WO2024022447A1 - 铋-高分子复合物在消化道可视化中的用途 - Google Patents

铋-高分子复合物在消化道可视化中的用途 Download PDF

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WO2024022447A1
WO2024022447A1 PCT/CN2023/109604 CN2023109604W WO2024022447A1 WO 2024022447 A1 WO2024022447 A1 WO 2024022447A1 CN 2023109604 W CN2023109604 W CN 2023109604W WO 2024022447 A1 WO2024022447 A1 WO 2024022447A1
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bismuth
use according
acid
complex
polymer
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PCT/CN2023/109604
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English (en)
French (fr)
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田萌
刘臻
谢欣然
张诗宜
罗洁
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上海交通大学
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Publication of WO2024022447A1 publication Critical patent/WO2024022447A1/zh

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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/29—Antimony or bismuth compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/732—Pectin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds

Definitions

  • the present application relates to the field of biomedicine, and specifically to the use of a bismuth-polymer complex in preparing reagents for visualization of the digestive tract.
  • Contrast imaging technology is a method commonly used in clinical auxiliary diagnosis and/or treatment.
  • Existing gastrointestinal X-ray, CT and MR imaging require patients to take oral or enema contrast agents.
  • Commonly used contrast agents include, for example, sulfuric acid.
  • Barium and iodine preparations, etc. can enhance the effect of image observation to a certain extent, but the current contrast agents have the following defects and shortcomings: 1. When performing imaging of a large area of the digestive tract (such as enterography, colonography), it needs to be administered to the patient A large amount of contrast media causes great physical discomfort to the patient; 2.
  • the current contrast media does not have good adhesion in the digestive tract, and the adhesion effect in the digestive tract is poor. The doctor needs to press the digestive tract accordingly or change the patient.
  • the present application provides the use of a bismuth-polymer complex in preparing reagents for visualization of the digestive tract.
  • the bismuth-polymer complex has extensive encapsulation properties. When exposed to acid, it will aggregate and form a paste-like substance composed of tiny gel particles with digestive tract adhesion and high flow capabilities, which can be used in the digestive tract. Spread over a large area and stick to it. If the bismuth-polymer complex and functional substances such as contrast agents are mixed before contact with acid, the bismuth-polymer complex that aggregates after contact with acid can wrap the above-mentioned functional substances in the gel particles formed by it, loading the functions. The material spreads and adheres to a large area in the digestive tract, achieving more efficient visualization of the digestive tract.
  • the bismuth-polymer complex itself, or the bismuth-polymer gel particles coated with a contrast agent, can cover a large area in the animal's digestive tract and stay for a long time, thereby forming a clear digestive tract image that stays for a long time.
  • the same volume of contrast agent in the prior art does not have the same effect.
  • the bismuth-polymer gel particles wrapped with radiation-shielding materials can cover a large area in the animal's digestive tract for a long time, forming an intra-digestive tract barrier that can block radiation and reduce digestive tract damage caused by radiation.
  • the present application provides the use of a bismuth-polymer complex in preparing a reagent for visualization of the digestive tract.
  • the present application provides the use of a bismuth-polymer complex in preparing a digestive tract delivery carrier for functional substances.
  • the bismuth-polymer complex is formed by interaction between bismuth compound and polymer.
  • the bismuth-polymer complex is formed by complex bonds, covalent bonds and/or non-covalent interactions between bismuth compounds and polymers.
  • the bismuth compound is selected from one or more of the following group: bismuth hydroxide, bismuth oxide, bismuth carbonate, bismuth subcarbonate, bismuth nitrate, bismuth gallate, bismuth aluminate, bismuth Bismuth salicylate, bismuth subsalicylate, bismuth salicylate, bismuth acetate, bismuth oxalate, bismuth citrate, bismuth chloride and bismuth sulfide.
  • At least one free carboxylic acid or free carboxylate salt is present in the polymer.
  • the polymer is selected from one or more of the following group: pectin, low methoxy pectin, polyacrylic acid, alginic acid, and hyaluronic acid.
  • the bismuth-polymer complex is tested by TOF-SIMS and has the following fragment peak: BiO 3 -.
  • the structure of the bismuth-polymer complex is as shown in Formula I:
  • x is a number greater than or equal to 1
  • y, z, m, n are independently numbers greater than or equal to 0,
  • R1 and R2 are independently selected from any of the following (p is a number greater than or equal to 0):
  • R' is selected from any of the following structures:
  • R 3 is selected from any of the following structures:
  • R 4 and R 5 are independently selected from any of the following structures (p is a number greater than or equal to 0):
  • R 6 and R 7 are independently selected from any of the following structures (R is any group):
  • R 6 and R 7 can be any of the following structures:
  • the bismuth-polymer composite is tested using infrared spectroscopy and shows a characteristic peak at 1550-1700 cm -1 .
  • the mass content of bismuth element in the bismuth-polymer composite is between 0.5% and 70%.
  • the bismuth-polymer complex includes a bismuth hydroxide-pectin complex, a bismuth hydroxide-polyacrylic acid complex, a bismuth hydroxide-alginic acid complex, and a bismuth hydroxide-hyaluronic acid complex.
  • complex bismuth oxide-polyacrylic acid complex, bismuth nitrate-polyacrylic acid complex, bismuth subsalicylate-polyacrylic acid complex and/or bismuth citrate-polyacrylic acid complex.
  • the bismuth-polymer complex is acidified.
  • the acidification treatment includes using an acidic substance to mix with the bismuth-polymer composite.
  • the acidic material is solid or liquid.
  • the acidic substance is selected from one or more of the following group: hydrochloric acid, phosphoric acid, oxalic acid, lactic acid, citric acid, succinic acid, methanesulfonic acid, tartaric acid, benzoic acid, malic acid, p-toluenesulfonic acid, propionic acid, fumaric acid, fruit acid, salicylic acid, formic acid and acetic acid.
  • the pH value of the bismuth-polymer complex after acidification is about 0.1 to 4.5.
  • the bismuth-polymer composite has a microscopic form after acidification and is in the form of gel particles.
  • the gel particles have a particle size ranging from about 50 nm to 1000 ⁇ m.
  • the water content (mass fraction) of the gel particles is greater than or equal to 60%.
  • the bismuth-polymer complex is administered orally or anally.
  • the bismuth-polymer complex is administered by intestinal intubation.
  • the reagents for visualization of the digestive tract also include other functional substances.
  • the functional substances include poorly soluble or insoluble particles.
  • the functional substances include biologically active substances.
  • the functional substance includes a contrast agent.
  • the contrast agent includes X-ray contrast agent and/or MR contrast agent.
  • the X-ray contrast agent is selected from the group consisting of barium sulfate, iopromide, iohexol, iodixanol, ioversol, meglumine diatrizoate, sodium diatrizoate, and lipiodol.
  • the MR contrast agent is selected from: water, and gadolinium chelates.
  • the biologically active substance includes a drug, a protein, a polypeptide, a nucleic acid, a carbohydrate, a bacterium, a fungus, or a complex consisting of at least one thereof.
  • the nucleic acid includes DNA and/or RNA.
  • the poorly soluble or insoluble particulate matter includes: silicon oxide, metal oxide, metal sulfide, metal nitride, metal salt, or a composite containing one of them.
  • the sparingly soluble or insoluble particulate matter has a solubility of less than about 10 mg/mL.
  • the particle size of the poorly soluble or insoluble particles is about 0.5 nm to 1 mm.
  • the functional substance includes a radiation attenuating material.
  • the radiation attenuating material includes metallic substances.
  • the metallic species includes barium, lead, and/or silver.
  • the radiation attenuating material includes a metal salt.
  • the metal salt includes barium sulfate and/or silver chloride.
  • the atomic number of the metal element in the metal species or metal salt is greater than 50.
  • the functional substance includes a radioprotective drug.
  • the radioprotective drug includes: amifostine, acetylcysteine, GSH, GC4419, and/or superoxide dismutase analogs.
  • the means of visualizing the digestive tract includes X-ray imaging.
  • the means of visualizing the digestive tract includes MR imaging.
  • the methods for visualizing the digestive tract include: DF, DR, CT, MRI, DSA, PET-CT, PET-MRI and/or SPECT-CT.
  • the means of visualizing the digestive tract include CT, MRI, PET-CT, PET-MRI and/or SPECT-CT functions in radiotherapy equipment.
  • the uses include diagnosis of gastrointestinal diseases, assessment of gastrointestinal diseases, pre-radiation therapy simulation, Image-guided radiotherapy, real-time radiotherapy, imaging of the gastrointestinal tract required for intraoperative image guidance and/or radiation protection of the gastrointestinal tract.
  • the gastrointestinal disease includes: gastrointestinal cancer, gastrointestinal metastasis cancer, gastrointestinal inflammatory disease and/or gastrointestinal injury.
  • the digestive tract includes the esophagus, gastrointestinal tract, and/or anus.
  • the bismuth-polymer complex contains the other functional substances.
  • the inclusion includes a mode of action selected from the group consisting of non-covalent interactions, covalent interactions, complexing interactions, ionic interactions, and hydrogen bonding interactions.
  • the reagents for visualization of the digestive tract further include a pharmaceutically acceptable carrier.
  • the present application also provides a method for visualizing the digestive tract, which includes administering the bismuth-polymer complex described in the present application.
  • the present application also provides a method for radiotherapy simulation, which includes administering the bismuth-polymer complex described in the present application.
  • the present application also provides a method for diagnosing digestive tract diseases, which includes administering the bismuth-polymer complex described in the present application.
  • the present application also provides a method for gastrointestinal radiation protection, which includes administering the bismuth-polymer complex described in the present application.
  • this application also provides a pharmaceutical combination, which includes the bismuth-polymer complex described in this application and the functional substance described in this application.
  • this application also provides a kit, which includes the bismuth-polymer complex described in this application and the functional substance described in this application.
  • Figure 1 shows the structure of P1.
  • FIG. 1 shows the structure of P2.
  • Figure 3 shows the structure of P3.
  • Figure 4 shows the structure of P4.
  • Figure 5 shows the structure of P5.
  • Figure 6 shows the structure of P6.
  • Figure 7 shows the structure of P7.
  • Figure 8 shows the structure of P8.
  • Figure 9 shows the performance of the bismuth-polymer complex before and after acidification (taking P2 hydrochloric acid acidification as an example).
  • Figure 10 shows the performance of the bismuth-polymer complex before and after acidification (taking P1 hydrochloric acid acidification as an example).
  • Figure 11 shows the characteristic peaks in TOF-SIMS characterization of the bismuth-polymer complex after acidification (taking P1 as an example).
  • Figure 12 shows a schematic diagram of the experimental device for in vitro evaluation of the gastrointestinal adhesion effect of bismuth-polymer complex.
  • Figure 13 shows the blood cell analysis of rats 24 hours after oral administration of acidified bismuth-polymer complex.
  • Figure 14 shows the biochemical analysis of liver function in rats after oral administration of acidified bismuth-polymer complex for 24 hours.
  • Figure 15 shows the biochemical analysis of renal function in rats after oral administration of acidified bismuth-polymer complex for 24 hours.
  • Figure 16 shows the bismuth content in plasma and tissue after oral administration of acidified bismuth-polymer complex to rats.
  • Figure 17 shows a schematic diagram of the process and performance of bismuth-polymer composite encapsulating barium sulfate.
  • Figure 18 shows the barium sulfate particles coated with bismuth-polymer complex observed under a transmission electron microscope.
  • Figure 19 shows the gastrointestinal imaging effect of rats after oral administration of barium sulfate coated with bismuth-polymer complex.
  • Figure 20 shows the gastrointestinal imaging effect of rats after oral administration of barium sulfate.
  • Figure 21 shows the gastrointestinal tract imaging effect of rats after oral administration of iohexol encapsulated in bismuth-polymer complex.
  • Figure 22 shows the gastrointestinal tract imaging effect after tail vein injection of iohexol in rats.
  • Figure 23 shows the gastrointestinal tract imaging effect after oral administration of iohexol in rats.
  • Figure 24 shows the esophageal X-ray imaging effect of rats after oral administration of acidified bismuth-polymer complex containing barium sulfate.
  • Figure 25 shows the gastrointestinal imaging effect of pigs after oral administration of barium sulfate encapsulated by bismuth-polymer complex.
