WO2021238088A1 - N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 - Google Patents

N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 Download PDF

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WO2021238088A1
WO2021238088A1 PCT/CN2020/128050 CN2020128050W WO2021238088A1 WO 2021238088 A1 WO2021238088 A1 WO 2021238088A1 CN 2020128050 W CN2020128050 W CN 2020128050W WO 2021238088 A1 WO2021238088 A1 WO 2021238088A1
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crystal form
hydroxybenzoyl
amino
potassium
octanoate
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PCT/CN2020/128050
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English (en)
French (fr)
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王宏阳
江师月
李尧
潘海
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杭州先为达生物科技有限公司
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Priority to JP2022573605A priority Critical patent/JP2023527238A/ja
Priority to AU2020450589A priority patent/AU2020450589B2/en
Priority to EP20937944.5A priority patent/EP4159712A4/en
Priority to US17/999,945 priority patent/US20230234916A1/en
Priority to KR1020227044941A priority patent/KR20230015414A/ko
Publication of WO2021238088A1 publication Critical patent/WO2021238088A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic 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
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to the field of chemistry and medicine, in particular to a potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal polymorph and its preparation method and application.
  • Macromolecular drugs such as peptides and protein drugs often have the characteristics of large molecular weight and low fat solubility, which are unstable to gastric acid and can be destroyed by various digestive enzymes in the gastrointestinal tract. Oral administration cannot smoothly enter the intestinal tract for absorption. In response to the above problems, people try to overcome drug absorption barriers in many ways. In addition to some attempts in dosage forms, gastrointestinal absorption enhancers are often used to improve the permeability of the drug's biomembrane. Although the absorption of drugs is increased, It also increases the absorption of toxins in the intestines, and it is not safe for long-term use.
  • NAC N-[8-(2-hydroxybenzoyl)amino]octanoic acid
  • NAC octanoic acid
  • SNAC monosodium N-[8-(2-hydroxybenzoyl)amino]octanoate
  • SNAC is a new type of amino acid derivative delivery agent. Recent studies have shown that it does not require dosage form protection to promote the oral absorption of various protein drug solutions such as heparin and human growth hormone, but does not show obvious cytotoxicity.
  • the bioavailability, solubility, and fluidity of the salt type will vary depending on the compound. Different crystal forms of the same salt form will have different crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, and dissolution rate, which will directly or indirectly affect the ability of the drug to be delivered. This results in differences in the bioavailability, compressibility and stability of the delivered drugs.
  • the purpose of this application is to provide a N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph and its preparation method and use, pharmaceutical composition and its use.
  • a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate characterized in that the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the crystal polymorph is crystal form I, and the crystal form I has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, and 18.89 ⁇ 0.2.
  • a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate characterized in that the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the crystal polymorph is crystal form II, and the crystal form II has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, and 20.26 ⁇ 0.2.
  • a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid characterized in that the potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid
  • the crystal polymorph is crystal form III, and the crystal form III has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, and 21.44 ⁇ 0.2.
  • a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate characterized in that the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the crystal polymorph is crystal form IV, and the crystal form IV has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, and 22.08 ⁇ 0.2.
  • a method for preparing a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate characterized in that it comprises the following steps:
  • the preparation method according to item 33 characterized in that the filter cake is rinsed and placed in a drying box for drying, at a drying temperature of 60°C to 100°C, and a drying time of 30 to 40 hours, to obtain the The crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; preferably, the drying is divided into two steps, first drying at 60°C for 16h, and then the system is pressed at 100°C again after flat nitrogen pressure Dry for 24h;
  • the crystal form I is the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate described in any one of items 1-8.
  • the preparation method according to item 33 characterized in that the filter cake is prepared into uniform particles, and then the particles are put into the drying box to be dried, and the dried particles are evenly spread in 2 In a low temperature environment of -8°C, the relative humidity is controlled at 50% and placed for 2 days to form potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form III.
  • drying temperature at which the particles are put into the drying box is 60°C-100°C, and the drying time is 30-40h; preferably, the drying is divided into two parts. In two steps, first dry at 60°C for 16h, and then dry the system at 100°C for 24h after the system is pressed flat with nitrogen.
  • the crystal form III is the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 17-24.
  • the preparation method according to any one of items 33 to 37 characterized in that the concentration of the potassium hydroxide solution is 40% to 90%, preferably the concentration of the potassium hydroxide solution is 50%.
  • the system is heated to 48°C-52°C, and then potassium hydroxide solution is added dropwise. After the dropwise addition is completed, the temperature is kept and reacted for 1 hour.
  • a method for preparing the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid characterized in that the N-[8-(2-hydroxybenzoyl)amino]caprylic acid
  • the crystalline forms of potassium other than crystalline form I are heated to at least 75° C. to form crystalline form I.
  • a method for preparing potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystal form I characterized in that potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid
  • the crystal forms other than the crystal form I are freeze-dried to form the crystal form I.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form I are crystal form II and crystal form III , At least one or more than two of the crystal form IV.
  • a method for preparing the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid characterized in that N-[8-(2-hydroxybenzoyl)amino]caprylic acid
  • the crystal forms of potassium other than crystal form II are exposed to an environment with a relative humidity of 0-60% at room temperature for more than 24 hours to form the N-[8-(2-hydroxybenzoyl)amino] Crystal form II of potassium octoate.
  • a preparation method of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form IV characterized in that it comprises the following steps:
  • the crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than form IV forms a colloidal substance in an environment with a relative humidity higher than 80%;
  • the gel-like substance is exposed to an environment with a relative humidity of 20%-40% at room temperature for more than 120 hours to form crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form IV are crystal form I and crystal form II , At least one or more than two of the crystal form III.
  • the preparation method according to item 55 characterized in that the gel-like substance is exposed to an environment having a relative humidity of 20%, 30% or 40%, preferably, the gel-like substance is exposed to an environment having a relative humidity of 40%. Relative humidity environment.
  • a pharmaceutical composition characterized in that it comprises a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the pharmaceutical composition according to item 59 characterized in that the crystal polymorphs of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate are crystal form I, crystal form II, and crystal form III , One or at least two of the crystal form IV.
  • composition according to any one of items 59 to 60, characterized in that the pharmaceutical composition further comprises preventive and/or therapeutic drugs.
  • the pharmaceutical composition according to item 61 characterized in that the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate in the pharmaceutical composition and the prevention and/or treatment
  • the weight ratio of the sex drug is (20-60):1.
  • the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal polymorph and the preventive and/or The weight ratio of therapeutic drugs is 30:1.
  • the pharmaceutical composition according to item 62, wherein the preventive and/or therapeutic drug is glucagon-like peptide-1, insulin, PYY, human amylin, heparin, human growth hormone, Interferon, monoclonal antibody, protease inhibitor, thrombopoietin.
  • N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph or its pharmaceutical composition in the preparation of drugs for preventing and/or treating diabetes or diabetic complications or reducing weight use.
  • the N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorphs provided in this application have four crystal forms, which have high solubility and strong stability, and can deliver drugs more effectively and increase the delivery rate.
  • the permeability of the drug in the gastrointestinal tract facilitates the preparation of oral preparations, so that preventive and/or therapeutic drugs can be better delivered to the body to improve bioavailability.
  • FIG. 1 is an X-ray powder diffraction pattern of the crystalline form I of PNAC prepared in Example 1.
  • FIG. 1 is an X-ray powder diffraction pattern of the crystalline form I of PNAC prepared in Example 1.
  • FIG. 2a is a DSC chart of the crystalline form I of PNAC prepared in Example 1.
  • FIG. 2a is a DSC chart of the crystalline form I of PNAC prepared in Example 1.
  • FIG. 2b is a TGA diagram of the crystalline form I of the PNAC prepared in Example 1.
  • FIG. 2b is a TGA diagram of the crystalline form I of the PNAC prepared in Example 1.
  • Example 3 is an X-ray powder diffraction pattern of the crystalline form II of PNAC prepared in Example 2.
  • FIG. 4a is a DSC chart of the crystalline form II of PNAC prepared in Example 2.
  • FIG. 4a is a DSC chart of the crystalline form II of PNAC prepared in Example 2.
  • 4b is a TGA diagram of the crystalline form II of PNAC prepared in Example 2.
  • FIG. 6a is a DSC chart of the crystal form III of PNAC prepared in Example 3.
  • FIG. 6a is a DSC chart of the crystal form III of PNAC prepared in Example 3.
  • FIG. 6b is a TGA diagram of the crystal form III of the PNAC prepared in Example 3.
  • FIG. 6b is a TGA diagram of the crystal form III of the PNAC prepared in Example 3.
  • Example 7 is an X-ray powder diffraction pattern of the crystalline form IV of PNAC prepared in Example 4.
  • FIG. 8a is a DSC chart of the crystalline form IV of PNAC prepared in Example 4.
  • FIG. 8a is a DSC chart of the crystalline form IV of PNAC prepared in Example 4.
  • FIG. 8b is a TGA diagram of the crystalline form IV of PNAC prepared in Example 4.
  • FIG. 8b is a TGA diagram of the crystalline form IV of PNAC prepared in Example 4.
  • Fig. 9 is a trend graph of blood drug concentration-dose time in the intravenous administration group.
  • Fig. 10 is a trend graph of blood drug concentration-dose time of each group of oral administration.
  • Fig. 11 is an XRPD pattern of the solid state stability experiment of crystal form II.
  • Fig. 12 is an XRPD diagram of the crystal form II before and after the grinding experiment.
  • Figure 13 is the XRPD images of the crystal form II before and after the tableting experiment.
  • Fig. 14 is the XRPD images of the crystal form II before and after the jet pulverization experiment.
  • Fig. 15 is an XRPD pattern of the solid-state stability experiment of crystal form I.
  • Fig. 16 is the XRPD images of the crystal form I before and after the tabletting experiment.
  • Fig. 17 is the XRPD images of the crystal form I before and after the jet pulverization experiment.
  • Fig. 18 is an XRPD diagram of the crystal form I before and after the polishing experiment.
  • Figure 19 is a trend graph of blood drug concentration-dose time in the intravenous administration group.
  • Fig. 20 is a trend graph of blood drug concentration-dose time of each group of oral administration.
  • X-Ray Powder Diffraction is usually applied to the analysis of crystal structure.
  • X-ray is a kind of electromagnetic wave, when it is incident on the crystal, it produces a periodically changing electromagnetic field in the crystal. It causes the electrons and atomic nucleus in the atom to vibrate, and the vibration is negligible because of the large mass of the atomic nucleus.
  • the vibrating electron is the wave source of secondary X-rays, and its wavelength and phase are the same as the incident light.
  • the scattered waves of each electron in the crystal interfere with each other and superimpose each other, which is called diffraction.
  • the direction in which the scattering wave cycles are consistent and mutually reinforcing is called the diffraction direction, which produces diffraction lines.
  • Thermogravimetric Analysis refers to a thermal analysis technique that measures the relationship between the quality of the sample to be tested and the temperature change under program control temperature, and is used to study the thermal stability and composition of the material. TGA is a commonly used testing method in R&D and quality control. Thermogravimetric analysis is often used in combination with other analysis methods in actual material analysis to conduct comprehensive thermal analysis and analyze materials comprehensively and accurately. The curve recorded by the thermogravimetric analyzer is called the TGA curve.
  • Heating method linear heating
  • Temperature range room temperature ⁇ 350°C.
  • DSC Differential scanning calorimetry
  • W/g or mW/mg that is, the power per gram of the sample
  • T or time t the abscissa.
  • Thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc.
  • the method uses a wide temperature range (-175 ⁇ 725°C), high resolution, and small sample amount. It is suitable for the analysis of inorganic substances, organic compounds and drugs.
  • Heating method linear heating
  • This application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, and the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the form is crystal form I, and the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, and 18.89 ⁇ 0.2.
  • the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, and 5.24 ⁇ 0.2.
  • the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, and 21.59 ⁇ 0.2.
  • the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, and 21.59 ⁇ 0.2.
  • the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 24.29 ⁇ 0.2.
  • the crystal form I has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2.
  • the crystal form I has X-ray powder with characteristic peaks represented by 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2, 24.29 ⁇ 0.2 Diffraction pattern.
  • the crystal form I has characteristic peaks represented by 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2, 24.29 ⁇ 0.2, 6.61 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form I has 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2, 24.29 ⁇ 0.2, 6.61 ⁇ 0.2, 10.43 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks shown.
  • the crystal form I has 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2, 24.29 ⁇ 0.2, 6.61 ⁇ 0.2, 10.43 ⁇ 0.2 , X-ray powder diffraction pattern of the characteristic peak represented by 31.63 ⁇ 0.2.
  • the crystal form I has 2 ⁇ °: 7.83 ⁇ 0.2, 26.64 ⁇ 0.2, 18.89 ⁇ 0.2, 5.24 ⁇ 0.2, 21.59 ⁇ 0.2, 13.02 ⁇ 0.2, 24.29 ⁇ 0.2, 6.61 ⁇ 0.2, 10.43 ⁇ 0.2 , 31.63 ⁇ 0.2, 37.00 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks.
