CN1705681A

CN1705681A - GLP-2 compounds, formulations, and uses thereof

Info

Publication number: CN1705681A
Application number: CNA2003801013757A
Authority: CN
Inventors: L·蒂姆; S·邦; M·施莱因; N·C·卡尔肖尔姆; D·K·恩格伦德; A·S·尼尔森; N·L·约翰森; K·马森; M·曾德尔; P·蒂格森
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 2002-10-14
Filing date: 2003-10-14
Publication date: 2005-12-07

Abstract

The present invention relates to novel human glucagon-like peptide-2 (GLP-2) peptides and human glucagon-like peptide-2 derivatives which have a protracted profile of action as well as polynucleotide constructs encoding such peptides, vectors and host cells comprising and expressing the polynucleotide, pharmaceutical compositions, uses and methods of treatment.

Description

GLP-2 compound, preparation and uses thereof

Invention field

The present invention relates to new person's glucagon-like-peptide-2 (GLP-2) peptide and derivative thereof, it has the effect curves of prolongation.The invention still further relates to preparation and utilize described GLP-2 peptide and derivative, and the polynucleotide constructs of the described GLP-2 peptide of encoding and contain and express the method for the host cell of GLP-2 peptide, pharmaceutical composition is used to prepare method, purposes and the methods of treatment of described preparation.

Background of invention

Glucagon-like peptide-2 (GLP-2) is the peptide of 33 amino-acid residues producing in intestines L-cell, takes in the back at nutrition and discharges.The aminoacid sequence of people GLP-2 peptide is seen Fig. 1.

The GLP-2 peptide is the product of hyperglycemic-glycogenolytic factor protogene.Proglucagon is mainly expressed in pancreas and intestines, and expresses at the specific neurone that is arranged in brain to a certain extent.Yet, the translation post-treatment of Proglucagon in pancreas and intestines and (Fig. 2) inequality.In pancreas, Proglucagon mainly is processed to the relevant pancreas polypeptide (GRPP) of glucagon, hyperglycemic-glycogenolytic factor and main Proglucagon fragment.On the contrary, the processing in intestines obtains enteroglucagon, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2).

The GLP-2 peptide is quite conservative between planting, although there is sequence difference (Fig. 3).For example, pig GLP-2 peptide is compared with people GLP-2 and is had 4 replacements.Ironically, the GLP-2 of mouse compares with people GLP-2 only two replacements.

GLP-2 secretes from the L cell of small intestine and large intestine.Secretion is taken in regulation and control by nutrition.The plasma concentration of GLP-2 is about 15pM among the normal hungry experimenter, increases to about 60pM after mixed diet.

The effect of GLP-2 is by nearest clone's glucagon-like-peptide-2 acceptor transduction.The GLP-2 acceptor is represented a newcomer of the 7TM receptor superfamily of G albumen coupling.GLP-2R mainly expresses (Fig. 4) in height tissue specificity mode in gi tract, and the adenylate cyclase activity coupling mutually of the activation of GLP-2R and increase.The cell response of expressing GLP-2R does not still respond to other peptides (hyperglycemic-glycogenolytic factor, GLP-1 and GIP) of hyperglycemic-glycogenolytic factor family in GLP-2.

In rat, GLP-2R was reported in the brain already, or more specifically, expressed in the dorsal medial nucleus of thalamus.This part of brain it has been generally acknowledged that and participates in the behavior of feeding, and shown that when being injected directly into brain GLP-2 suppresses food intake.

Confirmed that also GLP-2 is to the outgrowth (Drucker that induces of enteric epithelium, D.J. wait the people, (1996) Proc.Natl.Acad.Sci.USA 93:7911-7916), and disclose by the cell smelting of in containing the substratum of GLP-2, growing and treated gastrointestinal tract disease (Drucker, D.J and Keneford, J.R., WO 96/32414).

WO 97/31943 relates to the GLP-2 peptide analogs and some GLP-2 peptide analogs is used for appetite inhibiting or full inductive purposes.

WO 98/08872 relates to the GLP-2 derivative, and it comprises lipophilic substituent.

WO 96/32414 and WO 97/39031 relate to specific GLP-2 peptide analogs.

WO 98/03547 relates to specific GLP-2 peptide analogs, and it shows antagonistic activity.

Though most pharmacological properties of noting all concentrating on the GLP-2 compound are known little about it to its physico-chemical property and solution structure character.This class knowledge is the prerequisite of rationally handling in for example preparation, purifying and preparation work, is even more important for understanding its architecture basics that prolongs mechanism.

For the medicine of numerous protein base, because intrinsic macromole unstable guarantees that in storing (shelf-lives) its long stability is the important techniques challenge.Because different with many small molecules, protein is all responsive for physics and chemical degradation.Chemical degradation relates to covalent linkage, as hydrolysis, racemization, oxidation or crosslinked.Mechanical degradation relates to the conformational change with respect to natural structure, and it comprises the forfeiture of higher ordered structure, assembles, and precipitates or is adsorbed to the surface.Known GLP-2 tends to instability owing to assembling.Above-mentioned two kinds of degradation pathway can finally cause the loss of bioactivity of pharmaceutical grade protein.

GLP-2 and GLP-2 analogue and fragment thereof are especially particularly useful in the treatment gastrointestinal tract disease.But, solubility limit and with respect to the low stability limit of endogenous diamino peptide acyl peptase the purposes of this compounds, therefore, need improve in this field.

In WO 99/43361, disclose some and comprised the pharmaceutical composition of the GLP-2 with lipophilic substituent.

In WO 01/49314, the pharmaceutical composition that comprises GLP-2 or GLP-2 analogue is disclosed, wherein said GLP-2 or GLP-2 analogue are containing the L-Histidine and are being selected from the physiological solution of volume agent of N.F,USP MANNITOL and sucrose pH5.5-7.9.

GLP-2 peptide and derivative thereof are useful in the treatment gastrointestinal tract disease.But high clearance rate has limited the purposes of this compounds, therefore, needs to improve in this field.Therefore, an object of the present invention is to provide GLP-2 peptide and derivative thereof, it has the effect curves of prolongation for natural GLP-2, still keeps the GLP-2 activity simultaneously.Another purpose of the present invention provides a kind of pharmaceutical composition that contains The compounds of this invention, and The compounds of this invention is used to provide the purposes of described composition.In addition, one object of the present invention is to provide a kind of method for the treatment of gastrointestinal tract disease.

Summary of the invention

Shown already that inhibition that GLP-2 derivative of the present invention dies by the stimulation and the accent of cell proliferation was to small intestine and the effect of the nutritious property of large intestine.GLP-2 derivative of the present invention also can stimulate the glucose transport of intestinal cells, reduces the intestines perviousness, suppresses stomach emptying and gastric acid secretion.

Generalized aspect the present invention relates to the derivative of GLP-2 peptide.Derivative according to the present invention has interested pharmacological property, and particularly it has the effect curves that prolongs than parent GLP-2 peptide.

Term " parent GLP-2 peptide " as used herein, is meant the aminoacid sequence skeleton of GLP-2 derivative.

Adopt simple system to describe GLP-2 peptide, its fragment, analogue and derivative below.Therefore, for example R20K-GLP-2 (1-31) is meant the fragment of GLP-2, it is derived from GLP-2, and method is the position 32 of deletion SEQ ID NO:1 and 33 amino-acid residue, and replaces the naturally occurring amino-acid residue arginine of SEQ ID NO:1 position 20 with Methionin.Similarly, R20K (N ^ε-tetradecanoyl)/K30R-GLP-2 (1-33) is meant the derivative of GLP-2 peptide analogs; it is derived from GLP-2; method is the naturally occurring amino-acid residue Methionin with arginine residues exchange SEQ ID NO:1 position 30; with the naturally occurring amino-acid residue arginine of lysine residue exchange SEQ IDNO:1 position 20, and will be with respect to the epsilon-amino tetradecanoylization of the lysine residue of the position 20 of SEQ IDNO:1. aminoacid sequence.

Similarly; L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) is meant the derivative of GLP-2 peptide analogs; it is derived from GLP-2; method is the naturally occurring amino-acid residue Methionin with arginine residues exchange SEQ ID NO:1 position 30; with the naturally occurring amino-acid residue leucine of lysine residue exchange SEQ ID NO:1 position 17 and will be with respect to the epsilon-amino of the lysine residue of the position 17 of SEQ ID NO:1. aminoacid sequence mode hexadecanoylization (Fig. 5 and 6) by the spacer Beta-alanine.

In first aspect, the present invention relates to the GLP-2 peptide, it contains the aminoacid sequence of formula I;

His-X ²-X ³-Gly-X ⁵-Phe-X ⁷-X ⁸-X ⁹-X ¹⁰-X ¹¹-X ¹²-X ¹³-X ¹⁴-X ¹⁵-X ¹⁶-X ¹⁷-X ¹⁸-Ala-Arg-X ²¹-Phe-Ile-X ²⁴-Trp-Leu-Ile-X ²⁸-Thr-Arg-Ile-Thr-X ³³(formula I);

Or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Glu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³³Be Asp, Glu or Lys.

In second aspect, the polynucleotide constructs of the GLP-2 peptide that the present invention relates to encode, described GLP-2 peptide contains the aminoacid sequence of formula I;

In third party's method, the present invention relates to contain the host cell of the polynucleotide constructs of coding GLP-2 peptide, described GLP-2 peptide contains the aminoacid sequence of formula I;

Or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Gllu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³³Be Asp, Glu or Lys.In one embodiment, host cell is an eukaryotic cell.In one embodiment, host cell is a yeast cell.

Aspect another, the present invention relates to the GLP-2 derivative, it comprises the GLP-2 peptide, and wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position S5 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position S7 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position D8 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position E9 with respect to SEQ IDNO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position M10 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment,, lipophilic substituent is connected with amino-acid residue at the position N11 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position T12 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position I13 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position L14 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position D15 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position N16 with respect to SEQ IDNO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position L17 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position A18 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position D21 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position N24 with respect to SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue at the position Q28 with respect to SEQID NO:1 aminoacid sequence.Should know, can be arbitrary amino-acid residue at amino-acid residue, and be not only at the naturally occurring amino-acid residue in this position with respect to the position of SEQ ID NO:1.In one embodiment, lipophilic substituent is connected with Methionin.

Aspect another, the present invention relates to a kind of pharmaceutical composition that comprises the GLP-2 derivative that comprises the GLP-2 peptide, wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, and described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

Aspect another, the GLP-2 derivative that the present invention relates to comprise the GLP-2 peptide is used to prepare the purposes of medicine, and wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, and described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

Aspect another, the GLP-2 derivative that the present invention relates to comprise the GLP-2 peptide is used to prepare the purposes of the medicine of the effect with prolongation, and wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, and described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

Aspect another, the GLP-2 derivative that the present invention relates to comprise the GLP-2 peptide is used to prepare the purposes of the medicine for the treatment of following disease, wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide, described disease is: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, and antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis comprises atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, the healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, weight loss in the parkinsons disease, the intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy and bone photo related disorders comprises osteoporosis, the hypercalcemia of malignant tumour, because the bone amount that bone shifts reduces, periodontopathy, hyperparathyroidism, wearing and tearing around the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia disease is because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture, because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, the BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

Aspect another, the present invention relates to the purposes that the GLP-2 receptor stimulant is used to prepare the medicine for the treatment of following disease: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia disease, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

Term " premature infant " is meant the baby who was born before pregnant 37 weeks.Term has comprised healthy babies and with babies that damage and/or immature intestines.

Term " antenatal baby " is meant arbitrary antenatal baby.Term has comprised healthy babies and with babies that damage and/or immature intestines.

Zooscopy shows that GLP-2 is very important to the formation of fetus small intestine and large intestine.Baby's born after the normal gestation period intestines can be used for the digestion immediately of food, yet, not like this for the premature infant.Therefore, the present invention relates to the general sophisticated purposes that the GLP-2 receptor stimulant is used for the PN intestines, to quicken and to improve per os and feed and be used for the treatment that this class baby causes the damage tissue of appearance.

Aspect another, the present invention relates to the purposes of GLP-2 derivative of the present invention as medicine.

Aspect another, it is depleted or cause the method for the bad other diseases of dietetic alimentation in the intestines to the present invention relates to a kind of intestines that are used for the treatment of, and described method comprises that wherein lipophilic substituent connects at one or more amino-acid residues that the aminoacid sequence with respect to SEQ ID NO:1 independently is selected from following position: S5 to the GLP-2 derivative that comprises the GLP-2 peptide of experimenter's administering therapeutic of needs or prevention significant quantity, S7, D8, E9, M10, N11, T12,113, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

Aspect another, the present invention relates to a kind of method for the treatment of following disease: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia disease, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces, described method comprises the GLP-2 derivative that comprises the GLP-2 peptide to experimenter's administering therapeutic of needs or prevention significant quantity, lipophilic substituent connects at the one or more amino-acid residues that are selected from following position with respect to SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not to be connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

Aspect another, the present invention relates to a kind of method for the treatment of following disease: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour, because the bone amount that bone shifts reduces, periodontopathy, hyperparathyroidism, wearing and tearing around the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, malignant hypercalcemia, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture, because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduces or the bone amount of glucocorticoid inducible reduces, and described method comprises the GLP-2 receptor stimulant of administering therapeutic or prevention significant quantity.

Aspect another, the present invention relates to a kind of method of the GLP-2 of preparation peptide, described peptide comprises the aminoacid sequence of formula I

Or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Glu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³³Be Asp, Glu or Lys, described method is included in and cultivates the host cell that contains polynucleotide constructs in the suitable growth medium under the condition that allows polynucleotide constructs to express, described polynucleotide constructs coding contains the GLP-2 peptide of formula I aminoacid sequence, and the peptide that reclaims gained from described nutrient solution.

We also find, GLP-2 and analogue thereof, modified GLP-2 and analogue thereof are when being formulated into aqueous solution with buffer reagent, and it is physically stable to be maintained at about about 10 o'clock of 8-in the pH scope.Preparation of the present invention is physically stablized (generally at 2-8 ℃ of 2-3) in given shelf-lives under the storing temp of recommending.In addition, preparation in use of the present invention physically stable (general 1 month) in quickening temperature as 25 ℃ or 37 ℃.Preparation of the present invention is chemically also stable, so its stable storing, and is suitable for invasive mode (as injection, subcutaneous injection, intramuscularly, intravenous injection or infusion) and the Noninvasive mode is used (as nose or lung, transdermal or saturating mucous membrane as through cheek).Be lower than 8.0 same preparation as the preparation of the present invention that contains the GLP-2 compound and pH and compare, physical stability obviously increases, and usually, in used test, shelf-lives is increased to the several months from the several seconds.

An object of the present invention is to provide the pharmaceutical preparation of a kind of GLP-2 of containing compound and buffer reagent, wherein said GLP-2 compound is that the concentration with 0.1mg/ml-100mg/ml exists, and the pH that wherein said preparation has is 8.0-10.

Another object of the present invention provides the method for the pharmaceutical preparation of the physically stable GLP-2 compound of a kind of preparation, comprise that preparation contains the GLP-2 compound, preparation with buffer reagent, wherein said GLP-2 compound is that the concentration with 0.1mg/ml-100mg/ml exists, and the pH that wherein said preparation has is from 8.0-10.

In one aspect of the invention, described preparation contains the GLP-2 compound of 1mg/ml-100mg/ml.

In another aspect of this invention, described preparation has the pH from 8.0-9.

We find that also the GLP-2 derivative is maintained at about 7-in the pH scope and physically stablized at about 10 o'clock when being formulated into aqueous solution with buffer reagent.Preparation of the present invention is physically stablized (generally at 2-8 ℃ of 2-3) in given shelf-lives under the storing temp of recommending.In addition, preparation in use of the present invention physically stable (general 1 month) in quickening temperature as 25 ℃ or 37 ℃.Preparation of the present invention is chemically also stable, so its stable storing, and is suitable for invasive mode (as injection, subcutaneous injection, intramuscularly, intravenous injection or infusion) and the Noninvasive mode is used (as nose or lung, transdermal or saturating mucous membrane as through cheek).Be lower than 7.0 same preparation as the preparation of the present invention that contains the GLP-2 derivative and pH and compare, physical stability obviously increases, and usually, in used test, shelf-lives is increased to the several months from the several seconds.

Therefore, an object of the present invention is to provide the pharmaceutical preparation of a kind of GLP-2 of containing derivative and buffer reagent, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

Another object of the present invention provides the method for the pharmaceutical preparation of the physically stable GLP-2 derivative of a kind of preparation, comprise that preparation contains the preparation of GLP-2 derivative and buffer reagent, wherein said GLP-2 compound exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

In one aspect of the invention, described preparation contains the GLP-2 derivative of 1mg/ml-100mg/ml.In another aspect of this invention, described preparation has the pH from 7.0-9.

Aspect another, the present invention relates to the pharmaceutical preparation of a kind of GLP-2 of containing derivative and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through, be connected with the one or more amino-acid residues that independently are selected from as upper/lower positions at aminoacid sequence: S5, S7, D8 with respect to SEQ ID NO:1, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

The present invention relates to the pharmaceutical preparation of a kind of GLP-2 of containing derivative aqueous solution and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through is connected with the one or more amino-acid residues that independently are selected from as upper/lower positions at the aminoacid sequence with respect to SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

Aspect another, the present invention relates to the method for the pharmaceutical preparation of the physically stable GLP-2 derivative of a kind of preparation, comprise that preparation contains the preparation of GLP-2 derivative and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through, be connected with the one or more amino-acid residues that independently are selected from as upper/lower positions at aminoacid sequence: S5, S7, D8 with respect to SEQ ID NO:1, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

Aspect another, the present invention relates to the method for the pharmaceutical preparation of the physically stable GLP-2 derivative of a kind of preparation, comprise that preparation contains the aqueous formulation of GLP-2 derivative and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through, be connected with the one or more amino-acid residues that independently are selected from as upper/lower positions at aminoacid sequence: S5, S7, D8 with respect to SEQ ID NO:1, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

Aspect another, the present invention relates to the method for the pharmaceutical preparation of the physically stable GLP-2 derivative of a kind of preparation, comprise that preparation contains the GLP-2 derivative, the preparation of water and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through, be connected with one or more amino-acid residues that aminoacid sequence with respect to SEQ ID NO:1 independently is selected from as upper/lower positions: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.

Aspect another, it is depleted or cause the method for the bad other diseases of dietetic alimentation in the intestines to the present invention relates to a kind of intestines that are used for the treatment of, and described method comprises that wherein said GLP-2 derivative is the GLP-2 peptide to experimenter's administering therapeutic of needs or the aqueous solution that comprises the GLP-2 derivative of prevention significant quantity and the pharmaceutical preparation of buffer reagent, lipophilic substituent wherein, the optional spacer that passes through is connected with one or more amino-acid residues that aminoacid sequence with respect to SEQ ID NO:1 independently is selected from as upper/lower positions: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, wherein said GLP-2 derivative exists with the concentration of 0.1mg/ml-100mg/ml, and wherein said preparation has the pH from 7.0-10.In one embodiment, intestines are depleted or cause that other disease of nutrition malabsorption is selected from the intestines: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia (the special property sent out) syndrome, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

Detailed Description Of The Invention

Short bowel syndrome (SBS) is the destructive clinical disease that runs in the illness in medicine and operation widely.The modal cause of disease comprises irradiation, tumour, mesentery vascular disease, Crohn ' s disease and wound.Along with the improvement of SBS patient care, a large amount of patients can be survived the long period, therefore, need therapeutic intervention with reduction or the elimination long-standing problem relevant with SBS.Though SBS patient advances 7 meal every day at most, it still is faced with the problem of keeping body weight, and no matter these patients are (HPN) or usually keep by the gastrointestinal nutrition thing in hospital at home.

Be used for the chemotherapy (CT) of cancer therapy and change treatment (RT) at be quick splitted cell.Because intestinal crypts (simple tubular gland of small intestine) fast breeding, CT/RT is easy to produce the side effect of intestinal mucosal injury.May cause gastro-enteritis, diarrhoea, dehydration and, in some cases, microbemia and Sepsis.Owing to following two these side effects of reason are serious: it has limited the dosage of treatment, therefore, has limited the efficient of treatment; And it has represented the life-threatening disease of a kind of potential, needs to strengthen and expensive processing.

Zooscopy shows, because strong intestines nutrition (intestinotrophic) activity of GLP-2, CT-inductive intestinal mucosa damages and can be offset by the GLP-2 peptide, this causes the increase of intestines weight, height of naps, the crypts degree of depth and pit cell multiplication rate, and, important, pit cell is transferred the minimizing of dying.The principle of the potential provide protection of damage of RT-inductive gi tract and GLP-2 peptide is identical with CT.

Inflammatory bowel (IBD) comprises Crohn ' s disease, and it mainly influences small intestine; And ulcerative colitis, it mainly appears at DC and rectum.The pathological characters of IBD is the destruction of chronic inflammatory diseases and gastrointestinal tract epithelial cell.Treatment at present is the inhibition at mediator of inflammation.By the agent of intestines trophicity, stimulate epithelial reparation and regeneration can represent substituting or subplan of a kind of IBD of treatment as GLP-2 derivative of the present invention.

Sulfuric acid glucose (DS)-inductive colitis is similar to ulcerative colitis among the mankind in the rodent, with myxedema, crypts erosion and abscess, cause polyp to form and make progress being dysplasia and gland cancer, still, the toxic accurate mechanism of experience DS is still unknown.Confirmed the beneficial effect of GLP-2 peptide in mouse DS inductive colitis already.The mouse of accepting the drinking-water of 5%DS formed loose blood cake ight soil after 4-5 days, forfeiture 20-25% body weight after 9-10 days.And the obvious less body weight of additionally handling with 350ng or twice subcutaneous injection 750ng A2G-GLP-2 (1-33) every day in omnidistance (9-10 days) of mouse forfeiture shows more healthy.Its effect has dose-dependently.According to histology, the DS mouse of using A2G-GLP-2 (1-33) to handle shows the complete mucomembranous epithelial cell of higher proportion, the colon length of increase, the crypts degree of depth and mucous membrane area.These agency parts are to mediate by the mucomembranous epithelial cell propagation that increases.The present inventor thinks that GLP-2 derivative according to the present invention has the effect of treatment IBD, especially with anti-inflammatory drug.Therefore, GLP-2 derivative according to the present invention has the possibility as the auxiliary of IBD anti-inflammatory treatment.The main effect of GLP-2 derivative according to the present invention in IBD is the regeneration that strengthens the intestinal epithelial cells of irresistance.

Natural GLP-2 (1-33) supposition was studied in great detail already by the degraded of two acyltransferase polypeptide peptase IV (DPP-IV) in the human body.The blood plasma level that increases complete GLP-2 (1-33) is eliminated by the T  value with 7 minutes from the GLP-2 infusion (0.8pmol/kg*min) of 9pM-131pM.Adopt subcutaneous injection GLP-2 (1-33) (400mg=106.000pmol), plasma concentration is increased to maximum value 1500pM after 45 minutes.After the subcutaneous injection 1 hour, the GLP-2 of 69% injection (1-33) still was complete GLP-2 (1-33).In above-mentioned research, be GLP-2 (3-33) by the detected only degraded product of HPLC, therefore think may GLP-2 extensively be degraded to GLP-2 (3-33) by DPP-IV among the mankind.Therefore, an object of the present invention is to provide the GLP-2 derivative, its tolerance DPP-IV degraded, therefore, more effective than natural GLP-2 peptide in vivo.

Term " GLP-2 peptide " is meant arbitrary protein or its analogue that contains natural human GLP-2 (SEQ IDNO:1) aminoacid sequence 1-33 as used herein.This includes but not limited to natural human GLP-2 and analogue thereof.

Term " GLP-2 " is intended to comprise the protein with natural human GLP-2 aminoacid sequence 1-33 as used herein, and described natural human GLP-2 has the aminoacid sequence of SEQ ID NO:1.Also comprise the protein that has the aminoacid sequence of modifying a little, for example, modified N-terminal comprises-terminal amino acid deletion or interpolation, as long as described protein is gone up the activity that keeps GLP-2 substantially." GLP-2 " of above-mentioned definition also comprises natural allelic variant, and it can exist in one or another individuality or find.In addition, different according to selected host and host cell environment, glycosylated degree also can be different with position or other posttranslational modifications.

Term " analogue " or " a plurality of analogue ", as used herein, be intended to refer to have the GLP-2 peptide of SEQ IDNO:1, wherein the proteinic one or more amino acid of parent GLP-2 were replaced by another amino acid already, and/or wherein the proteinic one or more amino acid of parent GLP-2 were deleted already, and/or wherein in the parent GLP-2 protein already by one or more aminoacid insertion, and/or wherein parent GLP-2 protein had added one or more amino acid already.Described interpolation can be at the proteinic N-end of parent GLP-2 or at the C-end or at two ends." analogue " in the described definition or " a plurality of analogue " still have the GLP-2 activity, as measuring by the ability to the trophicity effect of small intestine or large intestine.In one embodiment, analogue is 70% identical with the sequence of SEQ ID NO:1.In one embodiment, analogue is 80% identical with the sequence of SEQID NO:1.In another embodiment, analogue is 90% identical with the sequence of SEQ IDNO:1.In yet another embodiment, analogue is 95% identical with the sequence of SEQ ID NO:1.In yet another embodiment, analogue is the GLP-2 peptide, and wherein nearly amino-acid residue quilt and the arbitrary amino-acid residue of 10 SEQ ID NO:1 exchange sum.In yet another embodiment, analogue is the GLP-2 peptide, and wherein nearly amino-acid residue quilt and the arbitrary amino-acid residue of 5 SEQ ID NO:1 exchange sum.In yet another embodiment, analogue is the GLP-2 peptide, and wherein nearly amino-acid residue quilt and the arbitrary amino-acid residue of 3 SEQ ID NO:1 exchange sum.In yet another embodiment, analogue is the GLP-2 peptide, and wherein nearly amino-acid residue quilt and the arbitrary amino-acid residue of 2 SEQ ID NO:1 exchange sum.In yet another embodiment, analogue is the GLP-2 peptide, and the amino-acid residue that wherein adds up to 1 SEQ ID NO:1 is exchanged with arbitrary amino-acid residue.

Term " its fragment " as used herein, is meant the arbitrary fragment that has at least 15 amino acid and have the peptide of active formula I of biological GLP-2 or II.Can measure the GLP-2 activity by GLP-2 receptors bind avidity.In one embodiment, fragment has at least 20 amino acid.In one embodiment, fragment has at least 25 amino acid.In one embodiment, fragment has at least 30 amino acid.In one embodiment, fragment is formula I or the II that has 1 aminoacid deletion at the C-end.In one embodiment, fragment is formula I or the II that has 2 aminoacid deletion at the C-end.In one embodiment, fragment is formula I or the II that has 3 aminoacid deletion at the C-end.In one embodiment, fragment is formula I or the II that has 4 aminoacid deletion at the C-end.

In one embodiment, fragment is formula I or the II that has 1 aminoacid deletion at the N-end.In one embodiment, fragment is formula I or the II that has 2 aminoacid deletion at the N-end.In one embodiment, fragment is formula I or the II that has 3 aminoacid deletion at the N-end.In one embodiment, fragment is formula I or the II that has 4 aminoacid deletion at the N-end.

The term " derivative " that is used for herein is meant that wherein one or more amino-acid residues are formed by for example alkylation, acylations, ester or acid amides forms and the chemical modification.

The used in this article derivative that is meant the GLP-2 peptide of term " GLP-2 derivative ".In one embodiment, GLP-2 derivative according to the present invention has the GLP-2 activity, as by in conjunction with the ability of GLP-2 acceptor (GLP-2R) and/or show and measure for the trophism of small intestine or large intestine.In one embodiment, the GLP-2 acceptor is selected from rat GLP-2R, mouse GLP-2R and people GLP-2R.

Term " lipophilic substituent " is characterised in that and contains 4-40 carbon atom, and has the solubleness of 20 ℃ of following scopes from about 0.1mg/100ml water to about 250mg/100ml water in the water, and for example scope is from about 0.3mg/100ml water about 75mg/100ml water extremely.For example, sad (C8) has the solubleness of 20 ℃ of following 68mg/100ml in the water, and capric acid (C10) has the solubleness of 20 ℃ of following 15mg/100ml in the water, and octadecanoic acid (C18) has the solubleness of 20 ℃ of following 0.3mg/100ml in the water.

Term " polynucleotide constructs " is intended to represent based on Nucleotide section (segment) more than the naturally occurring nucleotide sequence of complete or part of coding target peptide.Choose wantonly, construct can contain other polynucleotide sections.Similarly, term " can by the polynucleotide constructs amino acids coding " is contained can be by the polynucleotide constructs amino acids coding of above-mentioned definition, that is, and and amino acid Ala for example, Val, Leu, Ile, Met, Phe, Trp, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln.

Term " host cell " as used herein, is represented arbitrary cell, comprises hybrid cell, but expressing heterologous DNA wherein.Generally, host cell includes but not limited to insect cell, yeast cell, mammalian cell (comprise people's cell, as BHK, CHO, HEK and COS cell).

In context, the prevention that term " treatment (treatment) " is intended to comprise the intestines depletion of expection or causes other illness (as atrophy after the radiotherapy) of nutrition malabsorption in the intestines, and the adjusting of the intestines depletion (as inflammatory bowel syndrome) that had taken place already, purpose is to suppress or reduce to cause the effect of nutrition malabsorption in the intestines.The preventative of GLP-2 derivative of the present invention used so is included in the term " treatment ".

Term " experimenter " is meant arbitrary animal, particularly Mammals as used herein, as the people, and suitable, can replace with term " patient " and use.

As used herein, term " suitable growth medium " is meant the nucleotide sequence expression desirable ingredients that contains nutrition and growth of other cells and code book invention GLP-2 peptide.

For obtaining the effect curves that satisfied GLP-2 derivative prolongs, the lipophilic substituent (as an example) that is connected in the GLP-2 part contains 4-40 carbon atom, as 8-25 carbon atom.Lipophilic substituent can be connected with the amino of GLP-2 part by the carboxyl of lipophilic substituent, the amino acid whose amino amido linkage that forms that it is connected with it.Perhaps, lipophilic substituent can be connected with described amino acid, makes the amino of lipophilic substituent and amino acid whose carboxyl form amido linkage.As another selection, lipophilic substituent can partly be connected with GLP-2 by ester bond.In form, carboxyl that can be by GLP-2 part forms ester with reaction between the substituting group hydroxyl to be replaced, or the reaction formation ester between hydroxyl by the GLP-2 part and the substituent carboxyl to be replaced.

In one embodiment, the GLP-2 peptide is isolating GLP-2 compound.

In one embodiment, the GLP-2 derivative is isolating GLP-2 compound.

In one embodiment, the GLP-2 compound is isolating GLP-2 compound.

Term " isolating GLP-2 compound " is meant compound of the present invention, and it is separated (1) with free polynucleotide, lipid, carbohydrate or other natural material that combines with it (that is: pollutent) at least about 50%.Preferably, isolated compound or polypeptide are substantially free of arbitrary other contaminative polypeptide, or other sees the pollutent that can influence its treatment, diagnosis, prevention or research purposes in its natural surroundings.

Preferably, isolated compound or polypeptide were separated with free polynucleotide, lipid, carbohydrate or other natural material that combines with it (that is: pollutent) at least about 70%, as 80%, as 90%, as 95% already.

In one embodiment, GLP-2 peptide of the present invention is made up of following aminoacid sequence

His-X ²-X ³-Gly-X ⁵-Phe-X ⁷-X ⁸-X ⁹-X ¹⁰-X ¹¹-X ¹²-X ¹³-X ¹⁴-X ¹⁵-X ¹⁶-X ¹⁷-X ¹⁸-Ala-X ²⁰-X ²¹-Phe-Ile-X ²⁴-Trp-Leu-Ile-X ²⁸-Thr-Arg-Ile-Thr-X ³³

Or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Glu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²⁰Be Arg or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³³Be Asp, Glu or Lys.