  • Figure 26 shows the gastrointestinal imaging effect of pigs after oral administration of barium sulfate.
  • Figure 27 shows the gastrointestinal tract imaging effect after oral administration of bismuth-polymer complex in rats.
  • Figure 28 shows the MR imaging effect of the gastrointestinal tract after oral administration of acidified bismuth-polymer complex in rats.
  • Figure 29 shows the MR imaging effect of the gastrointestinal tract after oral administration of mannitol aqueous solution to rats.
  • Figure 30 shows the gastrointestinal X-ray/MR fusion imaging of rats after oral administration of barium sulfate coated with bismuth-polymer complex.
  • Figure 31 shows the X-ray/MR fusion imaging of the gastrointestinal tract after oral administration of mannitol aqueous solution to rats.
  • Figure 32 shows the X-ray/MR fusion imaging of the gastrointestinal tract after oral administration of barium sulfate in rats.
  • Figure 33 shows the body weight changes of rats after irradiation.
  • Figure 34 shows diarrhea in rats after irradiation.
  • Figure 35 shows the changes in food intake of rats after irradiation.
  • Figure 36 shows the intestinal permeability results after irradiation in rats.
  • Figure 37 shows the intestinal section results of rats after irradiation.
  • the term “complex” generally refers to a structure formed by interaction between two or more compounds or structures. For example, these interactions can be through chemical interactions, such as covalent bonds, ionic bonds, or secondary bonds (such as hydrogen bonds), or through physical interactions, such as encapsulation, entrapment, etc.
  • the term "bismuth-polymer complex” generally refers to a type of polymer complex containing bismuth.
  • the bismuth-polymer composite may be composed of a bismuth compound and a polymer compound.
  • polymer generally refers to a molecular weight greater than 2000 Daltons, greater than 3000 Daltons, greater than 4000 Daltons, greater than 5000 Daltons, greater than 6000 Daltons, greater than 7000 Daltons , any compound greater than 8000 Daltons, greater than 9000 Daltons, greater than 10000 Daltons, greater than 12000 Daltons, greater than 15000 Daltons or greater than 20000 Daltons.
  • the term "digestive tract” generally includes any part of the tract from the mouth to the anus.
  • the digestive tract may include an upper gastrointestinal tract and a lower gastrointestinal tract.
  • the digestive tract may include the oral cavity, pharynx, esophagus, stomach, intestines, and anus.
  • the term "visualization of the digestive tract” generally includes visualization of digestive tract function and/or digestive tract structure. Visualization methods may include any method known in the art. Examples include gastrointestinal imaging, e.g., gastrointestinal radioprotection. Visualization of the digestive tract as described herein can be used to provide an assessment of, for example, the absorptive capacity of the digestive tract; the ability of the digestive tract to absorb nutrients; the permeability of the digestive tract; the ability of the digestive tract to hydrolyze compounds; the ability of the digestive tract and/or the small intestine Surface area; functional surface area of the digestive tract and/or small intestine; barrier function of the digestive tract; damage to the digestive tract; extent of mucosal damage in the digestive tract; damage to villi, alias, small intestine; villus height of the brush border of the small intestine; and, as in The presence of any disease or pathology associated with such changes in the function of the digestive tract; the presence of inflammatory conditions; the presence of infection; response to treatment to correct any or all
  • the term “acidification treatment” generally refers to contacting the bismuth-polymer complex with an acidic substance.
  • the term “acidic substance” generally refers to a substance that can donate a hydrogen proton or can accept an electron pair.
  • the acidic substance may include organic acids and inorganic acids.
  • the acidic substance may include a monoacid, a dibasic acid, a tribasic acid, or a polybasic acid.
  • the acidic substances may include strong acids and weak acids.
  • the acidic substances may include exogenous substances, such as common acidic compounds, or endogenous substances, such as gastric acid in humans or animals.
  • the acidification treatment can be performed in vitro or in vivo.
  • bioactive substance generally refers to inorganic or organic molecules, including small molecules, peptides (such as cell-penetrating peptides), proteins, carbohydrates (including monosaccharides, oligosaccharides and polysaccharides), Nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins; or small molecules linked to proteins, glycoproteins, sterols, nucleic acids (any form of DNA, including cDNA or RNA or fragments thereof), nucleotides, nucleosides, Inorganic or organic molecules such as oligonucleotides (including antisense oligonucleotides, LNA and siRNA), genes, lipids, hormones or combinations thereof.
  • peptides such as cell-penetrating peptides
  • carbohydrates including monosaccharides, oligosaccharides and polysaccharides
  • Nucleoproteins mucins, lipoproteins, synthetic polypeptides or proteins
  • polypeptide generally refers to a polymer of amino acid residues.
  • the term may be used to refer to amino acid polymers in which one or more amino acid residues are synthetic chemical mimetics of the corresponding natural amino acids. It may also be used to refer to natural amino acid polymers, those containing modified residues, and non- Natural amino acid polymer.
  • saccharide generally refers to a general term for a class of organic compounds of polyhydroxy aldehydes, polyhydroxy ketones, their condensation polymers and certain derivatives.
  • Sugars are also called carbohydrates, and their general molecular formula is Cx(H 2 O)y, and they can contain different amounts of sugar units, such as monosaccharides, disaccharides, polysaccharides, and complex sugars.
  • a drug generally refers to a molecule having a desired biological effect.
  • a drug can be preventive or therapeutic, for example, a drug can be used for diagnosis, for example, a drug can be protective for some specific purpose.
  • Drugs may include, but are not limited to: protein molecules, including but not limited to peptides, polypeptides, proteins, including post-translationally modified proteins, fusion proteins, antibodies, etc.; small molecules (less than 1000 daltons), including inorganic or organic compounds; nucleic acid molecules , including but not limited to double-stranded or single-stranded DNA, or double-stranded or single-stranded RNA (such as antisense (molecules), RNAi, etc.), intron sequences, triple helix nucleic acid molecules and aptamers; or vaccines. Drugs can be obtained from any known biological (including but not limited to: animals, plants, bacteria, fungi and protozoa or viruses) or synthetic molecule libraries.
  • Contrast agents allow the detection, imaging and/or monitoring of the presence and/or progression of pathologies, pathological conditions and/or diseases. Contrast agents can generally be administered to an individual to provide information about at least a portion of the individual (eg, a human). In some cases, contrast agents can be used to highlight specific areas of an individual, making organs, blood vessels, tissues, and/or other parts more detectable and more clearly imaged. The presence and extent of disease and/or injury can be determined by improving detectability and/or image quality of the area under study
  • radiation therapy simulation generally refers to the visualization of a target site before, during, and/or after radiation therapy.
  • the positioning of the digestive tract can be performed using any simulator and instrument with imaging capabilities known in the art.
  • radiation therapy simulation those skilled in the art can determine the information of the target site, such as its location, function, structure and other conditions.
  • non-covalent interaction is used interchangeably with “non-covalent interaction” and generally refers to non-covalent binding forces such as ionic interactions (e.g. salt bridges), non-ionic interactions (e.g. salt bridges) , hydrogen bonding), or hydrophobic interactions (e.g., van der Waals forces or ⁇ -stacking interactions).
  • ionic interactions e.g. salt bridges
  • non-ionic interactions e.g. salt bridges
  • hydrogen bonding hydrogen bonding
  • hydrophobic interactions e.g., van der Waals forces or ⁇ -stacking interactions
  • the term “about” is used to mean approximately (approximately), in the region of, roughly (roughly), or around (around).
  • the term “about” modifies the range by extending the upper and lower limits of the recited numerical value.
  • the term “about” is used herein to place a value 10% above and below the stated value, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% , modified by 9% or 10% changes.
  • the term "complexation” generally refers to the process in which an electron pair donor and an electron acceptor interact to form various complexes.
  • the donor is an atom or an ion, regardless of whether it is a simple substance or a compound, any substance that can provide an electron pair, and the acceptor is a metal ion or an organic compound.
  • the process in which molecules or ions combine with metal ions to form very stable new ions is called a complexation reaction, also called a coordination reaction.
  • electrostatic interaction generally refers to an intermolecular interaction between two or more positively or negatively charged moieties/groups when they have opposite charges (i.e., one is positively charged, When the other is negative), they can attract each other; when the two charges have the same sign (i.e., both are positive or both are negative), they can repel each other; or, the interaction can be the above-mentioned effect. combination.
  • hydrogen bond is a type of intermolecular force, which is a force between permanent dipoles.
  • a hydrogen bond occurs between a hydrogen atom that has been covalently bonded to another atom and another atom (XH...Y).
  • X hydrogen atom
  • Y hydrogen atom
  • Hydrogen bonds can be either intermolecular or intramolecular.
  • van der Waals forces generally refers to non-directional, non-saturated, weak interaction forces between molecules or atoms. Van der Waals forces usually include orientation forces, induction forces, and dispersion forces.
  • the term “pharmaceutical combination” generally refers to a product resulting from the mixing or combination of more than one ingredient, and includes both fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” means, for example, that a bismuth-polymer complex and one or more combination partners are both administered simultaneously to a subject as a single entity or dose.
  • non-fixed combination means, for example, that a bismuth-polymer complex and one or more combination partners are administered to a subject simultaneously, jointly, or sequentially (without specific time limits) as separate entities.
  • the term "kit” generally refers to any article of manufacture (eg, a package or container) that includes at least one reagent.
  • the kit may comprise a bismuth-polymer complex.
  • the kit may contain two or more components, such as bismuth-polymer complex, and other functional substances, and the components may or may not be packaged together.
  • the components of the kit may be contained in separate vials (ie, a kit with separate parts), or provided in a single vial.
  • the kit may also contain instructions for performing the method. Instructions are available in paper or electronic form as a user manual.
  • the manual may contain instructions for explaining the results obtained when performing the above-described method using the kit of the present application.
  • the term "subject” may be a human or a non-human mammal.
  • Non-human mammals may include any mammalian species other than humans, such as livestock animals (e.g., cattle, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or primates (e.g., gorillas and monkeys), or domestic animals (e.g., dogs and cats).
  • livestock animals e.g., cattle, pigs, sheep, chickens, rabbits, or horses
  • rodents e.g., rats and mice
  • primates e.g., gorillas and monkeys
  • domestic animals e.g., dogs and cats.
  • the present application provides the use of a bismuth-polymer complex in preparing a reagent for visualization of the digestive tract.
  • this application also provides the use of bismuth-polymer complex in preparing a digestive tract delivery carrier for functional substances.
  • the present application also provides a method for visualizing the digestive tract, which includes administering a bismuth-polymer complex.
  • the present application also provides a method of radiotherapy simulation, which includes administering a bismuth-polymer complex.
  • the present application also provides a method for diagnosing digestive tract diseases, which includes administering a bismuth-polymer complex.
  • the present application also provides a method for gastrointestinal radiation protection, which includes administering a bismuth-polymer complex.
  • the present application also provides a pharmaceutical combination, which includes a bismuth-polymer complex and other functional substances.
  • the present application provides a kit, which includes a bismuth-polymer complex and other functional substances.
  • the bismuth-polymer composite may include a polymer composite containing bismuth element.
  • the bismuth-polymer complex can be formed by interaction between bismuth compound and polymer.
  • the bismuth compound may include, but is not limited to, one or more selected from the following group: bismuth hydroxide, bismuth oxide, bismuth carbonate, bismuth subcarbonate, bismuth nitrate, bismuth gallate, aluminate Bismuth, bismuth subsalicylate, bismuth subsalicylate, bismuth salicylate, bismuth acetate, bismuth oxalate, bismuth citrate, bismuth chloride and bismuth sulfide.
  • At least one free carboxyl group or free carboxylate salt may be present in the polymer.
  • the polymer may include, but is not limited to, one or more selected from the following group: pectin, low methoxy pectin, polyacrylic acid, alginic acid, hyaluronic acid, carbomer, Polycarbophil.
  • the polymers also include simple modifications based on the specific polymers listed in this application.
  • the simple modification may include copolymerization, that is, a copolymerized polymer similar to the polymer obtained by copolymerizing monomers of the polymer with other monomers.
  • the simple modification may include grafting, that is, the modification of additional small molecules or polymers through reactions on the reactive groups of these polymers.