  • the melting point of Form I is 163.1°C.
  • the adsorption water removal temperature of crystal form I is 83.6°C.
  • the crystal form I loses 3.0% weight at 140°C.
  • This application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, and the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the form is crystal form II, and the crystal form II has at least 2 ⁇ ° X-ray powder diffraction patterns with characteristic peaks represented by 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, and 20.26 ⁇ 0.2.
  • the crystal form II has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, and 14.68 ⁇ 0.2.
  • the crystal form II has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 25.55 ⁇ 0.2.
  • the crystal form II has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2.
  • the crystal form II has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2.
  • the crystal form II has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 26.66 ⁇ 0.2.
  • the crystal form II has X-ray powder with characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2 Diffraction pattern.
  • the crystal form II has characteristic peaks represented by 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks shown.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2
  • the X-ray powder diffraction pattern of the characteristic peak represented by 28.47 ⁇ 0.2.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks represented by 28.47 ⁇ 0.2 and 12.07 ⁇ 0.2.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 , 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 , 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2, 23.38 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2
  • X-ray powder diffraction patterns of characteristic peaks represented by, 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2, 23.38 ⁇ 0.2, 29.48 ⁇ 0.2.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2
  • X-ray powder diffraction pattern of characteristic peaks represented by, 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2, 23.38 ⁇ 0.2, 29.48 ⁇ 0.2, 22.55 ⁇ 0.2.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 X-ray powder diffraction pattern of characteristic peaks represented by, 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2, 23.38 ⁇ 0.2, 29.48 ⁇ 0.2, 22.55 ⁇ 0.2, 27.79 ⁇ 0.2.
  • the crystal form II has 2 ⁇ °: 24.76 ⁇ 0.2, 6.73 ⁇ 0.2, 20.26 ⁇ 0.2, 14.68 ⁇ 0.2, 25.55 ⁇ 0.2, 13.41 ⁇ 0.2, 26.66 ⁇ 0.2, 21.08 ⁇ 0.2, 25.79 ⁇ 0.2 X-ray powder diffraction patterns of characteristic peaks represented by, 28.47 ⁇ 0.2, 12.07 ⁇ 0.2, 15.38 ⁇ 0.2, 23.38 ⁇ 0.2, 29.48 ⁇ 0.2, 22.55 ⁇ 0.2, 27.79 ⁇ 0.2, 8.91 ⁇ 0.2.
  • the melting point of Form II is 162.5°C.
  • the adsorption water removal temperature of crystal form II is 93°C.
  • Form II loses 5.6% in weight at 140°C.
  • This application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, and the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the form is crystal form III, and the crystal form III has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, and 21.44 ⁇ 0.2.
  • the crystal form III has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2.
  • the crystal form III has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 6.03 ⁇ 0.2.
  • the crystal form III has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2.
  • the crystal form III has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2.
  • the crystal form III has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, and 17.06 ⁇ 0.2.
  • the crystal form III has an X-ray powder with characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2 Diffraction pattern.
  • the crystal form III has characteristic peaks represented by 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks shown.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2 , X-ray powder diffraction pattern of the characteristic peak represented by 22.15 ⁇ 0.2.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2 X-ray powder diffraction pattern of characteristic peaks represented by, 22.15 ⁇ 0.2 and 15.11 ⁇ 0.2.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2 , 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2 , 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2, 22.54 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2
  • X-ray powder diffraction pattern of characteristic peaks represented by, 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2, 22.54 ⁇ 0.2, 30.71 ⁇ 0.2.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2
  • X-ray powder diffraction pattern of characteristic peaks represented by, 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2, 22.54 ⁇ 0.2, 30.71 ⁇ 0.2, 17.91 ⁇ 0.2.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2
  • X-ray powder diffraction pattern of characteristic peaks represented by, 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2, 22.54 ⁇ 0.2, 30.71 ⁇ 0.2, 17.91 ⁇ 0.2, 15.64 ⁇ 0.2.
  • the crystal form III has 2 ⁇ °: 9.06 ⁇ 0.2, 23.30 ⁇ 0.2, 21.44 ⁇ 0.2, 24.75 ⁇ 0.2, 6.03 ⁇ 0.2, 21.20 ⁇ 0.2, 17.06 ⁇ 0.2, 21.75 ⁇ 0.2, 29.52 ⁇ 0.2
  • X-ray powder diffraction pattern of characteristic peaks represented by, 22.15 ⁇ 0.2, 15.11 ⁇ 0.2, 28.47 ⁇ 0.2, 22.54 ⁇ 0.2, 30.71 ⁇ 0.2, 17.91 ⁇ 0.2, 15.64 ⁇ 0.2, 26.49 ⁇ 0.2.
  • the melting point of Form III is 162.0°C.
  • the adsorption water removal temperature of crystal form III is 94.5°C.
  • Form III loses 6.1% in weight at 140°C.
  • This application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, and the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the form is crystal form IV, and the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by at least 2 ⁇ ° of 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, and 22.08 ⁇ 0.2.
  • the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, and 13.16 ⁇ 0.2.
  • the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 19.39 ⁇ 0.2.
  • the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ ° of 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, and 19.39 ⁇ 0.2.
  • the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2.
  • the crystal form IV has an X-ray powder diffraction pattern with characteristic peaks represented by 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 9.68 ⁇ 0.2.
  • the crystal form IV has X-ray powder with characteristic peaks represented by 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2 Diffraction pattern.
  • the crystal form IV has characteristic peaks represented by 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks shown.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 , X-ray powder diffraction pattern of the characteristic peak represented by 29.91 ⁇ 0.2.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction pattern of characteristic peaks represented by 29.91 ⁇ 0.2 and 23.04 ⁇ 0.2.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 , 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2 X-ray powder diffraction pattern of the characteristic peaks.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 , 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2, 23.5 ⁇ 0.2 X-ray powder diffraction pattern.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction patterns of characteristic peaks represented by, 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2, 23.5 ⁇ 0.2, and 27.31 ⁇ 0.2.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction patterns of characteristic peaks represented by, 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2, 23.5 ⁇ 0.2, 27.31 ⁇ 0.2, 19.74 ⁇ 0.2.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction patterns of characteristic peaks represented by, 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2, 23.5 ⁇ 0.2, 27.31 ⁇ 0.2, 19.74 ⁇ 0.2, 34.34 ⁇ 0.2.
  • the crystal form IV has 2 ⁇ °: 16.25 ⁇ 0.2, 6.8 ⁇ 0.2, 22.08 ⁇ 0.2, 13.16 ⁇ 0.2, 19.39 ⁇ 0.2, 18.35 ⁇ 0.2, 9.68 ⁇ 0.2, 15.92 ⁇ 0.2, 11.71 ⁇ 0.2 X-ray powder diffraction patterns of characteristic peaks represented by, 29.91 ⁇ 0.2, 23.04 ⁇ 0.2, 16.56 ⁇ 0.2, 23.5 ⁇ 0.2, 27.31 ⁇ 0.2, 19.74 ⁇ 0.2, 34.34 ⁇ 0.2, 18.82 ⁇ 0.2.
  • the melting point of Form IV is 163.8°C.
  • the adsorption water removal temperature of crystal form IV is 96.1°C.
  • the crystal form IV has a weight loss of 8.21% at 150°C.
  • the crystalline forms I-IV of the PNAC provided in the present application all have good solubility, bioavailability and solid-state stability, especially the bioavailability and solid-state stability of the crystalline form I and the crystalline form II.
  • This application provides a method for preparing the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, which includes the following steps:
  • Step 1 Add organic solvent to the reaction vessel and stir, then add N-[8-(2-hydroxybenzoyl)amino]caprylic acid, stir evenly, add potassium hydroxide solution dropwise, after the dropwise addition, concentrate to obtain the crude product ;
  • Step 2 Add an organic solvent to the crude product to make a slurry and obtain a filter cake, which is rinsed and placed in a drying oven for drying.
  • the drying temperature is 60°C to 100°C, and the drying time is 30 to 40 hours.
  • the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate is obtained.
  • the drying temperature may be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C.
  • the drying time may be 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h.
  • the drying is divided into two steps, first drying at 60° C. for 16 hours, and then drying the system at 100° C. for 24 hours after the system is flat-pressed with nitrogen.
  • the organic solvent is isopropanol or acetone.
  • the concentration of the potassium hydroxide solution is 40% to 90%, and preferably the concentration of the potassium hydroxide solution is 50%.
  • the concentration of the potassium hydroxide solution can be 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%.
  • the temperature of the system is raised to 48°C-52°C, and then potassium hydroxide solution is added dropwise. After the addition is complete, keep it at 48°C-52°C The reaction temperature is 1h.
  • the temperature of the system can be 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.
  • the time of holding reaction can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.
  • the time for adding an organic solvent to the crude product for beating is 0.5h-1.5h, preferably 1h.
  • the time for adding organic solvent to beating the crude product can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.
  • This application provides a method for preparing the second crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, removing potassium N-[8-(2-hydroxybenzoyl)amino]caprylate
  • the crystal forms other than the crystal form I are heated to at least 75° C. to form the crystal form I.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I is at least one of crystal form II, crystal form III, and crystal form IV, or Two or more.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be the crystal form II.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be the crystal form III.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be the crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be the crystal form II and the crystal form III.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be crystal form II and crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be crystal form III and crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I may be crystal form II, crystal form III and crystal form IV.
  • the crystal forms of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than form I are heated to above 75°C under the protection of nitrogen, and the heating time is 0 ⁇ 300min to form Form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the heating temperature is preferably 110-140°C.
  • the heating temperature may be 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C.
  • the heating time can be 10min, 15min, 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min, 60min, 65min, 70min, 75min, 80min, 85min, 90min, 95min, 100min, 105min, 110min, 115min, 120min, 125min, 130min, 135min, 140min, 145min, 150min, 155min, 160min, 165min, 170min, 175min, 180min, 185min, 190min, 195min, 200min, 205min, 210min, 210min, 220min, 225min, 230min, 235min, 240min, 245min, 250min, 255min, 260min, 265min, 270min, 275min, 280min, 285min, 290min, 295min, 300min.
  • the crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 140°C under the protection of nitrogen to form N-[8-(2-hydroxybenzoyl) ) Amino] crystalline form I of potassium octoate.
  • the crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 110°C under the protection of nitrogen to form N-[8-(2-hydroxybenzoyl) ) Amino] crystalline form I of potassium octoate.
  • This application provides a third preparation method of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form I, which decrystallizes potassium N-[8-(2-hydroxybenzoyl)amino]octanoate Crystal forms other than Form I are freeze-dried to form Form I.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form I is at least one of crystal form II, crystal form III, and crystal form IV, or Two or more.
  • This application provides a method for preparing potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal removal form III, which includes the following steps:
  • Step 1 Add organic solvent to the reaction vessel and stir, then add N-[8-(2-hydroxybenzoyl)amino]caprylic acid, stir evenly, add potassium hydroxide solution dropwise, after the dropwise addition, concentrate to obtain the crude product ;
  • Step 2 Add organic solvent to the crude product to obtain a filter cake after beating and suction filtration.
  • the filter cake is prepared into uniform particles, and then the particles are placed in the drying box for drying.
  • the dried particles Spread evenly in a low temperature environment of 2-8°C, and control the relative humidity to 50% for 2 days to form potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form III.
  • the filter cake is passed through a 20-24 mesh sieve to obtain uniform particles.
  • the drying temperature is 60°C-100°C, and the drying time is 30-40h.
  • the drying temperature may be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C.
  • the drying time may be 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h.
  • the drying is divided into two steps, first drying at 60° C. for 16 hours, and then drying the system at 100° C. for 24 hours after the system is flat-pressed with nitrogen.
  • the organic solvent is isopropanol or acetone.
  • the concentration of the potassium hydroxide solution is 40% to 90%, and preferably the concentration of the potassium hydroxide solution is 50%.
  • the concentration of the potassium hydroxide solution can be 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%.
  • the temperature of the system is raised to 48°C-52°C, and then potassium hydroxide solution is added dropwise. After the addition is complete, keep it at 48°C-52°C The reaction temperature is 1h.
  • the temperature of the system can be 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.
  • the time of holding reaction can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.
  • the time for adding an organic solvent to the crude product for beating is 0.5h-1.5h, preferably 1h.
  • the time for adding organic solvent to beating the crude product can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.
  • This application provides a method for preparing the crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate, which decrystallizes potassium N-[8-(2-hydroxybenzoyl)amino]caprylate Crystal forms other than Form II are exposed to an environment with a relative humidity of 0-60% at room temperature for more than 24 hours to form the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate Form II.
  • the relative humidity is an environment of 20%, 30%, 40%, 50%, 60%.
  • the time for forming the crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate can be 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h , 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h, 48h, etc.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II is at least one of crystal form I, crystal form III, and crystal form IV, or Two or more.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be the crystal form I.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be the crystal form III.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be the crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be the crystal form I and the crystal form III.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be the crystal form I and the crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form II may be the crystal form III and the crystal form IV.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form II may be crystal form I, crystal form III and crystal form IV.