In one embodiment, GLP-2 peptide of the present invention is suc as formula II

His-X ²-X ³-Gly-X ⁵-Phe-X ⁷-X ⁸-X ⁹-X ¹⁰-X ¹¹-X ¹²-X ¹³-X ¹⁴-X ¹⁵-X ¹⁶-X ¹⁷-X ¹⁸-Ala-X ²⁰-X ²¹-Phe-Ile-X ²⁴-Trp-Leu-Ile-X ²⁸-Thr-X ³⁰-Ile-Thr-X ³³(formula II)

Or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Glu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²⁰Be Arg or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³⁰Be Arg or Lys; X ³³Be Asp, Glu or Lys (formula II).

In one embodiment, X ²Be Ala.In one embodiment, X ²Be Gly.In one embodiment, X ³Be Asp.In one embodiment, X ³Be Glu.In one embodiment, X ⁵Be Ser.In one embodiment, X ⁷Be Ser.In one embodiment, X ⁸Be Asp.In one embodiment, X ⁸Be Glu.In one embodiment, X ⁹Be Asp.In one embodiment, X ⁹Be Glu.In one embodiment, X ¹⁰Be selected from Met, Leu, Ile and nor-leucine.In one embodiment, X ¹¹Be Asn.In one embodiment, X ¹²Be Thr.In one embodiment, X ¹³Be Ile.In one embodiment, X ¹⁴Be Leu.In one embodiment, X ¹⁵Be Asp.In one embodiment, X ¹⁶Be Asn.In one embodiment, X ¹⁷Be Leu.In one embodiment, X ¹⁸Be Ala.In one embodiment, X ²¹Be Asp.In one embodiment, X ²⁴Be Asn.In one embodiment, X ²⁸Be Gln.In one embodiment, X ³³Be Asp.In one embodiment, X ³³Be Glu.In one embodiment, at least one is independently selected from X ⁵, X ⁷, X ⁸, X ⁹, X ¹⁰, X ¹¹, X ¹², X ¹³, X ¹⁴, X ¹⁵, X ¹⁶, X ¹⁷, X ¹⁸, X ²⁰, X ²¹, X ²⁴, X ²⁸And X ³³Amino acid be Lys.In one embodiment, independently be selected from X ⁵, X ⁷, X ⁸, X ⁹, X ¹⁰, X ¹¹, X ¹², X ¹³, X ¹⁴, X ¹⁵, X ¹⁶, X ¹⁷, X ¹⁸, X ²⁰, X ²¹, X ²⁴, X ²⁸And X ³³Amino acid be Lys.In one embodiment, amino acid X ⁵Be Lys.In one embodiment, amino acid X ⁷Be Lys.In one embodiment, amino acid X ⁸Be Lys.In one embodiment, amino acid X ⁹Be Lys.In one embodiment, amino acid X ¹⁰Be Lys.In one embodiment, amino acid X ¹¹Be Lys.In one embodiment, amino acid X ¹²Be Lys.In one embodiment, amino acid X ¹³Be Lys.In one embodiment, amino acid X ¹⁴Be Lys.In one embodiment, amino acid X ¹⁵Be Lys.In one embodiment, amino acid X ¹⁶Be Lys.In one embodiment, amino acid X ¹⁷Be Lys.In one embodiment, amino acid X ¹⁸Be Lys.In one embodiment, amino acid X ²⁰Be Lys.In one embodiment, amino acid X ²¹Be Lys.In one embodiment, amino acid X ²⁴Be Lys.In one embodiment, amino acid X ²⁸Be Lys.In one embodiment, amino acid X ³⁰Be Lys.In one embodiment, amino acid X ³⁰Be Arg.In one embodiment, amino acid X ³³Be Lys.

In one embodiment, GLP-2 peptide of the present invention is the GLP-2 peptide, sum 5 amino-acid residues nearly wherein, and as 4 amino-acid residues, 3 amino-acid residues, 2 amino-acid residues or 1 amino-acid residue are exchanged with arbitrary a-amino acid residue.

In one embodiment, GLP-2 peptide of the present invention is selected from: GLP-2 (1-33), A2G-GLP-2 (1-33), K30R-GLP-2 (1-33); S5K-GLP-2 (1-33); S7K-GLP-2 (1-33); D8K-GLP-2 (1-33); E9K-GLP-2 (1-33); M10K-GLP-2 (1-33); N11K-GLP-2 (1-33); T12K-GLP-2 (1-33); I13K-GLP-2 (1-33); L14K-GLP-2 (1-33); D15K-GLP-2 (1-33); N16K-GLP-2 (1-33); L17K-GLP-2 (1-33); A18K-GLP-2 (1-33); D21K-GLP-2 (1-33); N24K-GLP-2 (1-33); Q28K-GLP-2 (1-33); S5K/K30R-GLP-2 (1-33); S7K/K30R-GLP-2 (1-33); D8K/K30R-GLP-2 (1-33); E9K/K30R-GLP-2 (1-33); M10K/K30R-GLP-2 (1-33); N11K/K30R-GLP-2 (1-33); T12K/K30R-GLP-2 (1-33); I13K/K30R-GLP-2 (1-33); L14K/K30R-GLP-2 (1-33); D15K/K30R-GLP-2 (1-33); N16K/K30R-GLP-2 (1-33); L17K/K30R-GLP-2 (1-33); A18K/K30R-GLP-2 (1-33); D21K/K30R-GLP-2 (1-33); N24K/K30R-GLP-2 (1-33); Q28K/K30R-GLP-2 (1-33); K30R/D33K-GLP-2 (1-33); D3E/K30R/D33E-GLP-2 (1-33); D3E/S5K/K30R/D33E-GLP-2 (1-33); D3E/S7K/K30R/D33E-GLP-2 (1-33); D3E/D8K/K30R/D33E-GLP-2 (1-33); D3E/E9K/K30R/D33E-GLP-2 (1-33); D3E/M10K/K30R/D33E-GLP-2 (1-33); D3E/N11K/K30R/D33E-GLP-2 (1-33); D3E/T12K/K30R/D33E-GLP-2 (1-33); D3E/I13K/K30R/D33E-GLP-2 (1-33); D3E/L14K/K30R/D33E-GLP-2 (1-33); D3E/D15K/K30R/D33E-GLP-2 (1-33); D3E/N16K/K30R/D33E-GLP-2 (1-33); D3E/L17K/K30R/D33E-GLP-2 (1-33); D3E/A18K/K30R/D33E-GLP-2 (1-33); D3E/D21K/K30R/D33E-GLP-2 (1-33); D3E/N24K/K30R/D33E-GLP-2 (1-33); And D3E/Q28K/K30R/D33E-GLP-2 (1-33).

In one embodiment, GLP-2 receptor stimulant of the present invention is selected from: GLP-2 (1-33), A2G-GLP-2 (1-33), K30R-GLP-2 (1-33); S5K-GLP-2 (1-33); S7K-GLP-2 (1-33); D8K-GLP-2 (1-33); E9K-GLP-2 (1-33); M10K-GLP-2 (1-33); N11K-GLP-2 (1-33); T12K-GLP-2 (1-33); I13K-GLP-2 (1-33); L14K-GLP-2 (1-33); D15K-GLP-2 (1-33); N16K-GLP-2 (1-33); L17K-GLP-2 (1-33); A18K-GLP-2 (1-33); D21K-GLP-2 (1-33); N24K-GLP-2 (1-33); Q28K-GLP-2 (1-33); S5K/K30R-GLP-2 (1-33); S7K/K30R-GLP-2 (1-33); D8K/K30R-GLP-2 (1-33); E9K/K30R-GLP-2 (1-33); M10K/K30R-GLP-2 (1-33); N11K/K30R-GLP-2 (1-33); T12K/K30R-GLP-2 (1-33); I13K/K30R-GLP-2 (1-33); L14K/K30R-GLP-2 (1-33); D15K/K30R-GLP-2 (1-33); N16K/K30R-GLP-2 (1-33); L17K/K30R-GLP-2 (1-33); A18K/K30R-GLP-2 (1-33); D21K/K30R-GLP-2 (1-33); N24K/K30R-GLP-2 (1-33); Q28K/K30R-GLP-2 (1-33); K30R/D33K-GLP-2 (1-33); D3E/K30R/D33E-GLP-2 (1-33); D3E/S5K/K30R/D33E-GLP-2 (1-33); D3E/S7K/K30R/D33E-GLP-2 (1-33); D3E/D8K/K30R/D33E-GLP-2 (1-33); D3E/E9K/K30R/D33E-GLP-2 (1-33); D3E/M10K/K30R/D33E-GLP-2 (1-33); D3E/N11K/K30R/D33E-GLP-2 (1-33); D3E/T12K/K30R/D33E-GLP-2 (1-33); D3E/I13K/K30R/D33E-GLP-2 (1-33); D3E/L14K/K30R/D33E-GLP-2 (1-33); D3E/D15K/K30R/D33E-GLP-2 (1-33); D3E/N16K/K30R/D33E-GLP-2 (1-33); D3E/L17K/K30R/D33E-GLP-2 (1-33); D3E/A18K/K30R/D33E-GLP-2 (1-33); D3E/D21K/K30R/D33E-GLP-2 (1-33); D3E/N24K/K30R/D33E-GLP-2 (1-33); And D3E/Q28K/K30R/D33E-GLP-2 (1-33).

In one embodiment, GLP-2 receptor stimulant of the present invention is the GLP-2 peptide.

In one embodiment, GLP-2 receptor stimulant of the present invention is the GLP-2 derivative.

In one embodiment, GLP-2 derivative of the present invention comprises the GLP-2 peptide, and wherein the GLP-2 peptide is suc as formula II

In one embodiment, GLP-2 derivative of the present invention only has a lipophilic substituent that is connected with the GLP-2 peptide.

In one embodiment, lipophilic substituent of the present invention contains 4-40 carbon atom.

In one embodiment, lipophilic substituent of the present invention contains 8-25 carbon atom.

In one embodiment, lipophilic substituent of the present invention contains 12-20 carbon atom.

In one embodiment, lipophilic substituent of the present invention is connected with amino-acid residue by this way, makes the carboxyl of lipophilic substituent and the amino of amino-acid residue form amido linkage.

In one embodiment, lipophilic substituent of the present invention is connected in the Lys residue.

In one embodiment, lipophilic substituent of the present invention is connected with amino-acid residue by this way, makes the amino of lipophilic substituent and the carboxyl of amino-acid residue form amido linkage.

In one embodiment, lipophilic substituent of the present invention is connected with the GLP-2 peptide by the mode of spacer.

In one embodiment, spacer of the present invention is unbranched alkyl alpha, omega-dicarboxylic acid base, and it has 1-7 methylene radical, and as two methylene radical, spacer forms bridge between the amino of the amino of GLP-2 peptide and lipophilic substituent.

In one embodiment, spacer of the present invention is amino-acid residue or the dipeptides except the Cys residue.The example of suitable interval base comprises that (Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, succsinic acid, Lys, Glu or Asp, or dipeptides are as Gly-Lys.When spacer was succsinic acid, a carboxyl of succsinic acid can form amido linkage with the amino of amino-acid residue, and another carboxyl can form amido linkage with the amino of lipophilic substituent.When spacer is Lys, when Glu or Asp, carboxyl wherein can form amido linkage with the amino of amino-acid residue, and amino wherein can form amido linkage with the carboxyl of lipophilic substituent.When Lys when the spacer, can between the epsilon-amino of Lys and lipophilic substituent, insert an extra spacer sometimes.In one embodiment, described extra spacer is a succsinic acid, the epsilon-amino of itself and Lys and and be present between the amino of lipophilic substituent and form amido linkage.In another embodiment, described extra spacer is Glu or Asp, and the epsilon-amino of itself and Lys forms amido linkage, and (is that lipophilic substituent is N with being present in lipophilic substituent ^ε-acidylate lysine residue) forms another amido linkage between the carboxyl.

In one embodiment, spacer of the present invention be selected from (Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, Lys, Asp, Glu, contain Asp dipeptides, contain the dipeptides of Glu or contain the dipeptides of Lys.In one embodiment, spacer of the present invention is (a Beta-alanine.In one embodiment, spacer of the present invention is γ-An Jidingsuan (GABA).In one embodiment, spacer of the present invention is a gamma-glutamic acid.

In one embodiment, the carboxyl of parent GLP-2 peptide of the present invention and the amino of spacer form amido linkage, and the amino of amino acid whose carboxyl or dipeptides spacer and lipophilic substituent forms amido linkage.

In one embodiment, the amino of parent GLP-2 peptide of the present invention and the carboxyl of spacer form amido linkage, and the amino of spacer and the carboxyl of lipophilic substituent form amido linkage.

In one embodiment, lipophilic substituent of the present invention contains partially or completely hydrogenant cyclopentano phenanthrene (cyclopentanophenathrene) skeleton.

In one embodiment, lipophilic substituent of the present invention is straight chain or ramose alkyl.In one embodiment, lipophilic substituent of the present invention is the acyl group of straight chain or branched fatty acid.

In one embodiment, the acyl group of lipophilic substituent of the present invention is selected from CH ₃(CH ₂) _nCO-, wherein n is 4-38, as CH ₃(CH ₂) ₆CO-, CH ₃(CH ₂) ₈CO-, CH ₃(CH ₂) ₁₀CO-, CH ₃(CH ₂) ₁₂CO-, CH ₃(CH ₂) ₁₄CO-, CH ₃(CH ₂) ₁₆CO-, CH ₃(CH ₂) ₁₈CO-, CH ₃(CH ₂) ₂₀CO-and CH ₃(CH ₂) ₂₂CO-.

In one embodiment, lipophilic substituent of the present invention is the acyl group of straight chain or ramose alkyl alpha, omega-dicarboxylic acid.

In one embodiment, the acyl group of lipophilic substituent of the present invention is selected from HOOC (CH ₂) _mCO-, wherein m is 4-38, as HOOC (CH ₂) ₁₄CO-, HOOC (CH ₂) ₁₆CO-, HOOC (CH ₂) ₁₈CO-, HOOC (CH ₂) ₂₀CO-and HOOC (CH ₂) ₂₂CO-.

In one embodiment, lipophilic substituent of the present invention is following formula group CH ₃(CH ₂) _p((CH ₂) _qCOOH) CHNH-CO (CH ₂) ₂CO-, wherein p and q are integers, p+q is the integer of 8-40, as from 12-35.

In one embodiment, lipophilic substituent of the present invention is following formula group CH ₃(CH ₂) _rCO-NHCH (COOH) (CH ₂) ₂CO-, wherein r is the integer of 10-24.

In one embodiment, lipophilic substituent of the present invention is following formula group CH ₃(CH ₂) _sCO-NHCH ((CH ₂) ₂COOH) CO-, wherein s is the integer of 8-24.

In one embodiment, lipophilic substituent of the present invention is following formula group COOH (CH ₂) _tCO-wherein t is the integer of 8-24.

In one embodiment, lipophilic substituent of the present invention is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) _uCH ₃, wherein u is the integer of 8-18.

In one embodiment, lipophilic substituent of the present invention is following formula group-NHCH (COOH) (CH ₂) ₄NH-COCH ((CH ₂) ₂COOH) NH-CO (CH ₂) _wCH ₃, wherein w is the integer of 10-16.

In one embodiment, lipophilic substituent of the present invention is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NH-CO (CH ₂) _xCH ₃, wherein x is the integer of 10-16.

In one embodiment, lipophilic substituent of the present invention is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NHCO (CH ₂) _yCH ₃, wherein y is 0 or the integer of 1-22.

In one embodiment, lipophilic substituent of the present invention is a N-stone courage acyl group (Lithocholoyl).

In one embodiment, lipophilic substituent of the present invention is a N-courage acyl group.

In one embodiment, GLP-2 derivative of the present invention has a lipophilic substituent.In one embodiment, GLP-2 derivative of the present invention has two lipophilic substituents.In one embodiment, GLP-2 derivative of the present invention has three lipophilic substituents.In one embodiment, GLP-2 derivative of the present invention has four lipophilic substituents.

In one embodiment, GLP-2 derivative of the present invention is selected from

S5K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S5K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D3E/S5K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/S7K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D8K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/E9K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/M10K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N11K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/T12K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/I13K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L14K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D15K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N16K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(capryloyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(decane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(undecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(lauroyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tridecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tetradecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(pentadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(heptadecane acyl group amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(octadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonadecane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(eicosane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(heptadecane acyl group amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(decane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/A18K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D21K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N24K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33).

In yet another embodiment, the present invention relates to the GLP-2 derivative, wherein the C-terminal amino acid residue is the acid amides form.

In yet another embodiment, the present invention relates to the GLP-2 derivative, it has can electronegative lipophilic substituent.In one embodiment, can electronegative group be hydroxy-acid group.

Parent GLP-2 peptide can prepare by the following method, described method is included in and cultivates the host cell that contains dna sequence dna in the suitable nutritional medium under the condition that allows the GLP-2 peptide to express, described dna sequence encoding GLP-2 peptide, and the GLP-2 peptide that from described nutrient solution, reclaims gained.

The substratum that is used for culturing cell can be arbitrary conventional substratum that is suitable for the host cell growth, as contains the minimum or perfect medium of suitable complementary element.Suitable medium is commercially available, or can according to disclosed formulation (as, the catalogue of American type culture collection, American Type Culture Collection).Type according to target GLP-2 peptide, GLP-2 peptide by cell preparation can reclaim from substratum by conventional steps, comprise by centrifugal or filtration and from substratum, divide host cell, by salt (for example ammonium sulfate) precipitating proteins composition from supernatant liquor or filtrate, by multiple chromatographic step purifying, for example ion exchange chromatography, gel permeation chromatography, affinity chromatography etc.

The dna sequence dna of coding parent GLP-2 peptide can be suitable be genome or cDNA source, for example obtain by the following method: prepare genome or eDNA library, the secundum legem technology is hybridized with synthetic oligonucleotide probe, the dna sequence dna of screening encoding part or complete GLP-2 peptide (is seen, as Sambrook, J, Fritsch, EF and Maniatis, T, molecular cloning: laboratory manual, Cold Spring Harb or Laboratory Press, New York, 1989).The dna sequence dna of coding GLP-2 peptide also can be by the synthetic property preparation of existing standard method, for example, Beaucage and Caruthers, Tetrahedron Letters 22 (1981), people such as the phosphamide of 1859-1869g (phosphoamidite) method or Matthes, EMBO Journal 3 (1984) 801-805, the method dna sequence dna of describing also can use specific primer by polymerase chain reaction, for example US 4,683,202 or people such as Saiki, Science 239 (1988), obtain described in the 487-491.

Dna sequence dna can insert in the carrier of being convenient to recombinant DNA method arbitrarily, and host cell to be imported is usually depended in the selection of carrier.Therefore, carrier can be the self-replicating carrier, and promptly described carrier exists as the outer unit of karyomit(e).It duplicates and is independent of THE REPLICATION OF CHROMOSOME, for example plasmid.Perhaps, carrier can be integrated into the host cell gene group when importing host cell, and duplicates with its karyomit(e) of integrating.

Carrier is expression vector preferably, and the dna sequence dna of the GLP-2 peptide of wherein encoding and DNA transcribe other required sections, as promotor, effectively connects.Promotor shows any DNA sequence of transcriptional activity in can being in the selected host cell, and can derived from the gene of host cell homology or allogenic coded protein.Being used for instructing in the multiple host cell example of the suitable promotor that code book invention GLP-2 peptide transcribes is that this area is known, referring to, people such as Sambrook for example, the source is the same.

As needs, the dna sequence dna of coding GLP-2 peptide also with suitable terminator, polyadenylation signal, transcribe enhancement sequences and effectively be connected with the translation enhancement sequences.Recombinant vectors of the present invention can further comprise makes the dna sequence dna that duplicates in the target host cell in the carrier.

Carrier also can contain selective marker, for example, and the gene of the product of complementary host cell defective, or give the gene of drug resistance, for example penbritin, kantlex, tsiklomitsin, paraxin, Xin Meisu, Totomycin or methotrexate.

For parent GLP-2 peptide of the present invention being imported the Secretory Pathway of host cell, can in recombinant vectors, provide secretory signal sequence (being also referred to as leader, preceding former sequence or presequence).Secretory signal sequence is connected in correct reading frame with the dna sequence dna of coding GLP-2 peptide.Secretory signal sequence generally is positioned at 5 ' end of the dna sequence dna of coding GLP-2 peptide.Secretory signal sequence can be natural relevant with the GLP-2 peptide, maybe can come the proteinic gene of other excretory of own coding.

Be used to connect the dna sequence dna of code book invention GLP-2 peptide method, start neutralization optional terminator and/or secretory signal sequence, and be inserted into the method that contains the suitable carrier that duplicates required information be those of ordinary skills know (referring to.For example, people such as Sambrook, the source is the same).

To the host cell that wherein imports dna sequence dna or recombinant vectors can be the cell that can produce GLP-2 peptide of the present invention arbitrarily, comprises that bacterium, yeast, fungi close higher eucaryotic cells.The example of the host cell of suitable and use known for this area includes but not limited to intestinal bacteria, yeast saccharomyces cerevisiae (Saccharomyces cerevisiae) or Mammals BHK or Chinese hamster ovary celI system.

GLP-2 derivative of the present invention can utilize currently known methods that lipophilic substituent is imported parent GLP-2 peptide and produce, and for example sees that WO 95/07931, and its content is incorporated herein by reference herein in full.

The N of lysine residue ^ε-acidylate can be carried out as the activatory acid amides (acid amides that has benzotriazole for example) of acylating agent by utilizing acyl group that band imports.Acidylate is carried out in polar solvent in the presence of alkali.

Pharmaceutical composition

The pharmaceutical composition that contains with good grounds GLP-2 derivative of the present invention can parenteral route be applied to the patient of the described treatment of needs.Parenteral route is used can be by subcutaneous, intramuscular or the intravenously mode with syringe, and the optional mode with pen-type injector is implemented.Perhaps, parenteral route is used and can be implemented by the mode of infusion pump.Another selection is a kind ofly can be the composition that is used for the GLP-2 derivative used with nose or lung's Sprayable of pulvis or liquid.One select, GLP-2 derivative of the present invention also can transdermal administration again, for example from paster, and optional plasma electric osmose paster, or saturating mucosal administration, for example, through cheek.

The pharmaceutical composition that contains GLP-2 derivative of the present invention can prepare by routine techniques, for example as Remington ' s Pharmaceutical Sciences, 1985 or at Remington:The Science and Practice of Pharmacy, the 19th edition, described in 1995.

Therefore, the Injectable composition of GLP-2 derivative of the present invention can utilize the routine techniques preparation of pharmaceutical industry, and it comprises dissolving and mixes the composition of the end product that is suitable for producing expectation.

Therefore, according to a method, the GLP-2 derivative is dissolved in a certain amount of water, the amount of described water is less than the final volume of composition to be prepared.As required isotonic agent, sanitas and buffer reagent are added,, use acid (for example hydrochloric acid) or use the pH value of alkali (for example sodium hydroxide) regulator solution according to need as needs.At last, the constituent concentration of hope adjusted to the volume of solution by water.

The example of isotonic agent is sodium-chlor, N.F,USP MANNITOL and glycerine.

The example of sanitas is phenol, meta-cresol, methyl p-hydroxybenzoate and phenylcarbinol.

The example of suitable reducing is sodium acetate and sodium phosphate.

Except mentioned component, the solution that contains GLP-2 derivative of the present invention also can contain tensio-active agent, with solvability and/or the stability of improving derivative.

The composition that is used for the GLP-2 nasal administration can be for example according to preparation described in European patent 272097 (toNovo Nordisk A/S) or the WO 93/18785.

GLP-2 derivative of the present invention can be used for treating multiple disease.Concrete GLP-2 derivative to be used and the multiple factor that depends on disease to be treated and comprise following factor for arbitrary patient's preferred dosage level: the effect of used concrete peptide derivant, patient's age, body weight, physical activity and diet, also depend on the combination that other may medicine and the severity of disease.Suggestion is determined by those of ordinary skills according to the similar fashion shown in known parent GLP-2 peptide at the dosage of the GLP-2 derivative of the present invention to be administered of each individual patient.

Can be according to for example pharmacological property of the content test compound of the present invention described in our International Patent Application PCT/DK97/00086, described content is this complete being incorporated herein by reference.

Aspect another, the present invention relates to the pharmaceutical preparation of a kind of GLP-2 of containing compound and buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

Aspect another, the present invention relates to a kind of aqueous solution of the GLP-2 of containing compound and the pharmaceutical preparation of buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

Aspect another, the present invention relates to the method for the stable GLP-2 compound medicine preparation of a kind of prepared product Neo-Confucianism, comprise a kind of GLP-2 of containing compound of preparation, pharmaceutical preparation with buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

Aspect another, the present invention relates to the method for the stable GLP-2 compound medicine preparation of a kind of prepared product Neo-Confucianism, comprise the aqueous solution for preparing a kind of GLP-2 of containing compound, pharmaceutical preparation with buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

Aspect another, the present invention relates to the method for the stable GLP-2 compound medicine preparation of a kind of prepared product Neo-Confucianism, comprise a kind of GLP-2 of containing compound of preparation, the pharmaceutical preparation of water and buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

Aspect another, the present invention relates to a kind of method for the treatment of intestines depletion or causing other disease of nutrition malabsorption in the intestines, comprise that the patient to needs uses the aqueous solution that contains the GLP-2 compound, pharmaceutical preparation with the treatment significant quantity of damping fluid, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.In one embodiment, intestines are depleted or cause that other disease of nutrition malabsorption is selected from the intestines: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia (the special property sent out) syndrome, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

Term " treatment significant quantity " is the effective dose of being determined by qualified practitioner, the required dosage of replying of the titratable realization of described personnel.The factor that dosage is considered comprise effect, bioavailability, expectation pharmacokinetics/pharmacodynamics curve, treatment condition (for example, diabetes, obesity, weight loss, stomach ulcer), patient's factor (for example: body weight, health, age etc.) of being correlated with, (for example existing of co-administered medicine, Regular Insulin), time of application or the known other factors of medicine practitioner.

In one embodiment, pharmaceutical preparation of the present invention is a kind of aqueous formulation, promptly contains the preparation of water.Described preparation generally is solution or suspension.In yet another embodiment, pharmaceutical preparation of the present invention is a kind of aqueous solution.Term " aqueous formulation " is defined as and contains the preparation of 50%w/w water at least.Similarly, term " aqueous solution " is defined as the solution that contains 50%w/w water.Term " suspension " is defined as and contains the suspension of 50%w/w water at least.

In another embodiment, pharmaceutical preparation is a kind of freeze-drying (freeze-dried) preparation, and physician or patient are before use to wherein adding solvent.

Pharmaceutical preparation is a kind of freeze-drying (lyophilised) preparation in another embodiment, and physician or patient are before use to wherein adding solvent.

The pharmaceutical composition that contains with good grounds GLP-2 compound of the present invention can parenteral route be applied to the patient of the described treatment of needs.Parenteral route is used can be by subcutaneous, intramuscular or the intravenously mode with syringe, and the optional mode with pen-type injector is implemented.Perhaps, parenteral route is used and can be implemented by the mode of infusion pump.Another selection is a kind ofly can be the GLP-2 compound compositions used with nose or lung's Sprayable of being used for of pulvis or liquid.One select, GLP-2 compound of the present invention also can transdermal administration again, for example from paster, and optional plasma electric osmose paster, or saturating mucosal administration, for example, through cheek.

When it shows muddiness, find described pharmaceutical preparation physics instability.Under 5 ℃, but stable on the part preparation physics of the present invention above 11 months, and stable above 22 months.

The physics stability of preparation is assessed by visualize, and assesses opacity store preparation in the glass medicine bottle of filling with top under differing temps after in a plurality of time bars.The visualize of preparation focuses under dark background clearly to be carried out in the light.The muddiness of the preparation range estimation score sign of distinguishing from the opacity of 0-3 (the range estimation score that does not show muddy preparation correspondence is 0, and daylight shows that down the range estimation score of the preparation correspondence of the visible muddiness of naked eyes is 3).When daylight shows that down naked eyes are visible when muddy, it is unsettled according to protein aggregation preparation to be classified as physics.

In one embodiment, the pharmaceutical composition that comprises the GLP-2 compound of the present invention is physically stablized above 12 weeks and above 15 months under 5 ℃ by visual inspection.

In another embodiment, the pharmaceutical composition that comprises the GLP-2 compound of the present invention is physically stablized above 12 weeks under 25 ℃ by visual inspection.

In yet another embodiment, the pharmaceutical composition that comprises the GLP-2 compound of the present invention is physically stablized above 12 weeks under 37 ℃ by visual inspection.

In yet another embodiment, the pH scope that has of preparation of the present invention is 7.6-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 7.7-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 7.8-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 7.9-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.0-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.0-9.5.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.0-9.0.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.0-8.5.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.5-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.5-9.5.In yet another embodiment, the pH scope that has of preparation of the present invention is 8.5-9.0.In yet another embodiment, the pH scope that has of preparation of the present invention is 9.0-10.In yet another embodiment, the pH scope that has of preparation of the present invention is 9.0-9.5.In yet another embodiment, the pH scope that has of preparation of the present invention is 9.5-10.

In yet another embodiment, buffer reagent of the present invention is selected from sodium acetate, sodium bicarbonate, citric acid, Histidine, glycine, Methionin, arginine, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, sodium phosphate and tris (hydroxymethyl)-aminomethane or its mixture.Each described concrete buffer reagent all constitutes alternate embodiment of the present invention.In yet another embodiment, buffer reagent of the present invention is glycylglycine, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, sodium phosphate or its mixture.

An object of the present invention is to provide a kind of pharmaceutical composition with GLP-2 compound dissolution degree of increase.

In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1mg/ml-80mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 1mg/ml-80mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1mg/ml-50mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 1mg/ml-50mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1mg/ml-20mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 1mg/ml-20mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1mg/ml-10mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 1mg/ml-10mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1-5mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 1-5mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.1-0.5mg/ml.In yet another embodiment, the concentration of GLP-2 existence of the present invention is 0.6-1mg/ml.Each concrete concentration all constitutes alternate embodiment of the present invention.

In yet another embodiment, preparation of the present invention also contains the acceptable sanitas of pharmacy.In yet another embodiment, sanitas of the present invention is selected from phenol, meta-cresol, methyl p-hydroxybenzoate, propylparaben, 2-Phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethyl alcohol, benzylalcohol, butylene-chlorohydrin and Thiomersalate or its mixture.Each described concrete sanitas all constitutes alternate embodiment of the present invention.In the preferred embodiment of the invention, sanitas of the present invention is phenol or meta-cresol.

In yet another embodiment, the concentration of sanitas existence of the present invention is 0.1mg/ml-20mg/ml.In yet another embodiment, the concentration of sanitas existence of the present invention is 0.1mg/ml-5mg/ml.In yet another embodiment, the concentration of sanitas existence of the present invention is 5mg/ml-10mg/ml.In yet another embodiment, the concentration of sanitas existence of the present invention is 10mg/ml-20mg/ml.Each described concrete concentration range all constitutes alternate embodiment of the present invention.

In pharmaceutical composition, use sanitas known as those of ordinary skills.For example, referring to Remington:The Science and Practice of Pharmacy, the 19th edition, 1995.

