₂ which swelled the dissolvable sugar-based microneedles through the capsule outer layer to penetrate the epithelium. RaniPill can deliver more than 10 antibodies, polypeptides and protein drugs, in large animal experiments, oral administration of 3mg insulin corresponds to 80 units of subcutaneous injection, and the bioavailability is more than 50%. Good safety was demonstrated in completed phase I clinical studies delivering placebo. An endoluminal deployment microneedle injector (luminal unfolding microneedle injector, LUMI) is another type of oral microneedle developed by SOMA development team, and the system consists of an enteric capsule, a spring, and 3 degradable deployment arms. When the pH is more than or equal to 5.5, the coating on the surface of the capsule is dissolved, and the compression spring pushes the LUMI out of the capsule and expands the LUMI, so that the microneedle can be ensured to be always attached to the intestinal wall. By optimizing the deployment force, the system is free of perforation risk in the isolated intestines of humans and pigs, and the oral bioavailability of pigs is more than 10% relative to subcutaneous injection. LUMI can also deliver vaccines, monoclonal antibodies, hormones, and RNA, among other macromolecular drugs that present an oral barrier.

In summary, the prior art has limited solutions to the problem of difficulty in oral administration of polypeptide drugs, and few oral polypeptide products are successfully developed and marketed. However, the problems still exist in the aspects of application range, safety, absorption effect, stability and the like, and further solving and optimizing are needed.

Acyl carnitine is a compound produced by the combination of fatty acids and carnitine when fatty acids are transported to the inner membrane of mitochondria in a living body, and is generated from acyl-coa and carnitine due to the action of carnitine palmitoyl transferase I existing in the outer membrane of mitochondria. Acylcarnitine is reported to be used as an absorption enhancer, and can promote the absorption (Anwer,W.,Ratto Velasquez,A.,&Tsoukanova,V.(2020).Acylcarnitines at the Membrane Surface:Insertion Parameters for a Mitochondrial Leaflet Model.Biophysical journal,118(5),1032–1043.).Enteris company of polypeptide medicines at the cellular levelTechnology uses citric acid as pH regulator and acyl carnitine as penetration enhancer, and enteric delivery of polypeptide, and the products developed by this technology are tens of, including Ovarest, tobrate, tbriaTM, etc. In addition, the related art reported to date has proposed the use of acyl carnitines as absorption enhancers for the development of oral formulations of polypeptide molecules. However, as shown in the above description, there is still room for improvement and optimization in terms of stability, safety, and absorption.

Disclosure of Invention

In a first aspect, the present invention provides an oral polypeptide composition comprising a polypeptide molecule (a), a surfactant (B) and an amino acid single molecule or double molecule combination (C).

Further, the components of the oral polypeptide composition may interact to form nanoparticles having a diameter of 0-1000nm.

Further, the oral polypeptide composition further comprises a pH adjuster (D).

Further, the site of action of the oral polypeptide composition is the small intestine and/or the large intestine, and the composition can be stably absorbed in the small intestine and/or the large intestine.

Further, the polypeptide molecule is a compound containing a plurality of amino acids or at least one peptide bond and pharmaceutically acceptable salts thereof, and the molecular weight of the polypeptide molecule is 0.1 kDa-20 kDa, preferably 0.1kDa～15kDa,0.1kDa～10kDa,0.1kDa～9.0kDa,0.1kDa～5.0kDa,0.1kDa～2.0kDa;0.5kDa～20kDa,0.5kDa～15kDa,0.5kDa～10kDa,0.5kDa～9.0kDa,0.5kDa～5.0kDa,0.5kDa～2.0kDa;1.0kDa～20kDa,1.0kDa～15kDa,1.0kDa～10kDa,1.0kDa～9.0kDa,1.0kDa～5.0kDa,1.0kDa～2.0kDa;

5.0kDa~20kDa,5.0kDa~15kDa,5.0kDa~10kDa,5.0kDa~9.0kDa;10.0kDa~20kDa,10.0kDa~15kDa;

Further preferred is 0.1kDa、0.5kDa、1kDa、1.5kDa、2kDa、2.5kDa、3kDa、3.5kDa、4kDa、4.5kDa、5kDa、5.5kDa、6kDa、6.5kDa、7kDa、7.5kDa、8kDa、8.5kDa、9kDa、9.5kDa、10kDa、15kDa、20kDa.

Further, the polypeptide molecules include linear structures and cyclic structures.

Further, the polypeptide molecules include modified peptides, derivatized peptides, and peptidomimetics.

Further, the polypeptide molecules include, but are not limited to, glucagon-like peptide-1 (GLP-1), GLP-1 analogs, GLP-1 agonists, sempervirgine, liraglutide, elegance, exenatide-4, lixisenatide, tasraglutide, LANGLENATIDE, GLP-1 (7-37), GLP-1 (7-36) NH2, GLP-1 receptor, dual agonists of glucagon receptor, oxyntomodulin, GLP-2 agonists or analogs, goserelin, buserelin, peptide YY (PYY), PYY analogs, glatiramer, leuprolide, desmopressin, glycopeptide antibiotics, bortezomib, corticotropin, semorelin, luteinizing hormone releasing hormone, calcitonin, pentagastin, oxytocin, nesiritide, envirtup, eptin, cyclosporin, glucagon, viologen, puromycin, thyroxine releasing hormone, thyroxine (TRP-62), and parathion-63, and parathion-5, and parathion receptor (parathion-63, and parathion-E, and parathion-receptor).

