WO2018205233A1 - 多肽化合物在治疗急性胰腺炎中的应用 - Google Patents

多肽化合物在治疗急性胰腺炎中的应用 Download PDF

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WO2018205233A1
WO2018205233A1 PCT/CN2017/084013 CN2017084013W WO2018205233A1 WO 2018205233 A1 WO2018205233 A1 WO 2018205233A1 CN 2017084013 W CN2017084013 W CN 2017084013W WO 2018205233 A1 WO2018205233 A1 WO 2018205233A1
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Prior art keywords
peptide
ingap
hip
acute pancreatitis
analog
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PCT/CN2017/084013
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English (en)
French (fr)
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刘利平
白茹
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深圳君圣泰生物技术有限公司
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Priority to EP17909453.7A priority Critical patent/EP3639840A4/en
Priority to JP2019562654A priority patent/JP7169673B2/ja
Priority to PCT/CN2017/084013 priority patent/WO2018205233A1/zh
Priority to US16/094,881 priority patent/US10772929B2/en
Priority to BR112019023511A priority patent/BR112019023511A2/pt
Priority to AU2017414006A priority patent/AU2017414006B2/en
Priority to CA3063183A priority patent/CA3063183A1/en
Priority to CN201780090649.9A priority patent/CN110958885B/zh
Publication of WO2018205233A1 publication Critical patent/WO2018205233A1/zh
Priority to US17/011,052 priority patent/US11534477B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4733—Acute pancreatitis-associated protein

Definitions

  • the present application relates to the use of a polypeptide compound for the treatment of acute pancreatitis, and in particular to the use of an INGAP-PP peptide, a HIP peptide, or an analogue thereof for the treatment of acute pancreatitis.
  • Pancreatitis is generally thought to be a disease caused by the pancreatic self-digestion of the pancreas. According to the course of the disease, pancreatitis can be divided into acute pancreatitis (AP) and chronic pancreatitis (CP). According to reports, the annual incidence of pancreatitis is 13-45/100,000, and the incidence of acute pancreatitis has gradually increased over the past 30 years.
  • AP acute pancreatitis
  • CP chronic pancreatitis
  • Acute pancreatitis is a disease caused by a variety of factors that causes multiple organ dysfunction in the body. Typical symptoms include severe, persistent upper abdominal pain, usually painful to the back and ribs, and often accompanied by vomiting, bloating, fever, Increased heart rate, increased white blood cell count, elevated blood or urine amylase. The degree of lesions ranged from interstitial edema and fat necrosis seen under the microscope to pancreatic parenchyma or peripancreatic necrosis and hemorrhage visible to the naked eye. The pathogenesis and pathogenesis of acute pancreatitis are diverse, and various causes and mechanisms may interact, resulting in poor clinical prognosis.
  • the diagnostic criteria for acute pancreatitis at home and abroad are basically the same. It is believed that the diagnosis of acute pancreatitis must meet at least two of the following three criteria: (1) the abdomen consistent with acute pancreatitis Pain symptoms; (2) serum amylase and / or lipase ⁇ 3 times the upper limit of normal; (3) meet the imaging features of acute pancreatitis.
  • INGAP-PP peptide, HIP peptide, or the like can significantly reduce the increase of blood amylase and lipase levels caused by pancreatitis, reduce the degree of pancreatic pathological damage caused by pancreatitis, and significantly improve Survival rate of acute pancreatitis model animals induced by sodium taurocholate.
  • the application provides the use of an INGAP-PP peptide, a HIP peptide, or an analog thereof, in the treatment of acute pancreatitis.
  • the present application also provides a method of treating acute pancreatitis in a patient comprising administering to the patient a composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • Figure 1 compares the survival rate of animals in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 2 compares blood amylase levels in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 3 compares blood lipase levels in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 4 compares the results of pathological scoring of pancreatic edema in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 5 compares the results of pancreatic inflammatory pathology scores between the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 6 compares pancreatic hemorrhage between the administration group and the control group in an animal model of acute pancreatitis Pathological score results.
  • Figure 7 compares the results of pathological scoring of pancreatic acinar necrosis in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 8 compares the results of pathological scoring of total pancreatic lesions in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 9 compares the pancreatic coefficient results of the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 10 compares blood amylase levels in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 11 compares blood lipase levels in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 12 compares the results of pathological scoring of pancreatic edema in the administration group and the control group in an animal model of acute pancreatitis.
  • Figure 13 compares the results of pancreatic inflammatory pathology scores between the administration group and the control group in an animal model of acute pancreatitis.
  • parenteral administration and “parenteral administration” are terms well known in the art, including modes of administration other than enteral and topical administration, such as injection, and include, but are not limited to, intravenous, intramuscular, intrapleural, Intravascular, pericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and sternal Injection and infusion.
  • treating includes preventing the occurrence of a disease, disorder or condition in an animal that may be predisposed to a disease, disorder and/or condition but not yet diagnosed as having it; inhibiting the disease, disorder or condition, for example, preventing its development; and alleviating the disease, disorder Or a condition, for example, that causes a regression of a disease, disorder, and/or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition.
  • pharmaceutically acceptable refers to a composition, polymer that is in a range of reasonable medical judgment for use in contact with human and animal tissues without excessive toxicity, irritation, allergies, or other problems or complications. And other materials and / or dosage forms.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle that participates in the carriage or transport of any test composition from one organ or part of the body to another organ or portion of the body, For example, liquid or solid fillers, diluents, solvents or encapsulating materials. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the subject composition and not injurious to the patient.
  • the term "patient” refers to a mammal, such as a mouse, guinea pig, rat, dog or human, preferably a human.
  • INGAP-PP and HIP peptide analogs and their preparation are disclosed in the PCT applications PCT/CN2014/073483 and PCT/CN2013/072771, which are hereby incorporated by the present applicants, in which the INGAP-PP peptide, HIP peptide, and its analogs are A pharmacological activity, but no mention of anti-acute pancreatitis activity. Both PCT/CN2014/073483 and PCT/CN2013/072771 are hereby incorporated by reference in their entirety.
  • the Applicant has unexpectedly discovered that in the bombesin-induced mouse acute pancreatitis model, the INGAP-PP peptide, the HIP peptide, and its analogs (in the examples, the sequence Ac-IGLHD PSHGT LPAGS-OH, ie, the following table) Sequence 12 in 2) can reduce pathological damage such as edema and inflammation caused by bombesin, significantly reducing blood amylase and lipase levels in animals (see Figures 10 and 11), induced by sodium taurocholate
  • the INGAP-PP peptide, HIP peptide, its analog in the example, the sequence Ac-IGLHD PSHGT LPAGS-OH, ie, the sequence 12 in Table 2 below
  • the sequence Ac-IGLHD PSHGT LPAGS-OH ie, the sequence 12 in Table 2 below
  • Example 1 Three doses were tested in Example 1, which were low dose 0.05 mg/kg, medium dose 0.25 mg/kg, and high dose 1.25 mg/kg, respectively. Surviving animals in all drug-administered groups maintained good mental state and activity status, significantly Better than the control group.
  • the present application provides, in one aspect, the use of an INGAP-PP peptide, a HIP peptide or an analog thereof for treating acute pancreatitis in a patient. Accordingly, the present application also provides the use of an INGAP-PP peptide, a HIP peptide or an analog thereof for the preparation of a medicament for treating acute pancreatitis in a patient.
  • the INGAP-PP peptide analog is Ac-IGLHD PSHGT LPAGS-OH.
  • INGAP-PP peptides, HIP peptides, and exemplary analogs thereof are provided in Tables 1-3 below.
  • Peptide number/sequence number sequence 1 H-IGLHDPSHGTLPNGS-OH 2 (HIP) H-IGLHDPTQGTEPNGE-OH
  • the INGAP-PP peptide analog has the general formula:
  • X 1 is selected from Isoleucine (I), D-Isoleucine, L-NorValine or L-NorLeucine;
  • X 2 is selected from Alanine (A) or Aspartic Acid (D);
  • X 3 is selected from Serine (S) or Threonine (T)
  • X 4 is selected from Histidine (H) or Glutamine (Q);
  • X 5 is selected from Leucine (L) or Glutamic acid (E);
  • X 1 is Isoleucine (I)
  • X 2 is Aspartic Acid (D)
  • X 3 is Serine (S)
  • X 4 is Histidine (H)
  • X 5 is Leucine (L)
  • X 6 is selected from Alanine (A), ⁇ -Amino-isobutyric acid or N-methyl-L-Alanine;
  • X 1 is Isoleucine (I)
  • X 2 is Aspartic Acid (D)
  • X 3 is Serine (S)
  • X 4 is Histidine (H)
  • X 5 is Leucine (L)
  • X 6 is selected from Alanine ( A), Asparagine (N), ⁇ -Amino-isobutyric acid or N-methyl-L-Alanine.