In yet another embodiment, preparation of the present invention also contains isotonic agent.In yet another embodiment, isotonic agent of the present invention is selected from: salt (for example, sodium-chlor), and polyvalent alcohol is (for example, propylene glycol, Xylitol, N.F,USP MANNITOL, sorbyl alcohol or glycerine), monose (for example, glucose or maltose), disaccharide is (for example, sucrose), amino acid (for example, L-glycine, the L-Histidine, arginine, Methionin, Isoleucine, aspartic acid, tryptophane, Threonine), polyoxyethylene glycol (for example, PEG400) or its mixture.In yet another embodiment, isotonic agent of the present invention is selected from sodium-chlor, glycerine, N.F,USP MANNITOL, glucose, sucrose, L-glycine, L-Histidine, arginine, Methionin or its mixture.Each described concrete isotonic agent all constitutes alternate embodiment of the present invention.In one embodiment, isotonic agent of the present invention is a N.F,USP MANNITOL.In one embodiment, isotonic agent of the present invention is a glycerine.In one embodiment, isotonic agent of the present invention is a sucrose.

In yet another embodiment, the concentration of isotonic agent existence of the present invention is 1mg/ml-50mg/ml.In yet another embodiment, the concentration of isotonic agent existence of the present invention is 1mg/ml-7mg/ml.In yet another embodiment, the concentration of isotonic agent existence of the present invention is 8mg/ml-16mg/ml.In yet another embodiment, the concentration of isotonic agent existence of the present invention is 17mg/ml-50mg/ml.Each concrete concentration range all constitutes alternate embodiment of the present invention.

In pharmaceutical composition, use isotonic agent known as those of ordinary skills.For example, referring to Remington:The Science and Practice of Pharmacy, the 19th edition, 1995.

In yet another embodiment, preparation of the present invention also comprises intercalating agent.In yet another embodiment, intercalating agent of the present invention is selected from the salt of ethylenediamine tetraacetic acid (EDTA) (EDTA), citric acid and aspartic acid, and composition thereof.In the described concrete intercalating agent each all constitutes alternate embodiment of the present invention.

In yet another embodiment, the concentration of intercalating agent existence of the present invention is 0.1mg/ml-5mg/ml.In yet another embodiment, the concentration of intercalating agent existence of the present invention is 0.1mg/ml-2mg/ml.In yet another embodiment, the concentration of intercalating agent existence of the present invention is 2mg/ml-5mg/ml.

In pharmaceutical composition, use intercalating agent known as those of ordinary skills.For example, for example, referring to Remington:The Science and Practice of Pharmacy, the 19th edition, 1995.

In yet another embodiment, also contain stablizer in the preparation of the present invention, it is selected from high-molecular weight polymer or low-molecular weight compound.In yet another embodiment, stablizer of the present invention is selected from polyoxyethylene glycol (for example, PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxymethyl cellulose, different salt (for example, sodium-chlor), the L-glycine, the L-Histidine, imidazoles, arginine, Methionin, Isoleucine, aspartic acid, tryptophane, Threonine and composition thereof.Each described concrete stablizer constitutes alternate embodiment of the present invention.In the preferred embodiment of the invention, stablizer of the present invention is selected from the L-Histidine, imidazoles and arginine.

In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 0.1mg/ml-50mg/ml.In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 0.1mg/ml-5mg/ml.In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 5mg/ml-10mg/ml.In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 10mg/ml-20mg/ml.In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 20mg/ml-30mg/ml.In yet another embodiment, the concentration of high-molecular weight polymer existence of the present invention is 30mg/ml-50mg/ml.

In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 0.1mg/ml-50mg/ml.In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 0.1mg/ml-5mg/ml.In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 5mg/ml-10mg/ml.In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 10mg/ml-20mg/ml.In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 20mg/ml-30mg/ml.In yet another embodiment, the concentration of low-molecular weight compound existence of the present invention is 30mg/ml-50mg/ml.

The use of stablizer is known for those of ordinary skills in the pharmaceutical composition.For example, referring to Remington:The Science and Practice of Pharmacy, the 19th edition, 1995.

In yet another embodiment, preparation of the present invention also contains tensio-active agent.In yet another embodiment; tensio-active agent of the present invention is selected from stain remover; ethoxylated castor oil; polyglycolyzed glyceride; acetylated monoglyceride; dehydration Sorbic Acid fatty acid ester; poloxamers; as 188 and 407; the polyoxyethylene sorbitan fatty acid ester; polyoxyethylene deriv is (as alkylation and alkoxy derivative (tween; for example; Tween-20 or Tween-80); direactive glyceride or its ethoxylated derivative; two glyceryl ester or its polyoxyethylene deriv; glycerine; the cholic acid or derivatives thereof; Yelkin TTS; alcohols and phospholipid; glyceryl phosphatide (Yelkin TTS; kephalin; phosphatidylserine); glyceroglycolipid (semi-lactosi pyranoside); sphingophospholipid (sphingophospholipid) and sphingoglycolipid (ceramide; ganglioside); DSS (Docusate Sodium; CAS registration number [577-11-7]); dioctyl calcium sulfosuccinate; CAS registration number [128-49-4]); docusate potassium; CAS registration number [7491-09-0]); SDS (sodium lauryl sulphate or Sodium Lauryl Sulphate BP/USP); two palmityl phosphatidic acids; Sodium octoate; bile acide and salt thereof and glycine or taurine conjugate; ursodesoxycholic acid; Sodium cholic acid; sodium deoxycholate; Taurocholic acid sodium salt; Sodium glycocholate; N-hexadecyl-N; N-dimethyl-3-amino-1-propanesulfonic acid ester (salt); negatively charged ion (alkyl-aryl-sulfonic acid ester (salt) schedule of rates surface-active agent; palmityl-hemolytic phosphatidyl-L-Serine; lysophospholipid (for example; thanomin; choline; the 1-acyl group of Serine or Threonine-sn-glyceryl-3-phosphoric acid ester); alkyl; alkoxyl group (alkyl ester); the alkoxyl group of hemolytic phosphatidyl and phosphatidylcholine (alkyl ethyl) derivative; for example; the lauroyl of following material and mnyristoyl radical derivative: lyso-phosphatidylcholine; dipalmitoyl phosphatidylcholine; modification with polar head group; it is a choline; thanomin; phosphatidic acid; Serine; Threonine; glycerine; inositol; and the DODAC of positively charged; DOTMA; DCP; BISHOP; phosphatidylserine and hemolytic phosphatidyl Threonine; zwitterionics (for example; N-alkyl-N; N-dimethylamino-1-propanesulfonic acid ester (salt); 3-courage acid amides-1-propyl-dimethyl amino-1-propanesulfonic acid ester (salt); the lauryl phosphorylcholine; the myristyl lyso-phosphatidylcholine; hen ovum lysolecithin); cats product (quaternary ammonium salt and base) (for example; CETRIMIDE POWDER; cetylpyridinium chloride); nonionogenic tenside; polyoxyethylene/polyoxypropylene block copolymers (Pluronics/Tetronics; Triton X-100; dodecyl β-D-glycopyranoside) or poly tensio-active agent (Tween-40; Tween-80; Brij-35); fusidic acid derivatives (for example; ox dihydro Sodium Fusidate etc.); longer chain fatty acid and salt thereof; C6-C12 (for example, oleic acid and sad); acylcarnitines and derivative thereof; Methionin; the N of arginine or Histidine ^α-acylated derivatives, or Methionin or arginic side chain acylated derivatives comprise Methionin, the N of the dipeptides of arbitrary combination of arginine or Histidine and neutrality or acidic amino acid ^α-acylated derivatives comprises the N of the tripeptides of neutral amino acids and two charged amino acid whose arbitrary combinations ^α-acylated derivatives, or tensio-active agent can be selected from imidazolidine derivatives or its mixture.Each described tensio-active agent all constitutes other embodiments of the present invention.

The use of tensio-active agent is known for those of ordinary skills in the pharmaceutical composition.For example, referring to Remington:The Science and Practice of Pharmacy, the 19th edition, 1995.

In one embodiment, as visual inspection, the pharmaceutical composition that comprises the GLP-2 derivative of the present invention is stablized above 12 weeks on 5 ℃ of following physics, and above 12 months.

In another embodiment, as visual inspection, the pharmaceutical composition that comprises the GLP-2 derivative of the present invention is stablized above 12 weeks on 25 ℃ of following physics.

In yet another embodiment, as visual inspection, the pharmaceutical composition that comprises the GLP-2 derivative of the present invention is stablized above 12 weeks on 37 ℃ of following physics.

In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-9.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-9.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-8.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-8.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.0-7.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.5-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.0-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.5-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 9.0-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 9.5-10.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.5-9.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.5-9.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.5-8.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 7.5-8.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.0-9.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.0-9.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.0-8.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.5-9.5.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 8.5-9.0.In yet another embodiment, the pH scope that has of the preparation of the GLP-2 of comprising derivative of the present invention is 9.0-9.5.

An object of the present invention is to provide the pharmaceutical composition of the GLP-2 derivative of solubleness with increase.

In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1mg/ml-80mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 1mg/ml-80mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1mg/ml-50mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 1mg/ml-50mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1mg/ml-20mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 1mg/ml-20mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1mg/ml-10mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 1mg/ml-10mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1-5mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 1-5mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.1-0.5mg/ml.In yet another embodiment, the concentration of GLP-2 derivative existence of the present invention is 0.6-1mg/ml.Each of described concrete concentration range all constitutes alternate embodiment of the present invention.

In the present invention, GLP-2 compound and GLP-2 derivative preferably to be lower than 1 μ M, for example, are lower than the affinity costant (K of 100nM _D) or render a service (EC ₅₀) and the GLP-2 receptors bind.Term " GLP-2 compound " comprises GLP-2 peptide and GLP-2 derivative.Also for example, WO 96/29342 for the suitable GLP-2 examples for compounds that can be used for preparation of the present invention, and WO 97/31943, and WO 98/08872, and WO 96/32414, and open among the WO 97/39031, it is hereby incorporated by.

Spendable candidate GLP-2 examples for compounds according to the present invention can be a GLP-2 analogue for example, as WO 96/32414, WO 97/39031, disclosed among the WO 98/03547, the GLP-2 derivative, as WO 96/29342, WO 97/31943, WO 98/08872 is disclosed, is hereby incorporated by.

In one embodiment, GLP-2 compound of the present invention is the GLP-2 derivative that comprises the GLP-2 peptide, wherein lipophilic substituent be connected with respect to being selected from of SEQ ID NO:1 aminoacid sequence as the one or more amino-acid residues of upper/lower positions: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position S5 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position S7 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position D8 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position E9 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position M10 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position N11 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position T12 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position I13 of SEQID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position L14 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position D15 of SEQ IDNO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position N16 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position L17 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position A18 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position D21 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position N24 of SEQ ID NO:1 aminoacid sequence.In one embodiment, lipophilic substituent is connected with amino-acid residue with respect to the position Q28 of SEQ ID NO:1 aminoacid sequence.Being to be understood that at the amino-acid residue with respect to the position of SEQ ID NO:1 can be arbitrary amino acid residue, is not only at the naturally occurring amino-acid residue in described position.In one embodiment, lipophilic substituent is connected with Methionin.

Aspect another, lipophilic substituent can be connected with the GLP-2 peptide by the spacer mode, makes the carboxyl of spacer and the amino of GLP-2 peptide form amido linkage.Spacer must contain at least two functional groups, and one is connected with the functional group of lipophilic substituent, and another functional group with parent GLP-2 peptide is connected.Term " spacer " is meant divalent group as used herein, and it contains at least two functional groups, and one is connected with the functional group of lipophilic substituent, and another functional group with the GLP-2 compound is connected.The example of suitable interval base is as succsinic acid, Methionin base, L-glutamic acid base, aspartic acid base, glycine base, Beta-alanine base and gamma-amino butyryl radicals or as the dipeptides of Gly-Lys, each all constitutes independent embodiment of the present invention.When spacer was succsinic acid, the amino of its carboxyl and amino-acid residue formed amido linkage, and the amino of other carboxyl wherein and lipophilic substituent forms amido linkage.When spacer was Methionin base, L-glutamic acid base, aspartic acid base, glycine base, Beta-alanine base or gamma-amino butyryl radicals, the amino of its carboxyl and amino-acid residue formed amido linkage, and its amino carboxyl with lipophilic substituent forms amido linkage.When Lys when the spacer, can between the epsilon-amino of Lys and lipophilic substituent, insert extra spacer sometimes.In a preferred embodiment, described extra spacer is a succsinic acid, the epsilon-amino of itself and Lys and form amido linkage with amino in the lipophilic substituent.In another embodiment preferred, described extra spacer is Glu or Asp, and the epsilon-amino of itself and Lys forms amido linkage, forms another amido linkage with the carboxyl that exists in the lipophilic substituent.That is, lipophilic substituent is N ^ε-acidylate lysine residue.In one embodiment, spacer is amino-acid residue (except Cys or Met) or dipeptides, as Gly-Lys.For the present invention, phrase " as the dipeptides of Gly-Lys " is meant any two the amino acid whose combinations except Cys or Met, and usually, dipeptides wherein C-terminal amino acid residue is Lys, His or Trp generally are Lys, and the-terminal amino acid residue is Ala, Arg, Asp, Asn, Gly, Glu, Gln, Ile, Leu, Val, Phe, Pro, Ser, Tyr, Thr, Lys, His and Trp.Typically, the amino of GLP-2 compound and amino-acid residue or or the carboxyl of dipeptides spacer form amido linkage, the amino of amino-acid residue or dipeptides spacer and the carboxyl of lipophilic substituent formation amido linkage.

In yet another embodiment, lipophilic substituent of the present invention has from 8-40 carbon atom.In yet another embodiment, lipophilic substituent of the present invention has from 10-24 carbon atom.In yet another embodiment, lipophilic substituent of the present invention has from 12-24 carbon atom.In yet another embodiment, lipophilic substituent of the present invention has from 12-18 carbon atom.In yet another embodiment, lipophilic substituent of the present invention has from 14-18 carbon atom.

In yet another embodiment, there is spacer of the present invention.In yet another embodiment, spacer of the present invention is selected from amino acid.In yet another embodiment, of the present invention, spacer is the amino-acid residue except Cys or Met.In another embodiment, spacer is the dipeptides as Gly-Lys.In yet another embodiment, spacer is selected from Methionin base, L-glutamic acid base, aspartic acid base, glycine base, Beta-alanine base and gamma-amino butyryl radicals, and each all constitutes the independent embodiment of the present invention.The general spacer that uses is L-glutamic acid base, amino butyryl radicals and Beta-alanine base (β-Ala).

In another embodiment, spacer is a ramose alkyl alpha, omega-dicarboxylic acid group not, has the 1-7 methylene radical, and its spacer forms bridge between the amino of the amino of parent's peptide and lipophilic substituent.Usually, spacer is a succsinic acid.

Lipophilic substituent contains the functional group that can be connected with one of functional group of following parent GLP-2 peptide ammino acid:

(a) amino that is connected with the alpha-carbon of-terminal amino acid,

(b) carboxyl that is connected with the alpha-carbon of C-end amino acid,

(c) epsilon-amino of arbitrary Lys residue,

(d) carboxyl of arbitrary Asp and Glu residue R group,

(e) arbitrary Tyr, the hydroxyl of Ser and Thr residue R group,

(f) arbitrary Trp, Asn, Gln, the amino of Arg and His residue R group, or

(g) sulfydryl of arbitrary Cys residue R group.

In yet another embodiment, lipophilic substituent of the present invention is connected with the carboxyl of Glu residue R group with arbitrary Asp.

In yet another embodiment, lipophilic substituent of the present invention is connected in the carboxyl that is connected with the alpha-carbon of C-end amino acid.

In yet another embodiment, lipophilic substituent of the present invention is connected in the epsilon-amino of arbitrary Lys residue.

Each lipophilic substituent contains the functional group that can be connected with the functional group of the amino of parent GLP-2 peptide.For example, lipophilic substituent can contain the carboxyl of the amino that can be connected in parent GLP-2 peptide by the mode of amido linkage.

In yet another embodiment, lipophilic substituent of the present invention contains the partially or completely luxuriant and rich with fragrance skeleton of hydrogenant cyclopentano.

In yet another embodiment, lipophilic substituent of the present invention is straight chain or ramose alkyl.

In yet another embodiment, lipophilic substituent of the present invention is the acyl group of straight chain or ramose lipid acid.

In yet another embodiment, lipophilic substituent of the present invention is the acyl group CH with following formula ₃(CH ₂) _nCO-, wherein n is the integer of 4-38.In yet another embodiment, n is the integer of 12-38.In yet another embodiment, lipophilic substituent is selected from following independent embodiment: CH ₃(CH ₂) ₁₂CO-, CH ₃(CH ₂) ₁₄CO-, CH ₃(CH ₂) ₁₆CO-, CH ₃(CH ₂) ₁₈CO-, CH ₃(CH ₂) ₂₀CO-and CH ₃(CH ₂) ₂₂CO-.In a specific embodiments, lipophilic substituent is a tetradecanoyl.In another embodiment, lipophilic substituent is a hexadecanoyl.

In another embodiment, lipophilic substituent of the present invention is the electronegative group as hydroxy-acid group.For example lipophilic substituent can be the acyl group of following formula straight chain or ramose alkyl alpha, omega-dicarboxylic acid: HOOC (CH ₂) _mCO-, wherein m is the integer of 4-38, the integer of preferred 12-38 is most preferred, is HOOC (CH ₂) ₁₄CO-, HOOC (CH ₂) ₁₆CO-, HOOC (CH ₂) ₁₈CO-, HOOC (CH ₂) ₂₀CO-or HOOC (CH ₂) ₂₂CO-.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH8.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1mg/ml EDTA/1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 4mg/ml Poloxamer 188 or 30mg/mlPEG 35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 4mg/ml Poloxamer 188 or 30mg/mlPEG 35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 4mg/ml Poloxamer 188 or 30mg/mlPEG 35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 4mg/ml Poloxamer 188 or 30mg/mlPEG35000, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.0

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycylglycine, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC, 17.0mg/ml N.F,USP MANNITOL; with 18mg/ml phenylcarbinol, pH7.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 4mg/ml Poloxamer 188 or 30mg/mlPEG 35000, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine and 7mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL and 5mg/ml phenol, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.0

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH8.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH8.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL, 10mg/ml sucrose and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL, 10mg/ml sucrose and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL, 10mg/ml sucrose and 5mg/ml phenol, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), glycine, 36.9mg/ml N.F,USP MANNITOL, 10mg/ml sucrose and 5mg/ml phenol, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 1mg/mlEDTA/1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 1mg/ml EDTA or 1.55mg/ml L-His, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 4mg/ml Poloxamer188 or 30mg/ml PEG35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 4mg/ml Poloxamer188 or 30mg/ml PEG35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 4mg/ml Poloxamer188 or 30mg/ml PEG35000, pH9.4.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); glycine; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; 5mg/ml phenol and 4mg/ml Poloxamer188 or 30mg/ml PEG35000, pH9.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH8.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.0

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.1.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33); Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 38.5mg/ml N.F,USP MANNITOL; 10mg/ml sucrose; and 3mg/ml meta-cresol or 1.5mg/ml phenol, pH7.0.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.8.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic/SODIUM PHOSPHATE, MONOBASIC; 17.0mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 18mg/ml phenylcarbinol, pH7.8.

Typically; the present invention relates to the pharmaceutical preparation formed by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic, 16.0mg/ml glycerine; 7mg/ml phenol and 1.55 mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose and 5mg/ml phenol, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 1mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 2mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 3mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 5mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation of forming by following aqueous solution: 7mg/mlL17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), Sodium phosphate dibasic; 36.9mg/ml N.F,USP MANNITOL; 10mg/ml sucrose, 5mg/ml phenol and 1.55mg/ml L-His, pH7.4.

Typically, the present invention relates to the pharmaceutical preparation be made up of aqueous solution, wherein the concentration that exists of Sodium phosphate dibasic is 8mM.

The present invention also further shows by following embodiment, but it is not intended to and limits the scope of the invention.Aforementioned disclosed feature and the following examples can constitute realization multi-form content of the present invention in mode alone or in combination.

Embodiment:

1.GLP-2 peptide, it contains the aminoacid sequence of formula I:

His-X2-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X1 6-X17-X18-Ala-Arg-X21-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Ar g-Ile-Thr-X33 (formula I)

Or its fragment; Wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser or Lys; X7 is Ser or Lys; X8 is Asp, Glu or Lys; X9 is Asp, Glu or Lys; X10 is Met, Lys, Leu, Ile or nor-leucine; X11 is Asn or Lys; X12 is Thr or Lys; X13 is Ile or Lys; X14 is Leu or Lys; X15 is Asp or Lys; X16 is Asn or Lys; X17 is Leu or Lys; X18 is Ala or Lys; X21 is Asp or Lys; X24 is Asn or Lys; X28 is Gln or Lys; X33 is Asp, Glu or Lys.

2. according to the GLP-2 peptide of embodiment 1, form by following aminoacid sequence

His-X2-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-Ala-X20-X21-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Arg-Ile-Thr-X33

Or its fragment; Wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser or Lys; X7 is Ser or Lys; X8 is Asp, Glu or Lys; X9 is Asp, Glu or Lys; X10 is Met, Lys, Leu, Ile or nor-leucine; X11 is Asn or Lys; X12 is Thr or Lys; X13 is Ile or Lys; X14 is Leu or Lys; X15 is Asp or Lys; X16 is Asn or Lys; X17 is Leu or Lys; X18 is Ala or Lys; X20 is Arg or Lys; X21 is Asp or Lys; X24 is Asn or Lys; X28 is Gln or Lys; X33 is Asp, Glu or Lys.

3. according to the GLP-2 peptide of

embodiment

1 or 2, wherein X2 is Ala.

4. according to the GLP-2 peptide of

embodiment

1 or 2, wherein X2 is Gly.

5. according to each GLP-2 peptide among the embodiment 1-4, wherein X3 is Asp.

6. according to each GLP-2 peptide among the embodiment 1-4, wherein X3 is Glu.

7. according to each GLP-2 peptide among the embodiment 1-6, wherein X ⁵Be Ser.

8. according to each GLP-2 peptide among the embodiment 1-7, wherein X ⁷Be Ser.

9. according to each GLP-2 peptide among the embodiment 1-8, wherein X ⁸Be Asp.

10. according to each GLP-2 peptide among the embodiment 1-8, wherein X ⁸Be Glu.

11. according to each GLP-2 peptide among the embodiment 1-10, wherein X ⁹Be Asp.

12. according to each GLP-2 peptide among the embodiment 1-10, wherein X ⁹Be Glu.

13. according to each GLP-2 peptide among the embodiment 1-12, wherein X ¹⁰Be selected from Met, Leu, Ile and nor-leucine.

14. according to each GLP-2 peptide among the embodiment 1-13, wherein X ¹¹Be Asn.

15. according to each GLP-2 peptide among the embodiment 1-14, wherein X ¹²Be Thr.

16. according to each GLP-2 peptide among the embodiment 1-15, wherein X ¹⁵Be Ile.

17. according to each GLP-2 peptide among the embodiment 1-16, wherein X ¹⁴Be Leu.

18. according to each GLP-2 peptide among the embodiment 1-17, wherein X ¹⁵Be Asp.

19. according to each GLP-2 peptide among the embodiment 1-18, wherein X ¹⁶Be Asn.

20. according to each GLP-2 peptide among the embodiment 1-19, wherein X ¹⁷Be Leu.

21. according to each GLP-2 peptide among the embodiment 1-20, wherein X ¹⁸Be Ala.

22. according to each GLP-2 peptide among the embodiment 1-21, wherein X ²¹Be Asp.

23. according to each GLP-2 peptide among the embodiment 1-22, wherein X ²⁴Be Asn.

24. according to each GLP-2 peptide among the embodiment 1-23, wherein X ²⁸Be Gln.

25. according to each GLP-2 peptide among the embodiment 1-24,, X wherein ³³Be Asp.

26. according to each GLP-2 peptide among the embodiment 1-24, wherein X ³³Be G1u.

27. according to each GLP-2 peptide among the embodiment 1-26, wherein at least one is independently selected from X ⁵, X ⁷, X ⁸, X ⁹, X ⁹, X ¹⁰, X ¹¹, X ¹², X ¹³, X ¹⁴, X ¹⁵, X ¹⁶, X ¹⁷, X ¹⁸, X ²⁰, X ²¹, X ²⁴, X ²⁸And X ³³Amino acid be Lys.

28. according to each GLP-2 peptide among the embodiment 1-27, sum 5 amino-acid residues nearly wherein, as 4 amino-acid residues, 3 amino-acid residues, 2 amino-acid residues or 1 amino-acid residue are exchanged with arbitrary a-amino acid residue.

29. according to the GLP-2 peptide of embodiment 1, wherein peptide is selected from

K30R-GLP-2(1-33)；

S5K-GLP-2(1-33)；

S7K-GLP-2(1-33)；

D8K-GLP-2(1-33)；

E9K-GLP-2(1-33)；

M10K-GLP-2(1-33)；

N11K-GLP-2(1-33)；

T12K-GLP-2(1-33)；

I13K-GLP-2(1-33)；

L14K-GLP-2(1-33)；

D15K-GLP-2(1-33)；

N16K-GLP-2(1-33)；

L17K-GLP-2(1-33)；

A18K-GLP-2(1-33)；

D21K-GLP-2(1-33)；

N24K-GLP-2(1-33)；

Q28K-GLP-2(1-33)；

S5K/K30R-GLP-2(1-33)；

S7K/K30R-GLP-2(1-33)；

D8K/K30R-GLP-2(1-33)；

E9K/K30R-GLP-2(1-33)；

M10K/K30R-GLP-2(1-33)；

N11K/K30R-GLP-2(1-33)；

T12K/K30R-GLP-2(1-33)；

I13K/K30R-GLP-2(1-33)；

L14K/K30R-GLP-2(1-33)；

D15K/K30R-GLP-2(1-33)；

N16K/K30R-GLP-2(1-33)；

L17K/K30R-GLP-2(1-33)；

A18K/K30R-GLP-2(1-33)；

D21K/K30R-GLP-2(1-33)；

N24K/K30R-GLP-2(1-33)；

Q28K/K30R-GLP-2(1-33)；

K30R/D33K-GLP-2(1-33)；

D3E/K30R/D33E-GLP-2(1-33)；

D3E/S5K/K30R/D33E-GLP-2(1-33)；

D3E/S7K/K30R/D33E-GLP-2(1-33)；

D3E/D8K/K30R/D33E-GLP-2(1-33)；

D3E/E9K/K30R/D33E-GLP-2(1-33)；

D3E/M10K/K30R/D33E-GLP-2(1-33)；

D3E/N11K/K30R/D33E-GLP-2(1-33)；

D3E/T12K/K30R/D33E-GLP-2(1-33)；

D3E/I13K/K30R/D33E-GLP-2(1-33)；

D3E/L14K/K30R/D33E-GLP-2(1-33)；

D3E/D15K/K30R/D33E-GLP-2(1-33)；

D3E/N16K/K30R/D33E-GLP-2(1-33)；

D3E/L17K/K30R/D33E-GLP-2(1-33)；

D3E/A18K/K30R/D33E-GLP-2(1-33)；

D3E/D21K/K30R/D33E-GLP-2(1-33)；

D3E/N24K/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K/K30R/D33E-GLP-2(1-33)。

30. a coding is according to the polynucleotide constructs of each GLP-2 peptide among the embodiment 1-29.

31. host cell that comprises according to the polynucleotide constructs of embodiment 30.

32. according to the host cell of embodiment 31, it is an eukaryotic cell.

33. according to the host cell of embodiment 32, wherein said cell is a yeast cell.

34. a GLP-2 derivative that comprises the GLP-2 peptide, wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, and described position is independently selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

35. according to the GLP-2 derivative of embodiment 34, wherein the GLP-2 peptide is suc as formula II

His-X2-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X1 6-X17-X18-Ala-X20-X21-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-X3 0-Ile-Thr-X33 (formula II)

Or its fragment; Wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser or Lys; X7 is Ser or Lys; X8 is Asp, Glu or Lys; X9 is Asp, Glu or Lys; X10 is Met, Lys, Leu, Ile or nor-leucine; X11 is Asn or Lys; X12 is Thr or Lys; X13 is Ile or Lys; X14 is Leu or Lys; X15 is Asp or Lys; X16 is Asn or Lys; X17 is Leu or Lys; X18 is Ala or Lys; X20 is Arg or Lys; X21 is Asp or Lys; X24 is Asn or Lys; X28 is Gln or Lys; X30 is Arg or Lys; X33 is Asp, Glu or Lys (formula II).

36. according to the GLP-2 derivative of embodiment 34 or 35, wherein the GLP-2 peptide as according among the embodiment 1-29 each.

37., wherein only have a lipophilic substituent to be connected with described GLP-2 peptide according to each GLP-2 derivative among the embodiment 34-36.

38. according to each GLP-2 derivative among the embodiment 34-37, wherein said lipophilic substituent contains 4-40 carbon atom.

39. according to the GLP-2 derivative of embodiment 38, wherein said lipophilic substituent contains 8-25 carbon atom.

40. according to the GLP-2 derivative of embodiment 38, wherein said lipophilic substituent contains 12-20 carbon atom.

41. according to each GLP-2 derivative among the embodiment 34-40, wherein said lipophilic substituent is connected with amino-acid residue as follows, makes the carboxyl of lipophilic substituent and the amino of amino-acid residue form amido linkage.

42. according to the GLP-2 derivative of embodiment 41, wherein said amino-acid residue is the Lys residue.

43. according to each GLP-2 derivative among the embodiment 34-40, wherein said lipophilic substituent is connected with amino-acid residue as follows, makes the amino of lipophilic substituent and the carboxyl of amino-acid residue form amido linkage.

44. according to each GLP-2 derivative among the embodiment 34-43, wherein said lipophilic substituent is connected with described GLP-2 peptide in the mode of spacer.

45. according to the GLP-2 derivative of embodiment 44, wherein said spacer is a ramose alkyl alpha, omega-dicarboxylic acid group not, has 1-7 methylene radical, as two methylene radical, spacer forms bridge between the amino of the amino of GLP-2 peptide and lipophilic substituent.

46. according to the GLP-2 derivative of embodiment 44, wherein said spacer is the amino-acid residue except that the Cys residue, or dipeptides.

47. according to the GLP-2 derivative of embodiment 46, wherein said spacer is selected from: Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, Lys, Asp, Glu contains the dipeptides of Asp, contains the dipeptides of Glu or contains the dipeptides of Lys.

48. according to the GLP-2 derivative of embodiment 46 or 47, wherein the amino of the carboxyl of parent GLP-2 peptide and described spacer forms amido linkage, the carboxyl of amino acid or dipeptides spacer and the amino of lipophilic substituent form amido linkage.

49. according to the GLP-2 derivative of embodiment 46 or 47, wherein the carboxyl of the amino of parent GLP-2 peptide and described spacer forms amido linkage, the amino of spacer and the carboxyl of lipophilic substituent form amido linkage.

50. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent contains the partially or completely luxuriant and rich with fragrance skeleton of hydrogenant cyclopentano.

51. according to the GLP-2 derivative of embodiment 34-50, wherein lipophilic substituent is straight chain or ramose alkyl group.

52. according to the GLP-2 derivative of embodiment 34-50, wherein lipophilic substituent is the acyl group of straight chain or branched fatty acid.

53. according to the GLP-2 derivative of embodiment 52, wherein acyl group is selected from CH ₃(CH ₂) _nCO-, wherein n is 4-38, as CH ₃(CH ₂) ₆CO-, CH ₃(CH ₂) ₈CO-, CH ₃(CH ₂) ₁₀CO-, CH ₃(CH ₂) ₁₂CO-, CH ₃(CH ₂) ₁₄CO-, CH ₃(CH ₂) ₁₆CO-, CH ₃(CH ₂) ₁₈CO-, CH ₃(CH ₂) ₂₀CO-and CH ₃(CH ₂) ₂₂CO-.

54. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is the acyl group of straight chain or ramose alkyl alpha, omega-dicarboxylic acid.