In some embodiments, the GLP-1 analog is selected from the group consisting of an acylated GLP-1 analog, a di-acylated GLP-1 analog, a long acting albumin-binding fatty acid-derivatized GLP-1 analog.

In some embodiments, the GLP-2 agonist or analog includes, but is not limited to, tiludlutide and elsiglutide.

In some embodiments, the somatostatin analogs include, but are not limited to, octreotide and lanreotide or pasireotide.

In some embodiments, the goserelin includes, but is not limited to, goserelin acetate.

In some embodiments, the glatiramer includes, but is not limited to glatiramer acetate.

In some embodiments, the leuprorelin includes, but is not limited to, leuprorelin acetate.

In some embodiments, the desmopressin includes, but is not limited to desmopressin acetate and desmopressin monoacetate trihydrate.

In some embodiments, the glycopeptide antibiotic includes, but is not limited to, glycosylated cyclic or polycyclic non-ribosomal peptides.

Further, the glycosylated cyclic or polycyclic non-ribosomal peptides include, but are not limited to, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin or decaplanin), bortezomib, corticotropin, semorelin, luteinizing hormone releasing hormone.

In some embodiments, the calcitonin includes, but is not limited to salmon calcitonin.

In some embodiments, the alpha parathyroid hormone (PTH) fragments include, but are not limited to, teriparatide, PTH (1-31), and PTH (2-34).

In some embodiments, the polypeptide molecule is a peptide molecule and the prostaglandin F2a receptor modulator is selected from PDC31.

Further, the surfactant can be an acyl carnitine compound and/or an alkyl glycoside compound with a carbon chain length of between C ₈ and C ₁₂, and pharmaceutically acceptable salts or solvates thereof, wherein the structural formula of the acyl carnitine compound is shown as formula I:

In formula I, R ¹ may be an alkyl compound having a carbon chain length of C ₆ to C ₁₄.

Further, the surfactants include, but are not limited to, myristoyl-L-carnitine, decanoyl-L-carnitine, lauroyl-L-carnitine, dodecyl-beta-D-maltoside, tetradecyl-beta-D-maltoside, and b-dodecyl-D-glucopyranoside.

Further, the single molecule of amino acid is selected from any one or more of glycine, alanine, valine, leucine, proline, tryptophan, serine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and citrulline.

Further, the amino acid bimolecular is selected from any two amino acid single molecules of glycine, alanine, valine, leucine, proline, tryptophan, serine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and citrulline, and the amino acid bimolecular is connected through peptide bond.

Further, the amino acid bimolecular may be selected from one or more of bisglycine, bisalanine, bisvaline, bisleucine, bisproline, bistryptophan, bisserine, biscysteine, bisphenylalanine, bisasparagine, bisglutamine, bisthreonine, bisaspartic acid, bisglutamic acid, bislysine, bisarginine and biscitrulline.

Further, the D-component pH adjustor includes, but is not limited to, chemically stable physical forms of tartaric acid, oxalic acid, malic acid, citric acid, vitamin C, acetic acid, succinic acid, oxalic acid, succinic acid, and hydrates thereof.

Further, the dosage range of the pH regulator in the composition is 1-150 mg, 5-145 mg, 10-140 mg, 15-130 mg, 20-120 mg, 25-110 mg, 20-100 mg, 30-90 mg and 40-80 mg.

Further, the mass ratio of the polypeptide molecule (A), the surfactant (B), the amino acid single molecule or the double molecule combination (C) of the composition is 0-5:0.1-20:0.5-20, preferably 2-5:5-20:3-20, further preferably 1:6:10, 1:20:3, 1:10:20, 1:15:7.5, 1:8:4, 5:20:15

In one embodiment, the polypeptide composition is semaglutin, lauroyl-L-carnitine and bisglycine, wherein the mass ratio of the combination is 1:6:10;

In one embodiment, the composition is semaglutin, L-octanoyl carnitine and arginine, and the mass ratio of the composition is 1:6:10.

In one embodiment, the composition is octreotide and L-octanoyl carnitine (10) in a combined mass ratio of 1:10.

In one embodiment, the composition is thymopentin, bisglycine and citric acid in a mass ratio of 1:20:3.

In one embodiment, the composition is thymopentin, lauroyl-L-carnitine, bisglycine and citric acid in a mass ratio of 1:10:20:3.

In one embodiment, the composition is octreotide, L-octanoyl carnitine and bisglycine in a mass ratio of 1:15:7.5.

In one embodiment, the composition is linaclotide, L-octanoyl carnitine, and bisglycine in a mass ratio of 1:15:7.5.