  • the INGAP-PP peptide analog of formula (1) can be selected from the group consisting of:
  • H-IGLHDPSHGTLP N-methyl-L-Alanine
  • GS-OH sequence number: 11
  • the INGAP-PP peptide analog of formula (1) can be selected from the group consisting of
  • the INGAP-PP peptide analog has the general formula:
  • X 1 is selected from Glutamic acid (E), Cysteine (C) or Lysine (K);
  • X 1 is selected from Serine (S), Glutamic acid (E), Cysteine (C) or Lysine (K).
  • the INGAP-PP peptide analog of the general formula (2) may be selected from the group consisting of H-IGLHDPSHGTLPNGE-OH (SEQ ID NO: 21) and H-IGLHDPSHGTLPNGK-OH (SEQ ID NO: 22).
  • the INGAP-PP peptide analog of formula (2) can be selected from the group consisting of
  • the INGAP-PP peptide analog of formula (2) can be selected from the group consisting of
  • the INGAP-PP peptide analog of formula (2) can be selected from the group consisting of
  • the INGAP-PP peptide analog of formula (2) can be selected from the group consisting of
  • the INGAP-PP peptide analog has the general formula:
  • R 1 is -H
  • R 2 is -OH
  • m is 1
  • X 1 is selected from Glutamic acid (E), Cysteine (C) or Lysine (K);
  • X 1 is selected from Serine (S), Glutamic acid (E), Cysteine (C) or Lysine (K).
  • the INGAP-PP peptide analog of formula (3) can be selected from the group consisting of: H-IGLHDPSHGTLPAGE-OH (SEQ ID NO: 27) and H-IGLHDPSHGTLPAGK-OH (SEQ ID NO: 23).
  • the INGAP-PP peptide analog of formula (3) can be selected from the group consisting of: Ac-IGLHDPSHGTLPAGS-NH 2 (SEQ ID NO: 29),
  • the INGAP-PP peptide analog of formula (3) can be selected from the group consisting of:
  • the INGAP-PP peptide analog of formula (3) can be selected from the group consisting of:
  • the INGAP-PP peptide analog has the general formula:
  • X 2 is selected from Lysine (K) or Cysteine (C)
  • R 1 is selected from -H or -Ac
  • R 2 is selected from -OH or -NH 2 .
  • the INGAP-PP peptide analog of formula (4) can be selected from the group consisting of:
  • the HIP peptide analog has the general formula:
  • X 1 is selected from Isoleucine (I) or D-Isoleucine;
  • X 2 is selected from Glutamic acid (E) or Leucine (L);
  • X 1 is Isoleucine (I) and X 2 is Glutamic acid (E), X 3 is selected from Alanine (A) or ⁇ -Amino-isobutyric acid;
  • X 1 is Isoleucine (I) and X 2 is Glutamic acid (E), X 3 is selected from Alanine (A), Asparagine (N) or ⁇ -Amino-isobutyric acid.
  • HIP peptide analog of formula (5) can be selected from the group consisting of:
  • H-IGLHDPTQGTEP (Aib) GE-OH (sequence number: 51),
  • HIP peptide analog of formula (5) can be selected from the group consisting of:
  • H-IGLHDPTQGTLPAGE-OH (SEQ ID NO: 59).
  • the HIP peptide analog has the general formula:
  • R 1 is selected from -H or -Ac
  • R 2 is selected from -OH or -NH 2 ;
  • X 1 is selected from Serine (S) or Cysteine (C);
  • X 1 is selected from Serine (S), Glutamic acid (E) or Cysteine (C).
  • the HIP peptide analog of formula (6) can be selected from the group consisting of
  • H-IGLHDPTQGTEPNGE-NH 2 (sequence number: 63).
  • the HIP peptide analog of formula (6) can be selected from the group consisting of
  • the HIP peptide analog has the general formula:
  • R 1 is selected from -H or -Ac; R 2 is selected from -OH or -NH 2 ; n is 0 or 1; X 1 is selected from Serine (S) or Cysteine (C).
  • HIP peptide analog of formula (7) can be selected from the group consisting of:
  • HIP peptide analog of formula (7) can be selected from the group consisting of:
  • H-IGLHDPTQGTEPAGE-NH 2 (SEQ ID NO: 68).
  • the INGAP-PP peptide, HIP peptide, or analog thereof used in the present invention may exist in any pharmaceutically acceptable salt form. Particularly useful salt forms are acetates and hydrochlorides.
  • Particularly useful salt forms are acetates and hydrochlorides.
  • the INGAP-PP peptide, HIP peptide, or the like used in the present invention contains an acidic moiety or a basic moiety, it can be provided in the form of a pharmaceutically acceptable salt (for example, see Berge et al., J. Pharm. Sci). .1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA: Zurich, Switzerland, 2002).
  • Suitable acids for the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonate Acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, n-hexanoic acid, octanoic acid, cinnamic acid , citric acid, cyclaic acid, cyclohexylsulfamic acid, dodecyl sulfuric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid,
  • Suitable bases for the preparation of pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as Secondary, tertiary, and dibutyl, aliphatic and aromatic amines, including: L-arginine, phenylethylbenzylamine, dibenzylethylenediamine, choline, dimethylamine ethanol, diethanolamine, diethylamine, dimethyl Amine, propylamine, diisopropylamine, diethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, meglumine, heimbamin, 1H-imidazole, L-lysine, morphine, 4-(2 -hydroxyethyl)morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)pyr
  • the INGAP-PP peptide, HIP peptide, or analog thereof used in the present invention may be combined with a pharmaceutically acceptable carrier to prepare a composition for treating acute pancreatitis in a patient.
  • a pharmaceutically acceptable carrier can be, for example, water, sodium phosphate buffer, phosphate buffered saline, physiological saline or Ringer's solution or other physiologically buffered saline, or other solutions or vehicles such as ethylene glycol, glycerin, oils, etc. Olive oil or injectable organic esters.
  • the pharmaceutically acceptable carrier may include a physiologically acceptable compound, for example, a compound which stabilizes or enhances the absorption of the INGAP-PP peptide, HIP peptide, or the like thereof used in the present invention.
  • physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose or dextran; antioxidants such as ascorbic acid or glutathione; and ethylenediaminetetraacetic acid (EDTA) which can destroy a microbial membrane.
  • EDTA ethylenediaminetetraacetic acid
  • a chelating agent a divalent metal ion such as calcium or magnesium; a low molecular weight protein; or other stabilizer or adjuvant.
  • a pharmaceutically acceptable carrier including a physiologically acceptable compound, is selected as desired, for example, depending on the route of administration of the composition.
  • Suitable carriers and their formulations are well known to those skilled in the art (see, for example, Remington: The Science and Practice of Pharmacy, 19th ed., ed. A.R. Gennaro, Mack Publishing Company, Easton, PA (1995); and Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton PA (1990)).
  • an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to adjust the isotonicity of the formulation.
  • the pH of the solution is generally between 5 and 8, such as 7-7.5.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art. The most classic of these is a standard carrier for human administration, including solutions such as sterile water, physiological saline, and a physiological pH buffer solution as described above.
  • the pharmaceutical composition may include a carrier, a thickener, a diluent, a buffer, a preservative, a surfactant, and a substance which increases the molecular selection possibility of the INGAP-PP peptide, HIP peptide, or the like.
  • Other carriers may include carriers for sustained release or controlled release formulations, such as semipermeable matrices of solid hydrophobic polymers which are covalently or non-covalently bound to the INGAP-PP peptide, HIP peptide, or the like, which are Used in the form of shaped articles, such as films, liposomes, non-liposomal lipid complexes or microsomes, or the like, or other biocompatible polymers well known to those skilled in the art (see, for example, US Patent No) .6,824,822 and 8,329,648).
  • carriers for sustained release or controlled release formulations such as semipermeable matrices of solid hydrophobic polymers which are covalently or non-covalently bound to the INGAP-PP peptide, HIP peptide, or the like, which are Used in the form of shaped articles, such as films, liposomes, non-liposomal lipid complexes or microsomes, or the like, or other biocompatible polymers well known to those
  • Liposomes formed from phospholipids or other lipids are non-toxic, physiologically acceptable and degradable, and are relatively simple to prepare and consume (Gregoriadis, Liposome Technology, Vol. 1 (CRC Press, Boca Raton Fla., 1984).