55. according to the GLP-2 derivative of embodiment 52, wherein acyl group is selected from HOOC (CH ₂) _mCO-, wherein m is 4-38, as HOOC (CH ₂) ₁₄CO-, HOOC (CH ₂) ₁₆CO-, HOOC (CH ₂) ₁₈CO-, HOOC (CH ₂) ₂₀CO-and HOOC (CH ₂) ₂₂CO-.

56. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _p((CH ₂) _qCOOH) CHNH-CO (CH ₂) ₂CO-, wherein p and q are integers, and p+q is 8-40, as the integer of 12-35.

57. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _rCO-NHCH (COOH) (CH ₂) ₂CO-, wherein r is the integer of 10-24.

12. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _sCO-NHCH ((CH ₂) ₂COOH) CO-, wherein s is the integer of 8-24.

13. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group COOH (CH ₂) _tCO-wherein t is the integer of 8-24.

60. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) _uCH ₃, wherein u is the integer of 8-18.

61. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-COCH ((CH ₂) ₂COOH) NH-CO (CH ₂) _wCH ₃, wherein w is the integer of 10-16.

62. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NH-CO (CH ₂) _xCH ₃, wherein x is the integer of 10-16.

63. according to the GLP-2 derivative of embodiment 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NHCO (CH ₂) _yCH ₃, wherein y is 0 or the integer of 1-22.

64. according to the GLP-2 derivative of embodiment 34-63, it has two lipophilic substituents.

65. according to the GLP-2 derivative of embodiment 34-64, it is selected from

S5K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S5K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

I17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D3E/S5K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/S7K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D8K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/E9K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/M10K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N11K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/T12K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/I13K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L14K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D15K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N16K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(capryloyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(decane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(undecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(lauroyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tridecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tetradecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(pentadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(heptadecane acyl group amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(octadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonadecane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(eicosane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33 E-GLP-2 (1-33);

D3E/L17K (4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(decane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/A18K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D21K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N24K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/Q28K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33).

66. a pharmaceutical composition that contains the GLP-2 derivative that comprises the GLP-2 peptide, wherein lipophilic substituent is connected with one or more amino-acid residues in the position with respect to SEQ ID NO:1 aminoacid sequence, and described position is selected from: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, prerequisite is that described lipophilic substituent is not connected with the-terminal amino acid residue or the C-terminal amino acid residue of described GLP-2 peptide.

67. a GLP-2 derivative that contains among the with good grounds embodiment 34-65 each and, optional, the pharmaceutical composition of medicine acceptable carrier.

68. be used to prepare the purposes of medicine according to each GLP-2 derivative among the embodiment 34-65.

69. be used to prepare the purposes of the medicine of effect according to each GLP-2 derivative among the embodiment 34-65 with prolongation.

70. be used for preparing the purposes of the medicine of other disease that is used for the treatment of intestines depletion or causes intestines nutrition malabsorption according to each GLP-2 derivative among the embodiment 34-65.

71. be used to prepare the purposes of the medicine for the treatment of following disease according to each GLP-2 derivative among the embodiment 34-65, described disease is: little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia (the special property sent out) syndrome, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

72. one kind to be used for the treatment of intestines depleted or cause the method for other disease of nutrition malabsorption in the intestines, described method to comprise in the embodiment 34-65 of experimenter's administering therapeutic of needs treatment or prevention significant quantity each GLP-2 derivative.

73. the method for the following disease of treatment, little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, for example chemotherapy is induced endo-enteritis, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, vascular disease and graft-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour, because the bone amount that bone shifts reduces, periodontopathy, hyperparathyroidism, wearing and tearing around the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia (the special property sent out) syndrome, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture, because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduces or the bone amount of glucocorticoid inducible reduces, and described method comprises that the patient to needs uses as implementing among the scheme 34-65 each the treatment or the GLP-2 derivative of prevention significant quantity.

74. one kind is used for preparing each the method for GLP-2 peptide of embodiment 1-29, described method is included in the host cell of cultivating among the embodiment 31-33 each under the condition that allows polynucleotide constructs to express in suitable growth medium, reclaims the peptide of gained from substratum.

Other embodiment:

1b. pharmaceutical preparation or its freeze-dried preparation that contains GLP-2 compound and buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

2b., also contain water according to the preparation of embodiment 1b.

3b. one kind contains the aqueous solution of GLP-2 compound and the pharmaceutical preparation of buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

4b. according to each preparation among the embodiment 1b-3b, the concentration that wherein said GLP-2 compound exists is 1mg/ml-100mg/ml.

5b. according to each preparation among the embodiment 1b-4b, the pH of wherein said preparation is 8.5-10.

6b. according to each preparation among the embodiment 1b-5b, the pH of wherein said preparation is 9.0-10.

7b. according to each preparation among the embodiment 1b-6b, wherein the concentration that exists of GLP-2 compound is 0.1mg/ml-80mg/ml, 0.1mg/ml-50mg/ml, and 0.1mg/ml-20mg/ml, 0.1mg/ml-10mg/ml is generally 0.1-5mg/ml.

8b. according to each preparation among the embodiment 1b-7b, wherein the concentration that exists of GLP-2 compound is 1mg/ml-80mg/ml, 1mg/ml-50mg/ml, and 1mg/ml-20mg/ml, 1mg/ml-10mg/ml is generally 1-5mg/ml.

9b. according to each preparation among the embodiment 1b-8b, it also contains sanitas.

10b. according to the preparation of embodiment 9b, the concentration that wherein said sanitas exists is 0.1mg/ml-20mg/ml.

11b. according to each preparation among the embodiment 1b-10b, it also contains isotonic agent.

12b. according to the preparation of embodiment 11b, the concentration of wherein said existence is 1mg/ml-50mg/ml.

13b. according to each preparation among the embodiment 1b-12b, it also contains intercalating agent.

14b. according to the preparation of embodiment 13b, the concentration that wherein said intercalating agent exists is 0.1mg/ml-5mg/ml.

15b. according to each preparation among the embodiment 1b-14b, it also contains stablizer.

16b. according to the preparation of embodiment 15b, wherein said stablizer is selected from the L-Histidine, imidazoles and arginine.

17b. according to the preparation of embodiment 16b, wherein said stablizer is high-molecular weight polymer and/or low-molecular weight compound, the concentration of existence is 0.1mg/ml-50mg/ml.

18b., also contain tensio-active agent according to each preparation among the embodiment 1b-17b.

19b. according to each preparation among the embodiment 1b-18b, wherein said GLP-2 compound is selected from GLP-2 (1-33), A2G-GLP-2 (1-33) and its analogue.

20b. according to the preparation among the embodiment 1b-18b, wherein said GLP-2 compound is the GLP-2 derivative.

21b. according to the preparation of embodiment 20b, wherein said GLP-2 derivative is the GLP-2 peptide, wherein the amino-acid residue of parent's peptide has, optional spacer, the lipophilic substituent of connection of passing through.

22b. according to the preparation of claim 21b, wherein said GLP-2 derivative is the GLP-2 peptide, wherein lipophilic substituent is connected with one or more amino-acid residues in the following position that is independently selected from respect to the aminoacid sequence of SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, C14, D15, N16, L17, A18, D21, N24 and Q28.

23b. according to each preparation among the embodiment 22b, wherein the GLP-2 peptide is suc as formula II

24b. according to the preparation of embodiment 22b or 23b, wherein the GLP-2 peptide comprises the aminoacid sequence of formula I

25b. according to each preparation among the embodiment 22b-24b, wherein the GLP-2 peptide is made up of following aminoacid sequence

26b. according to each preparation among the embodiment 23b-25b, wherein X2 is Ala.

27b. according to each preparation among the embodiment 23b-25b, wherein X2 is Gly.

28b. according to each preparation among the embodiment 23b-27b, wherein X3 is Asp.

29b. according to each preparation among the embodiment 23b-27b, wherein X3 is Glu.

30b. according to each preparation among the embodiment 23b-29b, wherein X5 is Ser.

31b. according to each preparation among the embodiment 23b-30b, wherein X7 is Ser.

32b. according to each preparation among the embodiment 23b-31b, wherein X8 is Asp.

33b. according to each preparation among the embodiment 23b-31b, wherein X8 is Glu.

34b. according to each preparation among the embodiment 23-33, wherein X9 is Asp.

35b. according to each preparation among the embodiment 23b-33b, wherein X9 is Glu.

36b. according to each preparation among the embodiment 23b-35b, wherein X10 is selected from Met, Leu, Ile and nor-leucine.

37b. according to each preparation among the embodiment 23b-36b, wherein X11 is Asn.

38b. according to each preparation among the embodiment 23b-37b, wherein X12 is Thr.

39b. according to each preparation among the embodiment 23b-38b, wherein X13 is Ile.

40b. according to each preparation among the embodiment 23b-39b, wherein X14 is Leu.

41b. according to each preparation among the embodiment 23b-40b, wherein X15 is Asp.

42b. according to each preparation among the embodiment 23b-41b, wherein X16 is Asn.

43b. according to each preparation among the embodiment 23b-42b, wherein X17 is Leu.

44b. according to each preparation among the embodiment 23b-43b, wherein X18 is Ala.

45b. according to each preparation among the embodiment 23b-44b, wherein X21 is Asp.

46b. according to each preparation among the embodiment 23b-45b, wherein X24 is Asn.

47b. according to each preparation among the embodiment 23b-46b, wherein X28 is Gln.

48b. according to each preparation among the embodiment 23b-47b, wherein X33 is Asp.

49b. according to each preparation among the embodiment 23b-47b, wherein X33 is Glu.

50b. according to each preparation among the embodiment 23b-25b, the wherein at least a X5 that independently is selected from, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X20, X21, X24, the amino acid of X28 and X33 is Lys.

51b. according to each preparation among the embodiment 21b-50b, sum 5 amino-acid residues nearly wherein, as 4 amino-acid residues, 3 amino-acid residues, 2 amino-acid residues or 1 amino-acid residue by with arbitrary a-amino acid residue exchange.

52b. according to each preparation among the embodiment 21b-25b, wherein the GLP-2 peptide is selected from

K30R-GLP-2(1-33)；

S5K-GLP-2(1-33)；

S7K-GLP-2(1-33)；

D8K-GLP-2(1-33)；

E9K-GLP-2(1-33)；

M10K-GLP-2(1-33)；

N11K-GLP-2(1-33)；

T12K-GLP-2(1-33)；

I13K-GLP-2(1-33)；

L14K-GLP-2(1-33)；

D15K-GLP-2(1-33)；

N16K-GLP-2(1-33)；

L17K-GLP-2(1-33)；

A18K-GLP-2(1-33)；

D21K-GLP-2(1-33)；

N24K-GLP-2(1-33)；

Q28K-GLP-2(1-33)；

S5K/K30R-GLP-2(1-33)；

S7K/K30R-GLP-2(1-33)；

D8K/K30R-GLP-2(1-33)；

E9K/K30R-GLP-2(1-33)；

M10K/K30R-GLP-2(1-33)；

N11K/K30R-GLP-2(1-33)；

T12K/K30R-GLP-2(1-33)；

I13K/K30R-GLP-2(1-33)；

L14K/K30R-GLP-2(1-33)；

D15K/K30R-GLP-2(1-33)；

N16K/K30R-GLP-2(1-33)；

L17K/K30R-GLP-2(1-33)；

A18K/K30R-GLP-2(1-33)；

D21K/K30R-GLP-2(1-33)；

N24K/K30R-GLP-2(1-33)；

Q28K/K30R-GLP-2(1-33)；

K30R/D33K-GLP-2(1-33)；

D3E/K30R/D33E-GLP-2(1-33)；

D3E/S5K/K30R/D33E-GLP-2(1-33)；

D3E/S7K/K30R/D33E-GLP-2(1-33)；

D3E/D8K/K30R/D33E-GLP-2(1-33)；

D3E/E9K/K30R/D33E-GLP-2(1-33)；

D3E/M10K/K30R/D33E-GLP-2(1-33)；

D3E/N11K/K30R/D33E-GLP-2(1-33)；

D3E/T12K/K30R/D33E-GLP-2(1-33)；

D3E/I13K/K30R/D33E-GLP-2(1-33)；

D3E/L14K/K30R/D33E-GLP-2(1-33)；

D3E/D15K/K30R/D33E-GLP-2(1-33)；

D3E/N16K/K30R/D33E-GLP-2(1-33)；

D3E/L17K/K30R/D33E-GLP-2(1-33)；

D3E/A18K/K30R/D33E-GLP-2(1-33)；

D3E/D21K/K30R/D33E-GLP-2(1-33)；

D3E/N24K/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K/K30R/D33E-GLP-2(1-33)。

53b., wherein only have a lipophilic substituent to be connected with described GLP-2 peptide according to each preparation among the embodiment 21b-52b.

54b. according to each preparation among the embodiment 21b-53b, wherein said lipophilic substituent contains 4-40 carbon atom.

55b. according to the preparation of embodiment 54b, wherein said lipophilic substituent contains 8-25 carbon atom.

56b. according to the preparation of embodiment 55b, wherein said lipophilic substituent contains 12-20 carbon atom.

57b. according to each preparation among the embodiment 21b-56b, wherein said lipophilic substituent is connected with amino-acid residue, makes the carboxyl of lipophilic substituent and the amino of amino-acid residue form amido linkage.

58b. according to the preparation of embodiment 57b, wherein said amino-acid residue is a lysine residue.

59b. according to each preparation among the embodiment 21b-58b, wherein said lipophilic substituent is connected with amino-acid residue, makes the amino of lipophilic substituent and the carboxyl of amino-acid residue form amido linkage.

60b. according to each preparation among the embodiment 21b-59b, wherein said lipophilic substituent is connected with described GLP-2 peptide by the mode of spacer.

61b. according to the preparation of embodiment 60b, wherein said spacer is a ramose alkyl alpha, omega-dicarboxylic acid not, it has 1-7 methylene radical, and as two methylene radical, spacer forms bridge between the amino of the amino of GLP-2 peptide and described lipophilic substituent.

62b. according to the preparation of embodiment 60b, wherein said spacer is except the amino-acid residue of Cys residue or dipeptides.

63b. according to the preparation of embodiment 62b, wherein said spacer is selected from Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, Lys, Asp, Glu, contain the dipeptides of Asp, contain the dipeptides of Glu or contain the dipeptides of Lys.

64b. according to the preparation of embodiment 62b or 63b, wherein the amino of the carboxyl of parent GLP-2 peptide and described spacer forms amido linkage, the carboxyl of amino acid or dipeptides spacer and the amino of lipophilic substituent form amido linkage.

65b. according to the preparation of embodiment 62b or 63b, wherein the carboxyl of the amino of parent GLP-2 peptide and described spacer forms amido linkage, the amino of described spacer and the carboxyl of lipophilic substituent form amido linkage.

66b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent contains the partially or completely luxuriant and rich with fragrance skeleton of hydrogenant cyclopentano.

67b. according to each preparation among the embodiment 21b-66b, wherein lipophilic substituent is straight chain or branch's alkyl.

68b. according to each preparation among the embodiment 21b-66b, wherein lipophilic substituent is the acyl group of straight chain or branched fatty acid.

69b. preparation according to embodiment 68b; wherein acyl group is selected from CH3 (CH2) nCO-; wherein n is 4-38, as CH3 (CH2) 6CO-, and CH3 (CH2) 8CO-; CH3 (CH2) 10CO-; CH3 (CH2) 12CO-, CH3 (CH2) 14CO-, CH3 (CH2) 16CO-; CH3 (CH2) 18CO-, CH3 (CH2) 20CO-and CH3 (CH2) 22CO-.

70b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is the acyl group of straight chain or branch's alkyl alpha, omega-dicarboxylic acid.

71b. according to the preparation of embodiment 68b, wherein acyl group is selected from HOOC (CH2) mCO-, wherein m is 4-38, as HOOC (CH2) 14CO-, and HOOC (CH2) 16CO-, HOOC (CH2) 18CO-, HOOC (CH2) 20CO-and HOOC (CH2) 22CO-.

72b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is following formula group CH3 (CH2) p ((CH2) qCOOH) CHNH-CO (CH2) 2CO-, wherein p and q are integers, and p+q is the integer of 8-40, as 12-35.

73b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is (CH2) 2CO-of following formula group CH3 (CH2) rCO-NHCH (COOH), wherein r is the integer of 10-24.

74b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is following formula group CH3 (CH2) sCO-NHCH ((CH2) 2COOH) CO-, wherein s is the integer of 8-24.

75b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is following formula group COOH (CH2) tCO-, wherein t is the integer of 8-24.

76b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) uCH3 of following formula group NHCH (COOH), wherein u is the integer of 8-18.

77b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is (CH2) 4NH-COCH ((CH2) 2COOH) NH-CO (CH2) wCH3 of following formula group NHCH (COOH), wherein w is the integer of 10-16.

78b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) 2CH (COOH) NH-CO (CH2) xCH3 of following formula group NHCH (COOH), wherein x is the integer of 10-16.

79b. according to each preparation among the embodiment 21b-65b, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) 2CH (COOH) NHCO (CH2) yCH3 of following formula group NHCH (COOH), wherein y is 0 or the integer of 1-22.

80b. according to each preparation among the embodiment 21b-79b, it has two lipophilic substituents.

81b. according to the preparation of embodiment 20b, wherein the GLP-2 derivative is selected from

S5K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S5K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D3E/S5K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/S7K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D8K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/E9K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/M10K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N11K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/T12K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/I13K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L14K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D15K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N16K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(capryloyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(decane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(undecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(lauroyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tridecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tetradecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(pentadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(heptadecane acyl group amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(octadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonadecane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(eicosane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(decane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/A18K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D21K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N24K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33).

82b. the method for the pharmaceutical preparation of stable GLP-2 compound on the prepared product Neo-Confucianism, comprise that preparation contains the GLP-2 compound, with the preparation of buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 8.0-10.

83b. according to the method for embodiment 82b, each defines wherein said pharmaceutical preparation among the scheme 1b-81b as implementing.

84b. composition or its freeze-dried preparation that contains GLP-2 compound and buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said composition has is 8.0-10.

85b. according to the composition of embodiment 84b, it also contains water.

86b. one kind contains the aqueous solution of GLP-2 compound and the composition of buffer reagent, the concentration that wherein said GLP-2 compound exists is 0.1mg/ml-100mg/ml, and the pH that wherein said composition has is 8.0-10.

Other embodiments:

1c. pharmaceutical preparation or its freeze-dried preparation that contains GLP-2 derivative and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through is connected with one or more amino-acid residues that independently are selected from following position with respect to the aminoacid sequence of SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24 and Q28, the concentration that wherein said GLP-2 derivative exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 7.0-10.

2c. according to the preparation of embodiment 1c, it also contains water.

3c. one kind contains the aqueous solution of GLP-2 derivative and the pharmaceutical preparation of buffer reagent, the concentration that wherein said GLP-2 derivative exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 7.0-10.

4c. according to each preparation among the embodiment 1c-3c, the concentration that wherein said GLP-2 derivative exists is 1mg/ml-100mg/ml.

5c. according to each preparation among the embodiment 1c-4c, the pH of wherein said preparation is 7.0-9.0.

6c. according to each preparation among the embodiment 1c-5c, the pH of wherein said preparation is 7.0-8.0.

7c. according to each preparation among the embodiment 1c-6c, wherein the concentration that exists of GLP-2 derivative is 0.1mg/ml-80mg/ml, 0.1mg/ml-50mg/ml, and 0.1mg/ml-20mg/ml, 0.1mg/ml-10mg/ml is generally 0.1-5mg/ml.

8c. according to each preparation among the embodiment 1c-7c, wherein the concentration that exists of GLP-2 derivative is 1mg/ml-80mg/ml, 1mg/ml-50mg/ml, and 1mg/ml-20mg/ml, 1mg/ml-10mg/ml is generally 1-5mg/ml.

9c. according to each preparation among the embodiment 1c-8c, it also contains sanitas.

10c. according to the preparation of embodiment 9c, the concentration that wherein said sanitas exists is 0.1mg/ml-20mg/ml.

11c. according to each preparation among the embodiment 1c-10c, it also contains isotonic agent.

12c. according to the preparation of embodiment 11c, the concentration of wherein said existence is 1mg/ml-50mg/ml.

13c. according to each preparation among the embodiment 1c-12c, it also contains intercalating agent.

14c. according to the preparation of embodiment 13c, the concentration that wherein said intercalating agent exists is 0.1mg/ml-5mg/ml.

15c. according to each preparation among the embodiment 1c-14c, it also contains stablizer.

16c. according to the preparation of embodiment 15c, wherein said stablizer is selected from the L-Histidine, imidazoles and arginine.

17c. according to the preparation of embodiment 16c, wherein said stablizer is high-molecular weight polymer and/or low-molecular weight compound, the concentration of existence is 0.1mg/ml-50mg/ml.

18c. according to each preparation among the embodiment 1c-17c, it also contains tensio-active agent.

19c. according to each preparation among the embodiment 1c-18c, wherein the GLP-2 peptide is suc as formula II

20c. according to each preparation among the embodiment 1c-19c, wherein the GLP-2 peptide comprises the aminoacid sequence of formula I

21c. according to each preparation among the embodiment 1c-20c, wherein the GLP-2 peptide is made up of following aminoacid sequence

Or its fragment; Wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser or Lys; X7 is Ser or Lys; X8 is Asp, Glu or Lys; X9 is Asp, Glu or Lys; X10 is Met, Lys, Leu, Ile or nor-leucine; X11 is Asn or Lys; X12 is Fhr or Lys; X13 is Ile or Lys; X14 is Leu or Lys; X15 is Asp or Lys; X16 is Asn or Lys; X17 is Leu or Lys; X18 is Ala or Lys; X20 is Arg or Lys; X21 is Asp or Lys; X24 is Asn or Lys; X28 is Gln or Lys; X33 is Asp, Glu or Lys.

22c. according to each preparation among the embodiment 19c-21c, wherein X2 is Ala.

23c. according to each preparation among the embodiment 19c-21c, wherein X2 is Gly.

24c. according to each preparation among the embodiment 19c-23c, wherein X3 is Asp.

25c. according to each preparation among the embodiment 19c-23c, wherein X3 is Glu.

26c. according to each preparation among the embodiment 19c-25c, wherein X5 is Ser.

27c. according to each preparation among the embodiment 19c-26c, wherein X7 is Ser.

28c. according to each preparation among the embodiment 19c-27c, wherein X8 is Asp.

29c. according to each preparation among the embodiment 19c-27c, wherein X8 is Glu.

30c. according to each preparation among the embodiment 19c-29c, wherein X9 is Asp.

31c. according to each preparation among the embodiment 19c-29c, wherein X9 is Glu.

32c. according to each preparation among the embodiment 19c-31c, wherein X10 is selected from Met, Leu, Ile and nor-leucine.

33c. according to each preparation among the embodiment 19c-32c, wherein X11 is Asn.

34c. according to each preparation among the embodiment 19c-33c, wherein X12 is Thr.

35c. according to each preparation among the embodiment 19c-34c, wherein X13 is Ile.

36c. according to each preparation among the embodiment 19c-35c, wherein X14 is Leu.

37c. according to each preparation among the embodiment 19c-36c, wherein X15 is Asp.

38c. according to each preparation among the embodiment 19c-37c, wherein X16 is Asn.

39c. according to each preparation among the embodiment 19c-38c, wherein X17 is Leu.

40c. according to each preparation among the embodiment 19-39, wherein X18 is Ala.

41c. according to each preparation among the embodiment 19c-40c, wherein X21 is Asp.

42c. according to each preparation among the embodiment 19c-41c, wherein X24 is Asn.

43c. according to each preparation among the embodiment 19c-42c, wherein X28 is Gln.

44c. according to each preparation among the embodiment 19c-43c, wherein X33 is Asp.

45c. according to each preparation among the embodiment 19c-44c, wherein X33 is Glu.

46c. according to each preparation among the embodiment 19c-45c, wherein at least one independently is selected from X5, X7, and X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X20, X21, X24, the amino acid of X28 and X33 is Lys.

47c. according to each preparation among the embodiment 1c-46c, sum 5 amino-acid residues nearly wherein, as 4 amino-acid residues, 3 amino-acid residues, 2 amino-acid residues or 1 amino-acid residue are by arbitrary a-amino acid residue exchange.

48c. according to each preparation among the embodiment 1c-47c, wherein the GLP-2 peptide is selected from

K30R-GLP-2(1-33)；

S5K-GLP-2(1-33)；

S7K-GLP-2(1-33)；

D8K-GLP-2(1-33)；

E9K-GLP-2(1-33)；

M10K-GLP-2(1-33)；

N11K-GLP-2(1-33)；

T12K-GLP-2(1-33)；

I13K-GLP-2(1-33)；

L14K-GLP-2(1-33)；

D15K-GLP-2(1-33)；

N16K-GLP-2(1-33)；

L17K-GLP-2(1-33)；

A18K-GLP-2(1-33)；

D21K-GLP-2(1-33)；

N24K-GLP-2(1-33)；

Q28K-GLP-2(1-33)；

S5K/K30R-GLP-2(1-33)；

S7K/K30R-GLP-2(1-33)；

D8K/K30R-GLP-2(1-33)；

E9K/K30R-GLP-2(1-33)；

M10K/K30R-GLP-2(1-33)；

N11K/K30R-GLP-2(1-33)；

T12K/K30R-GLP-2(1-33)；

I13K/K30R-GLP-2(1-33)；

L14K/K30R-GLP-2(1-33)；

D15K/K30R-GLP-2(1-33)；

N16K/K30R-GLP-2(1-33)；

L17K/K30R-GLP-2(1-33)；

A18K/K30R-GLP-2(1-33)；

D21K/K30R-GLP-2(1-33)；

N24K/K30R-GLP-2(1-33)；

Q28K/K30R-GLP-2(1-33)；

K30R/D33K-GLP-2(1-33)；

D3E/K30R/D33E-GLP-2(1-33)；

D3E/S5K/K30R/D33E-GLP-2(1-33)；

D3E/S7K/K30R/D33E-GLP-2(1-33)；

D3E/D8K/K30R/D33E-GLP-2(1-33)；

D3E/E9K/K30R/D33E-GLP-2(1-33)；

D3E/M10K/K30R/D33E-GLP-2(1-33)；

D3E/N11K/K30R/D33E-GLP-2(1-33)；

D3E/T12K/K30R/D33E-GLP-2(1-33)；

D3E/I13K/K30R/D33E-GLP-2(1-33)；

D3E/L14K/K30R/D33E-GLP-2(1-33)；

D3E/D15K/K30R/D33E-GLP-2(1-33)；

D3E/N16K/K30R/D33E-GLP-2(1-33)；

D3E/L17K/K30R/D33E-GLP-2(1-33)；

D3E/A18K/K30R/D33E-GLP-2(1-33)；

D3E/D21K/K30R/D33E-GLP-2(1-33)；

D3E/N24K/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K/K30R/D33E-GLP-2(1-33)。

49c., wherein only have a lipophilic substituent to be connected with described GLP-2 peptide according to each preparation among the embodiment 1c-48c.

50c. according to each preparation among the embodiment 1c-49c, wherein said lipophilic substituent contains 4-40 carbon atom.

51c. according to the preparation of embodiment 50c, wherein said lipophilic substituent contains 8-25 carbon atom.

52c. according to the preparation of embodiment 51c, wherein said lipophilic substituent contains 12-20 carbon atom.

53c. according to each preparation among the embodiment 1c-52c, wherein said lipophilic substituent is connected with amino-acid residue, its mode is that the carboxyl of lipophilic substituent and the amino of amino-acid residue form amido linkage.

54c. according to each preparation among the embodiment 53c, wherein said amino-acid residue is a lysine residue.

55c. according to each preparation among the embodiment 1c-54c, wherein said lipophilic substituent is connected with amino-acid residue, makes the amino of lipophilic substituent and the carboxyl of amino-acid residue form amido linkage.

56c. according to each preparation among the embodiment 1c-55c, wherein said lipophilic substituent is connected with described GLP-2 peptide by the mode of spacer.

57c. according to the preparation of embodiment 56c, wherein said spacer is a ramose alkyl alpha, omega-dicarboxylic acid not, it has 1-7 methylene radical, and as two methylene radical, spacer forms bridge between the amino of the amino of GLP-2 peptide and described lipophilic substituent.

58c. according to the preparation of embodiment 56c, wherein said spacer is except the amino-acid residue of Cys residue or dipeptides.

59c. according to the preparation of embodiment 58c, wherein said spacer is selected from Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, Lys, Asp, Glu, contain the dipeptides of Asp, contain the dipeptides of Glu or contain the dipeptides of Lys.

60c. according to the preparation of embodiment 58c or 59c, wherein the amino of the carboxyl of parent GLP-2 peptide and described spacer forms amido linkage, the carboxyl of amino acid or dipeptides spacer and the amino of lipophilic substituent form amido linkage.

61c. according to the preparation of embodiment 58c or 59c, wherein the carboxyl of the amino of parent GLP-2 peptide and described spacer forms amido linkage, the amino of described spacer and the carboxyl of lipophilic substituent form amido linkage.

62c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent contains the partially or completely luxuriant and rich with fragrance skeleton of hydrogenant ring valeryl.

63c. according to each preparation among the embodiment 1c-62c, wherein lipophilic substituent is straight chain or branch's alkyl.

64c. according to each preparation among the embodiment 1c-62c, wherein lipophilic substituent is the acyl group of straight chain or branched fatty acid.

65c. preparation according to embodiment 64c; wherein acyl group is selected from CH3 (CH2) nCO-; wherein n is 4-38, as CH3 (CH2) 6CO-, and CH3 (CH2) 8CO-; CH3 (CH2) 10CO-; CH3 (CH2) 12CO-, CH3 (CH2) 14CO-, CH3 (CH2) 16CO-; CH3 (CH2) 18CO-, CH3 (CH2) 20CO-and CH3 (CH2) 22CO-.

66c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is the acyl group of straight chain or ramose alkyl alpha, omega-dicarboxylic acid.

67c. according to the preparation of embodiment 66c, wherein acyl group is selected from HOOC (CH2) mCO-, wherein m is 4-38, as HOOC (CH2) 14CO-, and HOOC (CH2) 16CO-, HOOC (CH2) 18CO-, HOOC (CH2) 20CO-and HOOC (CH2) 22CO-.

68c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is following formula group CH3 (CH2) p ((CH2) qCOOH) CHNH-CO (CH2) 2CO-, wherein p and q are integers, and p+q is the integer of 8-40, as 12-35.

69c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is (CH2) 2CO-of following formula group CH3 (CH2) rCO-NHCH (COOH), wherein r is the integer of 10-24.

70c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is following formula group CH3 (CH2) sCO-NHCH ((CH2) 2COOH) CO-, wherein s is the integer of 8-24.

71c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent be following formula group COOH (CH2) tCO-wherein t be the integer of 8-24.

72c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) uCH3 of following formula group NHCH (COOH), wherein u is the integer of 8-18.

73c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is (CH2) 4NH-COCH ((CH2) 2COOH) NH-CO (CH2) wCH3 of following formula group NHCH (COOH), wherein w is the integer of 10-16.

74c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) 2CH (COOH) NH-CO (CH2) xCH3 of following formula group NHCH (COOH), wherein x is the integer of 10-16.

75c. according to each preparation among the embodiment 1c-61c, wherein lipophilic substituent is (CH2) 4NH-CO (CH2) 2CH (COOH) NHCO (CH2) yCH3 of following formula group NHCH (COOH), wherein y is 0 or the integer of 1-22.

76c. according to each preparation among the embodiment 1c-75c, it has two lipophilic substituents.