In one embodiment, the composition is semaglutin and lauroyl-L-carnitine in a mass ratio of 1:0.1.

In one embodiment, the composition is semaglutin and lauroyl-L-carnitine in a mass ratio of 1:0.2.

In one embodiment, the composition is semaglutin and lauroyl-L-carnitine in a mass ratio of 1:0.3.

In one embodiment, the composition is semaglutin and lauroyl-L-carnitine in a mass ratio of 1:0.4.

In one embodiment, the composition is semaglutin and lauroyl-L-carnitine in a mass ratio of 1:0.6.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine, bisglycine and citric acid, and the mass ratio of the composition is 1:8:4:4.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine, arginine and citric acid, wherein the mass ratio of the composition is 1:8:4:4.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine, bisglycine, arginine and citric acid in a mass ratio of 1:8:4:4:4.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine and arginine in a mass ratio of 1:8:4.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine, bisglycine and citric acid, wherein the mass ratio of the composition is 5:20:15:20.

In one embodiment, the composition is semaglutin, lauroyl-L-carnitine, bisglycine, and citric acid in a ratio of 5:20:15:10.

In one embodiment, the composition is semaglutin, L-octanoyl carnitine, bisglycine and citric acid, and the mass ratio of the composition is 5:20:15:20.

In a second aspect, the invention provides a pharmaceutical formulation comprising a composition of a polypeptide molecule (a), a surfactant (B) and an amino acid single molecule or combination (C), and a pharmaceutically acceptable carrier.

Further, the polypeptide molecule (A), the surfactant (B) and the amino acid single molecule or combination (C) are as described in the first aspect of the invention.

Further, the oral formulations include tablets, capsules, caplets in capsules, mini-patch systems in capsules, lozenges, tablets, ovules, solutions, emulsions, suspensions, syrups, other agents, powders and granules for reconstitution, dispersible powders and granules, pharmaceutically acceptable gums, chewable tablets, effervescent tablets, and multiparticulate dosage forms.

Further, the pharmaceutically acceptable carrier may include fillers, glidants, excipients, granulating binders, lubricants, disintegrants, and the like.

Further, the fillers include, but are not limited to, starches, sugars, celluloses, and inorganic salts.

Further, the excipients include, but are not limited to, non-reducing sugars, microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine, disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates.

Further, the granulation binders include, but are not limited to, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, and acacia.

Further, the lubricants include, but are not limited to, magnesium stearate, stearic acid, glyceryl behenate, and talc. Solid compositions of a similar type may also be used as fillers in hard capsules.

Further, the pharmaceutically acceptable carrier also includes various sweeteners, flavoring agents, coloring agents or dyes, combinations and emulsifying and/or suspending agents and combinations and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

In a third aspect, a composition comprising a combination of a polypeptide molecule (A), a surfactant (B) and an amino acid single or double molecule (C), and a pharmaceutically acceptable carrier, is used in the manufacture of a medicament for the treatment of a disease.

Further, the diseases include, but are not limited to, endocrine diseases including disorders of sugar metabolism, diabetes, obesity, hormone deficiency and osteoporosis, neurodegenerative diseases including Alzheimer's disease and other forms of dementia, parkinson's disease, multiple sclerosis and Huntington's disease, cardiovascular diseases including atherosclerosis, hypercoagulable states (hyper-coagulable state) and hypercoagulable states (hypocoagulable state), coronary artery diseases and cerebrovascular events, hypertension, metabolic disorders including obesity and vitamin deficiency, kidney diseases including renal failure, blood diseases including anemia of different entities, immune and rheumatic diseases including autoimmune diseases and immune dysfunction, inflammatory diseases, infectious diseases including viral, bacterial, fungal and parasitic infections, neoplastic diseases, and multifactorial diseases including chronic pain, depression, different fibrotic states and short stature.

Advantageous effects

The composition system of the application remarkably improves the stability of polypeptide drugs in small intestine fluid and colon fluid, and simultaneously remarkably promotes the absorption effect of polypeptide drugs in vivo.

Drawings

Figure 1 stability analysis of semaglutin and its combination system in small intestine.

Figure 2 stability analysis of octreotide and its combination system in the small intestine.

FIG. 3 analysis of the stability of thymopentin and its combination system in the small intestine.

Figure 4 stability analysis of octreotide and its combination system in colonic fluid.

Figure 5 analysis of stability of linaclotide and its combination system in colonic fluid.

FIG. 6OLP-C102TEM characterization.

FIG. 7OLP-C103TEM characterization.

FIG. 8OLP-C104TEM characterization.

FIG. 9OLP-C105TEM characterization.

Analysis of intestinal absorption in rats of the composition system of fig. 10. The effect is based on the blood concentration of the polypeptide medicine, and the higher the concentration is, the better the effect is.

FIG. 11 analysis of the absorption effect of mono/di amino acid components on semaglutin in a composition system.

Fig. 12 analysis of the absorption promoting effect of pH adjuster on semaglutin in the composition system.

Figure 13 in vivo absorption analysis in rats.

