Glp-2 analogues and uses thereof

Abstract

The application discloses a GLP-2 analogue and application thereof, and belongs to the technical field of biological medicines. The GLP-2 analogue is an oligopeptide formed by 1-5 amino acids at the N end of tildipirosin, the oligopeptide retains GLP-2 analogue activity, effectively improves the disease degree of intestinal injury enteropathy, and the effect is equivalent to that of tildipirosin; and since the oligopeptide only includes 5 amino acids, the difficulty and cost of preparation are significantly reduced, so that the development cost of clinical drugs is reduced, and the medication cost of the GLP-2 analogue is expected to be reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to GLP-2 analogues and application thereof. BACKGROUND

[0002] Glucagon-like peptide-2 (GLP-2) is derived from the enteroendocrine L cell, which is an intestinal-specific growth factor, and is processed by transcription and translation of the proglucagon (PG) gene, and belongs to the proglucagon-derived peptide (PGDP). The main role of GLP-2 is to stimulate the growth of intestinal mucosal cells, inhibit the apoptosis of intestinal mucosal epithelial cells and crypt cells, cause the increase of small intestinal villi, enhance the intestinal mucosal barrier, and the like; GLP-2 can also inhibit gastric emptying and gastric acid secretion, enhance intestinal nutrient absorption and blood flow, and promote the repair after intestinal injury. At present, the research of GLP-2 mainly focuses on gastrointestinal diseases, and GLP-2 is mainly used for the treatment of short bowel syndrome patients in clinic.

[0003] Natural GLP-2 is composed of 33 amino acids, and its amino acid sequence is: HADGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO. 1), which has high conservation, and its active cycle form is GLP-2 (1-33). However, natural GLP-2 is extremely easy to be degraded in the human body, specifically, the alanine (A) at the second position is recognized and cut by Dipeptidyl Peptidase IV (DPP-IV) to generate inactive GLP-2 (3-33), and its half-life in a healthy human body is about 7 minutes. Therefore, it is necessary to change the molecular structure of GLP-2 to prolong the half-life.

[0004] Teduglutide for injection is an existing GLP-2 analogue drug on the market, which is developed by Takeda Company, and its trade name is Revestive. The active ingredient of Teduglutide for injection is Teduglutide. The difference from natural GLP-2 is that the alanine (A) at the second position of the N-terminal of Teduglutide is replaced by glycine (G), which does not affect its active function, and prevents the hydrolysis of DDP-IV, thereby prolonging its half-life to about 3-5 hours. However, the price of the drug is very high, and in pediatric patients with short bowel syndrome, although the use of Teduglutide for injection can help achieve intestinal autonomy, the annual cost is more than 400,000 US dollars.

[0005] In addition, most GLP-2 analogs used in current clinical research are prepared using techniques such as chemical synthesis and gene recombination. Gene recombination technology has a complex preparation process, high synthesis cost, and unclear mechanism of action and target. On the other hand, chemical synthesis technology is difficult to synthesize peptides with more than 30 amino acids. These factors greatly limit the widespread application of GLP-2 analogs in clinical research. Summary of the Invention

[0006] 1. The problem to be solved

[0007] This application addresses the problems of high cost and high preparation difficulty of injectable tedulglutide in the prior art due to the large number of amino acids (>30) in the GLP-2 analog tedulglutide. It provides a GLP-2 analog and its application. This GLP-2 analog is an oligopeptide formed from 1-5 amino acids at the N-terminus of tedulglutide. This oligopeptide retains the activity of the GLP-2 analog and effectively improves the severity of intestinal injury-related enteropathy. Furthermore, because it contains only 5 amino acids, the preparation difficulty and cost are significantly reduced, thereby lowering the development cost of clinical drugs and potentially reducing the cost of using GLP-2 analogs.

[0008] 2. Technical Solution

[0009] To solve the above problems, the technical solution adopted in this application is as follows:

[0010] This application provides a GLP-2 analogue, which is a 5-amino acid oligopeptide with the amino acid sequence: histidine-glycine-aspartic acid-glycine-serine (HGDGS, SEQ ID NO.2). This oligopeptide is a truncated peptide of teduglutide (amino acid sequence: HGDGSFSDEMNTILDNLAARDFINWLIQTKITD, SEQ ID NO.3). The inventors unexpectedly discovered in their research that this oligopeptide retains the GLP-2 analogue activity and has a biological activity effect that is basically similar to teduglutide; while the 4-amino acid oligopeptide (HGDG, SEQ ID NO.4) does not have the GLP-2 analogue activity and cannot improve inflammatory damage.