  • Various modes of administration are well known to those skilled in the art (Langer, Nature 392 (Suppl): 5-10 (1998); Langer et al., Nature 428: 487-492 (2004)).
  • the carrier will be apparent to those skilled in the art, for example, depending on the route of administration and the concentration of the composition of the drug.
  • compositions may be administered in a number of ways depending on the needs of the topical or systemic treatment and the site of treatment.
  • routes of administration include systemic and topical routes of administration, and include, but are not limited to, intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal, transdermal or electrophoretic, inhaled, oral, topical , luminal administration, and sustained release delivery devices, including locally implanted sustained release devices, such as biodegradable or reservoir implants.
  • Administration can be topical (including ocular, vaginal, rectal, intranasal), oral Inhaled, parenteral, such as intravenous, subcutaneous, intraperitoneal or intramuscular.
  • Formulations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and emulsions.
  • non-aqueous solutions are vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable organic esters such as ethyl oleate.
  • the aqueous carrier is a liquid, an alcohol/water agent, an emulsion or a suspension comprising physiological saline and a buffering vehicle.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose chloride, Ringer's lactate, or fixed oils.
  • Intravenous vehicles include fluids, nutritional supplements, electrolyte supplements (such as Ringer's dextrose), and the like.
  • Preservatives and other additives may be, for example, antibacterial agents, antioxidants, chelating agents, and inert gases and the like.
  • Insulin is a well-known peptide therapeutic drug, and therefore, the method of insulin administration is particularly suitable for administration of the polypeptide of the present invention or the like, including but not limited to a syringe, an injection pen, an infusion pump, an inhaler, an oral spray. , tablets, etc.
  • the application provides a method of treating acute pancreatitis in a patient comprising administering to the patient a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • the INGAP-PP peptide analog is Ac-IGLHD PSHGT LPAGS-OH.
  • the present application provides a method of reducing blood amylase and lipase levels in a patient with acute pancreatitis comprising administering to the patient a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • the INGAP-PP peptide analog is Ac-IGLHD PSHGT LPAGS-OH.
  • the present application provides a method of treating acute pancreatitis in a patient by reducing the levels of blood amylase and lipase in a patient with acute pancreatitis comprising administering to the patient an INGAP-PP peptide, a HIP peptide, or the like Pharmaceutical composition of the substance.
  • the INGAP-PP peptide analog is Ac-IGLHD PSHGT LPAGS-OH.
  • the present application provides a method for preventing or reducing pancreatic damage due to acute pancreatitis comprising administering to a patient a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof .
  • a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof .
  • the INGAP-PP The peptide analog was Ac-IGLHD PSHGT LPAGS-OH.
  • the present application provides a method for treating an inflammatory pancreatic disease or condition comprising administering to the patient a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof.
  • the INGAP-PP peptide analog is Ac-IGLHD PSHGT LPAGS-OH.
  • the present application also provides the use of a pharmaceutical composition comprising an INGAP-PP peptide, a HIP peptide, or an analog thereof, in the treatment of acute pancreatitis in a patient.
  • the dose of the INGAP-PP peptide, HIP peptide, or the like contained in the pharmaceutical composition can be selected within a wide range, including but not limited to 0.0005 mg/kg/day to 100 mg/kg/day, for example, about 0.0005 mg/kg/day, about 0.001 mg/kg/day, about 0.005 mg/kg/day, about 0.01 mg/kg/day, about 0.025 mg/kg/day, about 0.05 mg/kg/day, about 0.1 mg. /kg/day, about 0.25 mg/kg/day, about 0.5 mg/kg/day, about 0.75 mg/kg/day, about 1.0 mg/kg/day, about 1.25 mg/kg/day, about 1.50 mg/kg.
  • exemplary dosage ranges include, but are not limited to, 0.0005 mg/kg/day to 0.005 mg/kg/day, 0.005 mg/kg/day to 0.05 mg/kg/day, and 0.025 mg/kg/day to 0.25 mg/kg/day.
  • the INGAP-PP peptide, HIP peptide, or the like thereof used in the present invention may also be administered to patients with acute pancreatitis in the same preparation in combination with other therapeutic agents for acute pancreatitis known or to be developed, or different preparations. Patients with acute pancreatitis were given separately.
  • Therapeutic drugs for acute pancreatitis that can be administered in combination with the INGAP-PP peptide, HIP peptide, or the like used in the present application include, but are not limited to, pancreatic enzyme secretion inhibiting drugs such as glucagon, calcitonin, growth inhibitory hormone And its analogues octreotide and the like; protease inhibitors such as ulinastatin, gabelide, etc; tumor necrosis factor alpha (TNF- ⁇ ) inhibitors, such as pentoxifylline; and other drugs for the treatment of acute pancreatitis, such as Antioxidant, platelet activating factor Antibiotics, probiotics and activated protein C.
  • pancreatic enzyme secretion inhibiting drugs such as glucagon, calcitonin, growth inhibitory hormone And its analogues octreotide and the like
  • protease inhibitors such as ulinastatin, gabelide, etc
  • Example 1 Therapeutic effect of peptide 12 on a model of pancreatitis induced by sodium taurocholate
  • Sprague-Dawley (SD) rats were 60 females and 70 males were fed for more than 7 days. They were fasted overnight before modeling. Five females were randomly selected and 8 males were normal controls. Females were randomly selected. Five male animals were opened in the abdominal cavity, and the duodenum and pancreas were turned into a sham operation group. The remaining animals were prepared by retrograde injection of a solution of sodium taurocholate from the common bile duct at a dose of 35 mg/kg to prepare an acute pancreatitis model.
  • model control group (10 mL/kg, normal saline), peptide 12 low dose group (0.05 mg/kg, peptide 12 physiological saline solution), and peptide 12 medium dose group (0.25 mg/kg, peptide).
  • peptide 12 low dose group 0.05 mg/kg, peptide 12 physiological saline solution
  • peptide 12 medium dose group (0.25 mg/kg, peptide).
  • the model was administered subcutaneously once a day after model establishment, and once every other day for a total of 2 days, and the experimental period was 3 days. Animals were observed by cages during the experiment. The observations included death or sudden death, mental state, behavioral activities, fecal traits, skin, coat, eyes, ears, nose, abdomen, external genitals, anus, limbs, feet. Breathing, etc. At the end of the experiment, all the surviving rats were weighed and blood samples were collected. The levels of amylase, blood calcium and lipase in the serum of each group were measured and dissected for general observation, focusing on pancreatic condition, gastrointestinal status, Whether ascites, bile duct obstruction, pulmonary congestion and saponification were observed and recorded. The pancreas was preserved in 10% formalin fixative for subsequent pathological analysis.
  • the survival of each group of animals is shown in Table 5 and Figure 1. It can be seen that there is no animal death in the normal control group and the sham-operated control group, the survival rate is 100%, and the survival rate of the model control group is 37.5%. The survival rate is improved, and the improvement in survival rate is correlated with the dose of peptide 12 administered. The dose of peptide 12 administered at 1.25 mg/kg can significantly improve the survival rate, and the survival rate is 66.7%. The ratio to the control group was 1.78. At the same time, the mental state and activity status of the surviving animals in the drug-administered group were significantly better than those in the control group, and the anatomy of the surviving animals was generally observed. The results showed that the edema and liquefaction of the pancreas of the administered group were Gastrointestinal obstruction, ascites volume, bile duct obstruction, pulmonary congestion and saponification spots have all been improved to varying degrees.
  • the degree of damage of the pancreas was determined by preparing the HE slices on the pancreas, and the pathological changes of the pancreas such as edema, inflammation, hemorrhage and necrosis were scored by Schmidt method. The specific scoring criteria are shown in Table 6 below. The total pancreatic injury is the above four items. Addition.
  • administration of peptide 12 can reduce the pathological damage caused by sodium taurocholate to the pancreas in a dose-dependent manner.
  • mice Male BALB/c mice, 6-8 weeks old, adaptively fed for more than 7 days. After fasting overnight, 10 animals were randomly selected as normal control group. The remaining animals were intraperitoneally injected with 50 ⁇ g/kg bombesin. The rats were injected once a day for 10 times to prepare an acute pancreatitis model, and were randomly divided into model control group, peptide 12, 0.025, 0.25, 2.5, and 25 mg/kg administration groups, with 10 rats in each group. A corresponding dose of peptide 12 or physiological saline was administered 5 minutes before the dermatan.