Figure 14 beagle in vivo absorption analysis.

Detailed Description

The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments described below may be combined with each other as long as they do not collide with each other.

The molecular weights of "polypeptide molecules", "peptides", "proteins", "protein drugs", "peptide molecular compounds" and "peptide molecular drugs" are specified herein in daltons (Da), which are the alternative names of the uniform atomic mass units (u). The term "kDa" refers to 1000Da.

The terms "polypeptide molecule", "peptide molecular compound" and "peptide molecular drug", "polypeptide" and "protein" as used herein are used interchangeably to refer to a polymer of amino acid residues comprising an amino acid chain of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds and have a molecular weight in the range of about 0.1kDa to 20kDa, and also include 0.1kDa、0.5kDa、1kDa、1.5kDa、2kDa、2.5kDa、3kDa、3.5kDa、4kDa、4.5kDa、5kDa、5.5kDa、6kDa、6.5kDa、7kDa、7.5kDa、8kDa、8.5kDa、9kDa、9.5kDa、10kDa、15kDa、20kDa.

The term "peptidomimetic" as used herein refers to a small protein-like chain designed to mimic a peptide.

The peptide molecule of the invention may be any peptide suitable for use as a medicament, for example, the peptide may be a linear peptide or a cyclic peptide (e.g., cyclic peptides cyclized via at least one amide bond). It may also be a modified or derivatized peptide drug, such as a pegylated or fatty acid-chilled skin drug or fatty diacid-chilled skin drug, or it may be an unmodified peptide drug. In particular, at its N-terminus and/or at its C-terminus, it may be unmodified, i.e. it may have a free N-terminus (-NH ₂) and/or a free C-terminus (-COOH) and thus the class drug may have a free (unmodified) N-terminus, or it may have a free (unmodified) C-terminus, or it may have a free N-terminus and a free C-terminus. Furthermore, the peptide drug may be free of histidine residues and/or free of cysteine residues.

In some embodiments, the polypeptide molecules include proteins such as, but not limited to, therapeutic agents, nutraceuticals, mucopolysaccharides, lipids, carbohydrates, steroids, hormones, growth Hormone (GH), growth Hormone Releasing Hormone (GHRH), epithelial growth factors, vascular endothelial growth and penetration factors (Vasculav endothelial growth and permeabilityfactor, vegff), nerve growth factors, cytokines, interleukins, interferons, GMCSF, hormonal products, nerve factors, neurotrophic factors, neurotransmitters, neuromodulators, enzymes, antibodies, peptides, protein fragments, vaccines, adjuvants, antigens, immunostimulatory or inhibitory factors, hematopoietic factors, anti-cancer products, anti-inflammatory agents, antiparasitic compounds, antimicrobial agents, nucleic acid fragments, plasmid DNA vectors, cell proliferation inhibitors or activators, cell differentiation factors, blood clotting factors, immunoglobulins, anti-angiogenic products, negative selection markers or "suicide" agents, toxic compounds, anti-angiogenic agents, polypeptides, and anticancer agents, nucleotides, and the like, and structurally similar equivalents thereof.

In some embodiments, polypeptide molecules include, but are not limited to: glucagon-like peptide-1 (GLP-1), GLP-1 analogs, GLP-1 agonists (also known as "glucagon-like peptide-1 receptor agonists" or "GLP-1 receptor agonists"), semaglutinin, liraglutide, exenatide-4, risilacome, tasraglutide, LANGLENATIDE, GLP-1 (7-37), GLP-1 (7-36) NH2, dual agonists of the GLP-1 receptor and glucagon receptor, oxyntomodulin, GLP-2 agonists or analogs, goserelin, buserelin, peptide YY (PYY), PYY analogs, glatiramer, leuprolide, desmopressin, glycopeptide antibiotics, bortezomib, corticotropin, semorelin, luteinizing hormone releasing hormone, calcitonin, pentagastrin, oxytocin, cil (schliensin), envirtide, epstein, cyclopeptide, cyclosporin, hyperforin, glucagon, parathyroid hormone, 52, parathyroid hormone, and parathyroid hormone receptor (TRP-62), and other substances (e), which are pharmaceutically acceptable to the use of the peptide, the receptor of the peptide, TRP-63, the peptide, and the peptide receptor.

Further, the glycosylated cyclic or polycyclic non-ribosomal peptides include, but are not limited to, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin or decaplanin), bortezomib, corticotropin, semorelin, luteinizing hormone releasing hormone (LHRH; also referred to as "gonadotropin releasing hormone").

In some embodiments, the alpha parathyroid hormone (PTH) fragment includes, but is not limited to, teriparatide (also known as

"PTH (1-34)"), PTH (1-31) and PTH (2-34).

In some embodiments, the prostaglandin F2a receptor modulator is selected from PDC31.