  • This application provides a method for preparing potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form IV, which includes the following steps:
  • the crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than form IV forms a colloidal substance in an environment with a relative humidity higher than 80%;
  • the gel-like substance is exposed to an environment with a relative humidity of 20%-40% at room temperature for more than 120 hours to form crystal form IV.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV is at least one of crystal form I, crystal form II, and crystal form III, or Two or more.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form I.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form II.
  • the crystal form of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form III.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form I and the crystal form III.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form I and the crystal form II.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylate other than the crystal form IV may be the crystal form III and the crystal form II.
  • crystal forms of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form IV may be crystal form I, crystal form II and crystal form III.
  • the gel-like substance is exposed to an environment with a relative humidity of 20%, 30% or 40%, preferably, the gel-like substance is exposed to an environment with a relative humidity of 40%.
  • crystalline forms other than crystalline form IV are placed in an environment with a relative humidity higher than 80% for at least two days to form a colloidal substance.
  • the placing time may be 48h, 50h, 55h, 60h, 65h, 72h, etc.
  • the gel-like substance is exposed to an environment with a relative humidity of 20% to 40% at room temperature, and the time for forming crystal form IV can be 120h, 121h, 122h, 123h, 124h, 125h, 126h, 127h, 128h, 129h , 130h, 131h, 132h, 133h, 134h, 135h, 136h, 137h, 138h, 139h, 140h, etc.
  • the application provides a pharmaceutical composition, which comprises a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition also includes a preventive and/or therapeutic drug, and the preventive and/or therapeutic drug may be glucagon-like peptide-1 (abbreviated as GLP-1), insulin, PYY, human amylin, Heparin, human growth hormone, interferon, monoclonal antibody, protease inhibitor, thrombopoietin.
  • GLP-1 glucagon-like peptide-1
  • insulin PYY
  • human amylin Heparin
  • human growth hormone interferon
  • monoclonal antibody monoclonal antibody
  • protease inhibitor thrombopoietin
  • the N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorphs in the pharmaceutical composition are crystal form I, crystal form II, crystal form III, and crystal form IV One or two or more of them.
  • the pharmaceutical composition contains the crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form I and the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the pharmaceutical composition contains the crystal form I and the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form I and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form II and the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form II and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form III and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
  • the pharmaceutical composition contains the crystal form I, the crystal form II and the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the pharmaceutical composition contains the crystal form II, the crystal form III and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the pharmaceutical composition comprises the crystal form I, the crystal form III and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the pharmaceutical composition contains the crystal form I, the crystal form II, the crystal form III and the crystal form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.
  • the weight ratio of the N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph to the preventive and/or therapeutic drug in the pharmaceutical composition may be (20-60 ):1.
  • the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystal polymorph to the preventive and/or therapeutic drug in the pharmaceutical composition may be 30:1.
  • the weight ratio of the N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph to the preventive and/or therapeutic drug in the pharmaceutical composition may be 20:1, 21:1, 22 :1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1 , 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47 :1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1 , 60:1.
  • the pharmaceutical composition may be a tablet.
  • This application provides a use of N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph or its pharmaceutical composition in the preparation of preventive and/or therapeutic drugs.
  • This application provides a use of N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph or its pharmaceutical composition in promoting drug delivery.
  • the application provides a use of N-[8-(2-hydroxybenzoyl)amino] potassium octanoate crystal polymorph or a pharmaceutical composition thereof in the preparation of a medicine for preventing and/or treating diabetes or diabetic complications.
  • Preventive and/or therapeutic drugs refer to drugs that can achieve the purpose of avoiding, curing, alleviating, alleviating, changing, treating, improving, improving or affecting the condition (for example, disease), symptoms of the disease, or susceptibility to the disease through use.
  • Preventive and/or therapeutic drugs can be proteins; polypeptides; peptides; hormones; specific mixtures of polysaccharides, mucopolysaccharides and mucopolysaccharides; carbohydrates; lipids; small polar organic molecules (ie, with 500 daltons or 500 daltons) Polar organic molecules with a molecular weight below ten tons); other organic compounds; and specific compounds that do not pass through the gastrointestinal mucosa by themselves (only through the portion of the administered dose) and/or are sensitive to the active cleavage of acids and enzymes in the gastrointestinal tract; or Any combination of them.
  • Preventive and/or therapeutic drugs may include (but are not limited to) the following substances: including their synthetic, natural or recombinant sources: growth hormones, including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth ( hGH), bovine growth hormone and porcine growth hormone; growth hormone releasing hormone; growth hormone releasing factor (such as GRF analog g); interferons, including ⁇ , ⁇ and ⁇ ; interleukin 1; interleukin 2; insulin, Including porcine, bovine, human and human recombinant insulin, optionally with counterions including zinc, sodium, calcium and ammonium; insulin-like growth factors, including IGF-1; heparin, including unfractionated heparin, heparin analogs , Dermatan, chondroitin, low molecular weight heparin, very low molecular weight heparin and ultra-low molecular weight heparin; calcitonin, including salmon, eel, pig and human
  • the preferred drugs in this application are polypeptides and protein drugs that are difficult to smoothly enter the intestinal absorption by oral administration.
  • Common drugs include insulin, monoclonal antibodies, heparin, glucagon-like peptides, PYY, human amylin, and human amylin. Long hormones, interferons, protease inhibitors, thrombopoietin, etc., including their analogs, fragments, mimetics and polyethylene glycol modified derivatives.
  • Insulin is a protein hormone secreted by the islet ⁇ -cells in the pancreas stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, and glucagon. Insulin is the only hormone in the body that lowers blood sugar, and at the same time promotes glycogen, fat, and protein synthesis. Exogenous insulin is mainly used for the treatment of diabetes. All crystal forms of insulin in this application, including but not limited to crystal forms of naturally occurring insulin and synthetic insulin. Because it is easily degraded by oral administration, subcutaneous injection is still the main method today.
  • PYY is secreted by endocrine cells in the distal gastrointestinal tract after a meal, and acts on the satiety of hypothalamic signaling. Recent studies have shown that obese subjects have lower fasting and postprandial PYY levels, which may be the reason for their high appetite and food consumption. When administered intravenously, it suppresses appetite and food intake in lean and obese subjects. Other peptides from the pancreatic peptide (PP) family, such as PYYY fragments (eg PYY[3-36]) and other PYY agonists can also suppress appetite. However, due to its low absorption and rapid degradation in the gastrointestinal tract, its oral activity is basically negligible.
  • PP pancreatic peptide
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 is a brain-gut peptide secreted by ileal endocrine cells. It is currently mainly used as a target for type 2 diabetes drugs. Since GLP-1 can inhibit gastric emptying and reduce bowel movements, it helps to control food intake and reduce weight. However, since GLP-1 is a polypeptide, it is easily degraded by oral administration and is difficult to reach the intestinal tract.
  • hIAPP Human amylin
  • pancreatic islet cells Human amylin
  • the physiological and pharmacological functions of hIAPP monomer are as follows: 1) affect the secretion of insulin and glucagon; 2) delay gastric emptying and reduce postprandial blood sugar; 3) increase renin and angiotensin II to regulate kidney growth; 4 ) Increase aldosterone and reduce blood calcium; 5) Adjust bone density; 6) Relax blood vessels and adjust hemodynamics; 7) Adjust immune effect.
  • hIAPP monomer can induce and regulate T cell differentiation, thereby regulating the inflammatory response and the secretion of immune factors.
  • hIAPP has potential application prospects in the prevention and treatment of obesity, diabetes, autoimmunity, osteoporosis and other diseases.
  • the pharmaceutical composition can also include pharmaceutically acceptable excipients, which can be non-toxic fillers, stabilizers, diluents, carriers, Solvent or other preparation excipients.
  • diluents such as microcrystalline cellulose, mannitol, etc.
  • fillers such as starch, sucrose, etc.
  • binders such as starch, cellulose derivatives, alginate, gelatin and/or polyethylene Pyrrolidone
  • disintegrants such as calcium carbonate and/or sodium bicarbonate
  • absorption enhancers such as quaternary ammonium compounds
  • surfactants such as cetyl alcohol
  • Lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, etc.
  • the pharmaceutical composition of the present application is preferably an injection.
  • the pharmaceutical composition is preferably a solid form of the pharmaceutical composition and they can be made into a solid dosage form.
  • the solid dosage form can be a capsule, tablet or granule, such as a powder or a sachet.
  • the powder may be a capsule that is mixed with a liquid and applied.
  • the solid dosage form can also be a topical delivery system, such as an ointment, cream, or semi-solid.
  • the solid dosage forms under consideration may include sustained or controlled release systems.
  • the solid dosage form is a dosage form for oral administration.
  • the powder can be packed into capsules or compressed into tablets, used in powder form or incorporated into ointments, creams or semi-solids. Methods for forming solid dosage forms are well known in the art.
  • the PNAC in this application can be used as a delivery agent in a pharmaceutical composition.
  • the amount of the delivery agent in the solid dosage form is an effective amount for delivery and can be determined for any specific compound or biologically or chemically active agent by methods well known to those skilled in the art.
  • the active agent in the unit dosage form is absorbed into the circulation. It is easy to evaluate the bioavailability of the active agent by measuring the known pharmacological activity in the blood (for example, the increase in clotting time caused by heparin or the decrease in the circulating level of calcium caused by calcitonin). Alternatively, the circulating level of the active agent itself can be directly measured.
  • the amount of the preventive and/or therapeutic drug (which can be referred to as the active agent) in the pharmaceutical composition used in the present application is an effective amount that achieves the purpose of the active agent for the target indication.
  • the amount of the active agent in the composition is generally a pharmacologically, biologically, therapeutically or chemically effective amount. However, the amount may be lower than when the composition is used in a unit dosage form, because the unit dosage form may contain multiple delivery agent compound/active agent compositions or may contain divided pharmacologically, biologically, therapeutically, or active effective amounts.
  • the total effective amount can be administered in cumulative units that contain the effective amount of the active agent in total.
  • the total amount of active agent used can be determined by methods known to those skilled in the art. However, because the composition of the present application can deliver the active agent more efficiently than other compositions or compositions containing a separate active agent, the subject can be administered to the subject lower than the biological or biological agent used in the existing unit dosage form or delivery system. The amount of chemically active agent can still achieve the same blood level and/or therapeutic effect at the same time.
  • the delivery agents disclosed in the present application facilitate the delivery of biological and chemically active agents, especially oral, sublingual, buccal, intraduodenal, colon, rectal, vaginal, mucosal, pulmonary, intranasal and ocular system delivery.
  • the compounds and compositions of the present application are used to administer biological or chemically active agents to any animal, including (but not limited to): birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, and spirits Long species, and especially humans; and insects.
  • compositions are particularly advantageous for the delivery of the following chemical or biologically active agents, which may otherwise be encountered before and after the conditions encountered by the active agent reaching the target area (ie, the area where the active agent of the delivery composition is released)
  • the animals to which they are administered are destroyed or reduced in activity.
  • the compounds and compositions of the present application are used for oral administration of active agents, especially those that are not commonly delivered orally or those that require enhanced delivery.
  • composition including the compound and the active agent has the effect of delivering the active agent to the selected biological system and increasing or improving the bioavailability of the active agent compared to delivering the active agent without using the delivery agent. Delivery can be improved by delivering more active agent within a period of time or within a specific period of time (such as faster action or delayed delivery) or within a period of time (such as sustained delivery).
  • the crude product was added to isopropanol (19310.0ml, 3.5vol) in batches for beating, and beating for 1h.
  • the system was suction filtered, and the filter cake was rinsed with isopropanol (2760.0ml, 0.5vol).
  • the filter cake is transferred to a vacuum drying oven, the drying system is compressed with nitrogen, and dried at 60°C for 16 hours, and then transferred to a vacuum drying oven at 100°C for 24 hours. After the drying is completed, a total of 4.52 kg of the product is obtained, with a yield of 72.8%, and its properties are off-white powdery solids.
  • the product is crystal form I.
  • the XRPD and TGA/DSC of crystal form I are shown in Figures 1 to 2b, respectively.
  • PNAC is crystal form I.
  • the characteristic XRPD peaks of crystal form I (characterized by °2 ⁇ ) are shown in Table 1 below. :
  • Table 1 shows the characteristic XRPD peaks of Form I (characterized by °2 ⁇ )
  • the PNAC crystal form I prepared in Example 1 was exposed to an environment with a relative humidity of 60% under room temperature conditions for more than 24 hours to obtain a product.
  • the product is determined to be crystal form II, and the XRPD and TGA/DSC of the product are shown in Figure 3-4b respectively.
  • the characteristic XRPD peaks of crystal form II (characterized by °2 ⁇ ) are shown in Table 2 below:
  • Table 2 shows the characteristic XRPD peaks of Form II (characterized by °2 ⁇ )
  • the DSC spectrum ( Figure 4a) shows that the melting endothermic peak of crystal form II starts at 157.1°C, with a peak value of 162.5°C; the combination of DSC ( Figure 4a) and TGA ( Figure 4b) patterns shows that the crystal form II is a 1/3 hydrate .