  • the polymer may also include simple group substitutions based on the specific polymers listed in this application.
  • the new polymer obtained after the replacement can still remain the same as the original polymer. or of similar nature.
  • the polymer may also include derivatives and/or analogs thereof.
  • the polymer may also include an esterified product obtained by esterification or partial esterification on the basis of the specific polymers listed in this application.
  • the polymer may also include an amidate obtained by amidation on the basis of the specific polymers listed in this application.
  • the polymer may also include a copolymer obtained by simple copolymerization based on the specific polymers listed in this application.
  • the polymer may be alkalized to form a salt with a metal ion.
  • TOF-SIMS time of flight-secondary ion mass spectroscopy
  • the bismuth-polymer composite was tested using infrared spectroscopy and showed characteristic peaks at approximately 1550 to 1700 cm -1 .
  • the bismuth-polymer complex may have the structure shown in Formula I:
  • x can be a number greater than or equal to 1.
  • x can be
  • y, z, m, n are independently numbers greater than or equal to 0.
  • y can be
  • R 1 can be selected from any of the following structures (p is a number greater than or equal to 0):
  • R 2 can be selected from any of the following structures (p is a number greater than or equal to 0):
  • R' is selected from any of the following structures:
  • R 3 can be selected from any of the following structures:
  • R 4 can be selected from any of the following structures (p is a number greater than or equal to 0):
  • R 5 can be selected from any of the following structures (p is a number greater than or equal to 0):
  • R 6 can be selected from any of the following structures (R is any group):
  • R 7 can be selected from any of the following structures (R is any group):
  • R 6 and R 7 can be any of the following structures:
  • the mass content of bismuth element in the bismuth-polymer composite can be between about 0.5% and 70%.
  • the mass content of bismuth element in the bismuth-polymer composite is about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20% , about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45% , about 46%, about 47%, about 48%, about 49%, about 50%, about 51%
  • the bismuth-polymer complex may include one or more selected from the following group: bismuth hydroxide-pectin complex, bismuth hydroxide-polyacrylic acid complex, bismuth hydroxide-seaweed Acid complex, bismuth hydroxide-hyaluronic acid complex, bismuth oxide-polyacrylic acid complex, bismuth nitrate-polyacrylic acid complex, bismuth subsalicylate-polyacrylic acid complex and/or bismuth citrate-polyacrylic acid complex Complex.
  • the bismuth hydroxide-pectin complex may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth hydroxide-polyacrylic acid composite may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth hydroxide-alginic acid complex may have The structure shown, where x is a number greater than 0 and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth hydroxide-hyaluronic acid complex may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth oxide-polyacrylic acid composite may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth nitrate-polyacrylic acid complex may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth subsalicylate-polyacrylic acid complex may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth citrate-polyacrylic acid complex may have The structure shown, where x is a number greater than 0, and y is a number greater than or equal to 0.
  • the structure may not be limited to potassium salt, but may also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth-polymer complex needs to be acidified to function.
  • the acidification treatment may comprise an in vitro acidification treatment.
  • the acidification treatment may include contacting the bismuth-polymer complex with an acidic substance.
  • an acidic substance is mixed with the bismuth-polymer complex.
  • the acidic material may be a solid acidic material.
  • the acidic substance may be a liquid acidic substance.
  • the acidic substance may be a strong acid.
  • the acidic substance may be a weak acid.
  • the acidic substance may be selected from one or more of the following group: hydrochloric acid, phosphoric acid, oxalic acid, lactic acid, citric acid, succinic acid, methanesulfonic acid, tartaric acid, benzoic acid, malic acid, p- Toluenesulfonic acid, propionic acid, fumaric acid, fruit acid, salicylic acid, formic acid and acetic acid.
  • the bismuth in the bismuth hydroxide is connected to the carboxylic acid in the pectin through complexation.
  • acidification for example, mixed with hydrochloric acid
  • the bismuth hydroxide-pectin complex The hydroxyl groups in the pectin will leave, and the exposed bismuth will interact with other carboxyl groups in the pectin, causing cross-linking, aggregation and other phenomena to form a gel.
  • said acidification may occur upon entry into the body.
  • the bismuth-polymer complex described in the present application is directly administered to a subject, the bismuth-polymer complex can react with acidic substances in the body (such as gastric acid) after entering the body.
  • the pH value of the bismuth-polymer complex after acidification treatment can be about 0.1 to 4.5.
  • the pH is About 0.1, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0 or about 4.5.
  • the bismuth-polymer composite may have a microscopic form of gel particles after acidification.
  • the particle size of the gel particles ranges from about 50 nm to 1000 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 900 ⁇ m.
  • the gel particles have a particle size ranging from about 50 nm to 800 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 700 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 600 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 500 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 400 ⁇ m.
  • the gel particles have a particle size ranging from about 50 nm to 300 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 200 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 100 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 50 ⁇ m.
  • the gel particles have a particle size ranging from about 50 nm to 40 ⁇ m.
  • the particle size of the gel particles ranges from about 50 nm to 30 ⁇ m.
  • the gel particles have a particle size ranging from about 50 nm to 20 ⁇ m.
  • the gel particles have a particle size ranging from about 100 nm to 20 ⁇ m.
  • the gel particles have a particle size ranging from about 500 nm to 20 ⁇ m.
  • the particle size of the gel particles ranges from about 800 nm to 20 ⁇ m.
  • the gel particles have a particle size ranging from about 1 ⁇ m to 20 ⁇ m.
  • the gel particles have a particle size ranging from about 1 ⁇ m to 15 ⁇ m.
  • the gel particles have a particle size ranging from about 1 ⁇ m to 10 ⁇ m.
  • the water content (mass fraction) of the gel particles is greater than or equal to 60%.
  • the gel particles have a water content of about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69% , about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94% , about 95%, about 96%, about 97%, about 98%, or about 99%.
  • the bismuth-polymer complex can be administered orally or anally.
  • the bismuth-polymer complex can be administered orally.
  • the bismuth-polymer complex can be administered via intestinal cannula.
  • the intestinal cannula may include a small intestinal cannula.
  • the intestinal cannula may include a colorectal cannula.
  • the bismuth-polymer complex can be applied alone, and it can function as a contrast agent, radiation protection, etc. by itself.
  • the reagents for visualization of the digestive tract may include other functional substances.
  • the bismuth-polymer complex can be administered together with other functional substances.
  • the bismuth-polymer complex can be administered separately from other functional substances.
  • the bismuth-polymer complex can be administered sequentially with other functional substances.
  • bismuth-polymer complex is administered for 0.1 hours, 0.2 hours, 0.5 hours, 1 hour, 2 hours, 3 hours hour, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or more before applying other functional substances.
  • the administration route of the bismuth-polymer complex and the administration route of the other functional substances can be the same.
  • the administration route of the bismuth-polymer complex and the administration route of the other functional substances may be different.
  • the bismuth-polymer complex can be encapsulated with other functional substances and administered together.
  • the manner in which the bismuth-polymer complex contains other functional substances may include non-covalent interaction, covalent interaction, complexation, ionic interaction, hydrogen bonding, etc.
  • the functional substance may include a solid preparation or a liquid preparation.
  • the functional substances may include biological substances or chemical substances.
  • the functional substance may include poorly soluble or insoluble particles.
  • the poorly soluble or insoluble particulate matter may include: silicon oxide, metal oxide, metal sulfide, metal nitride, metal salt, or a composite containing at least one of them.
  • the sparingly soluble or insoluble particulate matter has a solubility of less than about 10 mg/mL.
  • the solubility of the poorly soluble or insoluble particles is about 9 mg/mL, 8 mg/mL, 7 mg/mL, 6 mg/mL, 5 mg/mL, 4 mg/mL, 3 mg/mL, 2 mg/mL, 1 mg/mL, 0.5 mg/mL.
  • the particle size of the poorly soluble or insoluble particles is about 0.5 nm to 1 mm.
  • the particle size of the poorly soluble or insoluble particles is about 0.5 nm, about 5 nm, about 10 nm, about 100 nm, about 500 nm, about 1 ⁇ m, about 5 ⁇ m, about 10 ⁇ m, about 20 ⁇ m, about 50 ⁇ m, about 100 ⁇ m, about 200 ⁇ m, About 300 ⁇ m, about 400 ⁇ m, about 500 ⁇ m, about 600 ⁇ m, about 700 ⁇ m, about 800 ⁇ m, about 900 ⁇ m, or about 1 mm.
  • the functional substances may include biologically active substances.
  • the biologically active substance may include drugs, proteins, polypeptides, nucleic acids, carbohydrates, bacteria, fungi, or complexes composed of at least one thereof.
  • the nucleic acid may comprise DNA and/or RNA.
  • the bacteria may include cocci, bacilli, and/or spirillida.
  • the bacteria may comprise autotrophic and/or heterotrophic bacteria.
  • the bacteria may include aerobic bacteria and/or anaerobic bacteria.
  • the bacteria may comprise Gram-negative bacteria and/or Gram-positive bacteria.
  • the carbohydrates may include monosaccharides, disaccharides, and/or polysaccharides.
  • the functional substances may include substances with specific functions, such as contrast agents/imaging agents.
  • the contrast agent may include a high density contrast agent.
  • the contrast agent may include a low density contrast agent.
  • the contrast agent may include an MR contrast agent.
  • the contrast agent may include an X-ray contrast agent, for example, barium sulfate.
  • iodine preparations for example, iodine preparations.
  • the iodine preparation may comprise inorganic iodide, organic iodide, lipiodol or fatty acid iodide.
  • the organic iodide may include ionic organic iodide, nonionic organic iodide, and nonionic dimer organic iodide.
  • iodide Exemplary iodine preparations may include iopromide, iohexol, iodixanol, ioversol, diatrizoate meglumine, sodium diatrizoate, and/or lipiodol.
  • the functional substance may include a radiation attenuating material.
  • the ray attenuating material can block or weaken the intensity of rays.
  • the radiation attenuating material may include metallic substances.
  • the metallic species may include barium, lead, and/or silver.
  • the radiation attenuating material may include a metal salt.
  • the metal salt may contain barium sulfate and/or silver chloride.
  • the atomic sequence of the metal element in the metal substance or metal salt is greater than 50.
  • the functional substance may comprise a radioprotective drug.
  • the radioprotective drug may comprise any radioprotective drug known in the art.
  • the radioprotective drug may include amifostine, acetylcysteine, GSH, GC4419, and/or superoxide dismutase analogs.
  • the reagent for visualization of the digestive tract may also include one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers may include, but are not limited to, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media, antimicrobial substances, isotonic substances, buffers, antioxidants , anesthetics, suspending/dispersing agents, chelating agents, emulsifiers, diluents, adjuvants, excipients, non-toxic auxiliary substances, fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring Agents, thickeners, colorants, emulsifiers, other components known in the art or various combinations of the above.
  • visualization of the digestive tract may include any technique in the art to achieve visualization.
  • the method of visualizing the digestive tract may include X-ray imaging.
  • the method of visualizing the digestive tract may include MR imaging.
  • Exemplary digestive tract visualization modalities include DF, DR, CT, MRI, DSA, PET-CT, PET-MRI, and/or SPECT-CT.
  • the method of visualizing the digestive tract also includes the imaging function in the radiotherapy equipment.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET-CT magnetic resonance imaging
  • PET-MRI magnetic resonance imaging
  • PET-MRI magnetic resonance imaging
  • SPECT-CT positron emission computed tomography
  • visualization of the gastrointestinal tract may include: diagnosis of gastrointestinal diseases, assessment of gastrointestinal diseases, pre-radiotherapy simulation, image-guided radiotherapy, real-time radiotherapy, gastrointestinal imaging required in intraoperative image guidance and/ or radiation protection of the digestive tract.
  • the radiotherapy simulation method may include the use of CT simulators, MR simulators, PET-CT simulators, PET-MRI simulators, and medical linear accelerators with imaging functions, cyberknife, and tomotherapy ), the positioning of the digestive tract performed on the gamma knife (gamma knife), and the imaging simulation of the digestive tract necessary for internal irradiation radiotherapy using afterloading machines or radioactive seed implantation.
  • the radiation protection of the digestive tract may include radiation protection using medical linear accelerators, cyberknife, tomotherapy, gamma knife, after-loading machines, and may also include the use of radiation therapy. Internal radiation therapy using sex particles implanted into the human body.