77c. according to each preparation among the embodiment 1c-18c, wherein the GLP-2 derivative is selected from

S5K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S5K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(decane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(decane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D3E/S5K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/S7K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D8K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/E9K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/M10K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N11K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/T12K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/I13K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L14K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D15K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N16K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(capryloyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(decane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(undecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(lauroyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tridecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tetradecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(pentadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(heptadecane acyl group amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(octadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonadecane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(eicosane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S) 4-carboxyl-4-(heptadecane acyl group amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(decane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/A18K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D21K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N24K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33).

78c. the method for stabilised pharmaceutical on the physics for preparing the GLP-2 derivative, wherein said GLP-2 derivative is GLP-2 peptide, wherein lipophilic substituent, the optional spacer that passes through is connected with one or more amino-acid residues that independently are selected from following position with respect to the aminoacid sequence of SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, described method comprises that preparation contains the preparation that comprises GLP-2 derivative and buffer reagent, the concentration that wherein said GLP-2 derivative exists is 0.1mg/ml-100mg/ml, and the pH that wherein said preparation has is 7.0-10.

79c. according to the method for embodiment 82c, each defines wherein said pharmaceutical preparation among the scheme 1c-77c as implementing.

80c. composition or its freeze-dried preparation that comprises GLP-2 derivative and buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through is connected with one or more amino-acid residues that independently are selected from as upper/lower positions with respect to SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, the concentration that wherein said GLP-2 derivative exists is 0.1mg/ml-100mg/ml, and the pH that wherein said composition has is 7.0-10.

81c. according to the composition of embodiment 80c, it also contains water.

82c. one kind contains the aqueous solution of GLP-2 derivative and the composition of buffer reagent, wherein said GLP-2 derivative is the GLP-2 peptide, lipophilic substituent wherein, the optional spacer that passes through is connected with one or more amino-acid residues that independently are selected from as upper/lower positions with respect to SEQ ID NO:1: S5, S7, D8, E9, M10, N11, T12, I13, L14, D15, N16, L17, A18, D21, N24, and Q28, the concentration that wherein said GLP-2 derivative exists is 0.1mg/ml-100mg/ml, and the pH that wherein said composition has is 7.0-10.

In this article, amino acid whose three-character doctrine or monocase represent all to adopt conventional sense as shown in table 1.Unless otherwise indicated, amino acid described herein is L-amino acid.In addition, unless otherwise indicated, end is respectively N-and C-end about aminoacid sequence.

Table 1: amino acid abbreviations:

Amino acid	Three character code	Individual character coding
Amino acid	Three character code	Individual character coding	Glycine proline alanine valine leucine isoleucine methionine cystine phenylalanine tyrosine tryptophan histidine lysine arginine glutamine arginine glutamic acid aspartic acid serine threonine	?Gly ?Pro ?Ala ?Val ?Leu ?Ile ?Met ?Cys ?Phe ?Tyr ?Trp ?His ?Lys ?Arg ?Gln ?Asn ?Glu ?Asp ?Ser ?Thr	?G ?P ?A ?V ?L ?I ?M ?C ?F ?Y ?W ?H ?K ?R ?Q ?N ?E ?D ?S ?T

Accompanying drawing is described

The aminoacid sequence of the GLP-2 of 33 amino-acid residues of Fig. 1.The terminal His-Ala of N-is presented at the sequence of aminopeptidase dipeptide amido peptidase TV cutting in the GLP-2 metabolic process.Arg20 and Lys30 residue are two alkaline amino acid residues among the GLP-2.

The tissue specificity processing of Fig. 2 Proglucagon in pancreas and intestines.

The GLP-2 peptide sequence comparison of Fig. 3 high conservative.The amino-acid residue of runic is those different with people GLP-2 sequence.

Fig. 4 quantity that GLP-2R RNA distributes in different rat tissues.

Fig. 5 L17K/K30R-GLP-2 (1-33) is with Beta-alanine C16 acidylate.

Fig. 6 lipophilic substituent is the example according to the chemical structure of the purposes of different interval base of the present invention of hexadecanoyl.

Fig. 7 expresses and secretes the yeast saccharomyces cerevisiae plasmid of GLP-2 peptide analogs.

Fig. 8. the biological detection in the mouse.The docs-effect research of GLP-2 derivative.The data point that the small intestine weight data is observed (Means ± SD) and matched curve.

Fig. 9. the biological detection in the mouse.Dosage one effect study of GLP-2 derivative.Small intestine weight residual data.

Figure 10. the biological detection in the mouse.The docs-effect research of GLP-2 derivative.The data point that the small intestine weight data is observed (Means ± SD) and matched curve.

Figure 11. the biological detection in the mouse.The docs-effect research of GLP-2 derivative.Small intestine weight residual data.

Figure 12 .SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3.

Embodiment

Use following abbreviation

DDE:1-(4,4-dimethyl-2,6-dioxo hexamethylene-1-base subunit) ethyl.

DIC:N, N '-DIC.

DlEA: diisopropylethylamine.

HBTU:2-(1H-benzotriazole-1-yl)-l, 1,3,3-tetramethyl-urea hexafluorophosphate.

HOAt:N-hydroxyl-9-azepine benzotriazole.

TNBS:2,4,6 trinitro-benzene-sulfonic acids.

DMF:N, dinethylformamide.

DCC:N, the N-dicyclohexylcarbodiimide.

The NMP:N-N-methyl-2-2-pyrrolidone N-.

EDPA:N-ethyl 1-N, the N-diisopropylamine.

EGTA: ethylene glycol-two (beta-aminoethyl ether)-N, N, N ', N '-tetraacethyl.

GTP: guanosine 5 '-triphosphoric acid.

TFA: trifluoroacetic acid.

THF: tetrahydrofuran (THF).

H-Glu (OH)-0Bu ^t: L-L-glutamic acid α-tertiary butyl ester.

Cap-ONSu: sad 2,5-dioxo pyrrolidyl-1-base ester.

Lau-ONSu: laurostearic acid 2,5-dioxo pyrrolidyl-1-base ester.

Myr-ONSu: TETRADECONIC ACID 2,5-dioxo pyrrolidyl-1-base ester.

Pal-ONSu: palmitic acid 2,5-dioxo pyrrolidyl-1-base ester.

Ste-ONSu: stearic acid 2,5-dioxo pyrrolidyl-1-base ester.

HPLC: high performance liquid chromatography.

Amu: atomic mass unit.

Lit-Glu (ONSu)-OBu ^t: N ^α-stone courage acyl group-L-L-glutamic acid α--tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Cap-Glu (ONSu)-OBu ^t: N ^α-capryloyl-L-L-glutamic acid α--tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Cac-Glu (ONSu)-OBu ^t: N ^α-decanoyl-L-L-glutamic acid α--tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Lau-Glu (ONSu)-OBu ^t: N ^α-lauroyl-L-L-glutamic acid α--tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Myr-Glu (ONSu)-OBu ^t: N ^α-tetradecanoyl-L-L-glutamic acid α--tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Pal-Glu (ONSu)-OBu ^t: N ^α-hexadecanoyl-(L)-L-glutamic acid α--the tertiary butyl-γ-2,5-dioxo pyrrolidyl-1-base diester.

Ste-Glu (ONSu)-OBu ^t: N ^α-octadecanoyl-(L)-L-glutamic acid α-tertiary butyl-γ-2,5-dioxo pyrrolidyl-1-base diester.

Lau-β-Ala-ONSu:N ^β-lauroyl-Beta-alanine 2,5-dioxo pyrrolidyl-1-base ester.

Myr-β-Ala-ONSu:N ^β-tetradecanoyl-Beta-alanine 2,5-dioxo pyrrolidyl-1-base ester.

Pal-β-Ala-ONSu:N ^β-hexadecanoyl-Beta-alanine 2,5-dioxo pyrrolidyl-1-base ester.

Lau-GABA-ONSu:N ^γ-lauroyl-γ-An Jidingsuan 2,5-dioxo pyrrolidyl-1-base ester.

Myr-GABA-ONSu:N ^γ-tetradecanoyl-γ-An Jidingsuan 2,5-dioxo pyrrolidyl-1-base ester.

Pal-GABA-ONSu:N ^γ-hexadecanoyl-γ-An Jidingsuan 2,5-dioxo pyrrolidyl-1-base ester.

Ste-GABA-ONSu:N ^γ-octadecanoyl-γ-An Jidingsuan 2,5-dioxo pyrrolidyl-1-base ester.

Pal-Isonip-ONSu:N-hexadecanoyl-piperidines-4-carboxylic acid 2,5-dioxo pyrrolidyl-1-base ester.

Pal-Glu (OBu ^t)-ONSu:N ^α-hexadecanoyl-L-L-glutamic acid α-2,5-dioxo pyrrolidyl-1-base ester γ-tert-butyl ester.

HOOC-(CH ₂) ₆-COONSu: ω-carboxyl enanthic acid 2,5-dioxo pyrrolidyl-1-base.

HOOC-(CH ₂) ₁₀-COONSu: ω-carboxyl undeeanoic acid 2,5-dioxo pyrrolidyl-1-base.

HOOC-(CH ₂) ₁₂-COONSu: ω-carboxyl tridecylic acid 2,5-dioxo pyrrolidyl-1-base.

HOOC-(CH ₂) ₁₄-COONSu: ω-carboxyl pentadecanoic acid 2,5-dioxo pyrrolidyl-1-base.

HOOC-(CH ₂) ₁₆-COONSu: ω-carboxyl margaric acid 2,5-dioxo pyrrolidyl-1-base.

HOOC-(CH ₂) ₁₈-COONSu: ω-carboxyl nonadecanoic acid 2,5-dioxo pyrrolidyl-1-base.

Embodiment 1

Derivative by the synthetic preparation of peptide GLP-2 peptide analogs

The peptide that combines with resin with complete protecting group is carried out acidylate, and it is de-protected only remaining the epsilon-amino group of acidylate on this peptide.Use Fmoc chemosynthesis band due care base with the resin-bonded peptide, for example:

↓ Boc-[1-33, Lys (Dde)]-resin

↓ 2% hydrazine/DMF handles to remove the Dde group

↓ usefulness Fmoc-Glu (γ-OH)-OBu ^tCarry out acidylate by HOAt/DIC/DIEA/NMP

↓ piperidines is handled to remove the Fmoc group

↓ carry out acidylate with C16 acid by HOAt/DIC/DIEA/NMP

↓ trifluoroacetic acid goes protection

↓ high performance liquid chromatography (HPLC) purifying

↓ lyophilize

↓ analyze with liquid chromatography mass coupling (LC-MS) and analysis high performance liquid chromatography

The length of spacer and fatty acid chain can be different.Under acylation location fixed situation, to three kinds of spacers: gamma-glutamic acid, γ-An Jidingsuan, Beta-alanine and do not have spacer; And three kinds of lipid acid (C12, C14 and C16) and cholic acid, lithocholic acid and amylbenzene formic acid are tested.

Synthesizing of the peptide-based resin of band protecting group:

Use the amino acid derivative of following band protecting group:

Fmoc-Ala-OH，Fmoc-Arg(Pmc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Asp(OBut)-OH，Boc-His(Boc)-OH，Fmoc-His(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Glu(OBut)-OH，Fmoc-Gly-OH，Fmoc-Ile-OH，Fmoc-Leu-OH，Fmoc-Lys(Boc)-OH，Fmoc-Lys(Dde)-OH，Boc-Lys(Fmoc)-OH，Fmoc-Met-OH，Fmoc-Phe-OH，Fmoc-Ser(But)-OH，Fmoc-Thr(But)-OH，Fmoc-Trp(Boc)-OH

N ^α-hexadecanoyl-Glu (ONSu)-OBut's is synthetic

Toward H-Glu (OH)-OBu ^t(4.2g, 20.6mmol), (2.65g 20.6mmol) dropwise adds Pal-ONSu (7.3g, DMF 20.6mmol) (100ml) solution in the suspension for DMF (500ml) and EDPA.Stirred reaction mixture is after 64 hours under the room temperature, and vacuum concentration to cumulative volume is 20ml.Aqueous citric acid solution with 10% (300ml) and ethyl acetate (250ml) are carried out layering to dried residue, separate two-phase.The resistates that obtains behind the organic phase vacuum concentration is dissolved in DMF (50ml).The solution that obtains is dropwise added 10% aqueous citric acid solution (500ml) that is kept at 0 ℃, and the compound that collecting precipitation gets off is placed on for twice in the vacuum drying oven dry with the frozen water cleaning.Dried compound is dissolved in DMF (45ml), and (2.15g 18.7mmol), adds N afterwards again in the mixture that obtains, N '-dicyclohexylcarbodiimide (3.5g, dichloromethane solution 17mmol) (67ml) to add HONSu.Stirred reaction mixture is 16 hours under the room temperature, and sedimentary compound is leached.Throw out is just obtained title compound (6.6g, 72%) from normal heptane/2-propyl alcohol recrystallization.

Embodiment 2

D3E/L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2's (1-33) is synthetic

2.a the peptide-based resin of band protecting group is synthetic

According to the Fmoc strategy; 431A type peptide synthesizer with the Applied Biosystems 0.25mmol of company scale; the FastMoc ultraviolet test scheme that employing company provides; the peptide-based resin of anamorphic zone protecting group; promptly adopt HBTU (2-(1 hydrogen-benzotriazole-1-base-1; l, 3,3 tetramethyl-urea hexafluorophosphates) coupling in NMP (N-Methyl pyrrolidone) of mediation and ultraviolet detection Fmoc blocking group goes protection.Be used for synthetic material resin (400mg) for (4-((2 ', 4 '-dimethoxy phenyl)-(Fmoc-Glu (OBut)-O-is to benzyloxy benzyl resin (Wang resin) (Novabiochem, Bad Soden, Germany, production number: 04-12-2052), displacement capacity 0.53mmol/g.

The amino acid derivative of the band protecting group of using is Fmoc-Ala-OH, Fmoc-Arg (Pmc)-OH, Fmoc-Asn (Trt)-OH; Fmoc-Asp (OBut)-OH, Boc-His (Boc)-OH, Fmoc-Gln (Trt)-OH; Fmoc-Glu (OBut)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH; Fmoc-Leu-OH, Fmoc-Lys (DDE)-OH, Fmoc-Met-OH; Fmoc-Phe-OH; Fmoc-Ser (But)-OH, Fmoc-Thr (But)-OH, Fmoc-Trp (Boc)-OH.

The peptide-based resin of output 870mg.

2.bDde removal and acidylate

With NMP (N-Methyl pyrrolidone) (2ml) and the N-Methyl pyrrolidone solution (10ml) of 2% hydrazine hydrate of prepared fresh add the peptide-based resin (290mg, 72 μ mol) of the band protecting group that from (1.a), obtains.Stirred reaction mixture is 3 minutes under the room temperature, filters then by (glas filter).In filter, add more hydrazine solution (22ml), hydrazine was reacted in filter 15 minutes, leach with vacuum pump afterwards.

Fully clean resin with N-Methyl pyrrolidone, methylene dichloride and N-Methyl pyrrolidone then.

With N-C ₁₆-Glu-α-OtBu-γ-ONSu (N ^α-hexadecanoyl-L-L-glutamic acid-α-tertiary butyl ester-γ-succinimide ester) (4eq) and DIEA (diisopropylethylamine) (4eq) add the de-protected resin of Dde that places N-Methyl pyrrolidone (≈ 5ml).Stirred reaction mixture is 1 hour under the room temperature, adds more N-C then ₁₆-Glu-α-OtBu-γ-ONSu (4eq) and DIEA (4eq).Stirred reaction mixture spends the night under the room temperature.Filter reaction mixture, resin fully cleans with N-Methyl pyrrolidone, methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether.

2.c cracking acylated peptide from the resin

With TFA (trifluoroacetic acid) (2ml), the mixture of tri isopropyl silane (50 μ l) and water (50 μ l) stirred 60 minutes under the peptide-based resin room temperature of band protecting group, peptide cracking from the peptide-based resin of protection is got off.Filter cleavage mixture, filtrate is concentrated to about 1ml with nitrogen gas stream, uses diethyl ether (49.5ml) that thick peptide is precipitated from oily matter, and diethyl ether cleans 3 times (3 50ml), and drying obtains white powder.

2.d the purifying of peptide:

Thick peptide is dissolved in uses NH ₄OH transfers to water/acetonitrile (65: 35) of 7.5 (100ml) with the pH value, carries out purifying with partly preparing HPLC on 25mm * 250mm post of having clogged 7 μ C-18 silica gel.With 50～70% acetonitrile 0.1% trifluoroacetic acid/water was washed post 47 minutes with the current gradient of 10ml/min down for 40 ℃.Collection contains the part elutriant of peptide, with the water dilution of three volumes, lyophilize.

With RPLC/ionspray mass spectrum (LC-MS) (retention time and molecular mass) and analysis RPLC (RP-HPLC) (quantity of retention time and peptide) end product that obtains is carried out signature analysis.Amino acid analysis has been determined the quantity of GLP-2 standard substance, then the UV-detector of peptide is reacted the quantity that just can calculate peptide with the reaction comparison of GLP-2 standard substance.(The Separations Group carries out RP-HPLC on Hesperia) and analyzes 214nm place ultraviolet detection at Vydac 218TP type 54 4.6mm * 250mm 5 μ C-18 silicagel columns.With 0.1% trifluoroacetic acid/water balance post, 42 ℃ are descended with 0～90% acetonitrile the current gradient wash-out of 0.1% trifluoroacetic acid/water with 0.5ml/min.The retention time that obtains is 35.8 minutes, and peptide output is 29.3mg.

Carry out LC-MS with Symmetry 3.0mm * 150mm 5 μ C-18 silicagel columns (Waters, MilfordMA., the U.S.) and analyze, wash post under the room temperature, speed is 1ml/min.With 5% acetonitrile/0.1% trifluoroacetic acid/water balance silicagel column, in 15 minutes with 5% acetonitrile/0.1% trifluoroacetic acid/water to 90% acetonitrile/0.1% trifluoroacetic acid/washing post.Except that 214nm place ultraviolet detection, part post elutriant is introduced PE-Sciex API 100 mass spectrometric ionspray interfaces.Whole process scanned in the mass range of 300-3000 atomic mass unit (amu) in per 2 seconds.Use these conditions, the retention time that ultraviolet is followed the trail of the product record is 6.1 minutes, and the molecular mass that records is 4204.4amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 3

Synthetic (carboxyl terminal adds lysine residue) of D3E/K30R/D33E/34K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33)

The step that is used for the synthetic material resin and is providing according to company is by Fmoc-Lys (Dde)-OH (Novabiochem, Bad Soden, Germany, production number: 01-64-0114) and 2-chloro-trityl chloride resins and Fmoc-Lys (Dde)-2 chloro-trityl resin (displacement capacity 1.13mmol/g) of coming.

According to the peptide-based resin (200mg, 85 μ mols) of Fmoc strategy, go protection and use N-C according to (2.b) described Dde that carries out according to embodiment (2.a) anamorphic zone protecting group ₁₆-Glu-α-OtBu-γ-ONSu (N ^α-hexadecanoyl-L-L-glutamic acid-α-tertiary butyl ester-γ-succinimide ester) carries out acidylate.According to (2.c and 2.d) cleavage of peptide and purifying from the resin.The retention time that obtains under (2.d) described elution requirement is 36.7 minutes, and peptide output is 1.3mg.

Product is carried out LC-MS analyze, it is 6.6 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4319.4amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 4

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2's (1-33) is synthetic

According to the peptide-based resin (200mg, 21 μ mols) of Fmoc strategy, use N-C according to (2.b) according to embodiment (2.a) anamorphic zone protecting group ₁₆-Glu-α-OtBu-γ-described method of ONSu acidylate is carried out Dde and is gone protection and use C ₁₆-GABA-ONSu (N-hexadecanoyl-gamma-amino-butyric acid succinimide ester) carries out acidylate, according to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 36.5 minutes, and peptide output is 1.9mg.

Product is carried out LC-MS analyze, it is 4.9 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4161.0amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 5

D3E/L17K (3-(hexadecanoyl amino) propionyl) K30R/D33E-GLP-2's (1-33) is synthetic

According to the peptide-based resin (200mg, 21 μ mols) of Fmoc strategy, and use N-C according to (2.b) according to embodiment (2.a) anamorphic zone protecting group ₁₆-Glu-α-OtBu-γ-described method of ONSu acidylate is carried out Dde and is gone protection and use C ₁₆-acyl group-β-Ala-ONSu (N-hexadecanoyl-Beta-alanine succinimide ester) carries out acidylate.According to (2.c and 2.d) cleavage of peptide purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 36.0 minutes, and peptide output is 2.8mg.

Product is carried out LC-MS analyze, it is 4.7 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4146.6amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 6

D3E/L17K (hexadecanoyl)/K30R/D33E-GLP-2's (1-33) is synthetic

According to the peptide-based resin (200mg, 21 μ mols) of Fmoc strategy, use N-C according to (2.b) according to embodiment (2.a) anamorphic zone protecting group ₁₆-Glu-α-OtBu-γ-described method of ONSu acidylate is carried out Dde and is gone protection and use C ₁₆-acyl-ONSu (hexadecanoic acid succinimide ester) carries out acidylate.According to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under according to (2.d) described elution requirement is 36.9 minutes, and peptide output is 2.6mg.

Product is carried out LC-MS analyze, it is 5.1 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4076.4amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 7

D3E/L17K (courage acyl group)/K30R/D33E-GLP-2's (1-33) is synthetic

According to the peptide-based resin (250mg, 27 μ mol) of embodiment (2.a) anamorphic zone protecting group, remove the Dde blocking group according to embodiment (2.b).

(1: 1v/v) mixture of (4ml) adds cholic acid (817mg), HOAt (N-hydroxyl-9-azepine benzotriazole) (135mg) and the mixture of DIC (N, N '-DIC) (155 μ l) with N-Methyl pyrrolidone and methylene dichloride.Stirred reaction mixture is 15 minutes under the room temperature, adds peptide-based resin and DIEA (diisopropylethylamine) (170 μ l) then.Stirred reaction mixture spends the night under the room temperature.Filter resin then, use N-Methyl pyrrolidone, thoroughly clean with methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether then.

According to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 30.0 minutes, and peptide output is 2.2mg.

Product is carried out LC-MS analyze, it is 4.2 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4228.2amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 8

1H ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/D3E/K30R/D33E-GLP-2's (1-33) is synthetic

8.a the peptide-based resin of band protecting group is synthetic:

According to the Fmoc strategy; 431A type peptide synthesizer with the Applied Biosystems 0.25mmol of company scale; the FastMoc ultraviolet test scheme that employing company provides; the peptide-based resin of anamorphic zone protecting group; promptly adopt HBTU (2-(1H-benzotriazole-1-base-1; 1,3,3 tetramethyl-urea hexafluorophosphates) Jie Dao coupling in NMP (N-Methyl pyrrolidone) and ultraviolet detection Fmoc blocking group go the protection.Be used for synthetic material resin (454mg, 0.25mmoles) be (4-((2 ', 4 '-dimethoxy phenyl)-(Fmoc-Glu (OBut)-O-is to benzyloxy benzyl resin (Wang resin) (Novabiochem, Bad Soden, Germany, production number: 04-12-2052), displacement capacity 0.55mmol/g.

The amino acid derivative of the band protecting group of using is Fmoc-Ala-OH, Fmoc-Arg (Pmc)-OH, Fmoc-Asn (Trt)-OH; Fmoc-Asp (OBut)-OH, Fmoc-His (Trt)-OH, Fmoc-Gln (Trt)-OH; Fmoc-Glu (OBut)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Ser (But)-OH; Fmoc-Thr (But)-OH, Fmoc-Trp (Boc)-OH.

The peptide-based resin of output 1707mg.

8.b acidylate

With N-C ₁₆-Glu-α-OtBu-γ-ONSu (N ^α-hexadecanoyl-L-L-glutamic acid-α-tertiary butyl ester-γ-succinimide ester) (4eq) and DIEA (diisopropylethylamine) (4eq) add the peptide-based resin (200mg, 29 micromoles) that places N-Methyl pyrrolidone (≈ 5ml).Stirred reaction mixture is 1 hour under the room temperature, adds more N-C then ₁₆-Glu-α-OtBu-γ-ONSu (4eq) and DIEA (4eq).Stirred reaction mixture spends the night under the room temperature, filter reaction mixture, and resin fully cleans with N-Methyl pyrrolidone, methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether.

According to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 37.0 minutes, and peptide output is 6.0mg.

Product is carried out LC-MS analyze, it is 6.5 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4189.8amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 9

H1K-N ^ε-((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/D3E/K30R/D33E-GLP-2's (1-33) is synthetic

9.a the peptide-based resin of band protecting group is synthetic:

According to the Fmoc strategy; 431A type peptide synthesizer with the Applied Biosystems 0.25mmol of company scale; the FastMoc ultraviolet test scheme that employing company provides; the peptide-based resin of anamorphic zone protecting group; promptly adopt HBTU (2-(1H-benzotriazole-1-base-1; 1,3,3 tetramethyl-urea hexafluorophosphates) Jie Dao coupling in NMP (N-Methyl pyrrolidone) and ultraviolet detection Fmoc blocking group go the protection.Be used for synthetic material resin (434mg, 0.24mmoles) be (4-((2 ', 4 '-dimethoxy phenyl)-(Fmoc-Glu (OBut)-O-is to benzyloxy benzyl resin (Wang resin) (Novabiochem, Bad Soden, Germany, production number: 04-12-2052), displacement capacity 0.55mmol/g.

The amino acid derivative of the band protecting group of using is Fmoc-Ala-OH, Fmoc-Arg (Pmc)-OH, Fmoc-Asn (Trt)-OH; Fmoc-Asp (OBut)-OH, Fmoc-His (Trt)-OH, Fmoc-Gln (Trt)-OH; Fmoc-Glu (OBut)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH; Fmoc-Leu-OH, Boc-Lys (Fmoc)-OH, Fmoe-Met-OH; Fmoc-Phe-OH; Fmoc-Ser (But)-OH, Fmoc-Thr (But)-OH, Fmoc-Trp (Boc)-OH.

The peptide-based resin of output 1551mg.

9.b acidylate

With N-C ₁₆-Glu-α-OtBu-γ-ONSu (N ^α-hexadecanoyl-L-L-glutamic acid-α-tertiary butyl ester-γ-succinimide ester) (4eq) and DIEA (diisopropylethylamine) (4eq) add the peptide-based resin (200mg, 31 micromoles) that places N-Methyl pyrrolidone (≈ 5ml).Stirred reaction mixture is 1 hour under the room temperature, adds more N-C then ₁₆-Glu-α-OtBu-γ-ONSu (4eq) and DIEA (4eq).Stirred reaction mixture spends the night under the room temperature, filter reaction mixture, and resin fully cleans with N-Methyl pyrrolidone, methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether.

According to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 36.8 minutes, and peptide output is 4.4mg.

Product is carried out LC-MS analyze, it is 6.5 minutes that ultraviolet is followed the trail of the retention time that records, and molecular mass is 4180.2amu, the molecular mass with envisioned configuration in the scope that the method test error allows consistent (± 1amu).

Embodiment 10

H1K-N ^α-((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl) base/D3E/K30R/D33E-GLP-2's (1-33) is synthetic

10.a the peptide-based resin of band protecting group is synthetic:

According to the Fmoc strategy; 431A type peptide synthesizer with the Applied Biosystems 0.25mmol of company scale; the FastMoc ultraviolet test scheme that employing company provides; the peptide-based resin of anamorphic zone protecting group; promptly adopt HBTU (2-(1H-benzotriazole-1-base-1; 1,3,3 tetramethyl-urea hexafluorophosphates) Jie Dao coupling in NMP (N-Methyl pyrrolidone) and ultraviolet detection Fmoc blocking group go the protection.Be used for synthetic material resin (455mg, 0.25 mmole) be (4-((2 ', 4 '-dimethoxy phenyl)-(Fmoc-Glu (OBut)-O-is to benzyloxy benzyl resin (Wang resin) (Novabiochem, Bad Soden, Germany, production number: 04-12-2052), displacement capacity 0.55mmol/g.

The amino acid derivative of the band protecting group of using is Fmoc-Ala-OH, Fmoc-Arg (Pmc)-OH, Fmoc-Asn (Trt)-OH; Fmoc-Asp (OBut)-OH, Fmoc-His (Trt)-OH, Fmoc-Gln (Trt)-OH; Fmoc-Glu (OBut)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH; Fmoc-Leu-OH, Fmoc-Lys (Dde)-OH, Fmoc-Met-OH; Fmoc-Phe-OH; Fmoc-Ser (But)-OH, Fmoc-Thr (But)-OH, Fmoc-Trp (Boc)-OH.

The peptide-based resin of output 1167mg.

10.b acidylate

With N-C ₁₆-Glu-α-OtBu-γ-ONSu (N ^α-hexadecanoyl-L-L-glutamic acid-α-tertiary butyl ester-γ-succinimide ester) (4eq) and DIEA (diisopropylethylamine) (4eq) add the peptide-based resin (200mg, 43 μ moles) that places N-Methyl pyrrolidone (≈ 5ml).Stirred reaction mixture is 1 hour under the room temperature, adds more N-C then ₁₆-Glu-α-OtBu-γ-ONSu (4eq) and DIEA (4eq).Stirred reaction mixture spends the night under the room temperature, filter reaction mixture, and resin fully cleans with N-Methyl pyrrolidone, methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether.

Remove Dde protectiveness group according to (2.b).

According to (2.c and 2.d) cleavage of peptide and purifying from the resin.

The retention time that obtains under (2.d) described elution requirement is 37.0 minutes, and peptide output is 4.4mg.

Signature analysis comprises the retention time of analyzing in the RP-HPLC system, the mensuration of molecular weight in retention time in the LC-MS system and the LC-MS system.By recently calculating the total amount of synthetic peptide mutually with GLP-2 standard substance peak area.Table 2 has been summed up the result who obtains.

The feature of table 2:HPLC and mass spectroscopy synthetic GLP-2 derivative.HPLC, rt (mn): analyze the retention time in the RP-HPLC system, minute being unit (square method).LS-MS, rt (mn): the retention time in the PR-HPLC/ ionspray mass spectrometer system, minute being unit (square method).MW: molecular weight.