  • the crude product was added to isopropanol (19310.0ml, 3.5vol) in batches for beating, and beating for 1h. Suction the system to obtain a filter cake.
  • the filter cake is passed through a 24-mesh sieve to prepare uniform particles, and then the particles are transferred to a vacuum drying oven for drying.
  • the drying system is compressed with nitrogen and dried at 60°C for 16 hours. , Again transferred to a vacuum drying oven at 100 °C, dried for 24 hours to get the particles evenly spread in a low temperature environment of 5 °C, control the relative humidity to 50% placed for 2 days to obtain the product.
  • the product is crystal form III.
  • the XRPD and TGA/DSC of crystal form III are shown in Figure 5-6b, respectively.
  • the characteristic XRPD peaks of crystal form III (characterized by °2 ⁇ ) are shown in Table 3 below:
  • Table 3 shows the characteristic XRPD peaks of Form III (characterized by °2 ⁇ )
  • the PNAC crystal form I prepared in Example 1 was placed at room temperature and exposed to a relative humidity environment of 80%. After being placed for 3 days, it formed a gel-like substance. The gel-like substance was exposed to an environment with a relative humidity of 40%. Leave it for 5 days to form a product.
  • the product is determined to be crystalline form IV, and the XRPD and TGA/DSC of crystalline form IV are shown in Figure 7-8b, respectively.
  • the characteristic XRPD peaks of crystalline form IV (characterized by °2 ⁇ ) are shown in Table 4 below:
  • Table 4 shows the characteristic XRPD peaks of Form IV (characterized by °2 ⁇ )
  • the SNAC in the tablet (developed by the Danish pharmaceutical company Novo Nordisk) was found to be the same as the crystal form I in the patent WO2005107462. Therefore, SNAC in this article is prepared by referring to the preparation method of SNAC crystal form I in Example 1 of patent WO2005107462. The SNACs in the following examples are all prepared by this method.
  • the crystal form II (PNAC-II) was prepared in Example 2.
  • the PNAC crystal form I to IV samples prepared in the foregoing examples and the SNAC crystal form I samples prepared in the foregoing were separately dissolved in purified water and placed at 4°C and room temperature respectively. The changes in the solution were observed and compared with the high concentration (500mg The stability of different salt forms and different crystal forms in aqueous solution under the condition of /mL) is different, and the results are shown in Table 5 (there is no difference in the process of dissolving sample PNAC crystal form I-IV and placing the solution in the solution).
  • GLP-1 drug M4 (abbreviated as M4)
  • M4 GLP-1 drug M4
  • patent application WO2019201328 for the preparation method of GLP-1 drug M4 (abbreviated as M4), please refer to patent application WO2019201328.
  • the delivery agents (SNAC, PNAC-I, PNAC-II) are combined with M4 respectively.
  • the combined oral tablet prepared by combining SNAC and M4 is SNAC+M4.
  • the combined oral tablet prepared by combining PNAC-I and M4 is PNAC-I+M4.
  • the combined oral tablet prepared by combining PNAC-II and M4 is PNAC-II+M4.
  • the content of M4 is 10 mg, and the content of the delivery agent is 100 mg.
  • M4 is dissolved in 8mM, pH7.2 phosphate buffer, so that the final concentration of M4 is 1mg/mL.
  • Twenty-eight beagle dogs, 9-12kg, males were selected and divided into 4 groups.
  • compare PNAC The effect of crystal form on the bioavailability of M4 in Beagle dogs.
  • the beagle dogs of the oral administration group were fasted the night before and could not help water. After the administration, the tablets were taken with 10ml of water (quantity). The dogs resumed eating after 4 hours, and then the blood was collected according to the blood sampling plan in Table 6 for different time points. The blood drug concentration and the calculated exposure in the animal body AUC last , the specific results are shown in Tables 7, 8, 9 and Figures 9, 10.
  • Table 6 is the blood sampling plan
  • Intravenous injection M4 group 0 hours before administration, 0.5, 1, 3, 6, 12, 24, 48, 72, 96, 144 and 192 hours after administration; Oral administration group 0 hours before administration, 1.5, 3, 8, 24, 48, 72, 96 hours after administration
  • Table 7 is a summary of blood drug concentration at different time points in the intravenous administration group
  • Table 8 is a summary of the plasma concentration of each group at different time points for oral administration
  • the absolute bioavailability of the single oral PNAC-II group increased by 45.5%, and the absolute bioavailability of the single oral PNAC-I group increased by 26.1%.
  • GLP-1 drug M4 (abbreviated as M4)
  • M4 GLP-1 drug M4
  • patent application WO2019201328 for the preparation method of GLP-1 drug M4 (abbreviated as M4), please refer to patent application WO2019201328.
  • the delivery agents (SNAC, PNAC-I, PNAC-II) are combined with M4 respectively.
  • the combined oral tablet prepared by combining SNAC and M4 is SNAC+M4.
  • the combined oral tablet prepared by combining PNAC-I and M4 is PNAC-I+M4.
  • the combined oral tablet prepared by combining PNAC-II and M4 is PNAC-II+M4.
  • the content of each tablet is 10 mg, and the delivery agent content is 300 mg and 450 mg, respectively.
  • M4 is dissolved in 8mM, pH7.2 phosphate buffer, so that the final concentration of M4 is 1mg/mL.
  • the beagle dogs of the oral administration group were fasted the night before and could not help water. After the administration, the tablets were taken with 10ml of water (quantity). The dogs resumed eating after 4 hours, and then the blood was collected according to the blood sampling plan in Table 11 for different time points. The blood drug concentration and the calculated exposure in the animal body AUC last , the specific results are shown in Table 12-14 and Figures 19 and 20.
  • Table 10 shows grouping information
  • Table 11 is the blood sampling plan
  • Table 12 is a summary of blood drug concentrations at different time points in the intravenous administration group
  • Table 13 is a summary of the plasma concentration of each group at different time points for oral administration
  • the absolute bioavailability of the single oral SNAC (300mg) group was 0.70%
  • the absolute bioavailability of the single oral SNAC (450mg) group was 0.80%
  • the single oral PNAC-II group (300mg) had absolute bioavailability.
  • the availability is 1.20%
  • the absolute bioavailability of a single oral PNAC-II group (450mg) is 1.92%
  • the absolute bioavailability of a single oral PNAC-I group (300mg) is 1.01%
  • the absolute bioavailability of (450mg) is 1.72%, which is significantly higher than that of SNAC.
  • the absolute bioavailability increases significantly.
  • the absolute bioavailability of the single oral PNAC-II (300mg) group increased by 71%, and the absolute bioavailability of the single oral PNAC-I (300mg) group increased by 44% ;
  • the absolute bioavailability of the single oral PNAC-II (450mg) group increased by 140%, and the absolute bioavailability of the single oral PNAC-I (450mg) group increased by 115 %.
  • the absolute bioavailability of the single oral SNAC (300mg) group is only increased by 14% compared with the single oral SNAC (450mg) group.
  • the content of SNAC has little effect on absolute bioavailability.
  • the absolute bioavailability of the single oral PNAC-II (300mg) group was increased by 60%; the single oral PNAC-I (300mg) group was compared with the single oral PNAC-II (450mg) group.
  • the absolute bioavailability increased by 70%.
  • the crystal form II prepared in Example 2 was divided into three groups, and the first group was placed at 60° C. for 24 hours to obtain a solid sample. The second group was placed at 40°C and a relative humidity of 75% for two weeks to obtain a solid sample. The third group was placed under the condition of 25°C and 60% relative humidity for 2 weeks to obtain solid samples, and then the three groups of solid samples were tested by XRPD and HPLC to evaluate the physical and chemical stability.
  • the HPLC test method a C18 reversed-phase chromatographic column with a column length of 150mm is used, the mobile phase is an acetonitrile-water+0.05% trifluoroacetic acid system, a flow rate of 1.2ml/min, and the detection is performed under the condition of the detector wavelength UV-215nm.
  • the normalization method calculates the purity of the main peak.
  • the crystal form II obtained in Example 2 was divided into three groups. The first group was manually milled on the crystal form II for 10 minutes to obtain a solid sample. The second group pressed the crystal form II into a tablet (pressure 3 kN) to obtain a solid sample. The third group performs jet pulverization on the crystal form II (injection pressure 0.4 MPa, crushing pressure 0.2 MPa) to obtain a solid sample. The three groups of solid samples were characterized by XRPD to evaluate their physical stability. The specific results are shown in Figure 12-14.
  • Table 15 shows the stability test results of different crystal forms of PNAC