  • the radiation protection may also include the protection of the intrauterine fetus when pregnant women undergo X-ray imaging (X-ray imaging includes chest X-ray, DF, DR, CT, PET-CT and SPECT-CT).
  • the gastrointestinal disease may include any disease and/or disorder associated with functional and/or structural abnormalities of the digestive tract.
  • the digestive tract disease may include: digestive tract cancer, digestive tract metastatic cancer, digestive tract inflammatory disease, and/or digestive tract injury.
  • the digestive tract diseases may include: oral cancer, esophageal cancer, gastric cancer, small intestine cancer, colorectal cancer, anal cancer, and metastasis cancer of the above cancers.
  • the gastrointestinal diseases may also include metastasis of cancer in other parts of the mouth, esophagus, stomach, small intestine, colorectum, and anus.
  • the gastrointestinal disease may also include inflammatory bowel disease, ulcerative colitis, Crohn's disease, gastritis, enteritis, Helicobacter pylori infection, reflux esophagitis, esophagitis, upper gastrointestinal bleeding, gastric Bleeding, lower gastrointestinal bleeding, oral ulcers, gastric ulcers, duodenal ulcers, lower gastrointestinal ulcers, upper gastrointestinal ulcers, peptic ulcers, gastrointestinal mucosal damage, esophageal polyps, gastric polyps, intestinal polyps, colorectal polyps , duodenal polyps, familial adenomatous polyps, hemorrhoids, gastroptosis, esophageal and gastric mucosal ectopia, esophageal ectopia, intestinal ectopia, intestinal prolapse, intestinal structural abnormalities, digestive tract structural abnormalities, short bowel syndrome syndrome, radiation esophagitis, radiation gastritis, radiation
  • the gastrointestinal disease may also include partial resection of the digestive tract, including esophageal resection, gastrectomy, small bowel resection, colorectal resection, partial resection of the above organs, and fistula after gastrointestinal resection.
  • partial resection of the digestive tract including esophageal resection, gastrectomy, small bowel resection, colorectal resection, partial resection of the above organs, and fistula after gastrointestinal resection.
  • the gastrointestinal diseases may also include digestive tract damage and inflammation of the digestive tract after surgery, or caused by drugs or radiotherapy.
  • the digestive tract diseases may also include various digestive tract complications caused by implants in the digestive tract, digestive tract injury, and digestive tract inflammation.
  • the gastrointestinal diseases may also include bloating, flatulence, diarrhea, constipation, difficulty in defecation, intestinal incontinence, anal incontinence, fecal incontinence, intestinal bacterial overgrowth, bacterial imbalance in the intestinal tract, blood in the stool, abnormal intestinal motility, Nausea, vomiting, decreased appetite, bulimia, acid reflux, duodenogastric reflux.
  • Drug combinations, kits may also include bloating, flatulence, diarrhea, constipation, difficulty in defecation, intestinal incontinence, anal incontinence, fecal incontinence, intestinal bacterial overgrowth, bacterial imbalance in the intestinal tract, blood in the stool, abnormal intestinal motility, Nausea, vomiting, decreased appetite, bulimia, acid reflux, duodenogastric reflux.
  • This application also provides a pharmaceutical combination, which can include the bismuth-polymer complex described in this application and other functional substances.
  • the bismuth-polymer complex in the pharmaceutical combination may contain these functional substances, may be mixed with these functional substances, or may be administered separately from these functional substances.
  • the bismuth-polymer complex can be coated with these functional substances through interaction.
  • the bismuth-polymer complex can be mixed with these functional substances and administered.
  • the bismuth-polymer complex and the functional substance may exist in the same container at the same time.
  • the bismuth-polymer complex and the functional substance can be premixed and then administered together.
  • the bismuth-polymer complex can be administered separately from these functional substances.
  • the bismuth-polymer complex may exist in a different container from the functional substance.
  • the bismuth-polymer complex may be administered first, and then the functional substance may be administered.
  • the functional substance For example, 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes,
  • the functional substance is administered again after 80 minutes, 90 minutes, 2 hours, 3 hours or more.
  • the functional substance can be applied first, and then the bismuth-polymer complex can be applied.
  • the administration of the bismuth-polymer complex does not substantially affect the functions and/or effects of certain functional substances.
  • kits which can contain the bismuth-polymer complex described in this application and other functional substances.
  • the kit may also contain one or more other components.
  • the kit may also include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants, and emulsifiers.
  • instructions may also be included in the kit.
  • the description can provide that the bismuth-polymer complex claimed in this application can be used for visualization of the digestive tract.
  • the instructions may indicate that the bismuth-polymer complex may be co-administered with other ingredients.
  • the instructions may indicate a specific dosage regimen of the bismuth-polymer complex.
  • the dosage regimen may include administration route, administration mode, administration timing and/or administration dosage, etc.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension is Heat in an oil bath and stir (75°C).
  • P1 bismuth hydroxide-pectin complex
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth-polymer composite P5 described in this application that is, the bismuth oxide-polyacrylic acid composite, has the following synthesis steps.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth-polymer complex P6 described in this application that is, the bismuth nitrate-polyacrylic acid complex, has the following synthesis steps.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth-polymer complex P7 described in this application that is, the bismuth subsalicylate-polyacrylic acid complex, has the following synthesis steps.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10.5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the bismuth-polymer complex P8 described in this application that is, the bismuth citrate-polyacrylic acid complex, has the following synthesis steps.
  • Use potassium hydroxide to adjust the pH of the suspension to around pH 10..5.
  • the above suspension was heated in an oil bath and stirred (75°C). After 4 hours of reaction, the reaction solution was centrifuged (500 rpm, 5 minutes) and the bottom solid was removed after centrifugation.
  • the structure in the figure is not limited to potassium salt, but can also be sodium salt and other commonly used cationic salts, or acid form.
  • the polymer comparison ratio selected in this experiment is mainly biosafety polymers that are commonly used orally and have certain intestinal adhesion, including dextran (D1), pectin (D2), gelatin (D3), and chitosan. (D4), carboxymethylcellulose (D5), sodium alginate (D6), hydroxypropylmethylcellulose (D7). Dissolve the above polymer in water to prepare a polymer solution with a mass fraction of 2% for later use.
  • Acidification treatment can be done in vitro, or it can be done after entering the body through interaction with, for example, gastric acid.
  • the final formulation was adjusted by adding water during the experiments with the candidates described above (keeping the slides containing 1 mg in each experiment of dry matter and 50 mg of water).
  • the slides were compressed under a force of 20 N for 30 seconds.
  • a single test should be completed within 1 minute to avoid unwanted evaporation.
  • Adhesion was measured using a microcomputer-controlled electronic universal testing machine. The maximum force to pull apart the adhered slides was recorded as the mucoadhesion force of the candidate substances (P1 to P8, D1 to D9). The greater the pulling force, the better the adhesion effect.
  • mucin from pig stomach, purchased from Sigma-Aldrich Company
  • Mucin solution (10 mg/mL) was brushed onto a cell culture well plate (24-well plate) and dried at room temperature.
  • drop the candidate materials P1 to P8 and other comparative polymer materials D1 to D9, the configuration method of the comparative polymer can be seen in the following specific comparative example, 0.3 mL) into the center of the hole.
  • the well plate was then equipped with a shaker and vortexed at 1500 rpm.
  • the time it takes for a candidate material to spread to the edge of the orifice plate is recorded as a quantitative measure of flowability. The shorter the time it takes to spread to the edge, the better the fluidity of the candidate.
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. On the first day of the experiment, rats were given a single dose of bismuth-polymer complex (P1, 3 mL/100g after acidification), and body weight was recorded for 10 consecutive days. Rats administered PBS were set as control comparisons. Twenty-four hours after bismuth-polymer administration, whole blood samples were obtained for further blood cell counts and blood biochemical tests.
  • rats were given a single dose of bismuth-polymer complex (gavage) and whole blood samples were obtained at different time points. After centrifugation, serum samples were collected for ICP-MS analysis. Twenty-four hours after gavage, selected organs were obtained from the rats for further ICP-MS analysis.
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Two-dimensional X-ray plain scan and three-dimensional X-ray tomography were performed on rats using digital subtraction angiography (DSA) equipment (German, Siemens Healthineers, Artis Q Ceiling). Rats were orally administered barium sulfate (2.5 mL/100g) encapsulated in bismuth-polymer complexes at different time points, and oral administration here can be similar to gastric intubation, and the complex will not contact the esophagus), and then imaged. The same operation was performed on another group of rats using the same dose of barium sulfate suspension as a control group for comparison.
  • DSA digital subtraction angiography
  • DSA imaging parameters are as follows: tube current: 40 ⁇ A (three-dimensional tomography), 58 ⁇ A (two-dimensional plain scan); voltage: 70kV. Total imaging time: 20 seconds. Raw images were processed and reconstructed on Siemens software (syngo.via).
  • the rats were euthanized at appropriate time points, the gastrointestinal tract was dissected, and the length of the gastrointestinal tract covered by barium sulfate coated with bismuth-polymer complex was measured, and Compared with the full length of the gastrointestinal tract of the rat, the ratio of the coverage length of the bismuth-polymer complex to the total length of the gastrointestinal tract was obtained, and the gastrointestinal tract coverage ratio of the bismuth-polymer complex at this gavage dose was determined.
  • Barium sulfate encapsulated in bismuth-polymer complex achieved long-term, large-area gastrointestinal tract imaging in rats.
  • the barium sulfate contained in the bismuth-polymer complex achieved greater than 50% coverage of the gastrointestinal tract in rats and could maintain coverage for approximately 2 hours.
  • the rats that were only given barium sulfate (barium meal) suspension by intragastric administration did not show large-area and long-term coverage of the gastrointestinal tract. Only part of the stomach showed clearer imaging.
  • the specific data results are shown in Table 6.
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Two-dimensional X-ray plain scan and three-dimensional X-ray tomography were performed on rats using digital subtraction angiography (DSA) equipment (German, Siemens Healthineers, Artis Q Ceiling). Rats were orally administered iohexol-encapsulated bismuth-polymer complex (2.5mL/100g) at different time points, and then imaged. The same dose of iohexol was used to compare the other two groups of rats, one group was treated by intragastric administration and the other group was treated by tail vein injection. Prior to imaging, rats were anesthetized using avertin injection.
  • DSA digital subtraction angiography
  • the DSA imaging parameters are as follows: tube current: 40 ⁇ A (three-dimensional tomography), 58 ⁇ A (two-dimensional plain scan); voltage: 70kV. Total imaging time: 20 seconds.
  • Raw images were processed and reconstructed on Siemens software (syngo.via). After reconstruction, based on the information provided by the images, the rats were euthanized at appropriate time points, the gastrointestinal tract was dissected, and the gastrointestinal tract covered by the iohexol-loaded bismuth-polymer complex was measured.
  • the ratio of the gastrointestinal tract coverage length of the iohexol-encapsulated bismuth-polymer complex to the total length of the gastrointestinal tract was obtained, and was determined at this intragastric dose. Gastrointestinal tract coverage ratio of iohexol-loaded bismuth-polymer complex.
  • Iohexol encapsulated in bismuth-polymer complex achieved long-term and large-area gastrointestinal angiography in rats.
  • the bismuth-polymer complex encapsulating iohexol achieved a gastrointestinal tract coverage ratio of greater than 60% in rats, and could maintain coverage for approximately more than 2 hours (shown in Figure 21).
  • rats that were only intragastrically administered with aqueous thiiohexol solution or injected with iohexol did not show large-area, long-term gastrointestinal tract coverage (shown in Figures 22 and 23). Only part of the small intestine showed clearer imaging in the gavage treatment group. No gastrointestinal effects were observed in the intravenous injection group (shown in Figures 22 and 23). The specific data results are shown in Table 7.
  • Table 7 Gastrointestinal tract coverage ratio of iohexol encapsulated by bismuth-polymer complex in rats
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Two-dimensional X-ray plain scan and three-dimensional X-ray tomography were performed on rats using digital subtraction angiography (DSA) equipment (German, Siemens Healthineers, Artis Q Ceiling). Rats were orally administered bismuth-polymer complex-encapsulated barium sulfate (2.5mL/100g, acidified and swallowed through the mouth at different time points. This is an esophageal contact oral administration, which will contact the esophagus and produce esophagography). , and then imaged. Prior to imaging, rats were anesthetized using avertin injection.