Embodiment and compound number	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC， rt(mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)
Embodiment and compound number	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC， rt(mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)	????8		?[Glu ³，Arg ³⁰，Glu ³³]GLP-2	α-His1	?γ-Glu	N-C16 acyl group (Glu)	37.0	?6.5	?4189.8	?4190.2	?5.99
????10		?[Lys ¹，Glu ³，Arg ³⁰，Glu ³³]GLP-2	α-Lys1	?γ-Glu	N-C16 acyl group (Glu)	37.0	?6.5	?4180.2	?4181.3	?4.00	????8		?[Glu ³，Arg ³⁰，Glu ³³]GLP-2	α-His1	?γ-Glu	N-C16 acyl group (Glu)	37.0	?6.5	?4189.8	?4190.2	?5.99
????10		?[Lys ¹，Glu ³，Arg ³⁰，Glu ³³]GLP-2	α-Lys1	?γ-Glu	N-C16 acyl group (Glu)	37.0	?6.5	?4180.2	?4181.3	?4.00	????9		?[Lys ¹，Glu ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys1	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.4	?4180.2	?4181.3	?4.38
????11	????2	?[Lys ²，Glu ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys2	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.6	?4247.4	?4247.3	?4.41	????9		?[Lys ¹，Glu ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys1	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.4	?4180.2	?4181.3	?4.38
????11	????2	?[Lys ²，Glu ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys2	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.6	?4247.4	?4247.3	?4.41	????12	????2	?[Lys ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys3	?γ-Glu	N-C16 acyl group (Glu)	36.2	?6.2	?4189.8	?4189.3	?4.45
????13	????2	?[Glu ³，Lys ⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys4	?γ-Glu	N-C16 acyl group (Glu)	36.5	?6.6	?4261.8	?4261.4	?3.24	????12	????2	?[Lys ³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys3	?γ-Glu	N-C16 acyl group (Glu)	36.2	?6.2	?4189.8	?4189.3	?4.45
????13	????2	?[Glu ³，Lys ⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys4	?γ-Glu	N-C16 acyl group (Glu)	36.5	?6.6	?4261.8	?4261.4	?3.24	????14	????2	?[Glu ³，Lys ⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys5	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.4	?4231.8	?4231.3	?1.89
????15	????2	?[Glu ³，Lys ⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys6	?γ-Glu	N-C16 acyl group (Glu)	35.3	?6.3	?4169.4	?4171.2	?4.40	????14	????2	?[Glu ³，Lys ⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys5	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.4	?4231.8	?4231.3	?1.89
????15	????2	?[Glu ³，Lys ⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys6	?γ-Glu	N-C16 acyl group (Glu)	35.3	?6.3	?4169.4	?4171.2	?4.40	????16	????2	?[Glu ³，Lys ⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys7	?γ-Glu	N-C16 acyl group (Glu)	37.4	?6.6	?4231.6	?4230.9	?34.15
????17	????2	?[Glu ³，Lys ⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys8	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.5	?4204.2	?4202.8	?31.10	????16	????2	?[Glu ³，Lys ⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys7	?γ-Glu	N-C16 acyl group (Glu)	37.4	?6.6	?4231.6	?4230.9	?34.15
????17	????2	?[Glu ³，Lys ⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys8	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.5	?4204.2	?4202.8	?31.10	????18	????2	?[Glu ³，Lys ⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys9	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.5	?4189.8	?4189.3	?5.11
????19	????2	?[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	?γ-Glu	N-C16 acyl group (Glu)	35.4	?6.3	?4187.4	?4187.2	?10.08	????18	????2	?[Glu ³，Lys ⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys9	?γ-Glu	N-C16 acyl group (Glu)	36.8	?6.5	?4189.8	?4189.3	?5.11
????19	????2	?[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	?γ-Glu	N-C16 acyl group (Glu)	35.4	?6.3	?4187.4	?4187.2	?10.08	????20	????2	?[Glu ³，Lys ¹¹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys11	?γ-Glu	N-C16 acyl group (Glu)	37.2	?6.6	?4204.2	?4203.8	?35.50
????21	????2	?[Glu ³，Lys ¹²，Arg ³⁰，Glu ³³]GLP-2	ε-Lys12	?γ-Glu	N-C16 acyl group (Glu)	35.9	?6.8	?4216.2	?4217.3	?43.05	????20	????2	?[Glu ³，Lys ¹¹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys11	?γ-Glu	N-C16 acyl group (Glu)	37.2	?6.6	?4204.2	?4203.8	?35.50
????21	????2	?[Glu ³，Lys ¹²，Arg ³⁰，Glu ³³]GLP-2	ε-Lys12	?γ-Glu	N-C16 acyl group (Glu)	35.9	?6.8	?4216.2	?4217.3	?43.05	????22	????2	?[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	?γ-Glu	N-C16 acyl group (Glu)	35.6	?6.3	?4205.4	?4205.2	?1.56
????23	????2	?[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	?γ-Glu	N-C16 acyl group (Glu)	35.0	?6.4	?4205.4	?4205.2	?5.51	????22	????2	?[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	?γ-Glu	N-C16 acyl group (Glu)	35.6	?6.3	?4205.4	?4205.2	?1.56
????23	????2	?[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	?γ-Glu	N-C16 acyl group (Glu)	35.0	?6.4	?4205.4	?4205.2	?5.51	????24	????2	?[Glu ³，Lys ¹⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys15	?γ-Glu	N-C16 acyl group (Glu)	36.1	?6.4	?4204.2	?4203.3	?6.06
????25	????2	?[Glu ³，Lys ¹⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys16	?γ-Glu	N-C16 acyl group (Glu)	36.0	?6.4	?4204.2	?4204.3	?2.28	????24	????2	?[Glu ³，Lys ¹⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys15	?γ-Glu	N-C16 acyl group (Glu)	36.1	?6.4	?4204.2	?4203.3	?6.06
????25	????2	?[Glu ³，Lys ¹⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys16	?γ-Glu	N-C16 acyl group (Glu)	36.0	?6.4	?4204.2	?4204.3	?2.28	????2		?[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C16 acyl group (Glu)	35.8	?6.1	?4204.4	?4204.8	?29.30
????26	????2	?[Glu ³，Lys ¹⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys18	?γ-Glu	N-C16 acyl group (Glu)	35.7	?6.3	?4247.4	?4247.3	?6.51	????2		?[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C16 acyl group (Glu)	35.8	?6.1	?4204.4	?4204.8	?29.30
????26	????2	?[Glu ³，Lys ¹⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys18	?γ-Glu	N-C16 acyl group (Glu)	35.7	?6.3	?4247.4	?4247.3	?6.51	????27	????2	?[Glu ³，Lys ¹⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys19	?γ-Glu	N-C16 acyl group (Glu)	35.3	?6.2	?4250.7	?4247.3	?4.36
????28	????2	?[Glu ³，Lys ²⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys20	?γ-Glu	N-C16 acyl group (Glu)	37.5	?4.9	?4162.8	?4162.2	?2.33	????27	????2	?[Glu ³，Lys ¹⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys19	?γ-Glu	N-C16 acyl group (Glu)	35.3	?6.2	?4250.7	?4247.3	?4.36
????28	????2	?[Glu ³，Lys ²⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys20	?γ-Glu	N-C16 acyl group (Glu)	37.5	?4.9	?4162.8	?4162.2	?2.33	????29	????2	?[Glu ³，Lys ²¹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys21	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.3	?4204.2	?4203.3	?8.70
????30	????2	?[Glu ³，Lys ²²，Arg ³⁰，Glu ³³]GLP-2	ε-Lys22	?γ-Glu	N-C16 acyl group (Glu)	34.6	?6.6	?4170.6	?4171.2	?4.50	????29	????2	?[Glu ³，Lys ²¹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys21	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.3	?4204.2	?4203.3	?8.70
????30	????2	?[Glu ³，Lys ²²，Arg ³⁰，Glu ³³]GLP-2	ε-Lys22	?γ-Glu	N-C16 acyl group (Glu)	34.6	?6.6	?4170.6	?4171.2	?4.50	????31	????2	?[Glu ³，Lys ²³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys23	?γ-Glu	N-C16 acyl group (Glu)	35.0	?5.9	?4206.6	?4205.2	?0.82

Embodiment	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC，rt (mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)
Embodiment	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC，rt (mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)	????32	????2	[Glu ³，Lys ²⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys24	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.5	?4204.2	?4204.3	?5.40
????33	????2	[Glu ³，Lys ²⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys25	?γ-Glu	N-C16 acyl group (Glu)	35.7	?5.2	?4133.4	?4132.2	?2.40	????32	????2	[Glu ³，Lys ²⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys24	?γ-Glu	N-C16 acyl group (Glu)	36.3	?6.5	?4204.2	?4204.3	?5.40
????33	????2	[Glu ³，Lys ²⁵，Arg ³⁰，Glu ³³]GLP-2	ε-Lys25	?γ-Glu	N-C16 acyl group (Glu)	35.7	?5.2	?4133.4	?4132.2	?2.40	????34	????2	[Glu ³，Lys ²⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys26	?γ-Glu	N-C16 acyl group (Glu)	34.7	?6.0	?4206.6	?4205.2	?21.00
????35	????2	[Glu ³，Lys ²⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys27	?γ-Glu	N-C16 acyl group (Glu)	35.8	?6.1	?4205.4	?4205.2	?6.87	????34	????2	[Glu ³，Lys ²⁶，Arg ³⁰，Glu ³³]GLP-2	ε-Lys26	?γ-Glu	N-C16 acyl group (Glu)	34.7	?6.0	?4206.6	?4205.2	?21.00
????35	????2	[Glu ³，Lys ²⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys27	?γ-Glu	N-C16 acyl group (Glu)	35.8	?6.1	?4205.4	?4205.2	?6.87	????36	????2	[Glu ³，Lys ²⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys28	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.3	?4189.8	?4190.3	?17.20
????37	????2	[Glu ³，Lys ²⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys29	?γ-Glu	N-C16 acyl group (Glu)	36.4	?6.5	?4216.2	?4217.3	?4.26	????36	????2	[Glu ³，Lys ²⁸，Arg ³⁰，Glu ³³]GLP-2	ε-Lys28	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.3	?4189.8	?4190.3	?17.20
????37	????2	[Glu ³，Lys ²⁹，Arg ³⁰，Glu ³³]GLP-2	ε-Lys29	?γ-Glu	N-C16 acyl group (Glu)	36.4	?6.5	?4216.2	?4217.3	?4.26	????38	????2	[Glu ³，Lys ³⁰，Glu ³³]GLP-2	ε-Lys30	?γ-Glu	N-C16 acyl group (Glu)	38.1	?5.3	?4162.8	?4162.2	?12.69
????39	????2	[Glu ³，Arg ³⁰，Lys ³¹，Glu ³³]GLP-2	ε-Lys31	?γ-Glu	N-C16 acyl group (Glu)	36.0	?6.5	?4204.2	?4205.2	?2.85	????38	????2	[Glu ³，Lys ³⁰，Glu ³³]GLP-2	ε-Lys30	?γ-Glu	N-C16 acyl group (Glu)	38.1	?5.3	?4162.8	?4162.2	?12.69
????39	????2	[Glu ³，Arg ³⁰，Lys ³¹，Glu ³³]GLP-2	ε-Lys31	?γ-Glu	N-C16 acyl group (Glu)	36.0	?6.5	?4204.2	?4205.2	?2.85	????40	????2	[Glu ³，Arg ³⁰，Lys ³²，Glu ³³]GLP-2	ε-Lys32	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.3	?4216.2	?4217.2	?8.23
????41	????2	[Glu ³，Arg ³⁰，Lys ³³]GLP-2	ε-Lys33	?γ-Glu	N-C16 acyl group (Glu)	36.9	?6.6	?4188.6	?4189.3	?2.08	????40	????2	[Glu ³，Arg ³⁰，Lys ³²，Glu ³³]GLP-2	ε-Lys32	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.3	?4216.2	?4217.2	?8.23
????41	????2	[Glu ³，Arg ³⁰，Lys ³³]GLP-2	ε-Lys33	?γ-Glu	N-C16 acyl group (Glu)	36.9	?6.6	?4188.6	?4189.3	?2.08	????3		[Glu ³，Arg ³⁰，Glu ³³，Lys ³⁴]GLP-2	ε-Lys34	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.6	?4319.4	?4318.4	?1.30
????42	????2	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C14 acyl group (Glu)	33.5	?4.7	?4177.8	?4177.8	?2.05	????3		[Glu ³，Arg ³⁰，Glu ³³，Lys ³⁴]GLP-2	ε-Lys34	?γ-Glu	N-C16 acyl group (Glu)	36.7	?6.6	?4319.4	?4318.4	?1.30
????42	????2	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C14 acyl group (Glu)	33.5	?4.7	?4177.8	?4177.8	?2.05	????43		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C12 acyl group (Glu)	31.9	?4.4	?4149.0	?4148.8	?8.17
????5		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C16 acyl group (β Ala)	36.0	?4.7	?4146.6	?4147.6	?2.80	????43		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?γ-Glu	N-C12 acyl group (Glu)	31.9	?4.4	?4149.0	?4148.8	?8.17
????5		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C16 acyl group (β Ala)	36.0	?4.7	?4146.6	?4147.6	?2.80	????44	????5	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C14 acyl group (β Ala)	34.0	?4.3	?4119.6	?4119.7	?1.19
????45	????5	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C12 acyl group (β Ala)	32.2	?4.3	?4091.4	?4091.6	?0.87	????44	????5	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C14 acyl group (β Ala)	34.0	?4.3	?4119.6	?4119.7	?1.19
????45	????5	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?β-Ala	N-C12 acyl group (β Ala)	32.2	?4.3	?4091.4	?4091.6	?0.87	????6		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C16 acyl group	36.9	?5.1	?4076.4	?4076.1	?2.63
????46	????6	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C14 acyl group	34.7	?4.7	?4049.4	?4047.7	?1.63	????6		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C16 acyl group	36.9	?5.1	?4076.4	?4076.1	?2.63
????46	????6	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C14 acyl group	34.7	?4.7	?4049.4	?4047.7	?1.63	????47	????6	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C12 acyl group	32.9	?4.4	?4020.4	?4019.7	?4.25
????4		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C16 acyl group (GABA)	36.5	?4.9	?4161.0	?4161.2	?1.96	????47	????6	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	The N-C12 acyl group	32.9	?4.4	?4020.4	?4019.7	?4.25
????4		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C16 acyl group (GABA)	36.5	?4.9	?4161.0	?4161.2	?1.96	????48	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C14 acyl group (GABA)	34.3	?4.5	?4133.4	?4132.8	?6.04
????49	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C12 acyl group (GABA)	32.5	?4.3	?4104.6	?4104.8	?1.87	????48	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C14 acyl group (GABA)	34.3	?4.5	?4133.4	?4132.8	?6.04
????49	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?GABA	N-C12 acyl group (GABA)	32.5	?4.3	?4104.6	?4104.8	?1.87	????50	????7	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	N-stone courage acyl group	32.7	?4.5	?4196.0	?4195.8	?1.41
????7		[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	N-courage acyl group	30.0	?4.2	?4228.2	?4227.8	?2.18	????50	????7	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	?none	N-stone courage acyl group	32.7	?4.5	?4196.0	?4195.8	?1.41

Embodiment	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC， rt(mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)
Embodiment	Preparation is according to embodiment	Peptide	The acyl group site	Spacer	Lipid acid	HPLC， rt(mn)	?LC-MS， ?rt(mn)	The MW that records	The MW that calculates	Total amount (mg)	????51	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	GABA	N-4-amylbenzene formyl radical (GABA)	31.1	?4.2	?4097.4	?4096.6	?7.97
????52	????4	[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	GABA	N-C12 acyl group (GABA)	33.1	?4.4	?4104.6	?4104.8	?1.25	????51	????4	[Glu ³，Lys ¹⁷，Arg ³⁰，Glu ³³]GLP-2	ε-Lys17	GABA	N-4-amylbenzene formyl radical (GABA)	31.1	?4.2	?4097.4	?4096.6	?7.97
????52	????4	[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	GABA	N-C12 acyl group (GABA)	33.1	?4.4	?4104.6	?4104.8	?1.25	????53	????5	[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	β-Ala	N-C12 acyl group (β Ala)	31.8	?4.3	?4092.0	?4091.4	?6.01
????54	????4	[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	GABA	N-C12 acyl group (β Ala)	32.0	?4.5	?4105.8	?4104.8	?22.16	????53	????5	[Glu ³，Lys ¹⁴，Arg ³⁰，Glu ³³]GLP-2	ε-Lys14	β-Ala	N-C12 acyl group (β Ala)	31.8	?4.3	?4092.0	?4091.4	?6.01
????54	????4	[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	GABA	N-C12 acyl group (β Ala)	32.0	?4.5	?4105.8	?4104.8	?22.16	????55	????5	[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	β-Ala	N-Cl2 acyl group (β Ala)	32.0	?4.4	?4090.4	?4091.4	?1.32
????56	????4	[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	GABA	N-C12 acyl group (β Ala)	32.3	?4.5	?4087.6	?4086.8	?26.18	????55	????5	[Glu ³，Lys ¹³，Arg ³⁰，Glu ³³]GLP-2	ε-Lys13	β-Ala	N-Cl2 acyl group (β Ala)	32.0	?4.4	?4090.4	?4091.4	?1.32
????56	????4	[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	GABA	N-C12 acyl group (β Ala)	32.3	?4.5	?4087.6	?4086.8	?26.18	????57	????5	[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	β-Ala	N-C12 acyl group (β Ala)	32.0	?4.5	?4073.4	?4073.6	?30.53
????58	????5	[Glu ³，Leu ¹⁰，Lys ¹⁷，Arg ³⁰，Glu ³³] GLP-2	ε-Lys17	β-Ala	N-C14 acyl group (β Ala)	34.5	?4.7	?4101.6	?4101.7	?19.78	????57	????5	[Glu ³，Lys ¹⁰，Arg ³⁰，Glu ³³]GLP-2	ε-Lys10	β-Ala	N-C12 acyl group (β Ala)	32.0	?4.5	?4073.4	?4073.6	?30.53

Embodiment 2

Synthesizing of construction unit:

Construction unit 1 octadecane dicarboxylic acid list tertiary butyl ester:

Octadecane dicarboxylic acid (3g adds toluene (25ml) and N in 8.76mmol), N dimethyl formamide di-t-butyl acetal (2.1mL, 8.76mmol).Mixture heating up to 95 ℃, 30 minutes, with the hybrid filtering thing, be evaporated to oily, it is dissolved in methylene dichloride again and water cleans.Dry organic phase, evaporation obtains the title compound (21%) of 722mg, does not carry out any being further purified and is used for following embodiment.

¹H?NMR(CDCl ₃)：δ10.90(br?s，lH)，2.35(t，2H)，20(t，2H)，1.60(m，4H)，1.45(s，9H)；1.40-1.20(m，28H)

L17K (3-(ω-carboxyl pentadecanoyl amino) propionyl) K30R/D33E-GLP-2's (1-33) is synthetic

59.a the peptide-based resin of band protecting group is synthetic:

According to the Fmoc strategy; 431A type peptide synthesizer with the Applied Biosystems 0.25mmol of company scale; the FastMoc ultraviolet test scheme that employing company provides; the peptide-based resin of anamorphic zone protecting group; promptly adopt HBTU (2-(1H-benzotriazole-1-base-1; 1,3,3 tetramethyl-urea hexafluorophosphates) Jie Dao coupling in NMP (N-Methyl pyrrolidone) and ultraviolet detection Fmoc blocking group go the protection.Be used for synthetic material resin (400mg) for (4-((2 ', 4 '-dimethoxy phenyl)-(Fmoc-Glu (OBut)-O-is to benzyloxy benzyl resin (Wang resin) (Novabiochem, Bad Soden, Germany, production number: 04-12-2052), displacement capacity 0.53mmol/g.

The amino acid derivative of the band protecting group of using is Fmoc-Ala-OH, Fmoc-Arg (Pmc)-OH, Fmoc-Asn (Trt)-OH; Fmoc-Asp (OBut)-OH, Boc-His (Boc)-OH, Fmoc-Gln (Trt)-OH; Fmoc-Glu (OBut)-OH, Fmoc-(FmocHmb) Gly-OH, Fmoc-Ile-OH; Fmoc-Leu-OH, Fmoc-Lys (DDE)-OH, Fmoc-Met-OH; Fmoc-Phe-OH; Fmoc-Ser (But)-OH, Fmoc-Thr (But)-OH, Fmoc-Trp (Boc)-OH.

59.bDde removal and acidylate

The peptide-based resin (300mg, 75 μ mol) that the N-Methyl pyrrolidone solution (12ml) of 2% hydrazine hydrate of prepared fresh is added the band protecting group that from (59.a), obtains.Jolted reaction mixture under the room temperature 3 minutes, and filtered then.Add more hydrazine solution (20ml) in filter, reaction mixture jolts 15 minutes, filters then.(5 * 20mL) fully clean resin with N-Methyl pyrrolidone.

The Fmoc-Beta-alanine (93mg, 0.30mmol), 3-hydroxyl-1,2,3-phentriazine-4 (3H)-ketone (49mg, 0.30mmol) and diisopropylethylamine (13 μ L 0.075mmol) are dissolved in N-Methyl pyrrolidone (20ml), add Dde then and remove to protect resin.Add N, (46 μ L 0.3mmol), jolt mixture overnight to N '-DIC.Filter resin, and (5 * 20mL) clean with N-Methyl pyrrolidone.With piperidines (20% N-Methyl pyrrolidone solution, 20mL) process resin is 10 minutes, (20% N-Methyl pyrrolidone solution 20mL) is handled 10 minutes to use piperidines afterwards again.Filter resin, (5 * 20mL) clean to use N-Methyl pyrrolidone then.

(107mg 0.3mmol) is dissolved in N-Methyl pyrrolidone (20mL) to Thapsic acid list-(2,5-dioxo pyrrolidyl-1-yl) ester (people EP511600 such as Ebashi), joins then in the resin, and room temperature jolts spends the night.Filter reaction mixture fully cleans resin with N-Methyl pyrrolidone, methylene dichloride, 2-propyl alcohol, methyl alcohol and diethyl ether.

2.c cracking acylated peptide from the resin

With TFA (trifluoroacetic acid) (20ml), the mixture (500 μ l) of tri isopropyl silane (500 μ l) and water stirred 60 minutes under the peptide-based resin room temperature of band protecting group, peptide cracking from the resin is got off.Filter cleavage mixture, filtrate is concentrated to 2ml with nitrogen gas stream, uses diethyl ether (10ml) that thick peptide is precipitated from 2ml oily matter, and diethyl ether cleans 3 times (3 10ml), and drying obtains white powder.

2.d the purifying of peptide:

Thick peptide is dissolved in uses NH ₄OH transfers to water/acetonitrile (65: 35) of 7.5 with the pH value, carries out purifying with partly preparing HPLC on the 25mm that has clogged C-18 silica gel * 250mm post.Acetonitrile with 43～60% under the room temperature was washed post 40 minutes to 0.1% trifluoroacetic acid/water with the current gradient of 10ml/min.Collection contains the part elutriant of peptide, with the water dilution of three volumes, lyophilize.It is 21mg that the mensuration dry weight obtains output.

With RPLC/ionspray mass spectrum (liquid chromatography mass coupling) (LC-MS) (retention time and molecular mass) end product that obtains is carried out signature analysis.

Carry out LC-MS with Symmetry 3.0mm * 150mm 5 μ C-18 silicagel columns (Waters, MilfordMA., the U.S.) and analyze, wash post under the room temperature, speed is 1ml/min.With 5% acetonitrile/0.1% trifluoroacetic acid/water balance silicagel column, in 10 minutes with 5% acetonitrile/0.1% trifluoroacetic acid/water to 90% acetonitrile/0.1% trifluoroacetic acid/washing post.Except that 214nm place ultraviolet detection, part post elutriant is introduced PE-Sciex API 100 mass spectrometric ionspray interfaces.Whole process scanned in the mass range of 300-3000 atomic mass unit (amu) in per 2 seconds.

Use these conditions, the retention time that ultraviolet is followed the trail of the product record is 3.84 minutes, and the molecular mass peak of identifying is 1042.1 (m/4) and 1388.6 (m/3), the molecular mass with envisioned configuration in the scope of method test error permission consistent (± 1amu).

Embodiment 60

L17K (3-(ω-carboxyl 19 acyl aminos) propionyl) K30R/D33E-GLP-2's (1-33) is synthetic

According to the Fmoc strategy, according to the peptide-based resin (100mg, 25 μ mol) of embodiment (59.a) anamorphic zone protecting group, and go protection and carry out acidylate with the Fmoc-Beta-alanine according to (59.b) described Dde of carrying out, remove the Fmoc group afterwards.The step of carrying out acylation reaction with the octadecane dicarboxylic acid list tert-butyl ester is as follows.With the octadecane dicarboxylic acid list tert-butyl ester (40mg; 0.1mmol), 3-hydroxyl-1; 2; 3-phentriazine-4 (3H)-ketone (16mg, 0.1mmol) and diisopropylethylamine (4 μ L 0.025mmol) are dissolved in N-Methyl pyrrolidone (2ml); join Fmoc then and remove to protect resin; (15 μ L 0.1mmol), jolt mixture overnight to add DIC.

According to (59.c and 59.d) cleavage of peptide and purifying from the resin.

With RPLC/ionspray mass spectrum (LC-MS) (retention time and molecular mass) and analysis RPLC (RP-HPLC) (quantity of retention time and peptide) end product that obtains is carried out signature analysis.Amino acid analysis has been determined the quantity of GLP-2 standard substance, then the UV-detector of peptide is reacted the quantity that just can calculate peptide with the reaction comparison of GLP-2 standard substance.(TheSeparations Group Hesperia) carries out rp-hplc analysis, 214nm place ultraviolet detection with Vydac 218TP54 4.6mm * 250mm 5 μ C-18 silicagel columns.With 0.1% trifluoroacetic acid/water balance silicagel column, with 0～90% acetonitrile 0.1% trifluoroacetic acid/water is washed post with the current gradient of 0.5ml/min down for 42 ℃.The retention time that obtains is 35.0 minutes, and peptide output is 100 μ g.

Carry out LC-MS and analyze under described the same terms according to 59.d, it is 4.25 minutes that ultraviolet is followed the trail of the retention time that records, and the molecular mass peak of identifying is 1055.1 (m/4) and 1407.6 (m/3), and is consistent with the molecular mass of envisioned configuration.

Embodiment 61

The yeast recombinant technology prepares the GLP-2 peptide analogs

Yeast expression system

The host's strain that is used for expressing the GLP-2 precursor is a polyploid strain, is called ME1719.The phenotype of ME1719 lacks two aspartate proteases, that is, and and (1) yapsin1 (being called YAP3p in the past), carboxyl terminal (Egel-Mitani, M, Flygenring, the H.A.﹠amp of cracking list or two alkaline amino acid residues; Hansen, M.T., YEAST 6:127-137,1990) and (2) cavity protease A (Pralp), for example proteolytic enzyme B, carboxypeptidase y, aminopeptidase I, rnase, L-Ala Phosphoric acid esterase, acid trehalosease and circumscribed polyphosphoric acid enzyme of the proteolytic enzyme of being responsible for activating other.ME1719 a large amount production very stably contains the small-molecular peptides of single or two basic aminoacidss.Utilize this yeast strains in other peptide classes of for example hyperglycemic-glycogenolytic factor and GLP-1, GLP-2 the most favourable (Egel-Mitani,, M., Brandt, J. and Vad, K.: the preparation method of polypeptide sees US 6,110,703,29.08.2000, and Egel-Mitani, M., Anderson, A.S., Diers, I, Haeh, M., Thim, L., Hastrup, S. and Vad, K.:Enzyme and MicrobialTechnology 26:671-677,2000).In addition, in this yeast strains, (TPI1) is destroyed for phosphotriose isomerase gene, and this phenotype makes becomes possibility with glucose as the selected marker of Yeast transformant, thereby can access high biological yield, is that the middle output of continuously fermenting so far is high.

In order in yeast saccharomyces cerevisiae (S.cerevisiae), to express human GLP-2, quote the production that the yeast codon usage is optimized GLP-2, the human amino acid sequence in the yeast saccharomyces cerevisiae obtains from EMBL (V01515 HSGLUC).In the present embodiment, the data of four GLP-2 peptide analogs expression plasmids comprise: 1) A2G-GLP-2 (1-33), 2) M10K/K30R-GLP-2 (1-33), 3) M10L/L17K/K30R-GLP-2 (1-33), 4) L17K/K30R-GLP-2 (1-33).

According to wild-type human amino acid sequence (HADGSFSDEMNTILDNLAARDFINWLIQTKITD) and corresponding yeast codon usage DNA and amino acid are suddenlyd change.The dna sequence dna of GLP-2 peptide analogs is inserted expression vector (Fig. 7).As shown in Figure 7, the expression of GLP-2 is driven by TPI promotor and MF signal-leader sequence, is the GLP-2 encoding sequence that inserts NcoI and XbaI restriction enzyme site with that.The step for preparing DNA construct by the polymerase chain reaction that uses Auele Specific Primer is well-known (referring to PCRProtocols to the person skilled in art, 1990, Academic Press, San Diego, California, USA), be used for preparation according to any one GLP-2 peptide analogs of the present invention.

The mensuration of fermentation and output

For small-scale a collection of culture, the YPD that transformant is inoculated into 5ml adds Ca ²⁺Substratum (1% yeast extract, 2% peptone, 5mM CaCl ₂), jolt (200rpm) at 30 ℃ and cultivated three days.Behind the centrifugation cell, HPLC analyzes culture supernatant.Use following HLPC method:

Post: C4 Jupiter, 300 , 5um, 4,6 * 250mm

Buffer A: 0.10% trifluoroacetic acid

Buffer B: the acetonitrile solution of 0.07% trifluoroacetic acid

Flow velocity: 1ml/min

Gradient: 30-60%B in 15 minutes, room temperature.

Obtain the output of following GLP-2 peptide analogs in ME1729 host's strain small-scale (5ml) nutrient solution:

Construct	Plasmid	Yeast transformant	Output
Construct	Plasmid	Yeast transformant	Output	?A2G-GLP-2(1-33)	pKV220	?YES2651	?13.0mg/L
?M10K/K30R-GLP-2(1-33)	pME2794	?YES2795	?32.8mg/L	?A2G-GLP-2(1-33)	pKV220	?YES2651	?13.0mg/L
?M10K/K30R-GLP-2(1-33)	pME2794	?YES2795	?32.8mg/L	?M10L/L17K/K30R-GLP-2(1-33)	pME2765	?YES2766	?36.6mg/L
?L17K/K30R-GLP-2(1-33)	pME2735	?YES2736	?33.9mg/L	?M10L/L17K/K30R-GLP-2(1-33)	pME2765	?YES2766	?36.6mg/L

Purifying and signature analysis

All GLP-2 peptide analogs can use following total purification scheme to carry out purifying according to the present invention:

????No	Step	Ultimate production
????No	Step	Ultimate production
????1	Fermented liq	????100％
????1	Fermented liq	????100％	????
????2	Catch post	????75％	????
????2	Catch post	????75％	????
????3	Precipitation	????71％	????
????3	Precipitation	????71％	????
????4	Hydroxyapatite column	????60％	????
????4	Hydroxyapatite column	????60％	????
????5	The Source30Q post	????53％	????
????5	The Source30Q post	????53％	????
????6	The RP-HPLC post	????45％	????
????6	The RP-HPLC post	????45％	????
????7	Precipitation	????43％	????

Analyze the peptide of purifying with amino acid sequence analysis and mass spectrum.Use Applied Biosystem494 type protein sequencing instrument, the explanation that provides according to company is basically measured N-terminal aminoacid sequence with the automatic edman degradation method.If use optimized system, just might measure the partial sequence that resembles the so few peptide of 300-500fmol.

(Perseptive Biosystems Inc., Framingham MA) carries out mass spectroscopy with the Voyager RP MALDI-TOF instrument of being furnished with nitrogen laser (337nm).Extract with this instrument of linear mode operation with time-delay, ionogenic acceleration voltage is 25kV.

Be prepared as follows sample: 1 μ l sample solution and 1 μ l matrix solution (alpha-cyano-4-hydroxycinnamic acid is dissolved in 5: 4: 1 (v/v/v) acetonitrile: water: the mixture of 3% (v/v) trifluoroacetic acid) mix after, get 1 μ l and be placed on the sample panel, make its drying.Calibrate with outer standard substance, the accuracy of quality determination is within 0.1%.