[0011] This application also provides the use of the above-mentioned GLP-2 analogues in the preparation of medicaments for treating intestinal injury-like enteropathy.

[0012] Furthermore, the aforementioned intestinal injury-related intestinal diseases include one or more of the following: hypoxic injury, ulcerative colitis, and sepsis.

[0013] Furthermore, the aforementioned intestinal injury-related enteropathy includes hypoxic injury.

[0014] Further, the intestinal injury intestinal disease includes ulcerative colitis, and the intestinal injury after dextran sulfate sodium (DSS) is expressed as ulcerative colitis.

[0015] Further, the intestinal injury intestinal disease includes sepsis, and the intestinal injury after lipopolysaccharide (LPS) is expressed as sepsis.

[0016] The application also provides a pharmaceutical composition comprising the GLP-2 analogue or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] Further, the pharmaceutical composition comprises L-histidine, D-mannitol, sodium phosphate monohydrate, disodium hydrogen phosphate heptahydrate, and a pH adjuster.

[0018] Further, the mass ratio of the GLP-2 analogue, L-histidine, D-mannitol, sodium phosphate monohydrate, and disodium hydrogen phosphate heptahydrate is (4-6):(3.5-4):(10-20):(0.3-0.8):(3-4).

[0019] Further, the mass ratio of the GLP-2 analogue, L-histidine, D-mannitol, sodium phosphate monohydrate, and disodium hydrogen phosphate heptahydrate is 5:3.88:15:0.644:3.434.

[0020] Further, the pH adjuster comprises sodium hydroxide and / or hydrochloric acid.

[0021] The application also provides a pharmaceutical preparation comprising any of the above pharmaceutical compositions.

[0022] Further, the pharmaceutical preparation is in the form of an injection preparation.

[0023] Further, the injection preparation is in the form of a subcutaneous injection preparation.

[0024] Further, the injection preparation further comprises an injection diluent, and the injection diluent comprises water for injection.

[0025] Further, the GLP-2 analogue has a concentration of 5-15 mg / mL.

[0026] Further, the GLP-2 analogue has a concentration of 10 mg / mL.

[0027] Further, the pharmaceutical composition or the pharmaceutical preparation can be used for treating intestinal injury intestinal diseases.

[0028] Further, the intestinal injury intestinal disease includes one or more of hypoxic injury, ulcerative colitis, sepsis disease.

[0029] Further, the intestinal injury intestinal disease includes hypoxic injury.

[0030] Further, the intestinal injury intestinal disease includes ulcerative colitis, which is manifested as ulcerative colitis after dextran sulfate sodium (DSS) injury.

[0031] Further, the intestinal injury intestinal disease includes sepsis, which is manifested as sepsis after lipopolysaccharide (LPS) injury.

[0032] The application also provides the use of the above-mentioned pharmaceutical composition or pharmaceutical preparation in the preparation of a drug for treating intestinal injury intestinal disease, which comprises subcutaneously injecting an effective amount of the pharmaceutical composition.

[0033] Further, the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating intestinal injury intestinal disease, wherein the effective amount of the pharmaceutical composition is calculated according to the GLP-2 analogue as 0.05 mg / kg of body weight.

[0034] 3. Beneficial effects

[0035] Compared with the prior art, the application has the beneficial effects that:

[0036] (1) The GLP-2 analogue and the use thereof provided by the application, which is an oligopeptide formed by 5 amino acids, is used for treating intestinal injury intestinal disease or preparing a drug for treating intestinal injury intestinal disease, can promote the repair of intestinal barrier injury and inhibit intestinal cell apoptosis, and its biological activity effect is close to that of teduglutide.

[0037] (2) The GLP-2 analogue and the use thereof provided by the application, compared with natural GLP-2 or teduglutide (both of which are 33 amino acids), only includes 5 amino acids, can be prepared by Fmoc solid-phase synthesis method, and has a simpler and faster preparation process and lower cost, thereby reducing the development cost of the drug.