  • DSA digital subtraction angiography
  • the DSA imaging parameters are as follows: tube current: 40 ⁇ A (three-dimensional tomography), 58 ⁇ A (two-dimensional plain scan); voltage: 70kV. Total imaging time: 20 seconds.
  • Raw images were processed and reconstructed on Siemens software (syngo.via). When using software for reconstruction, the rib image is cleared to show the effect of esophageal imaging (as shown in Figure 25).
  • Barium sulfate encapsulated in the bismuth-polymer complex achieved large-area intraesophageal imaging in the esophagus of rats (shown in Figure 24).
  • the barium sulfate contained in the bismuth-polymer complex achieved an esophageal coverage ratio of greater than 80% in rats.
  • the specific data results are shown in Table 8.
  • Table 8 Esophageal coverage ratio of barium sulfate encapsulated by bismuth-polymer complex in rats.
  • Example 80 The gastrointestinal imaging effect of barium sulfate encapsulated in the bismuth-polymer complex described in this application under X-ray mode in pigs
  • mice Female Yorkshire white pigs (weight 30-45kg) were adaptively raised for one week. Two-dimensional X-ray plain scan and three-dimensional X-ray tomography imaging of pigs were performed on a computed tomography (CT) device (USA, GE Healthcare, revolution ACT). Briefly, pigs were given oral administration of bismuth-polymer complex-encapsulated barium sulfate or barium sulfate suspension (about 8 mL/kg, acidified and then intubated for intragastric administration), and then imaged at different time points. The same operation was performed on another group of pigs using the same dose of barium sulfate suspension as a control group for comparison.
  • CT computed tomography
  • Barium sulfate encapsulated in bismuth-polymer complex achieved long-term, large-area gastrointestinal angiography in pigs (as shown in Figure 25).
  • the barium sulfate contained in the bismuth-polymer complex achieved greater than 50% coverage of the gastrointestinal tract in pigs and could maintain coverage for approximately 2 hours.
  • pigs that were only given a barium sulfate (barium meal) suspension did not show large-area, long-term coverage of the gastrointestinal tract. Only part of the stomach was partially imaged (shown in Figure 26).
  • Example 81 The bismuth-polymer complex described in this application is used for gastrointestinal imaging in rats under X-ray mode
  • bismuth itself is a high-order element, it also has good X-ray imaging effects.
  • This example is to illustrate that when the bismuth content in the acidified bismuth-polymer composite paste is higher, it also has better gastrointestinal X-ray imaging effects.
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Two-dimensional X-ray plain scan and three-dimensional X-ray tomography were performed on rats using digital subtraction angiography (DSA) equipment (German, Siemens Healthineers, Artis Q Ceiling). Rats were orally administered bismuth-polymer complex (2.5 mL/100g, after acidification) at different time points. The water content during the acidification process was adjusted to increase the mass fraction of bismuth in the final bismuth-polymer complex after acidification. The configuration process is described below), and then imaged. Prior to imaging, rats were anesthetized using avertin injection.
  • DSA digital subtraction angiography
  • the DSA imaging parameters are as follows: tube current: 40 ⁇ A (three-dimensional tomography), 58 ⁇ A (two-dimensional plain scan); voltage: 70kV. Total imaging time: 20 seconds. Raw images were processed and reconstructed on Siemens software (syngo.via).
  • the bismuth-polymer complex (1 g, P2) was added to deionized water (5 mL) to form a suspension. After stirring and shaking the above suspension for 1 hour, add an acid solution (1 mol/L, including but not limited to hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, etc.) to adjust the pH to about 3 to 4.
  • the unacidified bismuth-polymer complex suspension forms a viscous paste-like substance.
  • the bismuth-polymer complex achieved long-term, large-area gastrointestinal tract imaging in rats.
  • the bismuth-polymer complex achieved a gastrointestinal tract coverage ratio of greater than 60% in rats (shown in Figure 27).
  • Example 82 The bismuth-polymer complex described in this application is used for gastrointestinal imaging under MR mode in rats
  • the acidified bismuth-polymer complex paste has a high water content and can be used as a good gastrointestinal contrast agent in MR mode.
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Imaging of rats was performed on an MRI device (German, Siemens Healthineers, Aera). Briefly, after oral administration of bismuth-polymer complex, rats (2.5mL/100g, orally after acidification) for 4 hours for imaging. Use the same dose of mannitol aqueous solution (2.5mg/mL, 2.5mL/100g) to perform the same operation on another group of rats as a control group for comparison. Prior to imaging, rats were anesthetized using avertin injection.
  • MR imaging parameters are as follows, echo time: 5.21s; repetition time: 11s; slice thickness: 1 mm; magnetic field strength: 1.5T; sequence: t1_fl3d_sag_iso; transmitting coil name: TxRx_Knee_15; original images in Siemens software (syngo.MR E11) processed and reconstructed.
  • Example 83 The bismuth-polymer complex described in this application is used for gastrointestinal imaging in rats under X-ray/MR fusion mode
  • mice Female SD rats (weight 200-300g) were adaptively raised for one week. Imaging of rats was performed on an MRI device (German, Siemens Healthineers, Aera). Briefly, rats were imaged after oral administration of bismuth-polymer complex-encapsulated barium sulfate (2.5 mL/100 g, acidified orally) for 4 hours. Use the same dose of mannitol aqueous solution and barium sulfate suspension (2.5mg/mL, 2.5mL/100g) to perform the same operation on the other two groups of rats as the control group for comparison. Prior to imaging, rats were anesthetized using avertin injection.