Peptide	The MW that records	The MW that calculates
Peptide	The MW that records	The MW that calculates	Natural GLP-2	3767	?3766.2
?A2G-GLP-2(1-33)	3751	?3752.1	Natural GLP-2	3767	?3766.2
?A2G-GLP-2(1-33)	3751	?3752.1	?M10K/K30R-GLP-2(1-33)	3793	?3805.2
?M10L/L17K/K30R-GLP-2(1-33)	3793	?3791.2	?M10K/K30R-GLP-2(1-33)	3793	?3805.2
?M10L/L17K/K30R-GLP-2(1-33)	3793	?3791.2	?L17K/K30R-GLP-2(1-33)	3809	?3809.2

The GLP-2 peptide that is made by the yeast recombinant technology prepares the GLP-2 derivative

With following general procedure the GLP-2 peptide that makes from the yeast recombinant technology is carried out acidylate:

Under 4 ℃, the peptide after the 50mg lyophilize is dissolved in the 3.2ml water.Sodium hydroxide with 1M is transferred pH to 12.2.Solution was placed 2 minutes at 10 ℃, transferred pH to 9.5 with the acetic acid of 1M.After adding the N-N-methyl-2-2-pyrrolidone N-(NMP) of 7ml4 ℃ of refrigeration, temperature is transferred to 10 ℃.Transfer pH to 11.5 with triethylamine.(for example Pal-β-Ala-ONSu) is dissolved in N-Methyl pyrrolidone, concentration 20mg/ml to acylating reagent.This solution of 0.78ml is added peptide solution, and 15 ℃ of following stirrings were proceeded acylation reaction in 15 minutes.The glycine solution stopped reaction that adds 0.65ml 100mg/ml is transferred pH to 8.5 with 5M acetic acid.RP-HPLC purifying acidylate GLP-2 peptide analogs.According to present embodiment, the example of operable different acylating reagent includes but not limited to:

Lau-Glu (ONSu)-OBu ^t: N ^α-lauroyl-L-L-glutamic acid α-tertiary butyl ester γ-2,5-dioxo pyrrolidyl-1-base ester.

Pal-Glu (ONSu)-OBu ^t: N ^α-hexadecanoyl-(L)-L-glutamic acid α-tertiary butyl ester-γ-2,5-dioxo pyrrolidyl-1-base diester.

Lau-β-Ala-ONSu:N ^β-lauroyl-Beta-alanine 2,5-dioxo pyrrolidyl-1-base ester.

Lau-GABA-ONSu:N ^γ-lauroyl-γ-An Jidingsuan 2,5-dioxo pyrrolidyl-1-base ester.

The purifying and the signature analysis of acidylate GLP-2 peptide analogs (GLP-2 derivative):

Analogue with following global schema purifying acidylate:

	Step	Ultimate production
	Step	Ultimate production
????1	The analogue peptide of GLP-2 peptide	????100％
????1	The analogue peptide of GLP-2 peptide	????100％	?
????2	Acidylate	????77％	?
????2	Acidylate	????77％	?
????3	The RP-HPLC post	????63％	?
????3	The RP-HPLC post	????63％	?
????4	Precipitation	????58％	?
????4	Precipitation	????58％	?
????5	Dissolving and lyophilize	????51％	?

According to the mass spectrometry of having stated the analogue of acidylate is carried out signature analysis.

Embodiment 62

Carry out biological activity determination with mouse.The dose-response research of GLP-2 derivative.

Table 3. pair dosage and carry out the model parameter estimation value that nonlinear regression analysis obtains with respect to the small intestine weight of body weight.

Table 4. pair dosage and small intestine weight are carried out the model parameter estimation value that nonlinear regression analysis obtains.

Table 5. gives body weight, small intestine weight and the relative small intestine weight of L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) mouse.

Table 6. gives body weight, small intestine weight and the relative small intestine weight of L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) mouse.

Table 7. gives body weight, small intestine weight and the relative small intestine weight of A2G-GLP-2 (1-33) mouse.

The body weight of table 8. control mice, small intestine weight and relative small intestine weight.

The GLP-2 derivative is being developed with platform and is treating some gastrointestinal tract disease, comprises little bowel syndrome.

The purpose of this research is to set up the dose-response relationship of the derivative induced small intestine growth of GLP-2 in mouse; method is to adopt subcutaneous derivative L 17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33), L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and A2G-GLP-2 (1-33), totally 10 days of giving every day.

Tested following GLP-2 derivative and analogue:

(1.L17K 3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)

(2.L17K 3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)

3.A2G-GLP-2(1-33)

All derivatives are dissolved in and contain Sodium phosphate dibasic 1.42mg/ml, N.F,USP MANNITOL 36.9mg/ml, phenol 5mg/ml, the damping fluid of pH8.0, and dilute with this damping fluid.

189 female C57b1 mouse have been used in this research.All animals are divided into four groups:

Group 1: contrast

Group 2:L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)

Group 3:L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)

Group 4:A2G-GLP-2 (1-33)

Dosage

All animal subcutaneous injection every day 100 μ l, totally 10 days, dosage was as follows:

		Dosage-μ g
		Dosage-μ g							Group	Treatment	A	?B	?C	?D	?E	?F	G
?1	Contrast	Physiological saline							Group	Treatment	A	?B	?C	?D	?E	?F	G
?1	Contrast	Physiological saline							?2	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	22	?11	?5.5	?2.75	?1.375	?0.678	?0.344
?3	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	35	?17.5	?8.75	?4.375	?2.188	?1.094	?0.547	?2	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	22	?11	?5.5	?2.75	?1.375	?0.678	?0.344
?3	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	35	?17.5	?8.75	?4.375	?2.188	?1.094	?0.547	?4	A2G-GLP-2(1-33)	33	?16.5	?8.25	?4.125	?2.063	?1.031	?0.512

Sampling

The 10th day all mouse weighed before putting to death, and carefully takes out the intestines and internal organs of the body of every mouse, separates the small intestine part, with normal saline flushing and weigh.

Data analysis

Report the body weight, small intestine weight of all mouse and with respect to the small intestine weight of body weight, and be used for setting up dose-response relationship.Calculate the increased value of the absolute and relative small intestine weight that each treatment group causes because of treatment, because this is considered to the relevant effectiveness parameters of pharmacology.

The dose-response model adopts general Michaelis-Menten model, the E of background level of performance when it has the shape factor γ of corresponding Hillslope in the semilog dose-response curve and represents D=0 ₀Emax is observed maximum effect, ED ₅₀For producing the dosage of 50%Emax.Using this model is because compare it with four parameter log10 dose-reaction models (1) better adaptability to be arranged.This model is fit in order to determine E _Max, ED ₅₀, γ and E ₀Estimated value and use the data of non-linear regression.

E = \frac{E_{\max} \cdot D^{γ}}{{ED}_{50}^{γ} + D^{γ}} + E_{0}

Suitable degree has shown that by visual inspection the figure of observed data point and matched curve and residual plot estimate, and provide estimates of parameters and threshold value % and 95% fiducial limit.

For the mutability of background efficacy levels is described, contrasting data is included in the nonlinear regression analysis, as the D=0 of all three treatment groups.

Use professional WinNonlin, 3.1 editions, Pharsight carries out nonlinear regression analysis.Carry out non-linear regression with Gauss-Newton (Levenberg and Hartley) algorithm.

The result

Table 5-8 has shown body weight, small intestine weight and the relative small intestine weight of each dosage level and all animals of treatment group.

Table 3 with 4 and Fig. 8-11 shown the result that small intestine weight and relative small intestine weight data are carried out nonlinear regression analysis and the match of dose-response model curve.

By Fig. 8 and 10 visible dose-response relationships.When using small intestine weight with relative small intestine weight during as effectiveness parameters; also can observe similar dose-response curve at derivative L 17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) with L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), point out treatment the influence of body weight not to be damaged the dose-response relationship of any one derivative.But, when using small intestine weight, observe tangible Emax-platform as effectiveness parameters for A2G-GLP-2 (1-33).This does not observe in relative small intestine weight, and the prompting treatment is influential to body weight, and perhaps level of performance and background level difference are not remarkable.

Fitting of a curve prompting among Fig. 8 and 10 is for all three test-compounds, and this model has been described the dose-response relationship of small intestine weight with dosage and relative small intestine weight and dosage fully.Systematic trend does not appear in Fig. 9 and 11 the residual plot.So not observing the model mistake establishes.

Table 3 and estimates of parameters in 4 have shown when examination small intestine weight during with relative small intestine weight data, to E ₀The estimation of level has quite high precision (CV%＜5).L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and L17K (3-(hexadecanoyl amino) propionyl)/Emax estimated value that K30R-GLP-2 (1-33) obtains are all than A2G-GLP-2 (1-33) height.When using relative small intestine weight as effectiveness parameters; compare with A2G-GLP-2 (1-33); L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and the L17K Emax that (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) obtains have increased by 33% and 16% respectively; when using small intestine weight, increased by 67% and 34%.

In curve fitting process, the increase of the small intestine weight that definite treatment causes and the increase (Emax-E0) of relative small intestine weight are as second parameter.Compare with A2G-GLP-2 (1-33); at L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33), small intestine weight has increased by 1.7 and 2.5 times respectively relatively.When measuring absolute small intestine weight, 4.9 and 8.6 times have been raise respectively.

At the ED that estimates A2G-GLP-2 (1-33) ₅₀The time observe lower precision because difference is little between background level and the Emax level, and using under the relative small intestine weight data situation, be because fail to obtain dose-response curve completely.This is at L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) also necessary being, because the effect that used lowest dose level causes is equivalent to the 30-40% of Emax on some degree.The shortage of the initial portion information of dose-response curve can reduce estimates ED ₅₀The precision of value.Usually, the L17K that obtains (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) ED ₅₀Estimated value can compare with the estimated value of A2G-GLP-2 (1-33) in size, and little a lot.Yet, because ED ₅₀Variation is big, and it is very difficult that estimation is tried the relative potency of derivative.

In a word, compare with A2G-GLP-2 (1-33), the Emax of L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) and L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33) has increased by 67% and 34%.Compare with A2G-GLP-2 (1-33), L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33) makes small intestine weight increase by 8 times.

Treatment	A2G-GLP-2(1-33)	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)
Treatment	A2G-GLP-2(1-33)	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)		Estimates of parameters (CV%)
E ₀	0.0425(2.4)	0.0426(3.0)	0.0424(2.9)		Estimates of parameters (CV%)
E ₀	0.0425(2.4)	0.0426(3.0)	0.0424(2.9)	E _max	0.0548(33.3)	0.0636(2.2)	0.0727(5.4)
ED ₅₀(μg)	15.04(470)	1.00(18.5)	0.90(41.3)	E _max	0.0548(33.3)	0.0636(2.2)	0.0727(5.4)
ED ₅₀(μg)	15.04(470)	1.00(18.5)	0.90(41.3)	E _max-E ₀	0.0123(151)	0.0211(9.3)	0.0303(13.7)
γ	0.6625(109)	2.0485(32.2)	0.7249(41.2)	E _max-E ₀	0.0123(151)	0.0211(9.3)	0.0303(13.7)
γ	0.6625(109)	2.0485(32.2)	0.7249(41.2)		95% fiducial limit
E ₀	0.0405-0.0446	?0.0400-0.0451	?0.0399-0.0449		95% fiducial limit
E ₀	0.0405-0.0446	?0.0400-0.0451	?0.0399-0.0449	E _max	0.0184-0.0912	?0.0609-0.0663	?0.0649-0.0805
ED ₅₀	0-156.17	?0.63-1.37	?0.16-1.65	E _max	0.0184-0.0912	?0.0609-0.0663	?0.0649-0.0805
ED ₅₀	0-156.17	?0.63-1.37	?0.16-1.65	E _max-E ₀	-0.0278-0.0503	?0.0234-0.0296	?0.0256-0.0407
γ	-0.7761-2.1012	?0.7336-3.3633	?0.1284-1.3214	E _max-E ₀	-0.0278-0.0503	?0.0234-0.0296	?0.0256-0.0407

Treatment	A2G-GLP-2(1-33)	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)
Treatment	A2G-GLP-2(1-33)	L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)		Estimates of parameters (CV%)
E ₀(g)	1.1095(2.0)	1.0993(3.5)	1.1008(3.8)		Estimates of parameters (CV%)
E ₀(g)	1.1095(2.0)	1.0993(3.5)	1.1008(3.8)	E _max(g)	1.2180(2.3)	1.6270(2.9)	2.0310(13.1)
ED ₅₀(μg)	3.98(70.9)	1.09(25.0)	1.99(111)	E _max(g)	1.2180(2.3)	1.6270(2.9)	2.0310(13.1)
ED ₅₀(μg)	3.98(70.9)	1.09(25.0)	1.99(111)	E _max-E ₀(g)	0.1085(34.8)	0.5278(12.3)	0.9302(29.3)
γ	8.4169(1869)	1.8184(38.9)	0.5889(52.9)	E _max-E ₀(g)	0.1085(34.8)	0.5278(12.3)	0.9302(29.3)
γ	8.4169(1869)	1.8184(38.9)	0.5889(52.9)		95% fiducial limit
E ₀(g)	1.0661-1.1529	1.0219-1.1768	1.0175-1.1842		95% fiducial limit
E ₀(g)	1.0661-1.1529	1.0219-1.1768	1.0175-1.1842	E _max(g)	1.1613-1.2748	1.5345-1.7195	1.4999-2.5621
ED ₅₀(μg)	0-9.60	0.55-1.64	0-6.40	E _max(g)	1.1613-1.2748	1.5345-1.7195	1.4999-2.5621
ED ₅₀(μg)	0-9.60	0.55-1.64	0-6.40	E _max-E ₀(g)	0.0345-0.1837	0.4021-0.6579	0.3967-1.4725
γ	-305.2302??????????- 322.0639	0.4085-3.2282	-0.0320-1.2099	E _max-E ₀(g)	0.0345-0.1837	0.4021-0.6579	0.3967-1.4725

Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight
Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight	????A	????22	????25.88	????1.45	????0.0560
????27.59	????1.75	????0.0634					????25.88	????1.45	????0.0560
????27.59	????1.75	????0.0634	????26.57	????1.60			????0.0602
????24.31	????1.54	????0.0633	????26.57	????1.60			????0.0602
????24.31	????1.54	????0.0633	????24.11	????1.27			????0.0527
????24.48	????1.53	????0.0625	????24.11	????1.27			????0.0527
????24.48	????1.53	????0.0625	????25.25	????1.78			????0.0705
????23.14	????1.23	????0.0532	????25.25	????1.78			????0.0705
????23.14	????1.23	????0.0532	On average ± SD				????25.17 ????±1.45	????1.5188± ????????0.1996	????0.0602±0.0060
????B	????11	????24.04	On average ± SD				????25.17 ????±1.45	????1.5188± ????????0.1996	????0.0602±0.0060
		????24.04	????27.14	????1.83			????0.0674
		????22.35	????27.14	????1.83	????1.60	????0.0716	????0.0674
		????22.35	????29.45	????2.09	????1.60	????0.0716	????0.0710
		????28.00	????29.45	????2.09	????1.55	????0.0554	????0.0710
		????28.00	????24.29	????1.83	????1.55	????0.0554	????0.0753
		????25.54	????24.29	????1.83	????1.63	????0.0638	????0.0753
		????25.54	????26.59	????1.71	????1.63	????0.0638	????0.0643
		On average ± SD		????1.71	????25.93 ????±2.32	????1.7486± ????????0.1857	????0.0643	????0.0670±0.0066
????C	????5.5	On average ± SD		????25.94	????25.93 ????±2.32	????1.7486± ????????0.1857	????1.51	????0.0670±0.0066	????0.0582
		????28.15	????2.00	????25.94	????0.0710		????1.51		????0.0582
		????28.15	????2.00	????22.40	????0.0710	????1.57	????0.0701
		????21.48	????1.44	????22.40	????0.0670	????1.57	????0.0701
		????21.48	????1.44	????24.72	????0.0670	????1.36	????0.0550
		????26.11	????1.59	????24.72	????0.0609	????1.36	????0.0550
		????26.11	????1.59	????24.33	????0.0609	????1.65	????0.0678
		????30.32	????1.66	????24.33	????0.0547	????1.65	????0.0678
		????30.32	????1.66	On average ± SD		????25.43 ????±2.89	????1.5975± ????????0.1921	????0.0631±0.0067
????D	????2.75	????25.31	????1.71	On average ± SD		????25.43 ????±2.89	????1.5975± ????????0.1921	????0.0631±0.0067	????0.0676
		????25.31	????1.71	????29.88	????1.64	????0.0549			????0.0676
		????25.64	????1.95	????29.88	????1.64	????0.0549	????0.0761
		????25.64	????1.95	????22.62	????1.48	????0.0654	????0.0761

		????25.10	????1.46	????0.0582
		????25.10	????1.46	????0.0582	????25.34	????1.46	????0.0576
		????22.39	????1.30	????0.0581	????25.34	????1.46	????0.0576
		????22.39	????1.30	????0.0581	????25.47	????1.45	????0.0569
		On average ± SD		????25.22 ????±2.29	????25.47	????1.45	????0.0569	????1.5563± ????????0.2025	????0.0618±0.0072
????E	????1.375	On average ± SD		????25.22 ????±2.29	????28.11	????1.51	????0.0537	????1.5563± ????????0.2025	????0.0618±0.0072
		????25.84	????1.50	????0.0580	????28.11	????1.51	????0.0537
		????25.84	????1.50	????0.0580	????23.86	????1.32	????0.0553
		????24.06	????1.42	????0.0590	????23.86	????1.32	????0.0553
		????24.06	????1.42	????0.0590	????23.98	????1.21	????0.0505
		????23.49	????1.24	????0.0528	????23.98	????1.21	????0.0505
		????23.49	????1.24	????0.0528	????23.04	????1.44	????0.0625
		????24.73	????1.41	????0.0570	????23.04	????1.44	????0.0625
		????24.73	????1.41	????0.0570	On average ± SD		????24.64 ????±1.64	????1.3813± ????????0.1131	????0.0561±0.0038
????F	????0.678	????28.54	????1.27	????0.0445	On average ± SD		????24.64 ????±1.64	????1.3813± ????????0.1131	????0.0561±0.0038
		????28.54	????1.27	????0.0445	????30.18	????1.49	????0.0494
		????25.83	????1.18	????0.0457	????30.18	????1.49	????0.0494
		????25.83	????1.18	????0.0457	????27.35	????1.62	????0.0592
		????24.24	????1.11	????0.0458	????27.35	????1.62	????0.0592
		????24.24	????1.11	????0.0458	????26.81	????1.30	????0.0485
		????24.59	????1.05	????0.0427	????26.81	????1.30	????0.0485
		????24.59	????1.05	????0.0427	????24.19	????1.30	????0.0537
		On average ± SD		????26.47 ????±2.17	????24.19	????1.30	????0.0537	????1.2900± ????????0.1896	????0.0487±0.0055
????G	????0.344	On average ± SD		????26.47 ????±2.17	????23.34	????1.01	????0.0433	????1.2900± ????????0.1896	????0.0487±0.0055
		????26.30	????1.08	????0.0411	????23.34	????1.01	????0.0433
		????26.30	????1.08	????0.0411	????24.58	????1.34	????0.0545
		????25.43	????1.11	????0.0436	????24.58	????1.34	????0.0545
		????25.43	????1.11	????0.0436	????24.68	????0.99	????0.0401
		????27.69	????1.41	????0.0509	????24.68	????0.99	????0.0401
		????27.69	????1.41	????0.0509	????25.13	????1.34	????0.0533
		????22.58	????0.85	????0.0376	????25.13	????1.34	????0.0533
		????22.58	????0.85	????0.0376	On average ± SD		????24.97 ????±1.60	????1.1413± ????????0.2003	????0.0456±0.0064

Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight
Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight	??A	????35	????29.69	????1.89	????0.0637
????26.35	????2.03	????0.0770					????29.69	????1.89	????0.0637
????26.35	????2.03	????0.0770	????28.34	????1.91			????0.0674
????25.24	????1.78	????0.0705	????28.34	????1.91			????0.0674
????25.24	????1.78	????0.0705	????26.16	????1.61			????0.0615
????23.80	????1.72	????0.0723	????26.16	????1.61			????0.0615
????23.80	????1.72	????0.0723	????27.05	????2.06			????0.0762
????25.65	????1.77	????0.0690	????27.05	????2.06			????0.0762
????25.65	????1.77	????0.0690	On average ± SD				????26.54±1.84	????1.8463±0.1546	????0.0697±0.0055
??B	????17.5	????29.80	On average ± SD		????1.90	????0.0638	????26.54±1.84	????1.8463±0.1546	????0.0697±0.0055
		????29.80	????26.57	????1.85	????1.90	????0.0638	????0.0696
		????32.71	????26.57	????1.85	????2.54	????0.0777	????0.0696
		????32.71	????24.96	????2.05	????2.54	????0.0777	????0.0821
		????24.66	????24.96	????2.05	????1.54	????0.0624	????0.0821
		????24.66	????21.39	????1.47	????1.54	????0.0624	????0.0687
		????27.99	????21.39	????1.47	????1.95	????0.0697	????0.0687
		????27.99	????26.74	????1.62	????1.95	????0.0697	????0.0606
		On average ± SD		????1.62	????26.85±3.44	????1.8650±0.3423	????0.0606	????0.0693±0.0075
??C	????8.75	On average ± SD		????23.32	????26.85±3.44	????1.8650±0.3423	????1.58	????0.0693±0.0075	????0.0678
		????27.39	????1.85	????23.32	????0.0675		????1.58		????0.0678
		????27.39	????1.85	????26.51	????0.0675	????2.01	????0.0758
		????23.53	????1.60	????26.51	????0.0680	????2.01	????0.0758
		????23.53	????1.60	????26.31	????0.0680	????1.67	????0.0635
		????27.07	????2.07	????26.31	????0.0765	????1.67	????0.0635
		????27.07	????2.07	????23.64	????0.0765	????2.08	????0.0880
		????26.72	????1.80	????23.64	????0.0674	????2.08	????0.0880
		????26.72	????1.80	On average ± SD		????25.56±1.74	????1.8325±0.2052	????0.0718±0.0079
??D	????4.375	????25.11	????1.47	On average ± SD		????25.56±1.74	????1.8325±0.2052	????0.0718±0.0079	????0.0585
		????25.11	????1.47	????26.06	????1.71	????0.0656			????0.0585
		????25.00	????1.68	????26.06	????1.71	????0.0656	????0.0672
		????25.00	????1.68	????25.36	????1.59	????0.0627	????0.0672
		????23.79	????1.41	????25.36	????1.59	????0.0627	????0.0593
		????23.79	????1.41	????27.40	????1.81	????0.0661	????0.0593
		????26.31	????1.48	????27.40	????1.81	????0.0661	????0.0563

		????23.73	????1.42	????0.0598
		????23.73	????1.42	????0.0598	On average ± SD		????25.35±1.25	????1.5713±0.1492	????0.0619±0.0040
????E	??2.188	????24.71	????1.36	????0.0550	On average ± SD		????25.35±1.25	????1.5713±0.1492	????0.0619±0.0040
		????24.71	????1.36	????0.0550	????21.35	????1.30	????0.0609
		????27.79	????1.80	????0.0648	????21.35	????1.30	????0.0609
		????27.79	????1.80	????0.0648	????28.66	????1.84	????0.0642
		????25.95	????1.45	????0.0559	????28.66	????1.84	????0.0642
		????25.95	????1.45	????0.0559	????26.62	????1.65	????0.0620
		????22.40	????1.58	????0.0705	????26.62	????1.65	????0.0620
		????22.40	????1.58	????0.0705	????27.71	????1.70	????0.0613
		On average ± SD		????25.65±2.64	????27.71	????1.70	????0.0613	????1.5850±0.1996	????0.0618±0.0050
????F	??1.094	On average ± SD		????25.65±2.64	????22.75	????1.36	????0.0598	????1.5850±0.1996	????0.0618±0.0050
		????25.35	????1.46	????0.0576	????22.75	????1.36	????0.0598
		????25.35	????1.46	????0.0576	????22.99	????1.50	????0.0652
		????26.65	????1.73	????0.0649	????22.99	????1.50	????0.0652
		????26.65	????1.73	????0.0649	????25.54	????1.41	????0.0552
		????24.68	????1.56	????0.0632	????25.54	????1.41	????0.0552
		????24.68	????1.56	????0.0632	????29.29	????1.72	????0.0587
		????24.51	????1.40	????0.0571	????29.29	????1.72	????0.0587
		????24.51	????1.40	????0.0571	On average ± SD		????25.22±2.09	????1.5175±0.1423	????0.0602±0.0038
????G	??0.547	????24.31	????1.28	????0.0527	On average ± SD		????25.22±2.09	????1.5175±0.1423	????0.0602±0.0038
		????24.31	????1.28	????0.0527	????25.29	????1.31	????0.0518
		????24.00	????1.44	????0.0600	????25.29	????1.31	????0.0518
		????24.00	????1.44	????0.0600	????26.59	????1.52	????0.0572
		????24.42	????1.27	????0.0520	????26.59	????1.52	????0.0572
		????24.42	????1.27	????0.0520	????25.95	????1.33	????0.0513
		????23.65			????25.95	????1.33	????0.0513
		????23.65			????29.00	????1.57	????0.0541
		On average ± SD		????25.40±1.77	????29.00	????1.57	????0.0541	????1.3886±0.1313	????0.0541±0.0033

Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight
Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight	??A	??33	??26.17	??1.25	??0.0478
??27.69	??1.30	??0.0469					??26.17	??1.25	??0.0478
??27.69	??1.30	??0.0469	??23.33	??1.40			??0.0600
??22.35	??1.10	??0.0492	??23.33	??1.40			??0.0600
??22.35	??1.10	??0.0492	??28.25	??1.28			??0.0453
??22.85	??1.17	??0.0512	??28.25	??1.28			??0.0453
??22.85	??1.17	??0.0512	??24.94	??1.41			??0.0565
??21.40	??0.93	??0.0435	??24.94	??1.41			??0.0565
??21.40	??0.93	??0.0435	On average ± SD				??24.62±2.55	??1.2300±0.1602	??0.0501±0.0057
??B	??16.5	??21.72	On average ± SD		??0.96	??0.0442	??24.62±2.55	??1.2300±0.1602	??0.0501±0.0057
		??21.72	??26.13	??1.17	??0.96	??0.0442	??0.0448
		??25.43	??26.13	??1.17	??1.37	??0.0539	??0.0448
		??25.43	??24.44	??1.28	??1.37	??0.0539	??0.0524
		??23.80	??24.44	??1.28	??1.07	??0.0450	??0.0524
		??23.80	??25.13	??1.24	??1.07	??0.0450	??0.0493
		??23.06	??25.13	??1.24	??1.25	??0.0542	??0.0493
		??23.06	??22.76	??1.08	??1.25	??0.0542	??0.0475
		On average ± SD		??1.08	??24.06±1.50	??1.1775±0.1337	??0.0475	??0.0489±0.0042
??C	??8.25	On average ± SD		??26.62	??24.06±1.50	??1.1775±0.1337	??1.26	??0.0489±0.0042	??0.0473
		??24.63	??1.16	??26.62	??0.0471		??1.26		??0.0473
		??24.63	??1.16	??24.27	??0.0471	??1.19	??0.0490
		??28.30	??1.37	??24.27	??0.0484	??1.19	??0.0490
		??28.30	??1.37	??26.94	??0.0484	??1.06	??0.0393
		??25.12	??1.23	??26.94	??0.0490	??1.06	??0.0393
		??25.12	??1.23	??24.89	??0.0490	??1.46	??0.0587
		??25.51	??1.24	??24.89	??0.0486	??1.46	??0.0587
		??25.51	??1.24	On average ± SD		??25.79±1.38	??1.2463±0.1235	??0.0484±0.0052
??D	??4.125	??26.28	??1.15	On average ± SD		??25.79±1.38	??1.2463±0.1235	??0.0484±0.0052	??0.0438
		??26.28	??1.15	??26.49	??1.04	??0.0393			??0.0438
		??27.19	??1.46	??26.49	??1.04	??0.0393	??0.0537
		??27.19	??1.46	??26.01	??1.19	??0.0458	??0.0537
		??28.58	??1.24	??26.01	??1.19	??0.0458	??0.0434
		??28.58	??1.24	??22.74	??1.15	??0.0506	??0.0434
		??23.49	??0.88	??22.74	??1.15	??0.0506	??0.0375

		??28.52	??1.26	??0.0442
		??28.52	??1.26	??0.0442	On average ± SD		??26.16±2.12	??1.1713±0.1687	??0.0448±0.0054
??E	??2.063	??21.54	??0.93	??0.0432	On average ± SD		??26.16±2.12	??1.1713±0.1687	??0.0448±0.0054
		??21.54	??0.93	??0.0432	??21.97	??0.98	??0.0446
		??26.21	??1.22	??0.0465	??21.97	??0.98	??0.0446
		??26.21	??1.22	??0.0465	??25.39	??1.18	??0.0465
		??26.80	??1.04	??0.0388	??25.39	??1.18	??0.0465
		??26.80	??1.04	??0.0388	??26.64	??1.21	??0.0454
		??23.36	??1.00	??0.0428	??26.64	??1.21	??0.0454
		??23.36	??1.00	??0.0428	??22.25	??1.04	??0.0467
		On average ± SD		??24.27±2.23	??22.25	??1.04	??0.0467	??1.0750±0.1124	??0.0443±0.0027
??F	??1.031	On average ± SD		??24.27±2.23	??24.10	??1.09	??0.0452	??1.0750±0.1124	??0.0443±0.0027
		??23.15	??1.10	??0.0475	??24.10	??1.09	??0.0452
		??23.15	??1.10	??0.0475	??26.06	??1.18	??0.0453
		??28.91	??1.31	??0.0453	??26.06	??1.18	??0.0453
		??28.91	??1.31	??0.0453	??27.15	??1.18	??0.0435
		??25.89	??1.11	??0.0429	??27.15	??1.18	??0.0435
		??25.89	??1.11	??0.0429	??23.41	??1.30	??0.0555
		??24.83	??1.08	??0.0435	??23.41	??1.30	??0.0555
		??24.83	??1.08	??0.0435	On average ± SD		25.44 the scholar 1.97	??1.1688±0.0923	??0.0461±0.0041
??G	??0.512	??24.03	??0.92	??0.0383	On average ± SD		25.44 the scholar 1.97	??1.1688±0.0923	??0.0461±0.0041
		??24.03	??0.92	??0.0383	??23.21	??1.09	??0.0470
		??26.10	??1.09	??0.0418	??23.21	??1.09	??0.0470
		??26.10	??1.09	??0.0418	??28.97	??1.24	??0.0428
		??27.31	??1.15	??0.0421	??28.97	??1.24	??0.0428
		??27.31	??1.15	??0.0421	??25.90	??1.18	??0.0456
		??23.55	??1.17	??O.0497	??25.90	??1.18	??0.0456
		??23.55	??1.17	??O.0497	??24.71	??1.02	??O.0413
		On average ± SD		??25.47±1.99	??24.71	??1.02	??O.0413	??1.1075±0.1014	??0.0436±0.0036

Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight
Dosage level	Dosage μ g	Body weight g	Small intestine weight g	Small intestine weight/body weight	Contrast	??0	????24.39	????0.99	????0.0406
????22.58	????0.86	????0.0381					????24.39	????0.99	????0.0406
????22.58	????0.86	????0.0381	????22.76	????1.08			????0.0475
????24.93	????1.03	????0.0413	????22.76	????1.08			????0.0475
????24.93	????1.03	????0.0413	????25.46	????0.99			????0.0389
????27.12	????1.13	????0.0417	????25.46	????0.99			????0.0389
????27.12	????1.13	????0.0417	????25.34	????1.42			????0.0560
????27.55	????1.20	????0.0436	????25.34	????1.42			????0.0560
????27.55	????1.20	????0.0436	????27.38	????1.02			????0.0373
????24.96	????1.02	????0.0409	????27.38	????1.02			????0.0373
????24.96	????1.02	????0.0409	????24.77	????1.31			????0.0529
????25.88	????1.05	????0.0406	????24.77	????1.31			????0.0529
????25.88	????1.05	????0.0406	????28.86	????1.08			????0.0374
????22.89	????1.06	????0.0463	????28.86	????1.08			????0.0374
????22.89	????1.06	????0.0463	????24.57	????1.07			????0.0435
????26.67	????1.08	????0.0405	????24.57	????1.07			????0.0435
????26.67	????1.08	????0.0405	????31.59	????1.26			????0.0399
????32.69	????1.36	????0.0416	????31.59	????1.26			????0.0399
????32.69	????1.36	????0.0416	????27.28	????1.03			????0.0378
????23.60	????0.97	????0.0411	????27.28	????1.03			????0.0378
????23.60	????0.97	????0.0411	On average ± SD				????26.06±2.70	????1.1005± ????0.1411	????0.0424±0.0050

Embodiment 63

The metabolic stability of selected GLP-2 derivative.The GLP-2 derivative is studied in the intravital degraded of pig, determined selected T  value (T : the whole last plasma clearance transformation period) (table 9) according to GLP-2 derivative of the present invention.