[0038] (3) The GLP-2 analogue and the use thereof provided by the application, which is an oligopeptide formed by 5 amino acids, however, as shown in Example 6, an oligopeptide (HGDG) composed of 4 amino acids does not have GLP-2 biological activity, only one amino acid is different, but the effect is significantly different, which also shows that the technical effect of the GLP-2 analogue and the use thereof provided by the application is unpredictable. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1 is a schematic diagram for preparing the GLP-2 analogue by Fmoc solid-phase synthesis method.

[0040] Figure 2 A is the result of CCK8 test, B is the result of cell scratch test.

[0041] Figure 3 A is the result of intracellular glucose level detection.

[0042] Figure 4 A is the result of cell number and lactate dehydrogenase (LDH) release after intestinal epithelial cell injury.

[0043] Figure 5 A is the result of immunofluorescence detection of junction protein ZO-1.

[0044] Figure 6 A is the result of WB detection of cyclin CDK4 and anti-apoptotic protein BCL2 protein levels.

[0045] Figure 7 A is the result of PCR detection of intracellular inflammatory factors IFN-β and IL-1b mRNA levels.

[0046] Figure 8 A is the result of blood glucose meter detection of blood glucose changes in mice.

[0047] Figure 9 A is the result of WB detection of cyclin junction protein ZO-1 and Occludin, mouse small intestine tissue cyclin CDK4 and CDK6, anti-apoptotic protein BCL2, and GLP-2 receptor protein levels.

[0048] Figure 10 A is the result of HE staining detection.

[0049] Figure 11 A is the design and process of dextran sulfate sodium (DSS) injury test.

[0050] Figure 12 A is the result of mouse body weight monitoring and DAI score.

[0051] Figure 13 A is the result of mouse colon length detection.

[0052] Figure 14 A is the result of HE staining detection.

[0053] Figure 15 A is the result of PCR detection of inflammatory factors TNF-a, IL-1b and IL-6 mRNA levels in intestinal epithelial cells with different amounts of peptides. DETAILED DESCRIPTION

[0054] The present application will be further described with reference to the following specific examples.

[0055] It should be noted that the terms such as "upper", "lower", "left", "right", "intermediate" and the like as cited in the present specification are merely intended to facilitate the description and are not intended to limit the scope of the application, and any change in relative relationship or adjustment without substantial change in technical content is also deemed to be within the scope of the application.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0057] Unless otherwise specified in the examples, the procedures were carried out under conventional conditions or under the conditions recommended by the manufacturer. The reagents or instruments used, if not specified by the manufacturer, were all conventional products that can be obtained commercially.

[0058] As used herein, the term "about" is used to provide flexibility to a given term, measurement, or value. The degree of flexibility of a particular variable can be readily determined by one of skill in the art.

[0059] As used herein, the term "at least one of" is intended to mean one or more of the listed items. For example, "at least one of A, B, and C" includes only A, only B, only C, as well as any combination thereof.

[0060] Concentrations, amounts, and other numerical data can be presented herein in a range format. It is to be understood that such range format is used merely for the convenience and brevity of the description and that the range format is to be interpreted flexibly to allow for variations defined by the specification as structurally and functionally equivalent. For example, a numerical range of "about 1 to about 4.5" should be interpreted to include not only the explicitly stated values and sub-ranges of the range, but also the range of values between the lower and upper values of the range, as well as the range of values outside the explicitly stated range, as if each numerical value and sub-range within the explicitly stated range were incorporated into the specification. For example, a range of "less than about 4.5" should be interpreted to include not only the explicitly stated value and sub-ranges of the range, but also the range of values between the lower value of the range and the upper value of the range, as well as the range of values outside the explicitly stated range, as if each numerical value and sub-range within the explicitly stated range were incorporated into the specification. In addition, this interpretation should apply regardless of the breadth of the range.

[0061] As used herein, "GLP-2", "native GLP-2", "GLP-2-33-aa", all refer to native GLP-2, which has the amino acid sequence: HADGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO. 1).

[0062] As used herein, "Teduglutide for injection" is a GLP-2 analogue drug on the market, developed by Takeda, with the trade name Revestive.

[0063] As used herein, "Teduglutide" is the active ingredient of "Teduglutide for injection", a GLP-2 analogue drug on the market, consisting of 33 amino acids, with the amino acid sequence of:

[0064] HGDGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO. 3).

[0065] As used herein, "GLP-2-5-aa edit" is a GLP-2 analogue of the present application, with the amino acid sequence of: HGDGS (SEQ ID NO. 2).