  • MR imaging parameters are as follows, echo time: 5.21s; repetition time: 11s; slice thickness: 1 mm; magnetic field strength: 1.5T; sequence: t1_fl3d_sag_iso; transmitting coil name: TxRx_Knee_15; DSA imaging parameters are: tube current: 40 ⁇ A (Three-dimensional tomography), voltage: 70kV. Total imaging time: 20 seconds.
  • Raw images were processed and reconstructed on software (syngo.MR E11). The obtained DSA and MR imaging raw data were fused on the software (syngo.via).
  • Barium sulfate encapsulated in bismuth-polymer complex achieved long-term, large-area MR/X-ray gastrointestinal fusion angiography in rats (shown in Figure 30).
  • rats that were only administered barium sulfate (barium meal) suspension or mannitol aqueous solution did not show large-area, long-term gastrointestinal tract fusion images (shown in Figures 31-32).
  • Example 84 The bismuth-polymer complex described in this application is used to alleviate radiotoxicity in the whole abdominal irradiation model of rats after encapsulating barium sulfate.
  • Group 1 was treated with PBS without any irradiation and served as a blank control group.
  • Group 2 received PBS orally and received 8Gy X-ray irradiation.
  • Group 3 received bismuth-polymer complex orally and received 8Gy X-ray irradiation.
  • Group 4 received oral administration of bismuth-polymer complex coated with barium sulfate and received 8Gy X-ray irradiation.
  • Rats that were orally administered a bismuth-polymer complex coated with barium sulfate showed lower damage and faster recovery after irradiation.
  • Rats protected by barium sulfate-coated bismuth-polymer complexes showed faster weight gain (shown in Figure 33), lower diarrhea (shown in Figure 34), and faster appetite recovery (shown in Figure 34). Shown in Figure 35), lower intestinal damage (shown in Figure 36). Better protection was also demonstrated in intestinal sections (shown in Figure 37).
  • Group 1 received oral dexamethasone alone.
  • Group 2 received dexamethasone-loaded bismuth-polymer complex orally. Rats were euthanized with carbon dioxide at various time points after oral administration. The intestine was isolated and analyzed for dexamethasone drug concentration within the intestinal tissue.
  • Rats that were orally administered the bismuth-polymer complex coated with dexamethasone showed higher intestinal drug concentration and longer sustained release time. Increased local drug concentration in the intestine.
  • the specific data are shown in Table 9 and Table 10.

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Abstract

本申请涉及铋-高分子复合物在制备试剂中的用途，所述试剂用于消化道可视化。本申请还提供了一种实现消化道可视化的方法，其包括向有需要的受试者施用所述铋-高分子复合物。

Description

铋-高分子复合物在消化道可视化中的用途 技术领域
本申请涉及生物医药领域，具体的涉及一种铋-高分子复合物在制备用于消化道可视化的试剂中的用途。
背景技术
造影技术是目前临床中常用的辅助诊断和/或治疗的方法，现有的胃肠道X线、CT以及MR的造影均需要患者口服或者灌肠造影剂来进行，常用的造影剂包括例如，硫酸钡、碘制剂等，能够一定程度上增强影像观察效果，但目前的造影剂存在以下缺陷及不足：1.对于大面积的消化道进行造影时(例如小肠造影，结肠造影)，需对患者施用大量的造影剂，这造成了患者极大的身体的不适；2.目前的造影剂不具备消化道内的良好的黏附性，消化道内附着效果差，需要医生对消化道进行相应的按压或者变换患者体位来进行相应的病灶的发现。造成了造影过程的繁琐与潜在的漏诊。3.目前的造影剂主要用于肠道疾病的诊断，而不适用于其他需要消化道造影的医用场合，例如放疗模拟过程中的肠道勾画。同时，在腹盆腔肿瘤放疗的过程中，仍然缺乏有效的消化道辐射保护的方法，造成放疗中经常发生消化道的放射毒性。
因此，亟需开发可在消化道内黏附的剂型，从患者体验、造影效果、应用场景等方面改善目前造影剂中存在的缺陷。
发明内容
本申请提供了一种铋-高分子复合物在制备用于消化道可视化的试剂中的用途。所述铋-高分子复合物具有广泛包裹性，在接触酸后，会发生聚集，并形成具备消化道黏附能力和较高流动能力的由微小凝胶颗粒组成的膏状物质，可在消化道内大面积铺开并黏附附着。如果接触酸之前混合铋-高分子复合物与造影剂等功能物质，在接触酸后发生聚集的铋-高分子复合物可以把上述功能物质包裹在其形成的凝胶颗粒中，负载所述功能物质在消化道内大面积铺开附着，实现更优效的消化道可视化。
所述铋-高分子复合物本身，或者包裹了造影剂的铋-高分子凝胶颗粒可以在动物消化道内大面积覆盖长时间停留，从而形成清晰并长时间停留的消化道影像。然而，同样体积的现有技术中的造影剂并不能具有相同的效果。
同时，包裹了辐射遮挡材料的铋-高分子凝胶颗粒，可以在动物消化道内大面积覆盖长时间停留，形成一个可以遮挡辐射的消化道内屏障，减少辐射造成的消化道损伤。
一方面，本申请提供了铋-高分子复合物在制备用于消化道可视化的试剂中的用途。
另一方面，本申请提供了铋-高分子复合物在制备功能物质消化道递送载体中的用途。
在某些实施方式中，所述铋-高分子复合物为铋化物与高分子之间通过相互作用复合而成。
在某些实施方式中，所述铋-高分子复合物为铋化物与高分子之间通过络合键、共价键和/或非共价的相互作用复合而成。
在某些实施方式中，所述铋化物选自下组中的一种或多种：氢氧化铋，氧化铋，碳酸铋，碱式碳酸铋，硝酸铋，没食子酸铋，铝酸铋，次水杨酸铋，碱式水杨酸铋，水杨酸铋，醋酸铋，草酸铋，柠檬酸铋，氯化铋和硫化铋。
在某些实施方式中，所述高分子中存在至少一个游离羧酸或游离羧酸盐。
在某些实施方式中，所述高分子选自下组中的一种或多种：果胶，低甲氧基果胶，聚丙烯酸，海藻酸，透明酯酸。
在某些实施方式中，所述铋-高分子复合物经过TOF-SIMS测试，具有以下碎片峰：BiO3-。
在某些实施方式中，所述BiO3-的碎片峰的出峰范围在约m/z＝256.5～257.5之间。
在某些实施方式中，所述铋-高分子复合物的结构如式Ⅰ所示：
其中，x为大于等于1的数字，
y,z,m,n分别独立地为大于等于0的数字，
当y不等于0时，x：y＝1：(0.000001～99)，
当z不等于0时，x：y＝1：(0.000001～99)；
其中，R1，R2分别独立地选自以下任一(p为大于等于0的数字)：
其中，R’选自以下任一结构：
其中，R3选自以下任一结构：
R4，R5分别独立地选自以下任一结构(p为大于等于0的数字)：
R6，R7分别独立地选自以下任一结构(R为任意基团)：
或R6，R7组合为以下任一结构：
在某些实施方式中，对所述铋-高分子复合物使用红外光谱测试，在1550～1700cm-1处显示特征峰。
在某些实施方式中，所述铋-高分子复合物中铋元素的质量含量在0.5％～70％之间。
在某些实施方式中，所述铋-高分子复合物包含氢氧化铋-果胶复合物、氢氧化铋-聚丙烯酸复合物、氢氧化铋-海藻酸复合物、氢氧化铋-透明质酸复合物、氧化铋-聚丙烯酸复合物、硝酸铋-聚丙烯酸复合物、次水杨酸铋-聚丙烯酸复合物和/或枸橼酸铋-聚丙烯酸复合物。
在某些实施方式中，所述铋-高分子复合物经酸化处理。
在某些实施方式中，所述酸化处理包括使用酸性物质与所述铋-高分子复合物混合。
在某些实施方式中，所述酸性物质为固体或液体。
在某些实施方式中，所述酸性物质选自下组中的一种或多种：盐酸、磷酸、草酸、乳酸、柠檬酸、丁二酸、甲磺酸、酒石酸、苯甲酸、苹果酸、对甲苯磺酸、丙酸、富马酸、果酸、水杨酸、甲酸和醋酸。
在某些实施方式中，所述铋-高分子复合物经酸化后，pH值为约0.1～4.5。
在某些实施方式中，所述铋-高分子复合物经酸化后的微观形态为凝胶颗粒。
在某些实施方式中，所述凝胶颗粒的粒径范围为约50nm～1000μm。
在某些实施方式中，所述凝胶颗粒的水含量(质量分数)大于或等于60％。
在某些实施方式中，所述铋-高分子复合物的施用方式为经口腔或经肛门施用。
在某些实施方式中，所述铋-高分子复合物的施用方式为肠道插管。
在某些实施方式中，所述用于消化道可视化的试剂还包括其他功能物质。
在某些实施方式中，所述功能物质包括难溶或不溶颗粒。
在某些实施方式中，所述功能物质包括生物活性物质。
在某些实施方式中，所述功能物质包括造影剂。
在某些实施方式中，所述造影剂包括X射线造影剂和/或MR造影剂。
在某些实施方式中，所述X射线造影剂选自：硫酸钡，碘普罗胺，碘海醇，碘克沙醇，碘佛醇，泛影葡胺，泛影酸钠和碘化油。
在某些实施方式中，所述MR造影剂选自：水，以及钆螯合物。
在某些实施方式中，所述生物活性物质包括药物、蛋白、多肽、核酸、糖类、细菌、真菌或由至少其中一种组成的复合物。
在某些实施方式中，所述核酸包括DNA和/或RNA。
在某些实施方式中，所述难溶或不溶颗粒物包括：硅氧化物、金属氧化物、金属硫化物、金属氮化物、金属盐，或包含其中一种组成的复合物。
在某些实施方式中，所述难溶或不溶颗粒物的溶解度小于约10mg/mL。
在某些实施方式中，所述难溶或不溶颗粒物的粒径为约0.5nm～1mm。
在某些实施方式中，所述功能物质包括射线衰减材料。
在某些实施方式中，所述射线衰减材料包括金属物质。
在某些实施方式中，所述金属物质包括钡、铅和/或银。
在某些实施方式中，所述射线衰减材料包括金属盐。
在某些实施方式中，所述金属盐包括硫酸钡和/或氯化银。
在某些实施方式中，所述金属物质或金属盐中金属元素的原子序数大于50。
在某些实施方式中，所述功能物质包括辐射保护药物。
在某些实施方式中，所述辐射保护药物包括：氨磷汀、乙酰半胱氨酸、GSH、GC4419和/或超氧歧化酶类似物。
在某些实施方式中，所述消化道可视化的方式包括X射线成像。
在某些实施方式中，所述消化道可视化的方式包括MR成像。
在某些实施方式中，所述消化道可视化的方式包括：DF、DR、CT、MRI、DSA、PET-CT、PET-MRI和/或SPECT-CT。
在某些实施方式中，所述消化道可视化的方式包括放疗设备中的CT、MRI、PET-CT、PET-MRI和/或SPECT-CT功能。
在某些实施方式中，所述用途包括消化道疾病的诊断、消化道疾病的评估、放疗前模拟、 图像引导的放疗、实时放疗、术中影像引导中所需的消化道影像和/或消化道的辐射保护。
在某些实施方式中，所述消化道疾病包括：消化道癌症、消化道转移癌、消化道炎性疾病和/或消化道损伤。
在某些实施方式中，所述消化道包括食管、胃肠道和/或肛门。
在某些实施方式中，所述铋-高分子复合物包载所述其他功能物质。
在某些实施方式中，所述包载包括选自下组的作用方式：非共价作用，共价作用，络合作用，离子作用和氢键作用。
在某些实施方式中，所述用于消化道可视化的试剂还包括药学上可接受的载剂。
另一方面，本申请还提供了一种实现消化道可视化的方法，其包括施用本申请所述的铋-高分子复合物。
另一方面，本申请还提供了一种放疗模拟的方法，其包括施用本申请所述的铋-高分子复合物。
另一方面，本申请还提供了一种诊断消化道疾病的方法，其包括施用本申请所述的铋-高分子复合物。
另一方面，本申请还提供了一种胃肠道辐射保护的方法，其包括施用本申请所述的铋-高分子复合物。
另一方面，本申请还提供了一种药物组合，其包括本申请所述的铋-高分子复合物，以及本申请所述的功能物质。