  • the experiment was terminated 1 hour after the 10th injection of bombesin, and blood was collected for blood amylase and lipase levels.
  • the pancreas was weighed and fixed in 10% formalin fixative for subsequent pathological analysis.
  • Pancreatic coefficient was calculated using pancreas weight/body weight, which reflects pancreatic edema.
  • the experimental statistical results are shown in Figure 9, where: ###: compared with the normal control group, P ⁇ 0.001; **: P ⁇ 0.01 compared with the model control group; ***: P ⁇ 0.001 compared with the model control group.
  • the pancreatic coefficient of the model group was significantly higher than that of the normal control group, and the pancreatic coefficient was significantly decreased at doses of 0.025, 0.25, and 2.5 mg/kg in the peptide 12 administration group, and was dose-dependent.
  • FIG. 12 The scoring of edema and inflammation is shown in Fig. 12 to Fig. 13. It should be noted that, in FIG. 12, ###: P ⁇ 0.001 compared with the normal control group; in FIG. 13, ###: P ⁇ 0.001 compared with the normal control group; *: compared with the model control group Ratio P ⁇ 0.05; **: P ⁇ 0.01 compared with the model control group. It can be seen from Fig. 12 to Fig. 13 that the model group has obvious edema and inflammatory damage compared with the normal control group, and the administration of the peptide 12 can reduce the pathological damage such as edema and inflammation caused by the bombardin.

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Abstract

INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途。所述多肽化合物能显著降低急性胰腺炎导致的血液淀粉酶和脂肪酶水平的升高，减轻胰腺炎导致的胰腺病理损伤程度，并显著降低急性胰腺炎导致的死亡。

Description

多肽化合物在治疗急性胰腺炎中的应用 技术领域
本申请涉及多肽化合物在治疗急性胰腺炎中的应用，具体的讲，涉及INGAP-PP肽、HIP肽、或其类似物在治疗急性胰腺炎中的应用。
背景技术
胰腺炎通常被认为是胰腺因胰蛋白酶的自身消化作用而引起的疾病。根据病程，胰腺炎可被分为急性胰腺炎(AP)和慢性胰腺炎(CP)两种。据报道，胰腺炎的年发病率为13-45/10万，而且，在过去30年中，急性胰腺炎发病率呈逐渐上升的趋势。
急性胰腺炎是由多种因素参与的引起全身多器官功能障碍的疾病，其典型症状包括剧烈、持续的上腹部疼痛，通常疼痛向背部和肋部放射，且常常伴有呕吐、腹胀、发热、心率增快、白细胞计数上升、血或尿淀粉酶升高。病变程度不等，从显微镜下所见的间质水肿和脂肪坏死，到肉眼可见的胰腺实质或胰周坏死和出血。急性胰腺炎的发病原因及发病机制多种多样，各种病因及机制可能相互作用，导致患者临床预后差。
目前现有的治疗手段仅限于缓解疼痛、补液以维持水和电解质平衡、营养支持、预防感染以及预防并发症等支持性保守治疗，尚没有针对急性胰腺炎的疗效显著的治疗药物。
因此，仍然需要开发能够有效治疗急性胰腺炎的新药物和方法。
发明内容
国内外关于急性胰腺炎的诊断标准基本一致，认为确诊急性胰腺炎至少须要符合以下3项标准中的2项：(1)与急性胰腺炎相一致的腹 痛症状；(2)血清淀粉酶和/或脂肪酶≥3倍正常值上限；(3)符合急性胰腺炎的影像学特征。
本申请人意外的发现，INGAP-PP肽、HIP肽、或其类似物能够显著降低胰腺炎导致的血液淀粉酶和脂肪酶水平的升高，减轻胰腺炎导致的胰腺病理损伤程度，并显著提高牛黄胆酸钠诱导的急性胰腺炎模型动物的存活率。
因此，在一些方面，本申请提供了INGAP-PP肽、HIP肽、或其类似物在治疗急性胰腺炎中的应用。
在另一些方面，本申请还提供了一种治疗患者急性胰腺炎的方法，包括给予所述患者包含INGAP-PP肽、HIP肽或其类似物的组合物。
根据本公开的以下描述并结合附图，本公开的这些和其他方面、特征和优点将变得显而易见。
附图说明
结合附图，从以下描述来看，本公开的上述和其他特点、方面和优点将容易的理解，其中：
图1比较了急性胰腺炎动物模型中，给药组和对照组的动物存活率。
图2比较了急性胰腺炎动物模型中，给药组和对照组的血淀粉酶水平。
图3比较了急性胰腺炎动物模型中，给药组和对照组的血脂肪酶水平。
图4比较了急性胰腺炎动物模型中，给药组和对照组的胰腺水肿病理评分结果。
图5比较了急性胰腺炎动物模型中，给药组和对照组的胰腺炎症病理评分结果。
图6比较了急性胰腺炎动物模型中，给药组和对照组的胰腺出血 病理评分结果。
图7比较了急性胰腺炎动物模型中，给药组和对照组的胰腺腺泡坏死病理评分结果。
图8比较了急性胰腺炎动物模型中，给药组和对照组的胰腺总损伤病理评分结果。
图9比较了急性胰腺炎动物模型中，给药组和对照组的胰腺系数结果。
图10比较了急性胰腺炎动物模型中，给药组和对照组的血淀粉酶水平。
图11比较了急性胰腺炎动物模型中，给药组和对照组的血脂肪酶水平。
图12比较了急性胰腺炎动物模型中，给药组和对照组的胰腺水肿病理评分结果。
图13比较了急性胰腺炎动物模型中，给药组和对照组的胰腺炎症病理评分结果。
具体实施方式
以下提供的每一个实施方案均有助于本公开某些方面的解释，但是不应解释为限制本公开的范围。另外，在整个说明书和权利要求书中，如本文中使用，近似的语言可应用于修饰任何数量表示，该数量表示可允许变化，而不会导致与其相关的基本功能的改变。因此，由一个术语或多个术语例如“约”修饰的值不限于指定的精确值。在一些情况，近似的语言可对应于用于测量数值的仪器的精密度。
短语“非肠道给予”和“肠胃外给予”为本领域熟知的术语，包括除肠内和局部给予以外的给予模式，例如注射，并且非限制性地包括静脉内、肌内、胸膜内、血管内、心包内、动脉内、鞘内、囊内、眶内、心脏内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、被膜下、蛛网膜下、脊柱内和胸骨内注射和输注。
术语“治疗”包括在可能易患疾病、障碍和/或病症但是尚未诊断为患有的动物中防止疾病、障碍或病症的发生；抑制疾病、障碍或病症，例如阻碍其发展；和缓解疾病、障碍或病症，例如导致疾病、障碍和/或病症的消退。治疗疾病或病症包括改善具体疾病或病症的至少一个症状。
短语“药学上可接受的”指的是处于合理的医疗判断范围内，适用于与人和动物的组织接触而没有过度的毒性、刺激、变态反应或者其它问题或并发症的组合物、聚合物及其它材料和/或剂型。
短语“药学上可接受的载体”指的是参与从一个器官或身体的部分运载或运输任何受试组合物至另一个器官或身体的部分的药学上可接受的材料、组合物或媒介物，比如液体或固体填充剂、稀释剂、溶剂或包封材料。每一种载体在与受试组合物的其它成分相容并且不伤害患者的意义上必须是“可接受的”。
如本文使用，术语“患者”是指哺乳动物，如小鼠、豚鼠、大鼠、狗或人，优选患者为人。
在本申请人之前提交的PCT申请PCT/CN2014/073483和PCT/CN2013/072771中公开了INGAP-PP和HIP肽类似物及其制备，其中表明INGAP-PP肽、HIP肽、其类似物具有多种药理学活性，但是没有提及抗急性胰腺炎活性。PCT/CN2014 /073483和PCT /CN2013/072771两者均通过引用而整体结合至本文中。