The term "unnatural amino acid" as used herein refers to an amino acid that is not one of the 20 common amino acids (i.e., alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, lysine, histidine, isoleucine, lysine, leucine, methionine, aspartyl amine, proline, gu Anku amine arginine, serine, threonine, amino acids, tryptophan, and tyrosine), or such allolysine (pyrolysine) or selenocysteine. Other terms that may be used synonymously with the term "unnatural amino acid" are "unnatural encoded amino acid", "unnatural amino acid (unnatural amino acid)" "non-naturally occurring amino acid". The term "unnatural amino acid" includes, but is not limited to, amino acids that naturally occur through modification of naturally encoded amino acids (including but not limited to 20 common amino acids or pyrrolysine and selenocysteine), but that do not incorporate themselves into a growing polypeptide chain through translation complexes. Examples of naturally occurring amino acids that are not naturally encoded include, but are not limited to, N-acetylglucosamine-L-serine, N-ethylglucosamine-L-threonine, and 0-phosphotyrosine. Furthermore, the term "unnatural amino acid" includes, but is not limited to, amino acids that are not naturally occurring and that can be obtained synthetically or by modification of unnatural amino acids. Unnatural amino acids can include amino acids that contain a D-isomer configuration. In addition to natural amino acids, the amino acids may be D-amino acids or unnatural amino acids, and the molecular structure may further comprise other substituents or modifications. For example, if the peptide active ingredient is fresh fish calcitonin, the fish calcitonin may be amidated at its C-terminus. Some peptides may be amidated at positions that are not amidated in nature, or may be otherwise modified.

Salts within the term "pharmaceutically acceptable salts" as used herein are meant to include water soluble and water insoluble salts such as acetate, aminostilbenesulfonate (4, 4-diaminostilbene-2, 2' -disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium ethylenediamine tetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, ethylenediamine tetraacetate, ethanedisulfonate, propionate laurylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycosyl para-aminobenzene arsenate (glycouylarsanilate), hexafluorophosphate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionic aldehyde, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate (METHYHIITRATE), methylsulfate, galactose-dioate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1, 1-methylene-bis-2-hydroxy-3-naphthoate, pamoate), pantothenate, phosphoric acid/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, chlorate, hypochlorite, toluene sulfonate, triethyliodide, and valerate.

The compositions of the present invention may additionally comprise a pharmaceutically acceptable carrier, which is an aqueous or anhydrous agent, e.g., alcoholic or oily, or mixtures thereof, and may contain surfactants, emollients, lubricants, stabilizers, dyes, fragrances, preservatives, acids or bases for adjusting pH, solvents, emulsifiers, gelling agents, skin creams, stabilizers, wetting agents, time-release agents, humectants, or other ingredients typically included in pharmaceutical compositions of particular form. Pharmaceutically acceptable carriers are known in the art and include, for example, aqueous solutions such as water or physiological buffered saline or other solvents or carriers such as ethylene glycol, glycerol, and oils such as olive oil or injectable organic esters. The pharmaceutically acceptable carrier may contain physiologically acceptable compounds, for example, which function, for example, to stabilize or increase the absorption of a particular inhibitor, for example, carbohydrates, such as glucose, sucrose or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The pharmaceutically acceptable carrier may also be selected from substances such as distilled water, benzyl alcohol, lactose, starch, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, silica gel, titanium dioxide, and flavoring agents.

The composition formulations described herein are intended to provide a composition system useful for oral administration of dosage forms, including, for example, tablets (e.g., coated or uncoated), capsules (e.g., gelatin capsules or HPM capsules), intra-capsule capsules, intra-capsule mini-patch systems, lozenges, tablets, ovules, solutions, emulsions, suspensions, syrups, powders and granules for reconstitution, dispersible powders and granules, pharmaceutically acceptable gums, chewable tablets, effervescent tablets, and multiparticulate dosage forms.

The composition described herein may be formulated into tablets, pills, capsules and the like, and may also contain binders such as tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate, and sweetening agents such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the type described above, a liquid carrier such as a fatty oil.

The diseases, disorders or conditions to which the invention relates include, but are not limited to, endocrine disorders including glucose metabolism disorders, diabetes, obesity, hormonal deficiencies and osteoporosis, neurodegenerative disorders including Alzheimer's disease and other forms of dementia, parkinson's disease, multiple sclerosis and Huntington's disease, cardiovascular disorders including atherosclerosis, hypercoagulable states (hyper-coagulable state) and hypercoagulable states (hypocoagulable state), coronary artery disease and cerebrovascular events, hypertension, metabolic disorders including obesity and vitamin deficiencies, kidney diseases including renal failure, blood disorders including anemia of different entities, immune disorders and rheumatic disorders including autoimmune diseases and immune deficiencies, inflammatory diseases, infectious diseases including viral, bacterial, fungal and parasitic infections, neoplastic diseases, and multifactorial diseases including chronic pain, depression, different fibrotic states and short stature.

The term "subject" or "patient" as described herein may be an animal (e.g., a non-human animal), vertebrate, mammal, rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), canine (e.g., dog), feline (e.g., cat), porcine (e.g., pig), equine (e.g., horse), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, gorilla, gibbon), or human. In the context of the present invention, it is also envisaged to treat animals of economic or agricultural importance. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered economically important animals. Preferably, the subject/patient is a mammal, more preferably, the subject/patient is a human or non-human mammal (such as, for example, guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, gorilla, gibbon, sheep, cow or pig).