另一方面，本申请还提供了一种试剂盒，其包括本申请所述的铋-高分子复合物，以及本申请所述的功能物质。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示的是P1的结构。
图2显示的是P2的结构。
图3显示的是P3的结构。
图4显示的是P4的结构。
图5显示的是P5的结构。
图6显示的是P6的结构。
图7显示的是P7的结构。
图8显示的是P8的结构。
图9显示的是铋-高分子复合物酸化前后的表现(以P2盐酸酸化为例)。
图10显示的是铋-高分子复合物酸化前后的表现(以P1盐酸酸化为例)。
图11显示的是铋-高分子复合物酸化后在TOF-SIMS表征中的特征峰(以P1为例)。
图12显示的是铋-高分子复合物胃肠道粘附效果体外评价的实验装置示意图。
图13显示的是大鼠口服酸化后的铋-高分子复合物24小时后的血细胞分析。
图14显示的是大鼠口服酸化后的铋-高分子复合物24小时后的肝功能生化分析。
图15显示的是大鼠口服酸化后的铋-高分子复合物24小时后的肾功能生化分析。
图16显示的是大鼠口服酸化后的铋-高分子复合物后的血浆与组织中铋含量。
图17显示的是铋-高分子复合物包裹硫酸钡的过程与表现示意图。
图18显示的是投射电镜下观察到的铋-高分子复合物包裹的硫酸钡颗粒。
图19显示的是大鼠口服铋-高分子复合物包裹的硫酸钡后的胃肠道造影效果。
图20显示的是大鼠口服硫酸钡后的胃肠道造影效果。
图21显示的是大鼠口服铋-高分子复合物包载的碘海醇后的胃肠道造影效果。
图22显示的是大鼠尾静脉注射碘海醇后的胃肠道造影效果。
图23显示的是大鼠口服碘海醇后的胃肠道造影效果。
图24显示的是大鼠口服酸化后包载了硫酸钡的铋-高分子复合物后的食管X线造影效果。
图25显示的是猪口服铋-高分子复合物包载的硫酸钡后的胃肠道造影效果。
图26显示的是猪口服硫酸钡后的胃肠道造影效果。
图27显示的是大鼠口服铋-高分子复合物后的胃肠道造影效果。
图28显示的是大鼠口服酸化后铋-高分子复合物后的胃肠道MR造影效果。
图29显示的是大鼠口服甘露醇水溶液后的胃肠道MR造影效果。
图30显示的是大鼠口服铋-高分子复合物包裹的硫酸钡后的胃肠道X线/MR融合造影。
图31显示的是大鼠口服甘露醇水溶液后的胃肠道X线/MR融合造影。
图32显示的是大鼠口服硫酸钡后的胃肠道X线/MR融合造影。
图33显示的是大鼠辐照后的体重变化。
图34显示的是大鼠辐照后的腹泻情况。
图35显示的是大鼠辐照后的摄食量变化。
图36显示的是大鼠辐照后的肠道通透性结果。
图37显示的是大鼠辐照后的肠道切片结果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“复合物”通常指两种或多种化合物或结构之间通过相互作用所形成的结构。例如，这些相互作用可通过化学相互作用，例如共价键、离子键或次级键(如氢键)等，或通过物理相互作用，例如包裹、截留等。在本申请中，术语“铋-高分子复合物”通常指含有铋的一类高分子复合物。例如，所述铋-高分子复合物可以由铋化物和高分子化合物复合而成。
在本申请中，术语“高分子”通常是指分子量为大于2000道尔顿、大于3000道尔顿、大于4000道尔顿、大于5000道尔顿、大于6000道尔顿、大于7000道尔顿、大于8000道尔顿、大于9000道尔顿、大于10000道尔顿、大于12000道尔顿、大于15000道尔顿或大于20000道尔顿的任何化合物。
在本申请中，术语“消化道”通常包括从口腔至肛门的管道的任意部位。例如，所述消化道可包括上消化道和下消化道。例如，所述消化道可包括口腔、咽、食道、胃、肠和肛门。
在本申请中，术语“消化道可视化”通常包括消化道功能和/或消化道结构的可视化。可视化的方式可以包括任何本领域内已知的方法。例如，包括消化道造影，例如，消化道辐射保护。本申请所述的消化道可视化可用来提供例如如下指标的评估：消化道的吸收能力；消化道吸收营养素的能力；消化道的渗透性；消化道水解化合物的能力；消化道和/或小肠的表面积；消化道和/或小肠的功能表面积；消化道的屏障功能；消化道的损伤；消化道中粘膜损伤的程度；绒毛、alia、小肠的损伤；小肠的刷状缘的绒毛高度；与如在此所述的消化道功能的变化相关的任何疾病或病理的存在；炎性病症的存在；感染的存在；对治疗的反应，以校正任何或所有以上病变；以及对本领域技术人员是明显的消化道功能或消化道结构完整性的 任何其他方面。
在本申请中，术语“酸化处理”通常指将铋-高分子复合物与酸性物质进行接触。术语“酸性物质”通常指能够提供氢质子或者能够接受一个电子对的物质。例如，所述酸性物质可包括有机酸和无机酸。例如，所述酸性物质可包括一元酸、二元酸、三元酸或多元酸。例如，所述酸性物质可包括强酸和弱酸。在本申请中，所述酸性物质可包括外源性的，如常见的酸性化合物等，也可包括内源性的，如人或动物体内的胃酸等。在本申请中，所述酸化处理可以在体外进行，也可以在体内进行。
在本申请中，术语“生物活性物质”通常是指无机或有机分子，包含小分子、肽类(如穿透细胞的肽类)、蛋白质、碳水化合物(包括单糖、寡糖和多糖)、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白质；或与蛋白质连接的小分子，糖蛋白、甾醇、核酸(DNA的任何形式，包括cDNA或RNA或其片段)、核苷酸、核苷、寡核苷酸(包括反义寡核苷酸类、LNA和siRNA)、基因、脂质、激素或其组合的无机或有机分子。
在本申请中，术语“多肽”通常指氨基酸残基的聚合物。这个术语可用于指一个或多个氨基酸残基是其相应的天然氨基酸的人工合成化学模拟物的氨基酸聚合物，也可用于指天然的氨基酸聚合物，那些含修饰残基的氨基酸聚合物以及非天然的氨基酸聚合物。
在本申请中，术语“糖类”通常是指一类多羟基醛、多羟基酮及其缩聚物和某些衍生物的有机化合物的总称。糖类也称碳水化合物，分子通式为Cx(H2O)y，并且可以包含不同量的糖单位，例如单糖、二糖、多糖、复合糖。
在本申请中，术语“药物”通常是指具有所需生物学效力的分子。例如，药物可以是预防性或治疗性的，例如，药物是可以用于诊断的，例如，药物是可以用于某些具体目的的保护作用。药物可以包括不限于：蛋白分子，包括但不限于肽，多肽，蛋白质，包括翻译后修饰的蛋白质、融合蛋白、抗体等；小分子(小于1000道尔顿)，包括无机或有机化合物；核酸分子，包括但不限于双链或单链DNA、或双链或单链RNA(如反义(分子)、RNAi等)、内含子序列、三螺旋核酸分子和适体；或疫苗。药物可获自任何已知的生物(包括但不限于：动物、植物、细菌、真菌和原生动物或病毒)或合成分子库。
在本申请中，术语“造影剂”可以与“显像剂”互换使用。造影剂允许检测、造影和/或监测病状、病理病症和/或疾病的存在和/或进展。造影剂通常可投与个体以提供关于个体(例如人类)的至少一部分的信息。在一些情况下，造影剂可用以突出个体的特定区域，使得器官、血管、组织和/或其它部分更可检测且更清晰地造影。通过提高所研究区域的可检测性和/或图像品质，可测定疾病和/或损伤的存在和程度
在本申请中，术语“放疗模拟”通常指在放疗前、放疗中和/或放疗后对目标部位的可视化。可以使用任何本领域已知的模拟机以及具有成像功能的仪器进行消化道的定位。通过放疗模拟，可以使得本领域技术人员能够确定目标部位的信息，例如，位置、功能、结构等状况。
在本申请中，术语“非共价相互作用”可以和“非共价作用互换使用”，通常指非共价结合力如离子相互作用力(例如盐桥)，非离子相互作用力(例如，氢键)，或疏水相互作用力(例如，范德华力或π-堆积相互作用)。
在本申请中，术语“约”以意指大约(approximately)、在......的附近(in the region of)、粗略地(roughly)、或左右(around)。当术语“约”与一个数值范围结合使用时，它通过扩展列举的数值的上限和下限将该范围加以修饰。通常，在此使用术语“约”以将一个数值以高于和低于该规定值的10％，例如1％，2％，3％，4％，5％，6％，7％，8％，9％或10％的变化加以修饰。
在本申请中，除非另有注明，术语“包含”、“具有”、“包括”以及“含有”都应理解为开放性术语(即，意思是”包括，但不限于”)。
在本申请中，术语“一(a)”和“一个(an)”和“所述(the)”和“至少一种”以及相似指示词的使用应理解为包括单数和复数。除非在本文中另有说明或者与上下文明显矛盾，当使用的术语”至少一种”后接一项或多项列举项(例如，“至少一种A和B”)时，应理解为表示选自所列项的一项(A或B)或者所列项中两项或多项的任意组合(A和B)。
在本申请中，术语“络合作用”通常指电子对给予体与电子接受体，互相作用而形成各种络合物的过程。给予体有原子或离子，不论构成单质或化合物，凡能提供电子对的物质，接受体有金属离子和有机化合物。分子或者离子与金属离子结合，形成很稳定的新的离子的过程就叫络合反应，也称配位反应。
在本申请中，术语“静电相互作用”通常是指两个以上带正电或带负电的部分/基团间的分子间相互作用，当两者所带电荷相反(即，一个为正电、另一个为负电)时，可相互吸引；当两者电荷符号相同(即，两个均为正电或两个均为负电)时，则可相互排斥；或者，该相互作用可为上述作用的组合。
在本申请中，术语“氢键”是分子间作用力的一种，是一种永久偶极之间的作用力。氢键发生在已经以共价键与其它原子键结合的氢原子与另一个原子之间(X-H…Y)，通常发生氢键作用的氢原子两边的原子(X、Y)都是电负性较强的原子。氢键既可以是分子间氢键，也可以是分子内氢键。
在本申请中，术语“范德华力”通常指分子或原子之间非定向的、无饱和性的、较弱的相互作用力。范德华力通常可以包括取向力、诱导力、分散力。
在本申请中，术语“药物组合”通常是指由多于一种成分的混合或组合产生的产品，并且包括活性成分的固定和非固定组合。术语“固定组合”是指例如铋-高分子复合物和一种或多种组合搭档均以单一实体或剂量的形式同时施用于受试者。术语“非固定组合”是指例如铋-高分子复合物和一种或多种组合搭档作为分开的实体同时、共同或依次地(没有特定时间限制)施用于受试者。
在本申请中，术语“试剂盒”通常是指包括至少一种试剂的任何制品(例如包装或容器)。例如，在本申请中，所述试剂盒可以包含铋-高分子复合物。例如，在本申请中，所述试剂盒可以包含两种或多种组分，例如，铋-高分子复合物，以及其他功能物质，所述组分可或可不包装在一起。试剂盒的组分可包含在分开的小瓶中(即具有分开部分的试剂盒)，或在单个小瓶内提供。另外，试剂盒还可以包含实施所述方法的说明书。说明书可通过纸或电子形式的用户手册提供。例如，手册可包含用于解释当使用本申请的试剂盒实施上述方法时得到的结果的说明。
在本申请中，术语“受试者”可以是人或非人哺乳动物。非人哺乳动物可以包括任何除人之外的哺乳动物物种，例如家畜动物(例如，牛、猪、羊、鸡、兔或马)，或啮齿类动物(例如，大鼠和小鼠)，或灵长类动物(例如，大猩猩和猴子)，或家养动物(例如，狗和猫)。“受试者”可以是雄性或者雌性，也可以是不同年龄阶段。
发明详述
一方面，本申请提供了铋-高分子复合物在制备用于消化道可视化的试剂中的用途。
另一方面，本申请还提供了铋-高分子复合物在制备功能物质消化道递送载体中的用途。
另一方面，本申请还提供了一种实现消化道可视化的方法，其包括施用铋-高分子复合物。
另一方面，本申请还提供了一种放疗模拟的方法，其包括施用铋-高分子复合物。
另一方面，本申请还提供了一种诊断消化道疾病的方法，其包括施用铋-高分子复合物。
另一方面，本申请还提供了一种胃肠道辐射保护的方法，其包括施用铋-高分子复合物。
另一方面，本申请还提供了一种药物组合，其包括铋-高分子复合物以及其他功能物质。
另一方面，本申请提供了一种试剂盒，其包括铋-高分子复合物以及其他功能物质。
铋-高分子复合物
在本申请中，所述铋-高分子复合物可以包含具有铋元素的高分子复合物。例如，所述铋-高分子复合物可以通过铋化物与高分子之间通过相互作用复合而成。
在本申请中，所述铋化物可以包含但不限于选自下组中的一种或多种：氢氧化铋，氧化铋，碳酸铋，碱式碳酸铋，硝酸铋，没食子酸铋，铝酸铋，次水杨酸铋，碱式水杨酸铋，水杨酸铋，醋酸铋，草酸铋，柠檬酸铋，氯化铋和硫化铋。
在本申请中，所述高分子中可存在至少一个游离羧基或游离羧酸盐。
在本申请中，所述高分子可包含但不限于选自下组中的一种或多种：果胶，低甲氧基果胶，聚丙烯酸，海藻酸，透明质酸，卡波姆，聚卡波非。
在本申请中，所述高分子也包括在本申请所列举的具体高分子的基础上所做出的简单改性。例如，所述简单改性可以包含共聚，即通过所述高分子的单体与其他单体进行共聚得到的与所述高分子类似的共聚高分子。例如，所述简单改性可以包含枝接，即通过在这些高分子的可反应基团上通过反应进行额外的小分子或高分子的修饰。
在本申请中，所述高分子也可包含在本申请所列举的具体高分子的基础上所做出的简单的基团替换，替换后获得的新的高分子仍然能够维持与原高分子相同或相似的性质。
例如，所述高分子也可包含其衍生物和/或类似物。
例如，所述高分子也可包含在本申请所列举的具体高分子的基础上进行酯化或部分酯化得到的酯化物。
例如，所述高分子也可包含在本申请所列举的具体高分子的基础上进行酰胺化得到的酰胺化物。
例如，所述高分子也可包含在本申请所列举的具体高分子的基础上进行简单共聚得到的共聚物。
例如，也可以对所述高分子进行碱化，生成配金属离子的盐。
在本申请中，所述铋-高分子复合物经过飞行时间二次离子质谱仪(time of flight-secondary ion mass spectroscopy，TOF-SIMS)测试，可具有以下碎片峰：BiO3-(具体出峰范围在m/z256.5～257.5之间，例如，约m/z＝256.5、约m/z＝256.6、约m/z＝256.7、约m/z＝256.8、约m/z＝256.9、约m/z＝257、约m/z＝257.1、约m/z＝257.2、约m/z＝257.3、约m/z＝257.4、约m/z＝257.5)。
在本申请中，所述铋-高分子复合物使用红外光谱测试，在约1550～1700cm-1处可显示特征峰。
在本申请中，所述铋-高分子复合物可具有式Ⅰ所示的结构：
其中，x可以为大于等于1的数字，例如，x可以为
其中，y,z,m,n分别独立地为大于等于0的数字，例如，y可以为
当y不等于0时，x：y＝1：(0.000001～99)，例如，
当z不等于0时，x：y＝1：(0.000001～99)，例如，
其中，R1可以选自以下任一结构(p为大于等于0的数字)：
其中，R2可以选自以下任一结构(p为大于等于0的数字)：
其中，R’选自以下任一结构：