[0066] As used herein, "GLP-2-4-aa edit" is an oligopeptide consisting of amino acids 1-4 of Teduglutide, with the amino acid sequence of: HGDG (SEQ ID NO. 4).

[0067] As used herein, "GLP-2-5-aa" is the N-terminal 1-5 amino acids of natural GLP-2, and is also a GLP-2 analogue, with the amino acid sequence of: HADGS (SEQ ID NO. 5).

[0068] In the present application, the polypeptides or oligopeptides such as "GLP-2", "Teduglutide", "GLP-2-5-aa edit", "GLP-2-4-aa edit", "GLP-2-5-aa" are dissolved using a biological solvent (dimethyl sulfoxide, DMSO).

[0069] Example 1

[0070] The present embodiment provides a GLP-2 analogue and a method for preparing the same.

[0071] The GLP-2 analogue provided in the present embodiment has the amino acid sequence of: H-Histidine-Glycine-Aspartic acid-Glycine-Serine-OH (HGDGS, SEQ ID NO. 1).

[0072] The present application does not limit the method for preparing the GLP-2 analogue, which can be prepared by biological synthesis or solid-phase synthesis. In the present embodiment, an example of solid-phase synthesis is provided.

[0073] The GLP-2 analogue is prepared by Fmoc solid-phase synthesis, the principle of which is as follows: Figure 1As shown, on the polymer resin, according to the amino acid sequence of the GLP-2 analogue, starting from the carboxyl end, the amino acids are sequentially connected into the GLP-2 analogue (condensation → washing → deprotection → neutralization and washing → next round of condensation); finally, the peptide chain is cleaved from the resin, and after purification and other treatments, the desired GLP-2 analogue is obtained.

[0074] In this embodiment, the GLP-2 analogue is prepared and synthesized by Beijing ZK Yaguang Biotechnology Co., Ltd. The amino protecting group is removed by an alkaline solvent (piperidine), and then cross-linked with the activated carboxyl group of the next amino acid to form a peptide bond. After synthesis, it is eluted and deprotected by a deprotection agent (TFA) and purified by reverse HPLC chromatography, with a purification rate of >95%. Compared with synthetic GLP-2 or teduglutide, the GLP-2 oligopeptide product prepared has high purity, high product yield, and low production cost due to the reduction in the number of amino acids. The GLP-2 analogue prepared in this embodiment has a unit price of about 25 yuan / mg, which is about 5% of the unit price of natural GLP-2 (495 yuan / mg) and teduglutide (440 yuan / mg), greatly reducing the cost.

[0075] Embodiment 2

[0076] This embodiment provides the use of the GLP-2 analogue of the present application in the treatment of intestinal injury-related intestinal diseases.

[0077] In this embodiment, the intestinal injury is hypoxia / reoxygenation (H / R) injury of intestinal epithelial cells, specifically including:

[0078] After pre-treating Ncm460 and Caco-2 cells with different concentrations (100, 200, 400, 800, 1600 nM) of natural GLP-2 (GLP-2-33-aa) and the GLP-2 analogue (GLP-2-5-aa edit) of the present application for 2 h, the cells were cultured at 37°C with 95% O2 and 5% CO2 for 12 h, and then subjected to hypoxia for 12 h with a mixture of anaerobic gas containing 1% O2, 5% CO2 and 94% N2.

[0079] The cell activity was detected by CCK8, and the cell migration ability was detected by cell scratch.

[0080] Result analysis:

[0081] The CCK8 detection results are as follows: Figure 2(A) shows that after hypoxia / reoxygenation (H / R) injury, the proliferation ability of Ncm460 and Caco-2 cells is significantly reduced, and after giving a certain concentration of GLP-2-5-aa edit, the proliferation ability of intestinal epithelial cells is significantly increased.

[0082] The results of cell scratch detection are respectively shown in Figure 2 (B) shows that after hypoxia / reoxygenation (H / R) injury, the migration ability of Ncm460 and Caco-2 cells is significantly reduced, and after GLP-2-5-aa edit pretreatment, the migration ability of intestinal epithelial cells is significantly increased and higher than that of GLP-2-33-aa pretreatment, but no significant difference is found.

[0083] At the same time, neither natural GLP-2 (GLP-2-33-aa) nor GLP-2-5-aa edit shows toxic effects on intestinal epithelial cells.