本申请人意外的发现，在蛙皮素诱导的小鼠急性胰腺炎模型中，INGAP-PP肽、HIP肽、其类似物(在实施例中采用序列Ac-IGLHD PSHGT LPAGS-OH，即下表2中的序列12)能够降低蛙皮素对胰腺造成的水肿和炎症等病理损伤改变，显著降低动物的血淀粉酶和脂肪酶水平(见图10和图11)，在牛黄胆酸钠诱导的大鼠急性胰腺炎模型中，INGAP-PP肽、HIP肽、其类似物(在实施例中采用序列Ac-IGLHD PSHGT LPAGS-OH，即下表2中的序列12)能够显著提高动物的存活率。而且，INGAP-PP肽、HIP肽、其类似物的适用性很大，在实施 例1中实验了三个剂量，分别为低剂量0.05mg/kg、中剂量0.25mg/kg和高剂量1.25mg/kg，所有给药组中存活动物均保持良好的精神状态和活动状态，显著优于对照组。
因此，本申请在一个方面提供了INGAP-PP肽、HIP肽或其类似物在治疗患者急性胰腺炎中的应用。相应的，本申请还提供了INGAP-PP肽、HIP肽或其类似物在制备用于治疗患者急性胰腺炎的药物中的用途。在一个实施方案中，所述INGAP-PP肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
在以下表1-3中提供了INGAP-PP肽、HIP肽及其示例性类似物。
表1.INGAP-PP肽和HIP肽
肽编号/序列编号 序列
1(INGAP-PP) H-IGLHDPSHGTLPNGS-OH
2(HIP) H-IGLHDPTQGTEPNGE-OH
表2.示例性INGAP-PP肽类似物
Figure PCTCN2017084013-appb-000001
Figure PCTCN2017084013-appb-000002
Figure PCTCN2017084013-appb-000003
表3.示例性HIP肽类似物
Figure PCTCN2017084013-appb-000004
Figure PCTCN2017084013-appb-000005
如本领域技术人员所公知的，在肽序列中，各符号及其所代表的氨基酸如表4所示：
表4
Figure PCTCN2017084013-appb-000006
Figure PCTCN2017084013-appb-000007
在一个实施方案中，所述INGAP-PP肽类似物具有如下通式：
X1GLHX2PX3X4GTX5PX6GS    (1)；
其中，X1选自Isoleucine(I)、D-Isoleucine、L-NorValine或L-NorLeucine；X2选自Alanine(A)或Aspartic Acid(D)；X3选自Serine(S)或Threonine(T)；X4选自Histidine(H)或Glutamine(Q)；X5选自Leucine(L)或Glutamic acid(E)；
并且，当X1为Isoleucine(I)、X2为Aspartic Acid(D)、X3为Serine(S)、X4为Histidine(H)、X5为Leucine(L)成立时，X6选自Alanine(A)、α-Amino-isobutyric acid或N-methyl-L-Alanine；
当X1为Isoleucine(I)、X2为Aspartic Acid(D)、X3为Serine(S)、X4为Histidine(H)、X5为Leucine(L)不成立时，X6选自Alanine(A)、Asparagine(N)、α-Amino-isobutyric acid或N-methyl-L-Alanine。
在一个具体的实施方案中，通式(1)的INGAP-PP肽类似物可选自：
H-IGLHAPSHGTLPNGS-OH(序列编号：6)、
H-IGLHDPSHGTLP(Aib)GS-OH(序列编号：10)、
H-IGLHDPSHGTLP(N-methyl-L-Alanine)GS-OH(序列编号：11)、
H-(D-Isoleucine)GLHDPSHGTLPNGS-OH(序列编号：17)、
H-IGLHDPSHGTEPNGS-OH(序列编号：18)、
H-IGLHDPSQGTLPNGS-OH(序列编号：19)、和
H-IGLHDPTHGTLPNGS-OH(序列编号：20)。
在另一个具体的实施方案中，通式(1)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPAGS-OH(序列编号：7)、
H-IGLHAPSHGTLPAGS-OH(序列编号：8)、
H-(D-Isoleucine)GLHDPSHGTLPAGS-OH(序列编号：13)、
H-(L-NorValine)GLHDPSHGTLPAGS-OH(序列编号：14)、
H-(L-NorLeucine)GLHDPSHGTLPAGS-OH(序列编号：15)、
H-IGLHDPSHGTEPAGS-OH(序列编号：24)、
H-IGLHDPSQGTLPAGS-OH(序列编号：25)、和
H-IGLHDPTHGTLPAGS-OH(序列编号：26)。
在一个实施方案中，所述INGAP-PP肽类似物具有如下通式：
R1-IGLHDPSHGTLPNGX1(C)m-R2     (2)；
其中，m为0或1；R1选自-H或-Ac；R2选自-OH或-NH2；
并且，当R1为-H、R2为-OH且m为0成立时，X1选自Glutamic acid(E)、Cysteine(C)或Lysine(K)；
当R1为-H、R2为-OH且m为0不成立时，X1选自Serine(S)、Glutamic acid(E)、Cysteine(C)或Lysine(K)。
在一个具体的实施方案中，通式(2)的INGAP-PP肽类似物可选自：H-IGLHDPSHGTLPNGE-OH(序列编号：21)和H-IGLHDPSHGTLPNGK-OH(序列编号：22)。
在一个具体的实施方案中，通式(2)的INGAP-PP肽类似物可选自：
Ac-IGLHDPSHGTLPNGS-NH2(序列编号：31)、
H-IGLHDPSHGTLPNGS-NH2(序列编号：32)、和
Ac-IGLHDPSHGTLPNGS-OH(序列编号：16)。
在一个具体的实施方案中，通式(2)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPNGC-OH(序列编号：37)、
Ac-IGLHDPSHGTLPNGC-OH(序列编号：38)、
H-IGLHDPSHGTLPNGC-NH2(序列编号：39)、和
Ac-IGLHDPSHGTLPNGC-NH2(序列编号：40)。
在一个具体的实施方案中，通式(2)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPNGSC-OH(序列编号：33)、
Ac-IGLHDPSHGTLPNGSC-OH(序列编号：34)、
H-IGLHDPSHGTLPNGSC-NH2(序列编号：35)、和
Ac-IGLHDPSHGTLPNGSC-NH2(序列编号：36)。
在一个具体的实施方案中，通式(2)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPNG-OH(序列编号：74)、
Ac-IGLHDPSHGTLPNG-OH(序列编号：75)、
H-IGLHDPSHGTLPNG-NH2(序列编号：76)、和
Ac-IGLHDPSHGTLPNG-NH2(序列编号：77)。
在一个实施方案中，所述INGAP-PP肽类似物具有如下通式：
R1-IGLHDPSHGTLPAG(X1)m-R2     (3)；
其中，m为0或1；R1选自-H或-Ac；R2选自-OH或-NH2；
当R1为-H、R2为-OH且m为1成立时，X1选自Glutamic acid(E)、Cysteine(C)或Lysine(K)；
当R1为-H、R2为-OH且m为1不成立时，X1选自Serine(S)、Glutamic acid(E)、Cysteine(C)或Lysine(K)。
在一个具体的实施方案中，通式(3)的INGAP-PP肽类似物可选自：H-IGLHDPSHGTLPAGE-OH(序列编号：27)和H-IGLHDPSHGTLPAGK-OH(序列编号：23)。
在一个具体的实施方案中，通式(3)的INGAP-PP肽类似物可选自：Ac-IGLHDPSHGTLPAGS-NH2(序列编号：29)、
H-IGLHDPSHGTLPAGS-NH2(序列编号：41)、和
Ac-IGLHDPSHGTLPAGS-OH(序列编号：12)。
在一个具体的实施方案中，通式(3)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPAGC-OH(序列编号：46)、
Ac-IGLHDPSHGTLPAGC-OH(序列编号：47)、
H-IGLHDPSHGTLPAGC-NH2(序列编号：48)、和
Ac-IGLHDPSHGTLPAGC-NH2(序列编号：49)。
在一个具体的实施方案中，通式(3)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPAG-OH(序列编号：73)、
H-IGLHDPSHGTLPAG-NH2(序列编号：28)、和