Octreotide was first synthesized in 1979 as an octapeptide that mimics the pharmacology of natural somatostatin, although it is a growth hormone, glucagon and insulin inhibitor that is more potent than natural hormone. Octreotide or other somatostatin analogues may be administered according to one or more embodiments of the present invention for use in the treatment or prevention of a subject suffering from a disease or disorder such as acromegaly, gastrointestinal dyskinesia, carcinoid syndrome-associated flushing, portal hypertension, endocrine tumors (e.g. benign tumors, vasoactive intestinal peptide tumors), gastroparesis, diarrhea, pancreatic fistulae or pancreatic pseudocysts.

The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.

Example 1 stability test

1.1 Small intestine stability test

The preparation method of intestinal juice comprises directly separating small intestine from animal, squeezing out small intestine content, and collecting.

Small intestine stability the composition system is mixed with small intestine liquid in the ratio of 1 to 10, and blown. The reaction system was incubated at 100rpm in a 37℃incubator, and samples were aspirated at 0, 0.17, 0.33, 0.5, 1, 1.5, 2 h. The mixed sample was centrifuged at 10,000rpm at 4℃for 10min. The supernatant was collected for quantitative analysis of polypeptide drugs.

1.1.1A composition system is prepared by using a semaglutin liquid medicine with the concentration of 1mg/ml, the content of semaglutin in all the composition systems is the same, and the figures in brackets are the mass gram number of each component in the system.

Table 1 list of compositions for preparation of a drug solution of semaglutin in the small intestine

Composition System code	Polypeptide medicine	Acyl carnitines	Mono/di amino acids
				OLP-A100	Semaglutin (1)	-	-
OLP-A101	Semaglutin (1)	Lauroyl-L-carnitine (6)	Bisglycine (10)
				OLP-A102	Semaglutin (1)	L-octanoyl carnitine (6)	Arginine (10)

As can be seen from fig. 1, the composition systems OLP-a101 and OLP-a102 of the present application significantly improved the stability of the intestinal juice of semaglutinin.

1.1.2 Preparation of composition System with octreotide drug solution at 1mg/ml, the octreotide content in all composition System being identical, the figures in parentheses being the ratio of grams by mass of the Components in the System

TABLE 2 list of octreotide drug solution formulation compositions in the small intestine

Composition System code	Polypeptide medicine	Acyl carnitines	Mono/di amino acids
				OLP-A200	Octreotide (1)	-	-
OLP-A201	Octreotide (1)	L-octanoyl carnitine (10)	-

The results of the above graph indicate that the composition system OLP-A201 significantly improves the intestinal fluid stability of octreotide.

1.1.3 Preparing a composition system by using thymic pentapeptide liquid medicine with the concentration of 1mg/ml, wherein the content of thymic pentapeptide in all the composition systems is the same, and the figures in brackets are the mass gram ratio of each component in the system.

TABLE 3 list of compositions for preparing thymopentin drug solutions in small intestine

Composition System code	Polypeptide medicine	Acyl carnitines	Mono/di amino acids	PH regulator
					OLP-A300	Thymopentin (1)	-	-	-
OLP-A301	Thymopentin (1)	-	Bisglycine (20)	Citric acid (3)
					OLP-A302	Thymopentin (1)	Lauroyl-L-carnitine (10)	Bisglycine (20)	Citric acid (3)

The results in FIG. 3 show that the composition systems OLP-A301 and OLP-A302 significantly improved the intestinal fluid stability of thymopentin.

1.2 Colon (large intestine) stability experiments:

1. The substrate liquid preparation method comprises the following steps:

peptone water and yeast extract were weighed into a glass flask of distilled water, and 0.1g of NaCl, 0.04g K ₂HPO₄、0.01g MgSO₄.7H₂ O and 0.01g of CaCl ₂.6H₂ O were weighed into the glass flask in this order and dissolved with stirring. After all salts were dissolved, 0.5g L-cysteine, 0.05g hemin, 4ml of 0.025% resazurin solution and 2g NaHCO ₃ were added. Distilled water is added to make the final volume reach 1L, stirring is continued for 20-30 minutes until the solution is red to bright red for standby.

2. The preparation method of the colon fluid comprises the following steps:

2g of the large intestine content was weighed into a 50mL centrifuge tube, and the base solution was added to 20g. Mixing with spatula to obtain uniform 10% colon fluid.

3. Colon stability:

The composition system was mixed with 10% colon fluid in a 1:20 ratio and blown. The reaction system was incubated and cultivated in an anaerobic workstation (nitrogen: hydrogen: carbon dioxide=8:1:1, ambient temperature 37 ℃, humidity 75%). Samples were aspirated at 0, 0.5, 1,2, 3,4 h. The mixed sample was centrifuged at 10000rpm at 4℃for 10min. The supernatant was collected for quantitative analysis of polypeptide drugs.