  • PNAC crystal form I and crystal form II are very stable, and crystal form I can only be converted to crystal when placed in an environment of more than 60% RH for a long time. Crystal form II is very stable under any conditions in the test. Stablize.

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Abstract

本申请公开了一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I，所述晶型I至少具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2表示的特征峰的X射线粉末衍射图。本申请提供的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物有四种晶型，其溶解度高、稳定性强，能更有效地递送药物，增加所递送药物在胃肠道的渗透性，利于制成口服制剂，从而可以更好的将预防和/治疗药物递送到体内达到提高生物利用度的效果。

Description

N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 技术领域
本申请涉及化学医药领域，具体涉及一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途。
背景技术
大分子药物如多肽、蛋白质类药物常因分子量大、脂溶性低，对胃酸不稳定，可被胃肠道中多种消化酶破坏等特点，口服给药无法顺利进入肠道吸收。针对上述问题，人们尝试着从多方面克服药物吸收障碍，除在剂型方面做一些尝试外，常使用胃肠道吸收促进剂来提高药物的生物膜通透性，虽然增加了药物的吸收，但也增加了肠道内毒素的吸收，长期使用缺乏安全性。
1997年公开的美国专利US5,650,386中披露了新型的大分子药物递送剂N-[8-(2-羟基苯甲酰基)氨基]辛酸(简称NAC)及其盐，其分子式如式(I)所示。尤其2009年公开的美国专利US8636996披露了N-[8-(2-羟基苯甲酰基)氨基]辛酸一钠(简称SNAC)的多晶型、非晶型及其制备方法，其分子式如式(II)所示。
Figure PCTCN2020128050-appb-000001
SNAC是一种新型的氨基酸衍生物递送剂。近期研究表明其不需要剂型保护，就能促进肝素及人生长激素等多种蛋白质类药物溶液的口服吸收，却不显示明显的细胞毒性。因化合物的不同盐型的生物利用度、溶解度、流动性也会有所不同。同一种盐型不同晶型，会具有不同的晶体形状、密度、硬度、颜色、化学稳定性、熔点、吸湿性、可悬浮性和溶解速率等特性，会直接或间接影响所递送药物的能力，导致所递送药物的生物利用度、可压缩性和稳定性等方面的不同。
发明内容
本申请的目的是提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途、药物组合物及其用途。
本申请的技术方案如下：
1、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I，所述晶型I至少具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2表示的特征峰的X射线粉末衍射图。
2、根据项1所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：5.24±0.2、21.59±0.2之一表示的特征峰的X射线粉末衍射图。
3、根据项2所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：13.02±0.2、24.29±0.2之一表示的特征峰的X射线粉末衍射图。
4、根据项3所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：6.61±0.2、10.43±0.2、31.63±0.2、37.00±0.2之一表示的特征峰的X射线粉末衍射图。
5、根据项1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的X射线粉末衍射图如图1。
6、根据项1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的熔点为163.1℃。
7、根据项1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的吸附水脱除温度为83.6℃。
8、根据项1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I在140℃失重3.0％。
9、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型II，所述晶型II至少具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2表示的特征峰的X射线粉末衍射图。
10、根据项9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：14.68±0.2、25.55±0.2之一表示的特征峰的X射线粉末衍射图。
11、根据项10所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：13.41±0.2、26.66±0.2之一表示的特征峰的X射线粉末衍射图。
12、根据项11所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2、27.79±0.2、8.91±0.2之一表示的特征峰的X射线粉末衍射图。
13、根据项9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的X射线粉末衍射图如图3。
14、根据项9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的熔点为162.5℃。
15、根据项9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的吸附水脱除温度为93℃。
16、根据项9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II在140℃失重5.6％。
17、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型III，所述晶型III至少具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2表示的特征峰的X射线粉末衍射图。
18、根据项17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：24.75±0.2、6.03±0.2之一表示的特征峰的X射线粉末衍射图。
19、根据项18所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：21.20±0.2、17.06±0.2之一表示的特征峰的X射线粉末衍射图。
20、根据项19所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2、15.64±0.2、26.49±0.2之一表示的特征峰的X射线粉末衍射图。
21、根据项17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的X射线粉末衍射图如图5。
22、根据项17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的熔点为162.0℃。
23、根据项17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的吸附水脱除温度为94.5℃。
24、根据项17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III在140℃失重6.1％。
25、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型IV，所述晶型IV至少具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2表示的特征峰的X射线粉末衍射图。
26、根据项25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：13.16±0.2、19.39±0.2之一表示的特征峰的X射线粉末衍射图。
27、根据项26所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：18.35±0.2、9.68±0.2之一表示的特征峰的X射线粉末衍射图。
28、根据项27所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2、34.34±0.2、18.82±0.2之一表示的特征峰的X射线粉末衍射图。
29、根据项25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的X射线粉末衍射图如图7。
30、根据项25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的熔点为163.8℃。
31、根据项25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的吸附水脱除温度为96.1℃。
32、根据项25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV在150℃失重8.21％。
33、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶体多晶型物的制备方法，其特征在于，包括如下步骤：
在反应容器中加入有机溶剂并搅拌，然后加入N-[8-(2-羟基苯甲酰基)氨 基]辛酸，搅拌均匀，滴加氢氧化钾溶液，滴加完毕后，浓缩得粗品；
在所述粗品中加入有机溶剂打浆抽滤后得滤饼，将所述滤饼淋洗后放入干燥箱中干燥，得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物。
34、根据项33所述的制备方法，其特征在于，将所述滤饼淋洗后放入干燥箱中进行干燥，干燥温度为60℃～100℃，干燥时间为30～40h，得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I；优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h；
所述晶型I为项1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
35、根据项33所述的制备方法，其特征在于，将所述滤饼制备成均匀的颗粒，然后再将所述颗粒放入所述干燥箱中进行干燥，干燥后的颗粒均匀地铺散在2-8℃的低温环境，控制相对湿度为50％放置2天，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型III。
36、根据项35所述的制备方法，其特征在于，所述颗粒放入所述干燥箱中的干燥温度为60℃～100℃，干燥时间为30～40h；优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h。
37、根据项35所述的制备方法，其特征在于，将所述滤饼过20～24目筛得到均匀的颗粒；
所述晶型III为项17-24任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型III。
38、根据项33-37任一项所述的制备方法，其特征在于，所述有机溶剂为异丙醇或丙酮。
39、根据项33-37任一项所述的制备方法，其特征在于，所述氢氧化钾的溶液浓度为40％～90％，优选地所述氢氧化钾的溶液浓度为50％。
40、根据项33-37任一项所述的制备方法，其特征在于，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃以上，然后滴加氢氧化钾溶液，滴加完毕后，保温反应0.5～2h；
优选地，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃～52℃，然后滴加氢氧化钾溶液，滴加完毕后，保温反应1h。
41、根据项33-37任一项所述的制备方法，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸以及氢氧化钾溶液的添加摩尔比为1:1。
42、根据项33-37任一项所述的制备方法，其特征在于，所述粗品加入有机溶剂打浆的时间为0.5～1.5h，优选为1h。
43、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型加热至至少75℃以上，以形成晶型I。
44、根据项43所述的制备方法，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上。
45、根据项43所述的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型在氮气保护下加热至75℃以上，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
46、根据项43所述的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II在氮气保护下加热至140℃，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
47、根据项43所述的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV在氮气保护下加热至110℃以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
48、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型I的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型冻干，以形成晶型I。
49、根据项48所述的制备方法，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上。
50、根据项43-49任一项所述的制备方法，其特征在于，所述晶型I为项1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
51、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型，在室温条件下，暴露于具有0～60％的相对湿度环境中，24h以上，以形成所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
52、根据项51所述的制备方法，其特征在于，所述相对湿度为20％、30％、40％、60％的环境。
53、根据项51所述的制备方法，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型为晶型I、晶型III、晶型IV中的至少一种或两种以上。
54、根据项51-53任一项所述的制备方法，其特征在于，所述晶型II为项9-16任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
55、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型IV的制备方法，其特征在于，包括如下步骤：
将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型，在高于80％的相对湿度环境中形成胶样物质；
将所述胶样物质在室温条件下，暴露于具有20％～40％的相对湿度环境中，120h以上，以形成晶型IV。
56、根据项55所述的制备方法，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型为晶型I、晶型II、晶型III中的至少一种或两种以上。
57、根据项55所述的制备方法，其特征在于，所述胶样物质暴露于具有20％、30％或40％的相对湿度环境，优选地，所述胶样物质暴露于具有40％的相对湿度环境。
58、根据项55-57任一项所述的制备方法，其特征在于，所述晶型IV为项25-32任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV。
59、一种药物组合物，其特征在于，包括N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物。
60、根据项59所述的药物组合物，其特征在于，N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I、晶型II、晶型III、晶型IV中的一种或至少两种。
61、根据项59-60任一项所述的药物组合物，其特征在于，所述药物组合物还包括预防和/或治疗性药物。
62、根据项61所述的药物组合物，其特征在于，所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比为(20～60):1，优选地，所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比为30:1。
63、根据项62所述的药物组合物，其特征在于，所述预防和/或治疗性 药物为胰高血糖素样肽-1、胰岛素、PYY、人胰淀素、肝素、人生长激素、干扰素、单克隆抗体、蛋白酶抑制剂、血小板生成素。
64、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在制备预防和/或治疗性药物中的用途。
65、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在促进药物递送中的用途。
66、一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在制备预防和/或治疗糖尿病或糖尿病并发症或减轻体重的药物中的用途。
本申请提供的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物有四种晶型，其溶解度高、稳定性强，能更有效地递送药物，增加所递送药物在胃肠道的渗透性，利于制成口服制剂，从而可以更好的将预防和/治疗药物递送到体内达到提高生物利用度的效果。
附图说明
附图用于更好地理解本申请，不构成对本申请的不当限定。其中：
图1是实施例1制备的PNAC的晶型I的X射线粉末衍射图。
图2a是实施例1制备的PNAC的晶型I的DSC图。
图2b是实施例1制备的PNAC的晶型I的TGA图。
图3是实施例2制备的PNAC的晶型II的X射线粉末衍射图。
图4a是实施例2制备的PNAC的晶型II的DSC图。
图4b是实施例2制备的PNAC的晶型II的TGA图。
图5是实施例3制备的PNAC的晶型III的X射线粉末衍射图。
图6a是实施例3制备的PNAC的晶型III的DSC图。
图6b是实施例3制备的PNAC的晶型III的TGA图。
图7是实施例4制备的PNAC的晶型IV的X射线粉末衍射图。
图8a是实施例4制备的PNAC的晶型IV的DSC图。
图8b是实施例4制备的PNAC的晶型IV的TGA图。
图9是静脉给药组血药浓度-给药时间趋势图。
图10是口服给药各组血药浓度-给药时间趋势图。
图11是晶型II的固态稳定性实验的XRPD图。
图12是晶型II的研磨实验前后的XRPD图。
图13是晶型II的压片实验前后的XRPD图。
图14是晶型II的气流粉碎实验前后的XRPD图。
图15是晶型I的固态稳定性实验的XRPD图。
图16是晶型I的压片实验前后的XRPD图。
图17是晶型I的气流粉碎实验前后的XRPD图。
图18是晶型I的研磨实验前后的XRPD图。
图19是静脉给药组血药浓度-给药时间趋势图。
图20是口服给药各组血药浓度-给药时间趋势图。
具体实施方式
以下结合附图对本申请的示范性实施例做出说明，其中包括本申请的实施例的各种细节以助于理解，应当将它们认为仅仅是示范性的。因此，本领域普通技术人员应当认识到，可以对这里描述的实施例做出各种改变和修改，而不会背离本申请的范围和精神。在不与本说明书中的定义发生冲突的情况下，本说明书中的术语具有本领域技术人员通常理解的含义，但如有冲突，则以本说明书中的定义为准。