[0084] Example 3

[0085] This embodiment provides the application of the GLP-2 analog of the present application in the treatment of intestinal injury-related intestinal diseases.

[0086] In this embodiment, the intestinal injury is lipopolysaccharide (LPS) injury, which specifically includes:

[0087] After pretreating Ncm460 cells with 800 nM GLP-2-5-aa, GLP-2-33-aa (natural) and GLP-2-5-aa edit and Teduglutide for 2 h, 1 μg / ml LPS was used to stimulate Ncm460 for 24 h to establish an LPS stimulation model of intestinal epithelial cells.

[0088] The changes in the intracellular glucose content level of intestinal epithelial cells after injury were detected by ELISA; the effects on the proliferation ability of intestinal epithelial cells after injury were detected by LDH method and cell number counting method; the effects on the mRNA levels of cyclin, connexin, apoptosis protein and inflammatory factors IFN-β and IL-1b were detected by WB, immunofluorescence and PCR method.

[0089] Result analysis:

[0090] The detection results of the intracellular glucose content level of intestinal epithelial cells after injury are shown in Figure 3 As shown in the figure, after GLP-2-5-aa edit and Teduglutide pretreatment, the intracellular glucose level can be maintained at a relatively high level basically within 24 h, in contrast, after GLP-2-5-aa and GLP-2-33-aa pretreatment, the intracellular glucose level is significantly reduced at 6 h and 24 h.

[0091] Cell number and lactate dehydrogenase (LDH) release results after intestinal epithelial cell damage are shown in Figure 4 As shown in

[0092] The results of immunofluorescence detection of the connection protein ZO-1 are shown in Figure 5 As shown in

[0093] The results of WB detection of the protein levels of the cell cycle protein CDK4 and the anti-apoptotic protein BCL2 are shown in Figure 6 As shown in

[0094] The results of PCR detection of the mRNA levels of the inflammatory factors IFN-β and IL-1b in cells are shown in Figure 7 As shown in

[0095] Example 4

[0096] This example provides the use of the GLP-2 analogs of the present application in the treatment of intestinal damage enteropathy.

[0097] In this example, the intestinal damage is lipopolysaccharide (LPS) damage, specifically including:

[0098] This example provides verification that the GLP-2 analogs of the present application have intestinal protection after intestinal damage in mice after lipopolysaccharide (LPS) modeling. Specifically including:

[0099] After intraperitoneal injection of LPS (7.5 mg / kg) in mice, native GLP-2 and GLP-2 analogs (600 μg / kg) were subcutaneously injected, twice a day (9 am in the morning, 4 pm in the afternoon), for 5 consecutive days; every day, 1 h after the second injection of GLP-2, a blood glucose meter was used to detect the change in blood glucose in mice.

[0100] The effects on the mRNA levels of the small intestinal tissue cyclins, junction proteins, apoptosis proteins, GLP-2 receptors, and inflammatory factors IFN-β and IL-1b were detected by WB and PCR methods. In addition, the effects of GLP-2-5-aa, GLP-2-33-aa, and GLP-2-5-aa edit on the intestinal tissue after intestinal injury were observed by HE.

[0101] Result analysis:

[0102] The results of detecting the blood glucose changes of mice by a blood glucose meter are shown in Figure 8 After LPS stimulation, the blood glucose concentration of mice was significantly reduced, and the blood glucose concentration of mice was up-regulated on days 3-5 after treatment with GLP-2-5-aa, GLP-2-33-aa, and GLP-2-5-aa edit polypeptides.

[0103] The results of WB detection of the protein levels of cyclin junction proteins ZO-1 and Occludin, mouse small intestinal tissue cyclins CDK4 and CDK6, anti-apoptotic protein BCL2, and GLP-2 receptor protein are shown in Figure 9 After LPS treatment, the expression levels of mouse small intestinal tissue cyclins CDK4 and CDK6, junction proteins ZO-1 and Occludin, anti-apoptotic protein BCL2, and GLP-2 receptor protein were significantly reduced; GLP-2-5-aa edit treatment significantly up-regulated the protein level reduction caused by LPS, and the effect was significantly higher than that of GLP-2-5-aa and GLP-2-33-aa treatment groups.

[0104] The results of HE staining are shown in Figure 10 After treatment with GLP-2-5-aa, GLP-2-33-aa, and GLP-2-5-aa edit, the damage of LPS to the villi of mouse small intestine was improved.