Ac-IGLHDPSHGTLPAG-NH2(序列编号：30)。
在一个实施方案中，所述INGAP-PP肽类似物具有如下通式：
R1-IGLHDPSHGTLPAGSX2-R2    (4)；
其中，X2选自Lysine(K)或Cysteine(C)，R1选自-H或-Ac，R2选自-OH或-NH2。
在一个具体的实施方案中，通式(4)的INGAP-PP肽类似物可选自：
H-IGLHDPSHGTLPAGSK-OH(序列编号：9)、
H-IGLHDPSHGTLPAGSC-OH(序列编号：42)、
Ac-IGLHDPSHGTLPAGSC-OH(序列编号：43)、
H-IGLHDPSHGTLPAGSC-NH2(序列编号：44)、和
Ac-IGLHDPSHGTLPAGSC-NH2(序列编号：45)。
在一个实施方案中，所述HIP肽类似物具有如下通式：
X1GLHDPTQGTX2PX3GE       (5)；
X1选自Isoleucine(I)或D-Isoleucine；X2选自Glutamic acid(E)或Leucine(L)；
并且，当X1为Isoleucine(I)且X2为Glutamic acid(E)成立时，X3选自Alanine(A)或α-Amino-isobutyric acid；
当X1为Isoleucine(I)且X2为Glutamic acid(E)不成立时，X3选自 Alanine(A)、Asparagine(N)或α-Amino-isobutyric acid。
在一个具体的实施方案中，通式(5)的HIP肽类似物可选自：
H-IGLHDPTQGTEP(Aib)GE-OH(序列编号：51)、
H-(D-Isoleucine)GLHDPTQGTEPNGE-OH(序列编号：55)、和
H-IGLHDPTQGTLPNGE-OH(序列编号：58)。
在一个具体的实施方案中，通式(5)的HIP肽类似物可选自：
H-IGLHDPTQGTEPAGE-OH(序列编号：50)、
H-(D-Isoleucine)GLHDPTQGTEPAGE-OH(序列编号：53)、和
H-IGLHDPTQGTLPAGE-OH(序列编号：59)。
在一个实施方案中，所述HIP肽类似物具有如下通式：
R1-IGLHDPTQGTEPNGX1-R2       (6)；
其中，R1选自-H或-Ac；R2选自-OH或-NH2；
当R1为-H且R2为-OH成立时，X1选自Serine(S)或Cysteine(C)；
当R1为-H且R2为-OH不成立时，X1选自Serine(S)、Glutamic acid(E)或Cysteine(C)。
在一个具体的实施方案中，通式(6)的HIP肽类似物可选自：
Ac-IGLHDPTQGTEPNGE-OH(序列编号：54)、
Ac-IGLHDPTQGTEPNGE-NH2(序列编号：61)、和
H-IGLHDPTQGTEPNGE-NH2(序列编号：63)。
在一个具体的实施方案中，通式(6)的HIP肽类似物可选自：
H-IGLHDPTQGTEPNGS-OH(序列编号：56)、
H-IGLHDPTQGTEPNGC-OH(序列编号：64)、
Ac-IGLHDPTQGTEPNGC-OH(序列编号：65)、
H-IGLHDPTQGTEPNGC-NH2(序列编号：66)、和
Ac-IGLHDPTQGTEPNGC-NH2(序列编号：67)。
在一个实施方案中，所述HIP肽类似物具有如下通式：
R1-IGLHDPTQGTEPAG(X1)n-R2     (7)；
其中，R1选自-H或-Ac；R2选自-OH或-NH2；n为0或1；X1选 自Serine(S)或Cysteine(C)。
在一个具体的实施方案中，通式(7)的HIP肽类似物可选自：
H-IGLHDPTQGTEPAGS-OH(序列编号：57)、
Ac-IGLHDPTQGTEPAG-NH2(序列编号：60)、
H-IGLHDPTQGTEPAGC-OH(序列编号：69)、
Ac-IGLHDPTQGTEPAGC-OH(序列编号：70)、
H-IGLHDPTQGTEPAGC-NH2(序列编号：71)、和
Ac-IGLHDPTQGTEPAGC-NH2(序列编号：72)。
在一个具体的实施方案中，通式(7)的HIP肽类似物可选自：
Ac-IGLHDPTQGTEPAGE-OH(序列编号：52)、
Ac-IGLHDPTQGTEPAGE-NH2(序列编号：62)、和
H-IGLHDPTQGTEPAGE-NH2(序列编号：68)。
用于本发明的INGAP-PP肽、HIP肽、或其类似物可以任何药学上可接受的盐形式存在。尤其有用的盐形式是醋酸盐和盐酸盐。当用于本发明的INGAP-PP肽、HIP肽、或其类似物含有酸性部分或碱性部分时，其可以药学上可接受的盐形式提供(例如参见Berge et al.，J.Pharm.Sci.1977，66，1-19；and Handbook of Pharmaceutical Salts，Properties，and Use；Stahl and Wermuth，Ed.；Wiley-VCH and VHCA：Zurich，Switzerland，2002)。
用于制备药学上可接受的盐的适合的酸包括但不限于：醋酸、2，2-二氯醋酸、酰化氨基酸、己二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、正己酸、辛酸、肉桂酸、柠檬酸、环拉酸、环己基氨基磺酸、十二烷基硫酸、1，2-乙二磺酸、乙磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、L-谷氨酸、α-酮戊二酸、甘醇酸、马尿素、氢溴酸、盐酸、氢碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-苦杏仁酸、甲磺酸、2-萘磺酸、 1，5-萘二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、高氯酸、磷酸、L-焦谷氨酸、葡糖二酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、L-酒石酸、硫氰酸、对甲苯磺酸、十一烯酸和戊酸。
用于制备药学上可接受的盐的适合的碱包括但不限于：无机碱，如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌、或氢氧化钠；和有机碱，如伯、仲、叔、和丁、脂肪族和芳香族胺，包括：L-精氨酸、苯乙苄胺、二苄乙二胺、胆碱、二甲胺乙醇、二乙醇胺、二乙胺、二甲胺、丙胺、二异丙胺、二乙氨基乙醇、乙醇胺、乙胺、乙二胺、异丙胺、葡甲胺、海巴明、1H-咪唑、L-赖氨酸、吗啡林、4-(2-羟乙基)吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟乙基)吡咯烷、吡啶、奎宁环、喹啉、异喹啉、仲胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡萄糖胺、三羟甲基氨基甲烷、和氨丁三醇。
用于本发明的INGAP-PP肽、HIP肽、或其类似物可与药学上可接受的载体组合，配制成组合物，以治疗患者的急性胰腺炎。药学上可接受的载体可为：例如，水、磷酸钠缓冲液、磷酸缓冲盐溶液、生理盐水或林格溶液或其他生理缓冲盐水、或其他溶液或溶媒，如乙二醇、甘油、油脂如橄榄油或可注射的有机酯。
药学上可接受的载体可包括生理上可接受的化合物，例如，稳定或提高本发明使用的INGAP-PP肽、HIP肽、或其类似物的吸收的化合物。这些生理上可接受的化合物包括，如，葡萄糖、蔗糖或葡聚糖等的碳水化合物；抗坏血酸或谷胱甘肽等的抗氧剂；可破坏微生物膜的乙二胺四乙酸(EDTA)等的螯合剂；钙或镁等二价金属离子；低分子量蛋白；或其他稳定剂或辅料。本领域的技术人员应该了解根据需要选择药学上可接受的载体，包括生理上可接受的化合物，例如，依据组合物的给药途径进行选择。适合的载体和它们的配方是本领域的技术人员所熟知的(例如参见Remington：The Science and Practice of Pharmacy，19th ed.，ed.A.R.Gennaro，Mack Publishing Company， Easton，PA(1995)；and Remington’s Pharmaceutical Sciences，18th ed.，Mack Publishing Company，Easton PA(1990))。经典的比如，适量的药学上可接受的盐用在配方中调节制剂的等渗性。溶液的pH一般在5-8，比如7-7.5。
药学上可接受的载体是本领域的技术人员所熟知的。其中最经典的是人用药的标准载体，包括如无菌水、生理盐水和上述的生理pH的缓冲溶液等的溶液。药用组合物可包括载体、增稠剂、稀释剂、缓冲液、防腐剂、表面活性剂、和增加所述INGAP-PP肽、HIP肽、或其类似物分子选择可能性的物质。