N-[8-(2-羟基苯甲酰基)氨基]辛酸钾(简称PNAC)，如式(Ⅲ)所示：
Figure PCTCN2020128050-appb-000002
X射线粉末衍射
X射线粉末衍射(X-Ray Powder Diffraction，XRPD)通常应用于晶体结构的分析。X射线是一种电磁波，入射到晶体时在晶体中产生周期性变化的电磁场。引起原子中的电子和原子核振动，因原子核的质量很大振动忽略不计。振动着的电子是次生X射线的波源，其波长、周相与入射光相同。基于晶体结构的周期性，晶体中各个电子的散射波相互干涉相互叠加，称之为衍射。 散射波周相一致相互加强的方向称衍射方向，产生衍射线。
仪器型号：PANalytical Empyrean和X’Pert3射线粉末衍射分析仪；
射线：单色Cu-Kα射线(λ＝1.5406)；
扫描方式：θ/2θ，扫描范围：2-40°；
电压：40KV，电流：40mA。
热重分析
热重分析(Thermogravimetric Analysis，TGA)是指在程序控制温度下测量待测样品的质量与温度变化关系的一种热分析技术，用来研究材料的热稳定性和组分。TGA在研发和质量控制方面都是比较常用的检测手段。热重分析在实际的材料分析中经常与其他分析方法联用，进行综合热分析，全面准确分析材料。热重分析仪记录到的曲线称TGA曲线。
仪器型号：TA Q5000/Discovery 5500；
吹扫气：氮气；
升温方式：线性升温；
温度范围：室温～350℃。
差示扫描量热分析
差示扫描量热分析(differential scanning calorimetry，DSC)，在温度程序控制下，测量试样相对于参比物的热流速率随温度或时间变化的一种技术。差示扫描量热仪记录到的曲线称DSC曲线，一般以W/g或mW/mg(即流向每克样品的功率)为纵坐标，以温度T或时间t为横坐标，可以测量多种热力学和动力学参数，例如比热容、反应热、转变热、相图、反应速率、结晶速率、高聚物结晶度、样品纯度等。该法使用温度范围宽(-175～725℃)、分辨率高、试样用量少。适用于无机物、有机化合物及药物分析。
仪器型号：TAQ2000/Discovery 2500；
吹扫气：氮气；
升温方式：线性升温；
温度范围：25～300℃。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、21.59±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、24.29±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2、24.29±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2、24.29±0.2、6.61±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2、24.29±0.2、6.61±0.2、10.43±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2、24.29±0.2、6.61±0.2、10.43±0.2、31.63±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2、5.24±0.2、21.59±0.2、13.02±0.2、24.29±0.2、6.61±0.2、10.43±0.2、31.63±0.2、37.00±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型I的X射线粉末衍射图如图1。
在本申请中，晶型I的熔点为163.1℃。
在本申请中，晶型I的吸附水脱除温度为83.6℃。
在本申请中，晶型I在140℃失重3.0％。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型II，所述晶型II至少 具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、25.55±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、26.66±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、 14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2、27.79±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2、14.68±0.2、25.55±0.2、13.41±0.2、26.66±0.2、21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2、27.79±0.2、8.91±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型II的X射线粉末衍射图如图3。
在本申请中，晶型II的熔点为162.5℃。
在本申请中，晶型II的吸附水脱除温度为93℃。
在本申请中，晶型II在140℃失重5.6％。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型III，所述晶型III至少具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、6.03±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、 24.75±0.2、6.03±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、17.06±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、 24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2、15.64±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2、24.75±0.2、6.03±0.2、21.20±0.2、17.06±0.2、21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2、15.64±0.2、26.49±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型III的X射线粉末衍射图如图5。
在本申请中，晶型III的熔点为162.0℃。
在本申请中，晶型III的吸附水脱除温度为94.5℃。
在本申请中，晶型III在140℃失重6.1％。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型IV，所述晶型IV至少具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、19.39±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、9.68±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2表示的特征峰的X射线粉末衍射 图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2、34.34±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2、13.16±0.2、19.39±0.2、18.35±0.2、9.68±0.2、15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2、34.34±0.2、18.82±0.2表示的特征峰的X射线粉末衍射图。
在本申请中，所述晶型IV的X射线粉末衍射图如图7。
在本申请中，晶型IV的熔点为163.8℃。
在本申请中，晶型IV的吸附水脱除温度为96.1℃。
在本申请中，晶型IV在150℃失重8.21％。
本申请提供的PNAC的晶型I-IV均具有良好的溶解度、生物利用度以及固态稳定性，尤其以晶型I和晶型II的生物利用度和固态稳定性较好。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I的制备方法，包括如下步骤：
步骤一：在反应容器中加入有机溶剂并搅拌，然后加入N-[8-(2-羟基苯甲酰基)氨基]辛酸，搅拌均匀，滴加氢氧化钾溶液，滴加完毕后，浓缩得粗品；
步骤二：在所述粗品中加入有机溶剂打浆抽滤后得滤饼，将所述滤饼淋洗后放入干燥箱中干燥，干燥温度为60℃～100℃，干燥时间为30～40h，得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
所述干燥温度可以为60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃。所述干燥时间可以为30h、31h、32h、33h、34h、35h、36h、37h、38h、39h、40h。
优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h。
在本申请中，所述有机溶剂为异丙醇或丙酮。
在本申请中，所述氢氧化钾的溶液浓度为40％～90％，优选地所述氢氧化钾的溶液浓度为50％。
所述氢氧化钾的溶液浓度可以为40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％。
在本申请中，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃以上，然后滴加氢氧化钾溶液，滴加完毕后，保持48℃以上的温度反应0.5h-2h。
优选地，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃-52℃，然后滴加氢氧化钾溶液，滴加完毕后，保持48℃-52℃的温度反应1h。
所述体系温度可以为48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃。
保温反应的时间可以为0.5h、0.6h、0.7h、0.8h、0.9h、1h、1.1h、1.2h、1.3h、1.4h、1.5h、1.6h、1.7h、1.8h、1.9h、2h。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸以及氢氧化钾的摩尔比为1:1。
在本申请中，所述粗品中加入有机溶剂打浆的时间为0.5h-1.5h，优选为1h。
所述粗品中加入有机溶剂打浆的时间可以为0.5h、0.6h、0.7h、0.8h、0.9h、1h、1.1h、1.2h、1.3h、1.4h、1.5h、1.6h、1.7h、1.8h、1.9h、2h。
本申请提供第二种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I的制备方法，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型加热至至少75℃以上，以形成晶型I。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型II。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型II和晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型II和晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型III和晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型可以为晶型II、晶型III和晶型IV。
在本申请中，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型在氮气保护下加热至75℃以上，加热时间为0～300min，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
所述加热温度优选为110-140℃。所述加热温度可以为110℃、115℃、120℃、125℃、130℃、135℃、140℃。
所述加热时间可以为10min、15min、20min、25min、30min、35min、40min、45min、50min、55min、60min、65min、70min、75min、80min、85min、90min、95min、100min、105min、110min、115min、120min、125min、130min、135min、140min、145min、150min、155min、160min、165min、170min、175min、180min、185min、190min、195min、200min、205min、210min、210min、220min、225min、230min、235min、240min、245min、250min、255min、260min、265min、270min、275min、280min、285min、290min、295min、300min。
在本申请中，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II在氮气保护下加热至140℃，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
在本申请中，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV在氮气保护下加热至110℃，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
本申请提供第三种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型I的制备方法，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型冻干，以形成晶型I。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型III的制备方法，包括如下步骤：
步骤一：在反应容器中加入有机溶剂并搅拌，然后加入N-[8-(2-羟基苯甲酰基)氨基]辛酸，搅拌均匀，滴加氢氧化钾溶液，滴加完毕后，浓缩得粗品；
步骤二：在所述粗品中加入有机溶剂打浆抽滤后得滤饼，将所述滤饼制备成均匀的颗粒，然后再将所述颗粒放入所述干燥箱内进行干燥，干燥后的颗粒均匀地铺散在2-8℃的低温环境，控制相对湿度为50％放置2天，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型III。
在本申请中，将所述滤饼过20～24目筛得到均匀的颗粒。
在本申请中，所述干燥的温度为60℃～100℃，干燥时间为30～40h。优选地，所述干燥的温度可以为60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃。所述干燥时间可以为30h、31h、32h、33h、34h、35h、36h、37h、38h、39h、40h。
优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h。
在本申请中，所述有机溶剂为异丙醇或丙酮。
在本申请中，所述氢氧化钾的溶液浓度为40％～90％，优选地所述氢氧化钾的溶液浓度为50％。
所述氢氧化钾的溶液浓度可以为40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％。
在本申请中，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃以上，然后滴加氢氧化钾溶液，滴加完毕后，保持48℃以上的温度反应0.5h-2h。
优选地，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃-52℃，然后滴加氢氧化钾溶液，滴加完毕后，保持48℃-52℃的温度反应1h。
所述体系温度可以为48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃。
保温反应的时间可以为0.5h、0.6h、0.7h、0.8h、0.9h、1h、1.1h、1.2h、1.3h、1.4h、1.5h、1.6h、1.7h、1.8h、1.9h、2h。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸以及氢氧化钾的摩尔比为1:1。
在本申请中，所述粗品中加入有机溶剂打浆的时间为0.5h-1.5h，优选为1h。
所述粗品中加入有机溶剂打浆的时间可以为0.5h、0.6h、0.7h、0.8h、0.9h、1h、1.1h、1.2h、1.3h、1.4h、1.5h、1.6h、1.7h、1.8h、1.9h、2h。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II的制备方法，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型，在室温条件下，暴露于具有0～60％的相对湿度环境中，24h以上，以形成所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
在本申请中，所述相对湿度为20％、30％、40％、50％、60％的环境。
在本申请中，形成所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II的时间可以为24h、25h、26h、27h、28h、29h、30h、31h、32h、33h、34h、35h、36h、37h、38h、39h、40h、41h、42h、43h、44h、45h、46h、47h、48h等。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型为晶型I、晶型III、晶型IV中的至少一种或两种以上。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型I。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型I和晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型I和晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型III和晶型IV。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型可以为晶型I、晶型III和晶型IV。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型IV的制备方法，包括如下步骤：
将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型，在高于80％的相对湿度环境中形成胶样物质；
将所述胶样物质在室温条件下，暴露于具有20％～40％的相对湿度环境中，120h以上，以形成晶型IV。
在本申请中，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型为晶型I、晶型II、晶型III中的至少一种或两种以上。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型I。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型II。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型I和晶型III。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型I和晶型II。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型III和晶型II。
所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型可以为晶型I、晶型II和晶型III。
在本申请中，所述胶样物质暴露于具有20％、30％或40％的相对湿度环境，优选地，所述胶样物质暴露于具有40％的相对湿度环境。
在本申请中，将除晶型IV以外的晶型，在高于80％的相对湿度环境中放置至少两天以上形成胶样物质。所述放置的时间可以为48h、50h、55h、60h、65h、72h等。
所述胶样物质在室温条件下，暴露于具有20％～40％的相对湿度环境，形成晶型IV的时间可以为120h、121h、122h、123h、124h、125h、126h、127h、128h、129h、130h、131h、132h、133h、134h、135h、136h、137h、138h、139h、140h等。