[0105] Example 5

[0106] This example provides the use of the GLP-2 analogs of the present application in the treatment of intestinal damage in intestinal diseases.

[0107] In this example, the intestinal injury is dextran sulfate sodium (DSS) injury, which specifically includes:

[0108] The test design and process are shown in Figure 11 Acute colitis was induced by giving 2.5% DSS in the drinking water of mice for 7 days, and then pure water was regularly drunk until the end of the experiment; all drug groups were subcutaneously injected twice a day for 8 consecutive days (all drug injection concentrations were 600 μg / kg). The control group and the DSS group were injected with the same volume of normal saline.

[0109] During the whole experiment, the body weight and rectal bleeding were monitored daily. At the end of the experiment, the mice were euthanized and the colon was collected for analysis of HE injury.

[0110] Results analysis:

[0111] The results of mouse body weight monitoring and DAI score are shown in Figure 12 As shown in the table, the body weight of DSS-treated mice was significantly reduced, and the DAI score was significantly increased; while the GLP-2-5-aa edit-treated group and the positive control group GLP-2-33-aa and Teduglutide group effectively reversed the symptoms of colitis in mice.

[0112] The results of mouse colon length detection are shown in Figure 13 As shown in the table, compared with the normal group, the colon length of DSS-treated mice was significantly shortened, and the GLP-2-5-aa edit-treated group and the GLP-2-33-aa and Teduglutide group all alleviated the shortening of colon length.

[0113] The results of HE detection are shown in Figure 14 As shown in the table, GLP-2-5-aa edit, GLP-2-33-aa and Teduglutide polypeptide treatment can improve the colon injury of mice after acute colitis, and there is no significant difference between the GLP-2-5-aa edit-treated group and the Teduglutide-treated group.

[0114] Example 6

[0115] This example provides the application of GLP-2 analogues and other quantitative oligopeptides of the present application in the treatment of intestinal damage-related enteropathy.

[0116] In this example, the intestinal damage is lipopolysaccharide (LPS) damage, which specifically includes:

[0117] RAW cells were pretreated with 800 nM GLP-2-4-aa edit (HGDG), GLP-2-5-aa edit (HGDGS) and Teduglutide for 2 h, and then stimulated with 1 μg / ml LPS for 24 h to establish an LPS stimulation model of RAW cells (immune cells).

[0118] The effects of GLP-2 analogues with different peptide chain lengths on the levels of inflammatory factors IFN-β mRNA, TNF-a and IL-1b after RAW cell damage were detected by PCR method.

[0119] Results analysis:

[0120] As shown in the table, Figure 15The results show that GLP-2-5-aa edit and Teduglutide polypeptide treatment can improve the immune cell inflammatory response induced by LPS stimulation, while the GLP-2-4-aa edit treatment group does not improve this inflammatory damage, which also indicates that not any number of truncated Teduglutide will retain its biological activity.

Claims

1. A GLP-2 analogue, characterized in that, The amino acid sequence of the GLP-2 analogue is shown in SEQ ID NO.

2.

2. Use of the GLP-2 analogue of claim 1 in the preparation of a medicament for the treatment of intestinal damage in one or more of hypoxic damage, ulcerative colitis, and sepsis-induced intestinal damage.

3. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the GLP-2 analogue of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, wherein The excipient comprises L-histidine, D-mannitol, sodium phosphate monohydrate, disodium hydrogen phosphate heptahydrate, and a pH adjuster.

5. The pharmaceutical composition according to claim 4, wherein The pH adjuster comprises sodium hydroxide and / or hydrochloric acid.

6. The pharmaceutical composition of claim 5, wherein, The mass ratio of the GLP-2 analogue, L-histidine, D-mannitol, sodium phosphate monohydrate, and disodium hydrogen phosphate heptahydrate is (4-6):(3.5-4):(10-20):(0.3-0.8):(3-4).

7. A pharmaceutical preparation, characterized by, A pharmaceutical composition comprising any one of claims 3-6.

8. A pharmaceutical preparation according to claim 7, characterised in that The dosage form of the pharmaceutical dosage form is an injection preparation.

9. A pharmaceutical preparation according to claim 8, characterised in that The injection preparation further comprises a diluent for injection, and the concentration of the GLP-2 analogue in the injection preparation is 5-15 mg / mL.

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