All are tried material and are dissolved in 20mM phosphate buffered saline buffer pH7.4.

Use the female LYD hybridized pig of body weight as 50-75kg, all dosage that tried material are 0.5nmol/kg.The administration volume is every about 1ml of pig.

Right neck from the 9cm place's subcutaneous injection of neck middle part, has a clamp from the about 7cm of ear on the syringe needle, allow syringe needle to insert subcutaneous 0.5cm.

By ear vein conduit blood sample collection, the conduit physiological saline drip washing that contains the 50IE/ml heparin.In the sampling process, the 1ml blood of adopting at first abandons need not.(4 ℃, 4000rpm 10min) is prepended to and is no more than 20 minutes on ice blood sample centrifugal.After centrifugal, separated plasma also changes Micronic pipe, double sample over to.The elisa assay plasma sample.

Table 9:

The GLP-2 derivative	The GLP-2 peptide	The acyl group site	Acyl substituent	Spacer	The intravital T  of pig (h)
The GLP-2 derivative	The GLP-2 peptide	The acyl group site	Acyl substituent	Spacer	The intravital T  of pig (h)		GLP-2(1-33)	Do not have	Do not have	Do not have	0.25
L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C-12	Beta-alanine	8.5		GLP-2(1-33)	Do not have	Do not have	Do not have	0.25
L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C-12	Beta-alanine	8.5	L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C-12	??GABA	2.3
L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C14	Beta-alanine	3.5±1.8	L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C-12	??GABA	2.3
L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C14	Beta-alanine	3.5±1.8	L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C14	??GABA	4.5±2.4
L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C16	Beta-alanine	4.4±1.1		L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C14	??GABA	4.5±2.4
L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C16	Beta-alanine	4.4±1.1	L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33)	L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C16	??GABA	3.8±0.6
D3E/S7K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33)	D3E/S7K/K30R/D3 3E-GLP-2(1-33)	ε-Lys-7	?C16	Gamma-glutamic acid	280		L17K/K30R-GLP-2 (1-33)	ε-Lys-17	?C16	??GABA	3.8±0.6
	D3E/S7K/K30R/D3 3E-GLP-2(1-33)	ε-Lys-7	?C16	Gamma-glutamic acid	280	D3E/D8K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33)	D3E/D8K/K30R/D3 3E-GLP-2(1-33)	ε-Lys-8	?C16	Gamma-glutamic acid	31.9
D3E/N11K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33)	D3E/N11K/K30R/D 33E-GLP-2(1-33)	ε-Lys-11	?C16	Gamma-glutamic acid	53.1		D3E/D8K/K30R/D3 3E-GLP-2(1-33)	ε-Lys-8	?C16	Gamma-glutamic acid	31.9
	D3E/N11K/K30R/D 33E-GLP-2(1-33)	ε-Lys-11	?C16	Gamma-glutamic acid	53.1	D3E/T12K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33)	D3E/T12K/K30R/D 33E-GLP-2(1-33)	ε-Lys-12	?C16	Gamma-glutamic acid	29.4
D3E/L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33)	D3E/L17K/K30R/D 33E-GLP-2(1-33)	ε-Lys-17	?C16	Gamma-glutamic acid	16.2		D3E/T12K/K30R/D 33E-GLP-2(1-33)	ε-Lys-12	?C16	Gamma-glutamic acid	29.4

Embodiment 64

Pharmaceutical preparation

Dissolving buffer reagent and optional sanitas, optional grade is oozed reagent, and optional additive and the tensio-active agent that more is selected from sequestrant, stablizer (for example imidazoles or some amino acid (electrically charged-alkalescence) for example Histidine or arginine) transfers to pH and specifies the pH value.From now on, by slow stirring and dissolving GLP-2 compound.PH transfers to sodium hydroxide and/or hydrochloric acid and specifies the pH value.At last, filtering preparation with 0.22 μ m sterile filters sterilizes.

After preparation is stored in the time different from the Glass Containers that fill at the top, estimate the physical stability of preparation by visual inspection and turbidity.Glass Containers is stored in 5 ℃ ± 3 ℃ and/or higher temperature (for example 25 ℃ or 37 ℃).

Preparation is carried out visual inspection having under the strong focused light of black background, by muddy degree being divided into the turbidity that 0 to 3 vision mark shows preparation (do not have muddy preparation corresponding to vision 0 minute, the preparation that presents the vision muddiness under the daylight corresponded to vision 3 minutes).When presenting the vision muddiness under the daylight, considering has protein aggregation, and said preparation is classified as physical instability.

Turbidity is also measured with turbidometer, is expressed as scattering opacity unit (NTU), and calibrates with formal hydrazine (Formazin) standard substance.The preparation of turbidity＞10NTU is considered to physical instability.The GLP-2 compound concentrations is to use ε ₂₈₀=5700M ^-1Cm ^-1The UV absorbancy be foundation.

Analyze HPLC.By the reversed-phase HPLC that uses C4 post and standard trifluoroacetic acid/formonitrile HCN gradient elution the content of GLP-2 compound complete in the sample is carried out quantitative analysis.

The GLP-2 preparation can be estimated with equilibrium solubility; The GLP-2 compound is dissolved in the suitable damping fluid, and concentration is 2mg/mL, by 0.45 μ m filter filtering solution.Extract sample from stock solution, pH transfers to desired value, and sample was hatched 24 hours at 23 ℃.Behind each sample centrifugal (23 ℃, 20,000g, 20 minutes), measure pH value, and the light absorption value by the mensuration supernatant liquor (or HPLC analytically clear liquid) is estimated solubleness.

The GLP-2 preparation also can be estimated with accelerated stability test; Prepare 2mg/mL GLP-2 compound sample with damping fluid a-d, its 0.2mL HPLC bottle that changes sealing over to is avoided liquid-vapo(u)r interface.After hatching under the assigned temperature in 4-45 ℃ of scope, the content as the complete GLP-2 compound of the function of time is determined in the HPLC analysis.

The GLP-2 preparation also can be estimated with physical stability; Fluorescence dye thioflavine T (ThT) combines with starch albumen beta structure composition.The increase that obtains the fluorescence volume of combination dye has indicated that under all kinds of SOLVENTS condition, the GLP-2 compound has the trend of fibrillation.In brief, dissolving GLP-2 compound under the purpose condition, the ThT of adding trace, solution places 96 hole microtiter plates, uses the temperature of predetermined influence acceleration starch albumen formation and jolts condition, reads the fluorescent value as the function of time.The fluorescence that obtains has indicated that to the data of time under set condition GLP-2 compound has the relative trend of fibrillation.

The GLP-2 preparation also can be estimated with analytical ultracentrifugation; Under 23 ℃, with BechmanOptima XL-A ultracentrifuge, carry out the subsidence rate test, the equipment of this whizzer can use absorption and disturb optics to obtain data simultaneously.

The GLP-2 preparation also can be estimated by circular dichroism spectroscopy.With Jasco J-715 optically-active spectrograph record extreme ultraviolet and near ultraviolet CD spectrum, calibrate under the room temperature with (+)-10-camphorsulfonic acid.

Embodiment 65

The pharmaceutical preparation of GLP-2 derivative.

Dissolving buffer reagent and optional sanitas, optional grade is oozed reagent, and optional additive and the tensio-active agent that more is selected from sequestrant, stablizer (for example imidazoles or some amino acid (electrically charged-alkalescence) for example Histidine or arginine) transfers to pH and specifies the pH value.From now on, by slow stirring and dissolving GLP-2 derivative.PH transfers to sodium hydroxide and/or hydrochloric acid and specifies the pH value.At last, filtering preparation with 0.22 μ m sterile filters sterilizes.

Turbidity is also measured with turbidometer, is expressed as scattering opacity unit (NTU), and calibrates with formal hydrazine standard substance.The preparation of turbidity＞10NTU is considered to physical instability.The concentration of GLP-2 derivative is to use ε ₂₈₀=5700M ^-1Cm ^-1The UV absorbancy be foundation.

Analyze HPLC.By the reversed-phase HPLC that uses C4 post and standard trifluoroacetic acid/formonitrile HCN gradient elution the content of GLP-2 derivative complete in the sample is carried out quantitative analysis.

The GLP-2 preparation can be estimated with equilibrium solubility; The GLP-2 derivative is dissolved in the suitable damping fluid, and concentration is 2mg/mL, by 0.45 μ m filter filtering solution.Extract sample from stock solution, pH transfers to desired value, and sample was hatched 24 hours at 23 ℃.Behind each sample centrifugal (23 ℃, 20,000g, 20 minutes), measure pH value, and the light absorption value by the mensuration supernatant liquor (or HPLC analytically clear liquid) is estimated solubleness.

The GLP-2 preparation also can be estimated with accelerated stability test; Prepare 2mg/mLGLP-2 derivative sample with damping fluid a-d, its 0.2mLHPLC bottle that changes sealing over to is avoided liquid-vapo(u)r interface.After hatching under the assigned temperature in 4-45 ℃ of scope, the content as the complete GLP-2 derivative of the function of time is determined in the HPLC analysis.

The GLP-2 preparation also can be estimated with physical stability; Fluorescence dye thioflavine T (ThT) combines with starch albumen beta structure composition.The increase that obtains the fluorescence volume of combination dye has indicated that under all kinds of SOLVENTS condition, the GLP-2 derivative has the trend of fibrillation.In brief, dissolving GLP-2 derivative under the purpose condition, the ThT of adding trace, solution places 96 hole microtiter plates, uses the temperature of predetermined influence acceleration starch albumen formation and jolts condition, reads the fluorescent value as the function of time.The fluorescence that obtains has indicated that to the data of time under set condition GLP-2 derivative has the relative trend of fibrillation.

Embodiment 66

The medicine freeze-dried preparation

In the time will providing lyophilisation product, basic characteristics relate to the characteristic of lyophilize piece.It will have good form and structural performance, and promptly should not disintegrate becomes the lyophilize piece of disintegrating, and it is very hard or before use even can not dissolve (reorganization).On the contrary, the physical structure of lyophilize piece can not be too loose and soft.Therefore, produce the medicine freeze-dried preparation of GLP-2 and its varient with N.F,USP MANNITOL, sucrose (swelling agent) and the glycylglycine (buffer reagent) of following final concentration:

GLP-2 and varient thereof: 0.1-100mg/ml

Sucrose: 10mg/ml

N.F,USP MANNITOL: 37mg/ml

Glycylglycine: 1.32mg/ml

With 0.1N NaOH/HCl pH is transferred to 8.00 ± 0.03.

Solution is filled into suitable bottle and uses Wang etc., International Journal ofPharmaceutics 203 (2000): 1-60 (sees the 4th joint, the 16th page) the standard freeze-drying described carries out lyophilize, carries out the reorganization of freeze-dried preparation with an amount of water.

Sequence table

<110>Novo?Nordisk?A/S

＜120〉GLP-2 derivative

<130>6670.204-WO

<160>3

<170>PatentIn?version?3.1

<210>1

<211>33

<212>PRT

＜213〉people (Homo sapiens)

<400>l

His?Ala?Asp?Gly?Ser?Phe?Ser?Asp?Glu?Met?Asn?Thr?Ile?Leu?Asp?Asn

1???????????????5???????????????????10??????????????????15

Leu?Ala?Ala?Arg?Asp?Phe?Ile?Asn?Trp?Leu?Ile?Gln?Thr?Lys?Ile?Thr

20??????????????????25??????????????????30

Asp

<210>2

<211>33

<212>PRT

＜213〉artificial sequence

<220>

＜223〉artificial

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 2 is Ala, Val or Gly

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 3 is Asp or Glu

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 5 is Ser or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 7 is Ser or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 8 is Asp, Glu or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 9 is Asp, Glu or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 10 is Met, Lys, Leu, Ile or Nor-Leucine.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 11 is Asn or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 12 is Thr or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 13 is Ile or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 14 is Leu or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 15 is Asp or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 16 is Asn or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 17 is Leu or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 18 is Ala or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 21 is Asp or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 24 is Asn or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 28 is Gln or Lys.

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 33 is Asp, Glu or Lys.

<400>2

His?Xaa?Xaa?Gly?Xaa?Phe?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa

1???????????????5???????????????????10??????????????????15

Xaa?Xaa?Ala?Arg?Xaa?Phe?Ile?Xaa?Trp?Leu?Ile?Xaa?Thr?Arg?Ile?Thr

20??????????????????25??????????????????30

Xaa

<210>3

<211>33

<212>PRT

＜213〉artificial

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 2 is Ala, Val or Gly

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 3 is Asp or Glu

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 5 is Ser or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 7 is Ser or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 8 is Asp, Glu or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 9 is Asp, Glu or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 10 is Met, Lys, Leu, Ile or Nor-Leucine

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 11 is Asn or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 12 is Thr or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 13 is Ile or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 14 is Leu Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 15 is Asp or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 16 is Asn or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 17 is Leu or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 18 is Ala or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 20 is Arg or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 21 is Asp or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 24 is Asn or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 28 is Gln or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 30 is Arg or Lys

<220>

<221>MISC_FEATURE

<222>(1)..(33)

＜223〉Xaa of position 33 is Asp, Glu or Lys

<400>3

His?Xaa?Xaa?Gly?Xaa?Phe?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa

1???????????????5???????????????????10??????????????????15

Xaa?Xaa?Ala?Xaa?Xaa?Phe?Ile?Xaa?Trp?Leu?Ile?Xaa?Thr?Xaa?Ile?Thr

20??????????????????25??????????????????30

Xaa

Claims

1. GLP-2 peptide that contains the aminoacid sequence of formula I

His-X ²-X ³-Gly-X ⁵-Phe-X ⁷-X ⁸-X ⁹-X ¹⁰-X ¹¹-X ¹²-X ¹³-X ¹⁴-X ¹⁵-X ¹⁶-X ¹⁷-X ¹⁸-Ala-Arg-X ²¹-Phe-Ile-X ²⁴-Trp-Leu-Ile-X ²⁸-Thr-Arg-Ile-Thr-X ³³(formula I)

2. the GLP-2 peptide of claim 1 is made up of following aminoacid sequence

3. claim 1 or 2 GLP-2 peptide, wherein X ²Be Ala.

4. claim 1 or 2 GLP-2 peptide, wherein X ²Be Gly.

5. each GLP-2 peptide, wherein X among the claim 1-4 ³Be Asp.

6. each GLP-2 peptide, wherein X among the claim 1-4 ³Be Glu.

7. each GLP-2 peptide, wherein X among the claim 1-6 ⁵Be Ser.

8. each GLP-2 peptide, wherein X among the claim 1-7 ⁷Be Ser.

9. each GLP-2 peptide, wherein X among the claim 1-8 ⁸Be Asp.

10. each GLP-2 peptide, wherein X among the claim 1-8 ⁸Be Glu.

11. each GLP-2 peptide, wherein X among the claim 1-10 ⁹Be Asp.

12. each GLP-2 peptide, wherein X among the claim 1-10 ⁹Be Glu.

13. each GLP-2 peptide, wherein X among the claim 1-12 ¹⁰Be selected from Met, Leu, Ile and nor-leucine.

14. each GLP-2 peptide, wherein X among the claim 1-13 ¹¹Be Asn.

15. each GLP-2 peptide, wherein X among the claim 1-14 ¹²Be Thr.

16. each GLP-2 peptide, wherein X among the claim 1-15 ¹³Be Ile.

17. each GLP-2 peptide, wherein X among the claim 1-16 ¹⁴Be Leu.

18. each GLP-2 peptide, wherein X among the claim 1-17 ¹⁵Be Asp.

19. each GLP-2 peptide, wherein X among the claim 1-18 ¹⁶Be Asn.

20. each GLP-2 peptide, wherein X among the claim 1-19 ¹⁷Be Leu.

21. each GLP-2 peptide, wherein X among the claim 1-20 ¹⁸Be Ala.

22. each GLP-2 peptide, wherein X among the claim 1-21 ²¹Be Asp.

23. each GLP-2 peptide, wherein X among the claim 1-22 ²⁴Be Asn.

24. each GLP-2 peptide, wherein X among the claim 1-23 ²⁸Be Gln.

25. each GLP-2 peptide, wherein X among the claim 1-24 ³³Be Asp.

26. each GLP-2 peptide, wherein X among the claim 1-24 ³³Be Glu.

27. each GLP-2 peptide among the claim 1-26, wherein at least one is independently selected from X ⁵, X ⁷, X ⁸, X ⁹, X ¹⁰, X ¹¹, X ¹², X ¹³, X ¹⁴, X ¹⁵, X ¹⁶, X ¹⁷, X ¹⁸, X ²⁰, X ²¹, X ²⁴, X ²⁸And X ³³Amino acid be Lys.

28. each GLP-2 peptide among the claim 1-27, wherein sum reaches 5 amino-acid residues, as 4 amino-acid residues, and 3 amino-acid residues, 2 amino-acid residues or 1 amino-acid residue are exchanged with arbitrary a-amino acid residue.

29. the GLP-2 peptide of claim 1, wherein peptide is selected from

K30R-GLP-2(1-33)；

S5K-GLP-2(1-33)；

S7K-GLP-2(1-33)；

D8K-GLP-2(1-33)；

E9K-GLP-2(1-33)；

M10K-GLP-2(1-33)；

N11K-GLP-2(1-33)；

T12K-GLP-2(1-33)；

I13K-GLP-2(1-33)；

L14K-GLP-2(1-33)；

D15K-GLP-2(1-33)；

N16K-GLP-2(1-33)；

L17K-GLP-2(1-33)；

A18K-GLP-2(1-33)；

D21K-GLP-2(1-33)；

N24K-GLP-2(1-33)；

Q28K-GLP-2(1-33)；

S5K/K30R-GLP-2(1-33)；

S7K/K30R-GLP-2(1-33)；

D8K/K30R-GLP-2(1-33)；

E9K/K30R-GLP-2(1-33)；

M10K/K30R-GLP-2(1-33)；

N11K/K30R-GLP-2(1-33)；

T12K/K30R-GLP-2(1-33)；

I13K/K30R-GLP-2(1-33)；

L14K/K30R-GLP-2(1-33)；

D15K/K30R-GLP-2(1-33)；

N16K/K30R-GLP-2(1-33)；

L17K/K30R-GLP-2(1-33)；

A18K/K30R-GLP-2(1-33)；

D21K/K30R-GLP-2(1-33)；

N24K/K30R-GLP-2(1-33)；

Q28K/K30R-GLP-2(1-33)；

K30R/D33K-GLP-2(1-33)；

D3E/K30R/D33E-GLP-2(1-33)；

D3E/S5K/K30R/D33E-GLP-2(1-33)；

D3E/S7K/K30R/D33E-GLP-2(1-33)；

D3E/D8K/K30R/D33E-GLP-2(1-33)；

D3E/E9K/K30R/D33E-GLP-2(1-33)；

D3E/M10K/K30R/D33E-GLP-2(1-33)；

D3E/N11K/K30R/D33E-GLP-2(1-33)；

D3E/T12K/K30R/D33E-GLP-2(1-33)；

D3E/I13K/K30R/D33E-GLP-2(1-33)；

D3E/L14K/K30R/D33E-GLP-2(1-33)；

D3E/D15K/K30R/D33E-GLP-2(1-33)；

D3E/N16K/K30R/D33E-GLP-2(1-33)；

D3E/L17K/K30R/D33E-GLP-2(1-33)；

D3E/A18K/K30R/D33E-GLP-2(1-33)；

D3E/D21K/K30R/D33E-GLP-2(1-33)；

D3E/N24K/K30R/D33E-GLP-2 (1-33); With

D3E/028K/K30R/D33E-GLP-2(1-33)。

30. the polynucleotide constructs of each GLP-2 peptide among the claim 1-29 that encodes.

31. host cell that comprises the polynucleotide constructs of claim 30.

32. the host cell of claim 31, it is an eukaryotic cell.

33. the host cell of claim 32, wherein said cell is a yeast cell.

35. the GLP-2 derivative of claim 34, wherein the GLP-2 peptide is suc as formula II

His-X ²-X ³-Gly-X ⁵-Phe-X ⁷-X ⁸-X ⁹-X ¹⁰-X ¹¹-X ¹²-X ¹³-X ¹⁴-X ¹⁵-X ¹⁶-X ¹⁷-X ¹⁸-Ala-X ²⁰-X ²¹-Phe-Ile-X ²⁴-Trp-Leu-Ile-X ²⁸-Thr-X ³⁰-Ile-Thr-X ³³(formula II) or its fragment; X wherein ²Be Ala, Val or Gly; X ³Be Asp or Glu; X ⁵Be Ser or Lys; X ⁷Be Ser or Lys; X ⁸Be Asp, Glu or Lys; X ⁹Be Asp, Glu or Lys; X ¹⁰Be Met, Lys, Leu, Ile or nor-leucine; X ¹¹Be Asn or Lys; X ¹²Be Thr or Lys; X ¹³Be Ile or Lys; X ¹⁴Be Leu or Lys; X ¹⁵Be Asp or Lys; X ¹⁶Be Asn or Lys; X ¹⁷Be Leu or Lys; X ¹⁸Be Ala or Lys; X ²⁰Be Arg or Lys; X ²¹Be Asp or Lys; X ²⁴Be Asn or Lys; X ²⁸Be Gln or Lys; X ³⁰Be Arg or Lys; X ³³Be Asp, Glu or Lys (formula II).

36. the GLP-2 derivative of claim 34 or 35, wherein among GLP-2 peptide such as the claim 1-29 each.

37. each GLP-2 derivative among the claim 34-36 wherein only has a lipophilic substituent to be connected with described GLP-2 peptide.

38. each GLP-2 derivative among the claim 34-37, wherein said lipophilic substituent contains 4-40 carbon atom.

39. the GLP-2 derivative of claim 38, wherein said lipophilic substituent contain 8-25 carbon atom.

40. the GLP-2 derivative of claim 38, wherein said lipophilic substituent contain 12-20 carbon atom.

41. each GLP-2 derivative among the claim 34-40, wherein said lipophilic substituent is connected with amino-acid residue as follows, makes the carboxyl of lipophilic substituent and the amino of amino-acid residue form amido linkage.

42. the GLP-2 derivative of claim 41, wherein said amino-acid residue are the Lys residues.

43. each GLP-2 derivative among the claim 34-40, wherein said lipophilic substituent is connected with amino-acid residue as follows, makes the amino of lipophilic substituent and the carboxyl of amino-acid residue form amido linkage.

44. each GLP-2 derivative among the claim 34-43, wherein said lipophilic substituent is connected with described GLP-2 peptide by spacer.

45. the GLP-2 derivative of claim 44, wherein said spacer are unbranched alkyl alpha, omega-dicarboxylic acid groups, have 1-7 methylene radical, as two methylene radical, spacer forms bridge between the amino of the amino of GLP-2 peptide and described lipophilic substituent.

46. the GLP-2 derivative of claim 44, wherein said spacer are the amino-acid residues except that the Cys residue, or dipeptides.

47. the GLP-2 derivative of claim 46, wherein said spacer is selected from: Beta-alanine, γ-An Jidingsuan (GABA), gamma-glutamic acid, Lys, Asp, Glu, contain Asp dipeptides, contain the dipeptides of Glu or contain the dipeptides of Lys.

48. the GLP-2 derivative of claim 46 or 47, wherein the amino of the carboxyl of parent GLP-2 peptide and described spacer forms amido linkage, and the carboxyl of amino acid or dipeptides spacer and the amino of lipophilic substituent form amido linkage.

49. the GLP-2 derivative of claim 46 or 47, wherein the carboxyl of the amino of parent GLP-2 peptide and described spacer forms amido linkage, and the amino of described spacer and the carboxyl of lipophilic substituent form amido linkage.

50. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent contains the partially or completely luxuriant and rich with fragrance skeleton of hydrogenant cyclopentano.

51. each GLP-2 derivative among the claim 34-50, wherein lipophilic substituent is the alkyl group of straight chain or branching.

52. each GLP-2 derivative among the claim 34-50, wherein lipophilic substituent is the acyl group of straight chain or branching lipid acid.

53. the GLP-2 derivative of claim 52, wherein acyl group is selected from CH ₃(CH ₂) _nCO-, wherein n is 4-38, as CH ₃(CH ₂) ₆CO-, CH ₃(CH ₂) ₈CO-, CH ₃(CH ₂) ₁₀CO-, CH ₃(CH ₂) ₁₂CO-, CH ₃(CH ₂) ₁₄CO-, CH ₃(CH ₂) ₁₆CO-, CH ₃(CH ₂) ₁₈CO-, CH ₃(CH ₂) ₂₀CO-and CH ₃(CH ₂) ₂₂CO-.

54. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is the acyl group of the alkyl alpha, omega-dicarboxylic acid of straight chain or branching.

55. the GLP-2 derivative of claim 52, wherein acyl group is selected from HOOC (CH ₂) _mCO-, wherein m is 4-38, as HOOC (CH ₂) ₁₄CO-, HOOC (CH ₂) ₁₆CO-, HOOC (CH ₂) ₁₈CO-, HOOC (CH ₂) ₂₀CO-and HOOC (CH ₂) ₂₂CO-.

56. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _p((CH ₂) _qCOOH) CHNH-CO (CH ₂) ₂CO-, wherein p and q are integers, and p+q is 8-40, as the integer of 12-35.

57. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _rCO-NHCH (COOH) (CH ₂) ₂CO-, wherein r is the integer of 10-24.

58. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group CH ₃(CH ₂) _sCO-NHCH ((CH ₂) ₂COOH) CO-, wherein s is the integer of 8-24.

59. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group COOH (CH ₂) _tCO-wherein t is the integer of 8-24.

60. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) _uCH ₃, wherein u is the integer of 8-18.

61. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-COCH ((CH ₂) ₂COOH) NH-CO (CH ₂) _wCH ₃, wherein w is the integer of 10-16.

62. each GLP-2 derivative among the claim 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NH-CO (CH ₂) _xCH ₃, wherein x is the integer of 10-16.

63. the GLP-2 derivative of claim 34-49, wherein lipophilic substituent is following formula group-NHCH (COOH) (CH ₂) ₄NH-CO (CH ₂) ₂CH (COOH) NHCO (CH ₂) _yCH ₃, wherein y is 0 or the integer of 1-22.

64. the GLP-2 derivative of claim 34-63, it has two lipophilic substituents.

65. the GLP-2 derivative of claim 34-64, it is selected from

S5K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(decanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(decanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)-GLP-2 (1-33);

S5K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

S7K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D8K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

E9K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

M10K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N11K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

T12K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

I13K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L14K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D15K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N16K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(capryloyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(decanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(undecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(lauroyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tridecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(tetradecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(pentadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(heptadecane acyl group amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(octadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(nonadecane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K (3-(eicosane acyl amino) propionyl)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(decanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K ((S)-4-carboxyl-4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(capryloyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(decanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(undecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(lauroyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tridecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(heptadecane acyl group amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(octadecanoyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

L17K (4-(eicosane acyl amino) butyryl radicals)/K30R-GLP-2 (1-33);

A18K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D21K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

N24K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

Q28K (3-(hexadecanoyl amino) propionyl)/K30R-GLP-2 (1-33);

D3E/S5K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/S7K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D8K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/E9K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/M10K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N11K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/T12K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/I13K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L14K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D15K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N16K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(capryloyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(decanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(undecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(lauroyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tridecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(tetradecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(pentadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(heptadecane acyl group amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(octadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(nonadecane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (3-(eicosane acyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/L17K ((S)-4-carboxyl-4-(decanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(capryloyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(decanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(undecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(lauroyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tridecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(tetradecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(pentadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(hexadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(octadecanoyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(nonadecane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/L17K (4-(eicosane acyl amino) butyryl radicals)/K30R/D33E-GLP-2 (1-33);

D3E/A18K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/D21K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33);

D3E/N24K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33); With

D3E/Q28K (3-(hexadecanoyl amino) propionyl)/K30R/D33E-GLP-2 (1-33).

67. a GLP-2 derivative that contains among the claim 34-65 each and, optional, the pharmaceutical composition of medicine acceptable carrier.

68. each GLP-2 derivative is used to prepare the purposes of medicine among the claim 34-65.

69. each GLP-2 derivative is used to prepare the purposes of the medicine of the effect with prolongation among the claim 34-65.

70. each GLP-2 derivative is used for preparing the purposes of the medicine of other disease for the treatment of intestines depletion or causing intestines nutrition malabsorption among the claim 34-65.

71. each GLP-2 derivative is used to prepare the purposes of the medicine for the treatment of following disease among the claim 34-65, described disease is little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, chemotherapy inductive endo-enteritis for example, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, and vascular disease and graft are to versus-host disease, healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy, with the bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces, periodontopathy, wearing and tearing around the hyperparathyroidism, the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia disease, because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture is because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces.

72. one kind to treat intestines depleted or cause the method for other disease of nutrition malabsorption in the intestines, described method to comprise in the claim 34-65 of experimenter's administering therapeutic of needs or prevention significant quantity each GLP-2 derivative.

73. the method for the following disease of treatment, described disease is little bowel syndrome, inflammatory bowel, Crohn's disease, comprise collagen colitis, radiation colitis, the colitis of ulcerative colitis, the chronic radioactive enteritis, non-tropical (gluten tolerance) and intertropica stomatitis, coeliac disease (gluten susceptibility enteropathy), injured tissues after angiemphraxis or the wound, diarrhoea, for example suffer from diarrhoea in turista and infection back, chronic bowel dysfunction, dehydration, microbemia, Sepsis, anorexia nervosa, the tissue that damages after the chemotherapy, chemotherapy inductive endo-enteritis for example, antenatal baby comprises the intestines depletion among the antenatal baby, the premature infant comprises the intestines depletion among the premature infant, schleroderma, gastritis, comprise atrophic gastritis, atrophic gastritis and Hp gastritis after the antrectomy, pancreatitis, general septic shock ulcer, enteritis, conjunctival cul-de-sac, lymphatic vessel blocks, and vascular disease and graft be to versus-host disease, the healing behind the surgical procedure, atrophy behind the irradiation, and chemotherapy, the weight loss in the parkinsons disease, the intestines behind the surgical procedure change, parenteral route nutrition inductive mucosal atrophy, for example, total parenteral route nutrition (TPN)-inductive mucosal atrophy and bone photo related disorders, comprise osteoporosis, the hypercalcemia of malignant tumour is because the bone amount that bone shifts reduces periodontopathy, hyperparathyroidism, wearing and tearing around the joint in the rheumatoid arthritis, Paget (family name) disease, osteodystrophy, myositis ossificans, Bie Hejieliefu (family name) disease, pernicious hypercalcemia disease is because bone shifts the osteolytic lesion that produces, because the bone that immobilization causes forfeiture, because sex steroid hormone lacks the bone forfeiture that causes, because the bone that the steroid hormone treatment causes is unusual, because the bone that oncotherapy causes is unusual, osteomalacia, the BechetShi disease, osteomalacia, hyperosteogeny, osteopetrosis, metastatic bone disease, immobilization inductive bone amount reduce or the bone amount of glucocorticoid inducible reduces, and described method comprises in the claim 34-65 of experimenter's administering therapeutic of needs or prevention significant quantity each GLP-2 derivative.

74. method for preparing each GLP-2 peptide among the claim 1-29, described method is included in the suitable growth medium host cell of cultivating among the claim 31-33 each under the condition that allows described polynucleotide constructs to express, reclaims the gained peptide from substratum.