本申请提供一种药物组合物，包括N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物。
所述药物组合物还包括预防和/或治疗性药物，所述预防和/或治疗性药物可以为胰高血糖素样肽-1(简称GLP-1)、胰岛素、PYY、人胰淀素、肝素、人生长激素、干扰素、单克隆抗体、蛋白酶抑制剂、血小板生成素。
在本申请中，所述药物组合物中的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I、晶型II、晶型III、晶型IV中的一种或两种以上。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型III。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I和晶型II。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I和晶型III。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I和晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II和晶型III。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II和晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型III和晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I、晶型II和晶型III。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II、晶型III和晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I、晶型III和晶型IV。
所述药物组合物中包含N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I、晶型II、晶型III和晶型IV。
在本申请中，所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比可以为(20～60):1。
在本申请中，所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比可以为30:1。
所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比可以为20:1、21:1、22:1、23:1、24:1、25:1、26:1、27:1、28:1、29:1、30:1、31:1、32:1、33:1、34:1、35:1、36:1、37:1、38:1、39:1、40:1、41:1、42:1、43:1、44:1、45:1、46:1、47:1、48:1、49:1、50:1、51:1、52:1、53:1、54:1、55:1、56:1、57:1、58:1、59:1、60:1。
所述药物组合物可以为片剂。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在制备预防和/或治疗性药物中的用途。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在促进药物递送中的用途。
本申请提供一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物或其药物组合物在制备预防和/或治疗糖尿病或糖尿病并发症的药物中的用途。
预防和/或治疗性药物
预防和/或治疗性药物是指通过使用能达到避免、治愈、减轻、缓解、改变、治疗、改善、改进或影响病情(例如疾病)、疾病的症状或对疾病易感性的目的的药物。
预防和/或治疗性药物可以为蛋白质；多肽；肽；激素；多糖、粘多糖和粘多糖的特定混合物；碳水化合物；脂质；极性有机小分子(即具有500道尔顿或500道尔顿以下分子量的极性有机分子)；其它有机化合物；和自身不通过胃肠粘膜(仅通过给药剂量的部分)和/或对胃肠道中的酸和酶的活性裂解敏感的特定化合物；或它们的任何组合。
预防和/或治疗性药物可以为包括(但不限于)如下物质：包括它们的合成、天然或重组来源：生长激素，包括人生长激素(hGH)、重组人生长激素(rhGH)、牛生长(hGH)、牛生长激素和猪生长激素；生长激素释放激素；生长激素释放因子(例如GRF类似物g)；干扰素，包括α、β和γ；白细胞介素1；白细胞介素2；胰岛素，包括猪、牛、人和人重组的胰岛素，任选地带有包括锌、钠、钙和铵的平衡离子；胰岛素样生长因子，包括IGF-l；肝素，包括未分级分离的肝素、肝素类似物、皮肤素、软骨素、低分子量肝素、极低分子量肝素和超低分子量肝素；降钙素，包括鲑鱼、鳗鱼、猪和人的降钙素；促红细胞生成素；心房钠尿肽；抗原；单克隆抗体；生长抑素；蛋白酶抑制剂；促皮质素、促性腺素释放激素；催产素；促黄体生成激素释放激素；促卵胞激素；葡糖脑苷脂酶；血小板生成素；非格司亭；前列腺素；环孢霉素；加压素；色甘酸钠(色甘酸钠或色甘酸二钠(disodium chromoglycate))；万古霉素；去铁胺(DFO)；二膦酸盐，包括伊班膦酸盐、阿伦膦酸盐、替鲁膦酸盐、依替膦酸盐、氯膦酸盐、帕米膦酸盐、奥帕膦酸盐和伊卡膦酸盐及其可药用盐(例如伊班膦酸钠)；镓盐(诸如硝酸镓、硝酸镓九水合物和 gallium maltolate)；阿昔洛韦及其可药用盐(例如阿昔洛韦钠)；甲状旁腺素(PTH)，包括其片段；抗偏头痛药，诸如BIBN-4096BS和其它降钙素基因相关蛋白拮抗剂；抗微生物剂，包括抗生素(包括对革兰氏阳性菌起作用的杀菌、脂肽和环肽抗生素，包括潜霉素)、抗细菌和抗真菌剂；维生素；这些化合物的类似物、片段、模拟物或聚乙二醇(PEG)修饰的衍生物；或它们任意的组合。
本申请优选的药物是口服给药很难顺利进入肠道吸收的多肽、蛋白质类药物，常见的药物有胰岛素、单克隆抗体、肝素、胰高血糖素样肽、PYY、人胰淀素、人生长激素、干扰素、蛋白酶抑制剂、血小板生成素等，包括其类似物、片段、模拟物和聚乙二醇修饰的衍生物。
胰岛素
胰岛素是由胰脏内的胰岛β细胞受内源性或外源性物质如葡萄糖、乳糖、核糖、精氨酸、胰高血糖素等的刺激而分泌的一种蛋白质激素。胰岛素是机体内唯一降低血糖的激素，同时促进糖原、脂肪、蛋白质合成。外源性胰岛素主要用来糖尿病治疗。本申请中胰岛素的所有晶型，包括(但不限于)天然产生的胰岛素和合成的胰岛素的晶型。因口服易被降解，现今依然以皮下注射为主。
PYY
PYY由胃肠道远端的内分泌细胞在餐后分泌，并作用于下丘脑信号传导的饱腹感。最近的研究表明，肥胖受试者的禁食和餐后PYY水平较低，这可能是其食欲高和食物消耗的原因。当静脉内施用时，它抑制瘦和肥胖受试者的食欲和食物摄入。来自胰肽(PP)家族的其他肽，如PYY片段(例如PYY[3-36])和其他PYY激动剂也能抑制食欲。然而，由于其在胃肠道中的低吸收和快速降解，其口服活性基本可以忽略不计。
胰高血糖素样肽-1
胰高血糖素样肽-1(简称GLP-1)是回肠内分泌细胞分泌的一种脑肠肽，目前主要作为2型糖尿病药物作用的靶点。由于GLP-1可抑制胃排空，减少肠蠕动，故有助于控制摄食，减轻体重。但由于GLP-1是多肽，口服给药易 被降解很难达到肠道。
人胰淀素
人胰淀素(hIAPP)是由胰岛细胞合成分泌，37个氨基酸组成的多肽类激素，与胰岛素、胰高血糖素等协同调节糖稳态。hIAPP单体的生理药理功能如下：1)影响胰岛素与胰高血糖素的分泌；2)延缓胃排空，降低餐后血糖；3)升高肾素与血管紧张素II，调节肾生长；4)升高醛固酮，降低血钙；5)调节骨密度；6)舒张血管，调节血流动力学；7)调节免疫效应。hIAPP单体可诱导调节T细胞分化，从而调节炎症反应和免疫因子的分泌。hIAPP在肥胖以及糖尿病、自身免疫、骨质疏松等疾病的防治过程中，具有潜在应用前景。
药物组合物
药物组合物中除去本申请所述的PNAC和预防和/或治疗性药物之外，还可以包括药学上可接受的辅料，该辅料可以为无毒的填充剂、稳定剂、稀释剂、载体、溶剂或其他制剂辅料。例如，稀释剂、赋形剂，如微晶纤维素、甘露醇等；填充剂，如淀粉、蔗糖等；粘合剂，如淀粉、纤维素衍生物、藻酸盐、明胶和/或聚乙烯吡咯烷酮；崩解剂，如碳酸钙和/或碳酸氢钠；吸收促进剂，如季铵化合物；表面活性剂，如十六烷醇；载体、溶剂，如水、生理盐水、高岭土、皂粘土等；润滑剂，如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外，本申请的药物组合物优选为注射剂。
药物组合物优选固体形式的药物组合物并且可以将它们制成固体剂型。固体剂型可以为胶囊、片剂或颗粒，诸如粉末或囊剂。粉末可以为与液体混合并施用的囊剂。固体剂型还可以为局部递送系统，诸如软膏剂、霜剂或半固体。所考虑的固体剂型可以包括缓释或控释系统。优选固体剂型为用于口服给药的剂型。
可以将粉末包装入胶囊或压制成片剂，以粉末形式使用或掺入软膏剂、霜剂或半固体。用于形成固体剂型的方法为本领域众所周知。
本申请中的PNAC在药物组合物中可以作为递送剂。
固体剂型中递送剂的量为递送有效量并且可以通过本领域技术人员公知的方法对任一特定化合物或生物或化学活性剂进行测定。
给药后，单位剂型中的活性剂被吸收入循环。通过测定血液中的已知药理活性(例如肝素导致的凝血时间增加或降钙素导致的钙循环水平降低)易于评估活性剂的生物有效度。或者，可以直接测量活性剂自身的循环水平。
递送系统
用于本申请的药物组合物中的预防和/或治疗性药物(可以称为活性剂)的量为实现用于靶适应征的活性剂目的的有效用量。组合物中活性剂的用量一般为药理、生物、治疗或化学有效量。然而，该用量可以低于组合物用于单位剂型时的用量，因为单位剂型可以含有多种递送剂化合物/活性剂组合物或可以含有分次的药理、生物、治疗或活性有效量。可以以总计含有活性剂有效量的累积单位施用总有效量。
可以通过本领域技术人员公知的方法测定所用活性剂的总量。然而，因为本申请的组合物可以比其它组合物或含有单独的活性剂的组合物更有效地递送活性剂，所以可以对受试者施用低于现有单位剂型或递送系统中使用的生物或化学活性剂用量，同时仍然可以达到相同的血液水平和/或治疗作用。
本申请公开的递送剂促进递送生物和化学活性剂，特别是口服、舌下、口含、十二指肠内、结肠内、直肠、阴道、粘膜、肺、鼻内和眼部系统的递送。
本申请的化合物和组合物用于对任一的动物施用生物或化学活性剂，包括(但不限于)：鸟类，诸如鸡；哺乳动物，诸如啮齿动物、牛、猪、狗、猫、灵长类，且特别是人；和昆虫。
这些化合物和组合物特别有利于递送如下化学或生物活性剂，所述的化学或生物活性剂否则可能因活性剂达到靶区(即递送组合物活性剂释放的区域)遇到的情况前以及在它们所施用的动物体内被破坏或活性降低。特别地，本申请的化合物和组合物用于口服施用活性剂，尤其是那些不常通过口服递送的或那些需要提高递送的活性剂。
包括所述化合物和活性剂的组合物具有将活性剂递送至所选择的生物系统和比不使用递送剂递送活性剂增加或提高活性剂生物有效度的效用。可以通过在一段时间期限内递送更多的活性剂或在特定时间期限内(诸如作用更快或延缓递送)或在一段时间期限内(诸如持续递送)递送活性剂来改善递 送。
实施例
下述实施例中所使用的实验方法如无特殊要求，均为常规方法。
下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
参照国际专利申请WO2008/028859实施例1中的方法制备N-[8-(2-羟基苯甲酰基)氨基]辛酸NAC
制备PNAC晶型I
向50L反应釜中加入异丙醇(22070.0ml，4.0vol)，开启搅拌，加入NAC(5518g，1.0eq)。将体系升温至50℃，向体系中滴加配制好的50％氢氧化钾溶液(1304.0g，1.0eq)。滴毕，体系变为澄清透明的黄色溶液，保温50℃反应1h。将反应液40℃下分批浓缩，得到粗品的颜色为浅橙黄色。
将粗品合批加入异丙醇(19310.0ml，3.5vol)进行打浆，打浆1h。对体系进行抽滤，滤饼以异丙醇(2760.0ml，0.5vol)进行淋洗。将滤饼转移至真空干燥箱中，干燥体系氮气平压，60℃条件下干燥16h，再次转移至真空干燥箱在100℃条件下，干燥24h。干燥完成，共得到产品4.52kg，收率72.8％，性状为类白色粉末状固体。
经测定，产品为晶型I，晶型I的XRPD、TGA/DSC分别如图1～2b所示，PNAC为晶型I，其中晶型I的特征XRPD峰(用°2θ表征)如下表1：
表1为晶型I的特征XRPD峰(用°2θ表征)
Figure PCTCN2020128050-appb-000003
DSC图谱(图2a)表明晶型I在195.5℃开始出现熔融吸热峰，峰值为163.1℃；DSC(图2a)和TGA(图2b)图谱结合可看出晶型I为无水物。
实施例2
制备PNAC晶型II
将实施例1制备的PNAC晶型I在室温条件下，接触60％相对湿度的环境，放置时间大于24h即可，得到产品。
经测定，产品为晶型II，产品的XRPD、TGA/DSC分别如图3-4b所示，其中晶型II的特征XRPD峰(用°2θ表征)如下表2：
表2为晶型II的特征XRPD峰(用°2θ表征)
Figure PCTCN2020128050-appb-000004
DSC图谱(图4a)表明晶型II在157.1℃开始出现熔融吸热峰，峰值为 162.5℃；DSC(图4a)和TGA(图4b)图谱结合可看出晶型II为1/3水合物。
实施例3
参照国际专利申请WO2008/028859实施例1中的方法制备N-[8-(2-羟基苯甲酰基)氨基]辛酸NAC
制备PNAC晶型III
向50L反应釜中加入异丙醇(22070.0ml，4.0vol)，开启搅拌，加入NAC(5518g，1.0eq)。将体系升温至50℃，向体系中滴加配制好的50％氢氧化钾溶液(1304.0g，1.0eq)。滴毕，体系变为澄清透明的黄色溶液，保温50℃反应1h。将反应液40℃下分批浓缩，得到粗品的颜色为浅橙黄色。
将粗品合批加入异丙醇(19310.0ml，3.5vol)进行打浆，打浆1h。对体系进行抽滤，得到滤饼，将所述滤饼过24目筛制备成均匀的颗粒，然后将该颗粒转移至真空干燥箱中进行干燥，干燥体系氮气平压，60℃条件下干燥16h，再次转移至真空干燥箱在100℃条件下，干燥24h得到颗粒均匀地铺散在5℃的低温环境，控制相对湿度为50％放置2天，得到产品。
经测定，产品为晶型III，晶型III的XRPD、TGA/DSC分别如图5-6b所示，其中晶型III的特征XRPD峰(用°2θ表征)如下表3：
表3为晶型III的特征XRPD峰(用°2θ表征)
Figure PCTCN2020128050-appb-000005
Figure PCTCN2020128050-appb-000006
DSC图谱(图6a)表明晶型III在156.6℃开始出现熔融吸热峰，峰值为162.0℃；DSC(图6a)和TGA(图6b)图谱结合可看出晶型III为1/2水合物。
实施例4
制备PNAC晶型IV
将实施例1制备的PNAC晶型I放置于室温条件下，接触80％的相对湿度环境，放置时间3天使其形成胶样物质，将此胶样物质暴露于具有40％的相对湿度环境中，放置5天，以形成产品。
经测定，该产品为晶型IV，晶型IV的XRPD、TGA/DSC分别如图7-8b所示，其中晶型IV的特征XRPD峰(用°2θ表征)如下表4：
表4为晶型IV的特征XRPD峰(用°2θ表征)
Figure PCTCN2020128050-appb-000007
Figure PCTCN2020128050-appb-000008
DSC图谱(图8a)表明晶型IV熔融吸热峰峰值为163.8℃；DSC(图8a)和TGA(图8b)图谱结合可看出晶型IV为1水合物。
实验例
SNAC：
表征
Figure PCTCN2020128050-appb-000009
片剂(由丹麦制药企业诺和诺德公司开发)中的SNAC，发现与专利WO2005107462中的晶型I相同。因此本文中的SNAC为参照专利WO2005107462中实施例1SNAC晶型I的制备方法制得。以下实施例中的SNAC均是通过该方法制备。
晶型I(PNAC-Ⅰ)为实施例1制备所得。
晶型II(PNAC-Ⅱ)为实施例2制备所得。
晶型III(PNAC-Ⅲ)为实施例3制备所得。
晶型IV(PNAC-Ⅳ)为实施例4制备所得。
实验例1 PNAC不同晶型的在水溶液中溶液稳定性实验
将前述实施例制备得到的PNAC晶型I～IV样品与前述制备的SNAC晶型I样品分别溶于纯化水中，分别置于4℃及室温两种条件，观察溶液变化情况，对比高浓度(500mg/mL)条件下不同盐型及不同晶型在水溶液中的稳定性差异，结果见表5(样品PNAC晶型I-IV溶解及溶液放置过程无差异)。
表5不同溶解条件下PNAC不同晶型的溶解度情况
Figure PCTCN2020128050-appb-000010
Figure PCTCN2020128050-appb-000011
由表5可知，SNAC在4℃条件下溶解后，溶液于0.5h就开始出现絮状物，随着时间推移溶液流动性逐渐变差，至2h溶液中析出较大白色颗粒；温度升高至室温条件下SNAC溶液放置1h也会出现絮状物，至2h絮状物增加变得浑浊。而本申请制备的PNAC I-IV溶解的溶液4℃放置1h底部才会出现少量细丝状絮状物，直到2h溶液状态变化不大；室温放置2h溶液中才会出现少量絮状物。这表明，在相同条件下，本申请的PNAC I-IV在高浓度(500mg/mL)条件下溶液稳定性优于SNAC。
实验例2 PNAC不同晶型对GLP-1药物在比格犬体内生物利用度的影响
GLP-1药物M4(简称M4)制备方法参见专利申请WO2019201328。
联合口服片剂的制备方法参见专利WO2012080471中实施例1中的制备方法制得。其中递送剂(SNAC、PNAC-Ⅰ、PNAC-Ⅱ)分别与M4结合。SNAC与M4结合制备的联合口服片剂为SNAC+M4。PNAC-Ⅰ与M4结合制备的联合口服片剂为PNAC-Ⅰ+M4。PNAC-Ⅱ与M4结合制备的联合口服片剂为PNAC-Ⅱ+M4。
在联合口服片剂中：M4的含量为10mg，递送剂的含量为100mg。
静脉注射M4的处方：M4溶于8mM、pH7.2的磷酸盐缓冲液，使得M4终浓度为1mg/mL。
选用28只比格犬，9-12kg，雄性，分为4组，其中，第一组单次静脉注射M4(0.05mg/kg，N＝4)，第二组单次口服SNAC+M4(1片，N＝8)，第三组单次口服PNAC-Ⅰ+M4(1片，N＝8)，第四组单次口服PNAC-Ⅱ+M4(1片，N＝8)，比较PNAC不同晶型对M4在比格犬体内生物利用度的影响。
口服给药组前一天晚上比格犬禁食不禁水，当天给药后用10ml水(定量)将药片冲服，4小时后对犬恢复进食，然后按照表6的采血方案进行采血测 定不同时间点的血药浓度及计算在动物体内的暴露量AUC last，具体结果见表7、8、9和图9、10。
表6为采血方案
组别 采血时间点
静脉注射M4组 给药前0小时，给药后0.5、1、3、6、12、24、48、72、96、144和192小时；
口服给药组 给药前0小时，给药后1.5、3、8、24、48、72、96小时
注：各时间点至少500μl血浆
表7为静脉给药组不同时间点血药浓度汇总
Figure PCTCN2020128050-appb-000012
表8为口服给药各组不同时间点血药浓度汇总
Figure PCTCN2020128050-appb-000013
表9各组药物在动物体内暴露量(AUC last)对比汇总表
Figure PCTCN2020128050-appb-000014
由表7-9数据计算可知，单次口服SNAC组绝对生物利用度为0.88％，而单次口服PNAC-Ⅱ组绝对生物利用度为1.28％，单次口服PNAC-Ⅰ组绝对生物利用度为1.11％，PNAC两组生物利用度明显高于SNAC组。
与单次口服SNAC组相比，单次口服PNAC-Ⅱ组绝对生物利用度提升了45.5％，单次口服PNAC-I组绝对生物利用度为提升了26.1％。
实验例3 PNAC不同含量、不同晶型对GLP-1药物在比格犬体内生物利用度的影响
GLP-1药物M4(简称M4)制备方法参见专利申请WO2019201328。
联合口服片剂的制备方法参见专利WO2012080471中实施例1中的制备方法制得。其中递送剂(SNAC、PNAC-Ⅰ、PNAC-Ⅱ)分别与M4结合。SNAC与M4结合制备的联合口服片剂为SNAC+M4。PNAC-I与M4结合制备的联合口服片剂为PNAC-Ⅰ+M4。PNAC-II与M4结合制备的联合口服片剂为PNAC-Ⅱ+M4。
在联合口服片剂中每片成分：M4含量为10mg，递送剂含量分别为300mg和450mg。
静脉注射M4的处方：M4溶于8mM、pH7.2的磷酸盐缓冲液，使得M4终浓度为1mg/mL。
选用28只比格犬，9-15kg，雄性，分为7组，每组4只，比较PNAC不同晶型对M4在比格犬体内生物利用度的影响。其中，分组信息如下表10。
口服给药组前一天晚上比格犬禁食不禁水，当天给药后用10ml水(定量)将药片冲服，4小时后对犬恢复进食，然后按照表11的采血方案进行采血测定不同时间点的血药浓度及计算在动物体内的暴露量AUC last，具体结果见表12-14和图19、20。
表10为分组信息