1.2.1 Preparing a composition system by using octreotide liquid medicine with the concentration of 1mg/ml, wherein the content of the octreotide in all the composition systems is the same, and the figures in brackets are the mass gram ratio of each component in the system.

TABLE 4 list of octreotide drug solution formulation compositions in colon

Composition System code	Polypeptide medicine	Acyl carnitines	Mono/di amino acids
				OLP-B100	Octreotide (1)	-	-
OLP-B101	Octreotide (1)	L-octanoyl carnitine (15)	Bisglycine (7.5)

The results in fig. 4 show that the stability of octreotide in human intestinal fluid is significantly improved by the composition system OLP-B101.

1.2.2A composition system was prepared using a linaclotide drug solution at a concentration of 1mg/ml, the content of the selinaclotide in all composition systems being the same, the figures in brackets being the mass gram ratio of the components in the system.

TABLE 5 list of linaclotide drug solution formulation compositions in colon

Composition System code	Polypeptide medicine	Acyl carnitines	Mono/di amino acids
				OLP-B200	Linaclotide (1)	-	-
OLP-B201	Linaclotide (1)	L-octanoyl carnitine (15)	Bisglycine (7.5)

As shown in fig. 5, the composition system OLP-B201 significantly improved the stability of linaclotide in human intestinal fluid.

Example 2 characterization of composition System experiments

Characterization of the composition system particle size and particle size studies, a specific DLS (dynamic light scattering) particle size study, was performed by adding the composition system to a cuvette and determining the particle size and polydispersity index (PDI) of the composition system using Zetasizer Nano ZS (Malvern Instruments). A composition system is prepared by using a semaglutin liquid medicine with the concentration of 5mg/ml, particle size characterization and particle size research are carried out, and the figures in brackets are the mass gram number of each component in the system. As shown in table 6:

Table 6 particle size characterization of the composition system

In addition, TEM (transmission electron microscope) analysis was performed on the above composition system, and a specific TEM particle size study was to freeze-dry the composition system and re-dissolve it with ultrapure water. Dropping 20 mu L of the compound solution onto a copper mesh, adding a proper amount of 2% phosphotungstic acid aqueous solution onto the copper mesh when the liquid is basically air-dried, incubating for 30s, sucking the excessive liquid on the copper mesh by using a water absorbing paper, air-drying, observing the particle morphology of the combined object system by a transmission electron microscope (TEM, JEM-2010, JEOL), and the TEM results are shown in figures 6-9.

In summary, DLS and TEM data indicate that the composition system of the present application forms nanoparticles with particle sizes ranging from 0nm to 1000nm, and the characterization structure is specifically described in this patent, and belongs to the protection scope of the composition system.

Example 3 composition system rat intestinal absorption experiment:

the study was performed using SD rats, and intestinal tract opening was performed in the abdomen of the rats by experimental surgery, and the opening was closed using a communicating vessel to maintain the laboratory in a unobstructed and non-experimental state. After the operation of opening the intestinal tract of the rat is completed, the rat is observed for 3 days, and after normal physiological activities are recovered, the subsequent absorption experiment is carried out as an experimental rat.

Injection experiments the composition system was prepared on the day of the experiment, and the injection was given in a dose of 2mg/kg, after which the intestinal tract was closed and the blood was taken from the rat orbit at the following time points of 15min,30min,1h,2h,4h. Blank blood was taken as a 0-point blood sample standard for the experiment prior to dosing, and the amount of blood taken at each blood taking point was 200ul.

Sample treatment, namely collecting whole blood of the rat, centrifuging, taking a serum blood sample of the supernatant after centrifuging, and freezing at an angle of-20 degrees for later use in mass spectrometry detection and analysis.

3.1 The content of semaglutin in all the composition systems shown in the following table is the same, and the figures in brackets are the mass gram ratio of each component in the system.

TABLE 7 intestinal tract absorbed composition system for rats

As shown in FIG. 10, the absorption effect of the composition systems OLP-D101 and OLP-D102 was better than that of the blank group (OLP-D100) after administration, and the data showed that the peak of blood concentration was reached within 1 hour for all groups of semaglutin.

In addition, because the mono/di amino acid component has better promotion effect on the absorption of the semaglutin, whether the synergistic effect can occur by using a plurality of mono/di amino acid components is further explored, a group of system OLP-D103 is added, and compared with the OLP-D101 and OLP-D102 systems, the synergistic effect does not exist (as shown in figure 11).

In addition, a composition system OLP-D104 is newly added, the proportion of components is optimized, the use amount of CA is adjusted, namely, CA is not used, compared with OLP-D102 (the composition contains CA), the result shows (figure 12), the intestinal absorption of the semaglutin is slightly reduced when the CA is not used, but the composition system still has a great advantage compared with a single semaglutin group, namely, the absorption promoting effect of the CA on the semaglutin in the system is auxiliary materials rather than critical auxiliary materials, and the use concentration of the CA shows a 'bell-shaped' or 'linear' effect.