其他的载体可包括缓释或控释制剂用载体，比如与所述INGAP-PP肽、HIP肽、或其类似物以共价或非共价结合的固体疏水聚合物的半透基质，这些基质以成型制品的形式使用，如膜、脂质体、非脂质体的脂质复合物或微粒体等类似材料，或其它本领域技术人员熟知的生物相容性聚合物(例如参见U.S.Patent No.6,824,822和8,329,648)。由磷脂或其他脂类形成的脂质体是无毒的、生理上可接受和降解的，且制备和服用都相对简单(Gregoriadis，Liposome Technology，Vol.1(CRC Press，Boca Raton Fla.，1984)。各种给药方式是本领域技术人员所熟知的(Langer，Nature 392(Suppl)：5-10(1998)；Langer et al.，Nature 428：487-492(2004))。依据情况特定的载体，这对本领域的技术人员是显而易见的，比如说根据给药途径和给药组成的浓度选择。
药用组合物根据局部或系统治疗的需要和治疗部位，可以有许多给药方式。可以理解为可以采用多种给药途径来给予所述INGAP-PP肽、HIP肽、或其类似物。这些给药途径包括系统和局部给药途径，并且包括且不限于静脉注射、腹腔注射、肌肉注射、皮下注射、透皮给药、经皮扩散或电泳、吸入给药、口服给药、局部注射、腔道给药、和缓释传输装置，包括局部植入缓释装置，如生物可降解或储蓄池式植入体。给药可以是局部的(包括眼部、阴道、直肠、鼻内)、口服 的，吸入式的、非肠道的，例如静脉点滴、皮下注射、腹腔注射或肌肉注射。
非肠道给药的制剂包括无菌水溶液或非水溶液、混悬剂和乳剂。非水溶液的实例有丙二醇、聚乙二醇、橄榄油等植物油、和可注射的有机酯，如油酸乙酯。水性载体有包括生理盐水和缓冲溶媒在内的水剂、乙醇/水剂、乳剂或混悬剂。肠外溶媒包括氯化钠溶液、林格葡萄糖、葡萄糖氯化钠、林格乳酸盐，或不挥发油类。静脉注射溶媒包括流体、营养补充剂、电解质补充剂(如林格葡萄糖)等。防腐剂和其它添加剂可以为，例如抗菌剂、抗氧剂、螯合剂，和惰性气体等。胰岛素是熟知的肽类治疗药物，因此，胰岛素给药的方法特别适合用于本发明的多肽或其类似物的给药，这包括但不限于注射器、注射笔、输液泵、吸入器、口腔喷雾、片剂等。
在另一个方面，本申请提供了治疗患者急性胰腺炎的方法，包括给予所述患者包含INGAP-PP肽、HIP肽、或其类似物的药用组合物。在一个实施方案中，所述INGAP-PP肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
在还另一个方面，本申请提供了降低急性胰腺炎患者血液淀粉酶和脂肪酶水平的方法，包括给予所述患者包含INGAP-PP肽、HIP肽、或其类似物的药用组合物。在一个实施方案中，所述INGAP-PP肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
在还另一个方面，本申请提供了通过降低急性胰腺炎患者血液淀粉酶和脂肪酶的水平来治疗患者急性胰腺炎的方法，包括给予所述患者包含INGAP-PP肽、HIP肽、或其类似物的药用组合物。在一个实施方案中，所述INGAP-PP肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
在还一个方面，本申请提供了一种用于防止或减少由于急性胰腺炎导致的胰腺损伤的方法，包括给予所述患者包含INGAP-PP肽、HIP肽、或其类似物的药用组合物。在一个实施方案中，所述INGAP-PP 肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
在还一个方面，本申请提供了一种用于治疗炎性胰腺疾病或病症的方法，包括给予所述患者包含INGAP-PP肽、HIP肽、或其类似物的药用组合物。在一个实施方案中，所述INGAP-PP肽类似物为Ac-IGLHD PSHGT LPAGS-OH。
相应的，本申请也提供了包含INGAP-PP肽、HIP肽、或其类似物的药用组合物在治疗患者急性胰腺炎中的用途。
药用组合物中所含的INGAP-PP肽、HIP肽、或其类似物的给药剂量可在宽范围内选择，包括但不限于0.0005mg/kg/天-100mg/kg/天，例如约0.0005mg/kg/天，约0.001mg/kg/天，约0.005mg/kg/天，约0.01mg/kg/天，约0.025mg/kg/天，约0.05mg/kg/天，约0.1mg/kg/天，约0.25mg/kg/天，约0.5mg/kg/天，约0.75mg/kg/天，约1.0mg/kg/天，约1.25mg/kg/天，约1.50mg/kg/天，约1.75mg/kg/天，约2.0mg/kg/天，约2.5mg/kg/天，约5.0mg/kg/天，约10.0mg/kg/天，约15.0mg/kg/天，约25.0mg/kg/天，约50.0mg/kg/天，约75.0mg/kg/天，或约100mg/kg/天，等等。示例性剂量范围包括但不限于0.0005mg/kg/天-0.005mg/kg/天，0.005mg/kg/天-0.05mg/kg/天，0.025mg/kg/天-0.25mg/kg/天，0.05mg/kg/天-0.5mg/kg/天，0.25mg/kg/天-2.5mg/kg/天，0.5mg/kg/天-5.0mg/kg/天，2.5mg/kg/天-25.0mg/kg/天，5.0mg/kg/天-50.0mg/kg/天，或25.0mg/kg/天-100mg/kg/天，等等。
本发明中所用的INGAP-PP肽、HIP肽、或其类似物还可以与其他的已知或者待开发的急性胰腺炎治疗药物组合在同一制剂中同时给予急性胰腺炎患者，也可以不同的制剂分别给予急性胰腺炎患者。可以与本申请中所用INGAP-PP肽、HIP肽、或其类似物联合施用的急性胰腺炎治疗药物包括但不限于胰酶分泌抑制药物，如胰高血糖素、降血钙素、生长抑制激素及其类似物奥曲肽等；蛋白酶抑制剂，如乌司他丁、加贝酯等；肿瘤坏死因子α(TNF-α)抑制剂，如己酮可可碱；和其他治疗急性胰腺炎的药物，如抗氧化剂、血小板激活因子拈 抗剂、益生菌和活化蛋白C等。
下面的实施例意在举例说明本发明，不应以任何方式解释为限制本发明。
实施例1肽12对牛黄胆酸钠诱导的胰腺炎模型的治疗效果
Sprague-Dawley(SD)大鼠雌性60只，雄性70只适应性喂养7天以上，于造模前过夜禁食，随机选取雌性动物5只，雄性动物8只为正常对照组；随机选取雌性动物5只，雄性动物8只打开腹腔，翻十二指肠及胰腺作为假手术组。剩余动物按照35mg/kg的剂量从胆总管逆行注射给予牛磺胆酸钠溶液的方式制备急性胰腺炎模型。造模后，动物随机分成模型对照组(10mL/kg，生理盐水)、肽12低剂量组(0.05mg/kg，肽12的生理盐水溶液)、肽12中剂量组(0.25mg/kg，肽12的生理盐水溶液)和肽12高剂量组(1.25mg/kg，肽12的生理盐水溶液)，每组雌、雄大鼠各12只。
造模后当天皮下注射给药一次，第二天给药一次，共连续给药2天，实验周期3天。试验期间对动物进行笼旁观察，观察内容包括动物的死亡或濒死、精神状态、行为活动、粪便性状、皮肤、被毛、眼、耳、鼻、腹部、外生殖器、肛门、四肢、足、呼吸等。试验结束时，所有存活大鼠称重并采集血液样本，检测各组大鼠血清中的淀粉酶、血钙、脂肪酶各项指标水平，解剖进行大体观察，重点对胰腺状况、胃肠状况、是否有腹水、胆管阻塞、肺淤血和皂化斑等进行观察和记录，取胰腺保存于10％福尔马林固定液留待进行后续病理分析。
各组动物存活情况见表5和图1，可见正常对照组和假手术对照组无动物死亡，存活率为100％，模型对照组存活率为37.5％，三个给药组均可以使得模型动物的存活率提高，且对存活率的改善与肽12的给药剂量具有相关性，其中肽12给药剂量1.25mg/kg可使得存活率得到明显的提升，存活率为66.7％，其存活率与对照组的比值为1.78。同时给药组存活动物的精神状态和活动状态显著优于对照组，对存活动物解剖进行大体观察，结果显示，给药组动物胰腺的水肿和液化、 胃肠梗阻、腹水量、胆管阻塞、肺淤血和皂化斑等都有不同程度的改善。
表5各组动物存活情况
Figure PCTCN2017084013-appb-000008
模型对照组与正常组和假手术组相比，血淀粉酶和脂肪酶水平显著升高，肽12与模型对照组相比，可使得血淀粉酶和脂肪酶水平降低(如见图2和图3)。
胰腺的损伤程度通过对胰腺制备HE切片，利用Schmidt方法对胰腺的水肿、炎症、出血和坏死等各个方面的病理改变进行评分，具体评分标准如下表6所示，胰腺总损伤为以上四项的加和。
表6.胰腺组织病理学评分标准
Figure PCTCN2017084013-appb-000009
Figure PCTCN2017084013-appb-000010
病理评分结果显示在表7和图4～图8中。
表7.病理改变评分结果
Figure PCTCN2017084013-appb-000011
由图4～图8可见，肽12给药可以剂量相关性的降低牛黄胆酸钠对胰腺造成的病理损伤改变。
实施例2肽12对蛙皮素诱导胰腺炎模型的治疗效果
雄性BALB/c小鼠，6-8周龄，适应性喂养7天以上，禁食过夜后，随机选择10只动物作为正常对照组，剩余动物以50μg/kg蛙皮素腹腔注射，每隔1小时注射一次，共注射10次，制备急性胰腺炎模型，并随机分为模型对照组、肽12的0.025、0.25、2.5和25mg/kg给药组，每组10只，于第4次给予蛙皮素之前5分钟给予相应剂量的肽12或生理盐水。
于第10次注射蛙皮素后1小时结束实验，采集血液进行血淀粉酶和脂肪酶水平的测定，采集胰腺称重并固定于10％福尔马林固定液留待进行后续病理分析。