组别 给药途径 给药剂量 动物数量(只)
M4 i.v. 0.05mg/kg 4
SNAC(300mg)+M4 p.o. 300+10mg片剂1片 4
SNAC(450mg)+M4 p.o. 450+10mg片剂1片 4
PNAC-Ⅰ(300mg)+M4 p.o. 300+10mg片剂1片 4
PNAC-Ⅰ(450mg)+M4 p.o. 450+10mg片剂1片 4
PNAC-IⅠ(300mg)+M4 p.o. 300+10mg片剂1片 4
PNAC-IⅠ(450mg)+M4 p.o. 450+10mg片剂1片 4
表11为采血方案
Figure PCTCN2020128050-appb-000015
注：各时间点至少500μl血浆。
表12为静脉给药组不同时间点血药浓度汇总
组 血药浓度(nM)-给药时间(h)
别 0h 0.5h 1h 3h 6h 12h 24h 48h 72h 96h 144h 192h
M4 0 165.48 148.39 130.11 112.59 99.76 80.12 58.29 38.03 26.48 12.10 4.89
表13为口服给药各组不同时间点血药浓度汇总
Figure PCTCN2020128050-appb-000016
表14各组药物在动物体内暴露量(AUC last)对比汇总表
Figure PCTCN2020128050-appb-000017
由表14可知，单次口服SNAC(300mg)组绝对生物利用度为0.70％，单次口服SNAC(450mg)组绝对生物利用度为0.80％，而单次口服PNAC-Ⅱ组(300mg)绝对生物利用度为1.20％，单次口服PNAC-Ⅱ组(450mg)绝对生物利用度为1.92％，而单次口服PNAC-I组(300mg)绝对生物利用度为1.01％，单次口服PNAC-I组(450mg)绝对生物利用度为1.72％，均明显高于SNAC，同时PNAC随着含量的增加，绝对生物利用度增加明显。
与单次口服SNAC(300mg)组相比，单次口服PNAC-Ⅱ(300mg)组绝对生物利用度提升了71％，单次口服PNAC-I(300mg)组绝对生物利用度为提升了44％；与单次口服SNAC(450mg)组相比，单次口服PNAC-Ⅱ(450mg)组绝对生物利用度提升了140％，单次口服PNAC-I(450mg)组绝对生物利用 度为提升了115％。
从单个药物来看，单次口服SNAC(300mg)组与单次口服SNAC(450mg)组相比，绝对生物利用度仅仅提升了14％，两组间生物利用度相差不大，结合说明药物中SNAC的含量对绝对生物利用度没啥影响。而单次口服PNAC-Ⅱ(300mg)组与单次口服PNAC-Ⅱ(450mg)组相比，绝对生物利用度提升了60％；单次口服PNAC-I(300mg)组与单次口服PNAC-I(450mg)组相比，绝对生物利用度提升了70％。再结合实施例2的单次口服PNAC-Ⅱ和PNAC-I(100mg)组的绝对生物利用度，可以进一步验证了本申请的PNAC在药物中随着含量的增加，绝对生物利用度增加明显，并且发生了意想不到的质的提升。
实验例4
PNAC晶型II固态稳定性实验
将实施例2制备的晶型II分为三组，第一组在60℃条件下放置24小时，得到固体样品。第二组在40℃、相对湿度为75％的条件下放置两周，得到固体样品。第三组在25℃相对湿度为60％的条件下放置2周，得到固体样品，然后将三组固体样品分别通过XRPD和HPLC测试评估物理和化学稳定性。
其中，HPLC测试是指将实施例2获得的晶型II作为参比样品，其进行HPLC纯度测试得到的纯度设定为100area％，相对纯度＝HPLC纯度/参比样品纯度。HPLC测试方法中，使用柱长150mm的C18反相色谱柱，流动相为乙腈-水+0.05％三氟乙酸体系，1.2ml/min流速，在检测器波长UV-215nm条件下进样检测，按照归一化法计算主峰纯度。
测试后发现参比样品在放置不同环境设定的时间后，测得的HPLC相对纯度均为100％。实验后的XRPD叠图见图11，与参比样品特征峰完全相同，可知在固态稳定性实验中晶型均未发生变化。
使用上述同样的方法进行PNAC晶型I固态稳定性实验，结果见图15。
实验例5
制剂过程中的稳定性实验
将实施例2获得的晶型II分为三组，第一组对晶型II进行手动研磨10分 钟，得到固体样品。第二组对晶型II压片(压力3千牛)，得到固体样品。第三组对晶型II进行气流粉碎(进样压强0.4兆帕，粉碎压强0.2兆帕)，得到固体样品。并对三组固体样品进行XRPD表征以评估其物理稳定性。具体结果见图12-14。
由图12-14可知，晶型II在研磨、压片和气流粉碎后，样品的晶型均未发生变化。
使用上述同样的方法进行PNAC晶型I、晶型II、晶型III、晶型IV制剂过程中的稳定性实验，结果见表15。
PNAC晶型I的XRPD表征结果见图16-18，由图16-18可知，晶型I在研磨、压片和气流粉碎后，样品的晶型均未发生变化。
表15为PNAC不同晶型的稳定性实验结果
Figure PCTCN2020128050-appb-000018
从上述表中结果可知，PNAC晶型I和晶型II很稳定，晶型I只有在超过60％RH环境中长久放置才会转晶，晶型II无论在试验中的何种条件下都很稳定。
尽管以上结合对本申请的实施方案进行了描述，但本申请并不局限于上述的具体实施方案和应用领域，上述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本申请权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本申请保护之列。

Claims (47)

  1. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I，所述晶型I至少具有2θ°为：7.83±0.2、26.64±0.2、18.89±0.2表示的特征峰的X射线粉末衍射图。
  2. 根据权利要求1所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：5.24±0.2、21.59±0.2之一表示的特征峰的X射线粉末衍射图。
  3. 根据权利要求2所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：13.02±0.2、24.29±0.2之一表示的特征峰的X射线粉末衍射图。
  4. 根据权利要求3所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I至少还具有2θ°为：6.61±0.2、10.43±0.2、31.63±0.2、37.00±0.2之一表示的特征峰的X射线粉末衍射图。
  5. 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的X射线粉末衍射图如图1。
  6. 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的熔点为163.1℃。
  7. 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I的吸附水脱除温度为83.6℃。
  8. 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型I在140℃失重3.0％。
  9. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型II，所述晶型II至少具有2θ°为：24.76±0.2、6.73±0.2、20.26±0.2表示的特征峰的X射线粉末衍射图。
  10. 根据权利要求9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：14.68±0.2、25.55±0.2之一表示的特征峰的X射线粉末衍射图。
  11. 根据权利要求10所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：13.41±0.2、26.66±0.2之一表示的特征峰的X射线粉末衍射图。
  12. 根据权利要求11所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II至少还具有2θ°为：21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2、27.79±0.2、8.91±0.2之一表示的特征峰的X射线粉末衍射图。
  13. 根据权利要求9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的X射线粉末衍射图如图3。
  14. 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的熔点为162.5℃。
  15. 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II的吸附水脱除温度为93℃。
  16. 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型II在140℃失重5.6％。
  17. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型III，所述晶型III至少具有2θ°为：9.06±0.2、23.30±0.2、21.44±0.2表示的特征峰的X射线粉末衍射图。
  18. 根据权利要求17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：24.75±0.2、6.03±0.2之一表示的特征峰的X射线粉末衍射图。
  19. 根据权利要求18所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：21.20±0.2、17.06±0.2之一表示的特征峰的X射线粉末衍射图。
  20. 根据权利要求19所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III至少还具有2θ°为：21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2、15.64±0.2、26.49±0.2之一表示的特征峰的X射线粉末衍射图。
  21. 根据权利要求17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的X射线粉末衍射图如图5。
  22. 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的熔点为162.0℃。
  23. 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III的吸附水脱除温度为94.5℃。
  24. 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型III在140℃失重6.1％。
  25. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于， 所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型IV，所述晶型IV至少具有2θ°为：16.25±0.2、6.8±0.2、22.08±0.2表示的特征峰的X射线粉末衍射图。
  26. 根据权利要求25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：13.16±0.2、19.39±0.2之一表示的特征峰的X射线粉末衍射图。
  27. 根据权利要求26所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：18.35±0.2、9.68±0.2之一表示的特征峰的X射线粉末衍射图。
  28. 根据权利要求27所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV至少还具有2θ°为：15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2、34.34±0.2、18.82±0.2之一表示的特征峰的X射线粉末衍射图。
  29. 根据权利要求25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的X射线粉末衍射图如图7。
  30. 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的熔点为163.8℃。
  31. 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV的吸附水脱除温度为96.1℃。
  32. 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物，其特征在于，所述晶型IV在150℃失重8.21％。
  33. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶体多晶型物的制备方法，其特征在于，包括如下步骤：
    在反应容器中加入有机溶剂并搅拌，然后加入N-[8-(2-羟基苯甲酰基)氨基]辛酸，搅拌均匀，滴加氢氧化钾溶液，滴加完毕后，浓缩得粗品；
    在所述粗品中加入有机溶剂打浆抽滤后得滤饼，将所述滤饼淋洗后放入干燥箱中干燥，得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物。
  34. 根据权利要求33所述的制备方法，其特征在于，将所述滤饼淋洗后放入干燥箱中进行干燥，干燥温度为60℃～100℃，干燥时间为30～40h，得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I；优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h；
    所述晶型I为权利要求1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
  35. 根据权利要求33所述的制备方法，其特征在于，将所述滤饼制备成均匀的颗粒，然后再将所述颗粒放入所述干燥箱中进行干燥，干燥后的颗粒均匀地铺散在2-8℃的低温环境，控制相对湿度为50％放置2天，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型III；
    所述颗粒放入所述干燥箱中的干燥温度为60℃～100℃，干燥时间为30～40h；
    优选地，所述干燥分两个步骤，先60℃进行干燥16h，后体系氮气平压后再次在100℃干燥24h；将所述滤饼过20～24目筛得到均匀的颗粒；
    所述晶型III为权利要求17-24任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型III。
  36. 根据权利要求33-35任一项所述的制备方法，其特征在于，所述有机溶剂为异丙醇或丙酮；所述氢氧化钾的溶液浓度为40％～90％，优选地所述氢氧化钾的溶液浓度为50％。
  37. 根据权利要求33-35任一项所述的制备方法，其特征在于，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至48℃以上，然后滴加氢氧化钾溶液，滴加完毕后，保温反应0.5～2h；
    优选地，加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后，体系升温至 48℃～52℃，然后滴加氢氧化钾溶液，滴加完毕后，保温反应1h；
    所述N-[8-(2-羟基苯甲酰基)氨基]辛酸以及氢氧化钾溶液的添加摩尔比为1:1；
    所述粗品加入有机溶剂打浆的时间为0.5～1.5h，优选为1h。
  38. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型加热至至少75℃以上，以形成晶型I；
    所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上；
    将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型在氮气保护下加热至75℃以上，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
  39. 根据权利要求38所述的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II在氮气保护下加热至140℃，以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
  40. 根据权利要求38所述的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV在氮气保护下加热至110℃以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
  41. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型I的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型冻干，以形成晶型I；
    所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上；
    所述晶型I为权利要求1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
  42. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II的制备方法，其特征在于，将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型，在 室温条件下，暴露于具有0～60％的相对湿度环境中，24h以上，以形成所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
  43. 根据权利要求42所述的制备方法，其特征在于，所述相对湿度为20％、30％、40％、60％的环境；
    所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型为晶型I、晶型III、晶型IV中的至少一种或两种以上；
    所述晶型II为权利要求9-16任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
  44. 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型IV的制备方法，其特征在于，包括如下步骤：
    将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型，在高于80％的相对湿度环境中形成胶样物质；
    所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型为晶型I、晶型II、晶型III中的至少一种或两种以上；
    将所述胶样物质在室温条件下，暴露于具有20％～40％的相对湿度环境中，120h以上，以形成晶型IV；
    所述晶型IV为权利要求25-32任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV。
  45. 一种药物组合物，其特征在于，包括N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物；
    N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I、晶型II、晶型III、晶型IV中的一种或至少两种。
  46. 根据权利要求45所述的药物组合物，其特征在于，所述药物组合物还包括预防和/或治疗性药物；
    所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比为(20～60):1，优选地，所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的 重量比为30:1。
  47. 根据权利要求46所述的药物组合物，其特征在于，所述预防和/或治疗性药物为胰高血糖素样肽-1、胰岛素、PYY、人胰淀素、肝素、人生长激素、干扰素、单克隆抗体、蛋白酶抑制剂、血小板生成素。
PCT/CN2020/128050 2020-05-29 2020-11-11 N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 WO2021238088A1 (zh)

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