Example 4 oral administration experiments of the composition System

First, a composition system powder was prepared according to the following protocol. Specifically, the components are precisely weighed according to the mass configuration ratio shown in the following table, and are uniformly mixed after weighing.

Table 8 oral composition system

4.1 Rat experiments

The above prepared composition system powders OLP-E100, OLP-E101 and OLP-E102 were buried in the intestinal tract of the rat by surgical means and the opening was sutured, and then the orbital blood was taken from the rat at the following time points of 30min,1h,2h,3h,4h. Blank blood was taken as a 0-point blood sample standard for the experiment prior to dosing, and the amount of blood taken at each blood taking point was 200ul. Sample treatment, namely collecting whole blood of the rat, centrifuging, taking a serum blood sample of the supernatant after centrifuging, and freezing at an angle of-20 degrees for later use in mass spectrometry detection and analysis.

Rat absorption experiments prove that the composition systems OLP-E101 and OLP-E102 show remarkable effect of promoting absorption of polypeptide drugs (FIG. 13, table 9).

TABLE 9 in vivo absorption effects in rats

Composition system	Cmax(ng/ml)	Tmax
			OLP-E100	10.8+3.6	1h
OLP-E101	127.3+36.2	2h
			OLP-E102	410.7+179.1	1h

4.2 Beagle experiments

The above-prepared composition system powders OLP-E100 and OLP-E103 were administered to beagle dogs by gavage, and then blood was collected from forearm veins of beagle dogs at the following time points after administration for 30min,1h,2h,3h,4h,6h,8h,12h. Blank blood was taken as a 0-point blood sample standard for the experiment prior to administration, and the amount of blood taken at each blood taking point was 1ml. Sample treatment, namely collecting beagle whole blood, centrifuging, taking a supernatant serum blood sample after centrifuging, and freezing at an angle of-20 degrees for later use in mass spectrometry detection analysis.

Experiments with oral administration of beagle dogs demonstrated that the composition system OLP-E103 exhibited sustained significant enhancement of semaglutin absorption (see table 10 of fig. 14).

TABLE 10 absorption Effect in beagle dogs

Composition system	Cmax(ng/ml)	Tmax	AUC0-12h
				OLP-E100	2.8+2.5	2h	11.21
OLP-E103	402+169.1	8h	3886.77

Claims

1. An oral polypeptide composition comprising a polypeptide molecule (a), a surfactant (B), an amino acid single molecule or double molecule combination (C).

2. The oral polypeptide composition of claim 1, wherein the components of the oral polypeptide composition interact to form nanoparticles having a diameter of 0-1000nm.

3. The oral polypeptide composition of claim 1, wherein the oral polypeptide composition further comprises a pH adjuster (D).

4. The oral polypeptide composition according to claim 1, wherein the site of action of the oral polypeptide composition is the small intestine and/or the large intestine, and the composition is stably absorbable in the small intestine and/or the large intestine.

5. The oral polypeptide composition of claim 1, wherein the polypeptide molecule comprises, but is not limited to, glucagon-like peptide-1 (GLP-1), GLP-1 analogs, GLP-1 agonists, semaglutinin, liraglutide, exenatide-4, risilacome, tasraglutide, LANGLENATIDE, GLP-1 (7-37), GLP-1 (7-36) NH2, GLP-1 receptor, dual agonists of glucagon receptor, oxyntomodulin, GLP-2 agonists or analogs, goserelin, buserelin, peptide YY (PYY), PYY analogs, glatiramer, leuprolide, desmopressin, glycopeptide antibiotics, bortezomib, corticotropin, sertraline, luteinizing hormone releasing hormone, calcitonin, pentagastrin, oxytocin, cilirin, enweintide, cyclopeptide, cyclosporin, hyperforin, granorubin, thyroxine, granin, granatide-62, and parathion-5 h (a), and parathion-63, and pharmaceutically acceptable salts thereof.

6. The oral polypeptide composition according to claim 1, wherein the surfactant is an acyl carnitine compound and/or an alkyl glycoside compound having a carbon chain length of between C ₈ and C ₁₂, and pharmaceutically acceptable salts or solvates thereof, wherein the acyl carnitine compound has a structural formula as shown in formula I:

R ¹ may be an alkyl compound having a carbon chain length of C ₆ to C ₁₄.

7. The oral polypeptide composition of claim 1, wherein the amino acid single molecule is selected from any one or more of glycine, alanine, valine, leucine, proline, tryptophan, serine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and citrulline.

8. The oral polypeptide composition according to claim 1, wherein the amino acid bimolecular is selected from the group consisting of any two single amino acid molecules of glycine, alanine, valine, leucine, proline, tryptophan, serine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and citrulline linked by a peptide bond.

9. A pharmaceutical formulation comprising a composition of a polypeptide molecule (a), a surfactant (B) and an amino acid single molecule or combination (C), and a pharmaceutically acceptable carrier.

10. The application of a composition in preparing a medicament for treating diseases comprises a composition of polypeptide molecules (A), a surfactant (B) and a combination (C) of amino acid single molecules or double molecules and a pharmaceutically acceptable carrier.