胰腺系数的计算采用胰腺重/体重，该结果反应了胰腺水肿的情况。实验统计结果显示在图9中，其中：###：与正常对照组相比P ＜0.001；**：与模型对照组相比P＜0.01；***：与模型对照组相比P＜0.001。从图9可以看出，模型组胰腺系数较正常对照组显著升高，肽12给药组0.025、0.25和2.5mg/kg三个剂量下，可显著降低胰腺系数，且具有剂量依赖关系。如图10和图11所示，模型对照组与正常组相比，血淀粉酶和脂肪酶水平显著升高，肽12与模型对照组相比，0.025、0.25、2.5和25mg/kg四个给药剂量下，均可使得血淀粉酶和脂肪酶显著降低。需要说明的是，在图10中，###：与正常对照组相比P＜0.001；***：与模型对照组相比P＜0.001；在图11中，###：与正常对照组相比P＜0.001；***：与模型对照组相比P＜0.001。
胰腺的损伤程度通过对胰腺制备HE切片，按照上述胰腺组织病理学评分标准，利用Schmidt方法对胰腺的水肿、炎症、出血和坏死等各个方面的病理改变进行评分。
表8.病理改变评分结果
Figure PCTCN2017084013-appb-000012
病理评分结果显示，蛙皮素诱导的胰腺炎模型中并未见明显出血和坏死，水肿和炎症的评分情况如图12～图13所示。需要说明的是，在图12中，###：与正常对照组相比P＜0.001；在图13中，###：与正常对照组相比P＜0.001；*：与模型对照组相比P＜0.05；**：与模型对照组相比P＜0.01。从图12～图13可见，模型组与正常对照组相比，有明显的水肿和炎症损伤，肽12给药可降低蛙皮素对胰腺造成的水肿和炎症等病理损伤改变。
本发明已经根据一些具体的实施方案进行了描述。它们仅打算用于举例说明，不应以任何方式视为限制。因此，应理解可对其进行修 改，此类修改在本发明和所附权利要求的范围内。另外，本文提及的所有专利、专利申请、论文和教科书均通过引用而结合至本文中。

Claims (13)

  1. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    X1GLHX2PX3X4GTX5PX6GS   (1)
    其中，X1选自Isoleucine(I)、D-Isoleucine、L-NorValine或L-NorLeucine；X2选自Alanine(A)或Aspartic Acid(D)；X3选自Serine(S)或Threonine(T)；X4选自Histidine(H)或Glutamine(Q)；X5选自Leucine(L)或Glutamic acid(E)；
    并且，当X1为Isoleucine(I)、X2为Aspartic Acid(D)、X3为Serine(S)、X4为Histidine(H)、X5为Leucine(L)成立时，X6选自Alanine(A)、α-Amino-isobutyric acid或N-methyl-L-Alanine；
    当X1为Isoleucine(I)、X2为Aspartic Acid(D)、X3为Serine(S)、X4为Histidine(H)、X5为Leucine(L)不成立时，X6选自Alanine(A)、Asparagine(N)、α-Amino-isobutyric acid或N-methyl-L-Alanine。
  2. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    R1-IGLHDPSHGTLPNGX1(C)m-R2  (2)
    其中，m为0或1；R1选自-H或-Ac；R2选自-OH或-NH2；
    并且，当R1为-H、R2为-OH且m为0成立时，X1选自Glutamicacid(E)、Cysteine(C)或Lysine(K)；
    当R1为-H、R2为-OH且m为0不成立时，X1选自Serine(S)、Glutamic acid(E)、Cysteine(C)或Lysine(K)。
  3. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    R1-IGLHDPSHGTLPAG(X1)m-R2    (3)
    其中，m为0或1；R1选自-H或-Ac；R2选自-OH或-NH2；
    当R1为-H、R2为-OH且m为1成立时，X1选自Glutamic acid(E)、Cysteine(C)或Lysine(K)；
    当R1为-H、R2为-OH且m为1不成立时，X1选自Serine(S)、Glutamic acid(E)、Cysteine(C)或Lysine(K)。
  4. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    R1-IGLHDPSHGTLPAGSX2-R2  (4)
    其中，X2选自Lysine(K)或Cysteine(C)，R1选自-H或-Ac，R2选自-OH或-NH2。
  5. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    X1GLHDPTQGTX2PX3GE  (5)
    X1选自Isoleucine(I)或D-Isoleucine；X2选自Glutamic acid(E)或Leucine(L)；
    并且，当X1为Isoleucine(I)且X2为Glutamic acid(E)成立时，X3选自Alanine(A)或α-Amino-isobutyric acid；
    当X1为Isoleucine(I)且X2为Glutamic acid(E)不成立时，X3选自Alanine(A)、Asparagine(N)或α-Amino-isobutyric acid。
  6. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    R1-IGLHDPTQGTEPNGX1-R2  (6)
    其中，R1选自-H或-Ac；R2选自-OH或-NH2；
    当R1为-H且R2为-OH成立时，X1选自Serine(S)或Cysteine(C)；
    当R1为-H且R2为-OH不成立时，X1选自Serine(S)、Glutamicacid(E)或Cysteine(C)。
  7. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺炎的药物中的用途，其中所述肽类似物具有如下通式：
    R1-IGLHDPTQGTEPAG(X1)n-R2  (7)
    其中，R1选自-H或-Ac；R2选自-OH或-NH2；n为0或1；X1选自Serine(S)或Cysteine(C)。
  8. INGAP-PP肽、HIP肽、或其类似物在制备用于治疗急性胰腺 炎的药物中的用途，其中所述INGAP-PP肽和HIP肽分别为表1中的INGAP-PP肽和HIP肽，所述INGAP-PP肽类似物选自以下表2中所列的肽序列，且所述HIP肽类似物选自以下表3中所列的肽序列：
    表1.INGAP-PP肽和HIP肽
    肽编号/序列编号 序列 1(INGAP-PP) H-IGLHDPSHGTLPNGS-OH 2(HIP) H-IGLHDPTQGTEPNGE-OH
    表2.示例性INGAP-PP肽类似物
    Figure PCTCN2017084013-appb-100001
    Figure PCTCN2017084013-appb-100002
    Figure PCTCN2017084013-appb-100003
    表3.示例性HIP肽类似物
    Figure PCTCN2017084013-appb-100004
    Figure PCTCN2017084013-appb-100005
  9. 一种治疗患者急性胰腺炎的方法，所述方法包括给予所述患者包含权利要求1-8中任一项所述的INGAP-PP肽、HIP肽、或其类似物的药用组合物。
  10. 一种降低急性胰腺炎患者血液淀粉酶和脂肪酶水平的方法，所述方法包括给予所述患者包含权利要求1-8中任一项所述的INGAP-PP肽、HIP肽、或其类似物的药用组合物。
  11. 一种通过降低急性胰腺炎患者血液淀粉酶和脂肪酶的水平来治疗所述患者急性胰腺炎的方法，所述方法包括给予所述患者包含权利要求1-8中任一项所述的INGAP-PP肽、HIP肽、或其类似物的药用组合物。
  12. 一种用于防止或减少由于急性胰腺炎导致的胰腺损伤的方法，所述方法包括给予所述患者包含权利要求1-8中任一项所述的INGAP-PP肽、HIP肽、或其类似物的药用组合物。
  13. 一种用于治疗炎性胰腺疾病或病症的方法，所述方法包括给予所述患者包含权利要求1-8中任一项所述的INGAP-PP肽、HIP肽、或其类似物的药用组合物。
PCT/CN2017/084013 2017-05-11 2017-05-11 多肽化合物在治疗急性胰腺炎中的应用 WO2018205233A1 (zh)

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