其中，R3可以选自以下任一结构：
其中，R4可选自以下任一结构(p为大于等于0的数字)：
其中，R5可选自以下任一结构(p为大于等于0的数字)：
其中，R6可以选自以下任一结构(R为任意基团)：
其中，R7可以选自以下任一结构(R为任意基团)：
或R6，R7组合为以下任一结构：
在本申请中，所述铋-高分子复合物中铋元素的质量含量可以在约0.5％～70％之间。例如，所述铋-高分子复合物中铋元素的质量含量为约0.5％、约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约11％、约12％、约13％、约14％、约15％、约16％、约17％、约18％、约19％、约20％、约21％、约22％、约23％、约24％、约25％、约26％、约27％、约28％、约29％、约30％、约31％、约32％、约33％、约34％、约35％、约36％、约37％、约38％、约39％、约40％、约41％、约42％、约43％、约44％、约45％、约46％、约47％、约48％、约49％、约50％、约51％、约52％、约53％、约54％、约55％、约56％、约57％、约58％、约59％、约60％、约61％、约62％、约63％、约64％、约65％、约66％、约67％、约68％、约69％、约70％。
在本申请中，所述铋-高分子复合物可包含选自下组中的一种或多种：氢氧化铋-果胶复合物、氢氧化铋-聚丙烯酸复合物、氢氧化铋-海藻酸复合物、氢氧化铋-透明质酸复合物、氧化铋-聚丙烯酸复合物、硝酸铋-聚丙烯酸复合物、次水杨酸铋-聚丙烯酸复合物和/或枸橼酸铋-聚丙烯酸复合物。
例如，所述氢氧化铋-果胶复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述氢氧化铋-聚丙烯酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述氢氧化铋-海藻酸复合物可具有所示的结构，其中x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述氢氧化铋-透明质酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述氧化铋-聚丙烯酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述硝酸铋-聚丙烯酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述次水杨酸铋-聚丙烯酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
例如，所述枸橼酸铋-聚丙烯酸复合物可具有所示的结构，其中，x为大于0的数，y为大于等于0的数。所述结构可不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
酸化处理及酸化后的形态
在本申请中，所述铋-高分子复合物需要经过酸化处理后发挥作用。
在本申请中，所述酸化处理可以包含体外酸化处理。例如，所述酸化处理可以包含使用酸性物质与所述铋-高分子复合物接触。例如，使酸性物质与所述铋-高分子复合物混合。
例如，所述酸性物质可以为固体酸性物质。例如，所述酸性物质可以为液体酸性物质。
例如，所述酸性物质可以为强酸。例如，所述酸性物质可以为弱酸。
在本申请中，所述酸性物质可选自下组中的一种或多种：盐酸、磷酸、草酸、乳酸、柠檬酸、丁二酸、甲磺酸、酒石酸、苯甲酸、苹果酸、对甲苯磺酸、丙酸、富马酸、果酸、水杨酸、甲酸和醋酸。
以氢氧化铋-果胶复合物为例，氢氧化铋中的铋通过络合作用与果胶中的羧酸连接，在酸化后(例如，与盐酸混合)，氢氧化铋-果胶复合物中的氢氧根会离去，暴露的铋会与果胶中的其他羧基发生作用，产生交联、聚集等现象，形成凝胶。
在本申请中，所述酸化可以在进入体内后发生。例如，直接向受试者施用本申请所述的铋-高分子复合物，所述铋-高分子复合物在进入体内后，可以与体内的酸性物质(例如胃酸)进行反应。
在本申请中，所述铋-高分子复合物经酸化处理后，pH值可以为约0.1～4.5。例如，pH为 约0.1、约0.5、约1.0、约1.5、约2.0、约2.5、约3.0、约3.5、约4.0或约4.5。
在本申请中，所述铋-高分子复合物经酸化后，其微观形态可以为凝胶颗粒。
例如，所述凝胶颗粒的粒径范围为约50nm～1000μm。例如，所述凝胶颗粒的粒径范围为约50nm～900μm。例如，所述凝胶颗粒的粒径范围为约50nm～800μm。例如，所述凝胶颗粒的粒径范围为约50nm～700μm。例如，所述凝胶颗粒的粒径范围为约50nm～600μm。例如，所述凝胶颗粒的粒径范围为约50nm～500μm。例如，所述凝胶颗粒的粒径范围为约50nm～400μm。例如，所述凝胶颗粒的粒径范围为约50nm～300μm。例如，所述凝胶颗粒的粒径范围为约50nm～200μm。例如，所述凝胶颗粒的粒径范围为约50nm～100μm。例如，所述凝胶颗粒的粒径范围为约50nm～50μm。例如，所述凝胶颗粒的粒径范围为约50nm～40μm。例如，所述凝胶颗粒的粒径范围为约50nm～30μm。例如，所述凝胶颗粒的粒径范围为约50nm～20μm。例如，所述凝胶颗粒的粒径范围为约100nm～20μm。例如，所述凝胶颗粒的粒径范围为约500nm～20μm。例如，所述凝胶颗粒的粒径范围为约800nm～20μm。例如，所述凝胶颗粒的粒径范围为约1μm～20μm。例如，所述凝胶颗粒的粒径范围为约1μm～15μm。例如，所述凝胶颗粒的粒径范围为约1μm～10μm。
在本申请中，所述凝胶颗粒的水含量(质量分数)大于等于60％。例如，所述凝胶颗粒的水含量为约60％、约61％、约62％、约63％、约64％、约65％、约66％、约67％、约68％、约69％、约70％、约71％、约72％、约73％、约74％、约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％。
用法
在本申请中，所述铋-高分子复合物可以经口腔或经肛门施用。例如，所述铋-高分子复合物可以通过口服施用。例如，所述铋-高分子复合物可以通过肠道插管施用。例如，所述肠道插管可以包括小肠插管。例如，所述肠道插管可以包括结直肠插管。
在本申请中，所述铋-高分子复合物可以单独施用，其本身就能够起到造影剂、辐射保护等作用。
在本申请中，所述用于消化道可视化的试剂可包含其他功能物质。
在本申请中，所述铋-高分子复合物可配合其他功能物质一起施用。在本申请中，所述铋-高分子复合物可与其他功能物质分开施用。例如，所述铋-高分子复合物可与其他功能物质先后施用。例如，施用铋-高分子复合物0.1小时、0.2小时、0.5小时、1小时、2小时、3小 时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时或更久后，再施用其他功能物质。例如，所述铋-高分子复合物的施用途径和所述其他功能物质的施用途径可以相同。例如，所述铋-高分子复合物的施用途径和所述其他功能物质的施用途径可以不同。
在本申请中，所述铋-高分子复合物可以包载其他功能物质一起施用。
在本申请中，所述铋-高分子复合物包载其他功能物质的方式可以包括通过非共价作用、共价作用、络合作用、离子作用、氢键作用等。
在本申请中，所述功能物质可以包括固体制剂或液体制剂。
在本申请中，所述功能物质可以包括生物物质，也可以包括化学物质。
例如，所述功能物质可以包括难溶或不溶颗粒。例如，所述难溶或不溶颗粒物可以包括：硅氧化物、金属氧化物、金属硫化物、金属氮化物、金属盐，或包含其中至少一种组成的复合物。
例如，所述难溶或不溶颗粒物的溶解度小于约10mg/mL。例如，所述难溶或不溶颗粒物的溶解度为约9mg/mL、8mg/mL、7mg/mL、6mg/mL、5mg/mL、4mg/mL、3mg/mL、2mg/mL、1mg/mL、0.5mg/mL。
例如，所述难溶或不溶颗粒物的粒径为约0.5nm～1mm。例如，所述难溶或不溶颗粒物的粒径为约0.5nm、约5nm、约10nm、约100nm、约500nm、约1μm、约5μm、约10μm、约20μm、约50μm、约100μm、约200μm、约300μm、约400μm、约500μm、约600μm、约700μm、约800μm、约900μm或约1mm。
例如，所述功能物质可以包含生物活性物质。例如，所述生物活性物质可以包括药物、蛋白、多肽、核酸、糖类、细菌、真菌或由至少其中一种组成的复合物。例如，所述核酸可以包含DNA和/或RNA。例如，所述细菌可以包含球菌、杆菌和/或螺旋菌。例如，所述细菌可以包含自养菌和/或异养菌。例如，所述细菌可包含需氧菌和/或厌氧菌。例如，所述细菌可以包含革兰氏阴性菌和/或革兰氏阳性菌。例如，所述糖类可以包含单糖、二糖和/或多糖。
例如，所述功能物质可以包含具有特定功能的物质，例如造影剂/显像剂。例如，所述造影剂可以包括高密度造影剂。例如，所述造影剂可以包括低密度造影剂。
在本申请中，所述造影剂可以包括MR造影剂。例如，水，和/或钆螯合物。在本申请中，所述造影剂可以包括X射线造影剂，例如，硫酸钡。例如，碘制剂。
在本申请中，所述碘制剂可包含无机碘化物、有机碘化物、碘化油或脂肪酸碘化物。其中，有机碘化物可包含离子型有机碘化物、非离子型有机碘化物、以及非离子型二聚体有机 碘化物。示例性的碘制剂可包含碘普罗胺，碘海醇，碘克沙醇，碘佛醇，泛影葡胺，泛影酸钠和/或碘化油。
在本申请中，所述功能物质可以包含射线衰减材料。所述射线衰减材料能够阻挡或减弱射线的强度。例如，所述射线衰减材料可以包含金属物质。例如，所述金属物质可以包括钡、铅和/或银。例如，所述射线衰减材料可以包含金属盐。例如，所述金属盐可以包含硫酸钡和/或氯化银。例如，所述金属物质或金属盐中金属元素的原子序列要大于50。
在本申请中，所述功能物质可以包含辐射保护药物。所述辐射保护药物可以包含任何本领域内已知的辐射保护药物。例如，所述辐射保护药物可以包括氨磷汀、乙酰半胱氨酸、GSH、GC4419和/或超氧歧化酶类似物。
在本申请中，所述用于消化道可视化的试剂还可以包含一种或多种药学上可接受的载剂(carrier)。药学上可接受的载剂可以包括但不限于，例如，药学可接受的液体、凝胶或固体载剂、水相介质、非水相介质、抗微生物物质、等渗物质、缓冲液、抗氧化剂、麻醉剂、悬浮剂/分散剂、螯合剂、乳化剂、稀释剂、佐剂、辅料、无毒辅助物质、填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂、乳化剂、其他本领域公知的组分或以上的多种组合。
消化道可视化
在本申请中，所述消化道可视化可以包括任何本领域的实现显影的技术。例如，所述消化道可视化的方式可以包括X射线成像。例如，所述消化道可视化的方式可以包括MR成像。示例性的消化道可视化方式包括DF、DR、CT、MRI、DSA、PET-CT、PET-MRI和/或SPECT-CT。
在本申请中，所述消化道可视化的方式还包括放疗设备中的造影功能。例如，放疗设备中的CT、MRI、PET-CT、PET-MRI和/或SPECT-CT功能。
在本申请中，术语消化道的可视化可包括：消化道疾病的诊断、消化道疾病的评估、放疗前模拟、图像引导的放疗、实时放疗、术中影像引导中所需的消化道影像和/或消化道的辐射保护。
例如，所述放疗模拟方式可包括使用CT模拟机，MR模拟机，PET-CT模拟机，PET-MRI模拟机以及具有成像功能的医用直线加速器，赛博刀(cyberknife)，托姆刀(Tomotherapy)，伽马刀(gammaknife)上进行的消化道定位，也包括使用后装机或者放射性粒子植入等方式进行的内照射放疗中所必须的消化道影像学模拟。
例如，所述消化道辐射保护可包括使用医用直线加速器，赛博刀(cyberknife)，托姆刀(Tomotherapy)，伽马刀(gammaknife)，后装机进行的放疗的辐射保护，也可包括使用放射 性粒子植入人体的内照射放疗。其中，所述辐射保护也可包括孕期女性进行X线成像时的对宫内胎儿的保护(X线成像包括胸片、DF、DR、CT、PET-CT和SPECT-CT)。
在本申请中，所述消化道疾病可包括任何与消化道功能和/或结构异常相关的疾病和/或病症。例如，所述消化道疾病可以包括：消化道癌症、消化道转移癌、消化道炎性疾病和/或消化道损伤。
例如，所述消化道疾病可以包括：口腔癌，食管癌，胃癌，小肠癌，结直肠癌，肛门癌，及以上癌症的转移癌。
例如，所述消化道疾病也可以包括其他部位癌症发生在口腔，食管，胃，小肠，结直肠，肛门的转移灶。
例如，所述消化道疾病也可以包括炎性肠病，溃疡性结直肠炎，克罗恩病，胃炎，肠炎，幽门螺杆菌感染，反流性食管炎，食管炎，上消化道出血，胃出血，下消化道出血，口腔溃疡，胃溃疡，十二指肠溃疡，下消化道溃疡，上消化道溃疡，消化性溃疡，消化道黏膜损伤，食管息肉，胃息肉，肠息肉，结直肠息肉，十二指肠息肉，家族性腺瘤性息肉，痔疮，胃下垂，食管胃黏膜异位，食管异位，肠道异位，肠道脱垂，肠道结构异常，消化道结构异常，短肠综合征，放射性食管炎，放射性胃炎，放射性小肠炎，放射性结直肠炎，放射性肠病，放射性口炎，食管阻塞，胃阻塞，肠梗阻，小肠梗阻，结直肠梗阻，肛门闭锁，肛门狭窄，肠道狭窄，小肠狭窄，结直肠狭窄，食道狭窄。
例如，所述消化道疾病也可以包括消化道的部分切除，包括食管切除，胃切除，小肠切除，结直肠切除，以及以上器官的部分切除，消化道切除后的造瘘。
例如，所述消化道疾病也可以包括手术后，或者药物，放射疗法引起的消化道损伤，消化道炎症。
例如，所述消化道疾病也可以包括消化道内植入物引起的各种消化道并发症，消化道损伤，消化道炎症。
例如，所述消化道疾病也可以包括胃胀气，肠胀气，腹泻，便秘，排便困难，肠失禁，肛门失禁，大便失禁，肠道菌过度繁殖，肠道内细菌失调，便血，肠道蠕动异常，恶心，呕吐，食欲降低，暴食症，胃酸反流，十二指肠胃反流。药物组合、试剂盒
本申请还提供了药物组合，其能够包含本申请所述的铋-高分子复合物以及其他功能物质。所述药物组合中的铋-高分子复合物可以包载这些功能物质，也可以与这些功能物质混合施用，也可以与这些功能物质分开施用。
例如，所述铋-高分子复合物可以与这些功能物质通过相互作用包覆。例如，可以非共价 作用、共价作用、络合作用、离子作用、氢键作用等。
例如，所述铋-高分子复合物可以与这些功能物质混合施用。例如，所述铋-高分子复合物和所述功能物质可以同时存在于相同的容器中。例如，在施用前，可以将所述铋-高分子复合物与所述功能物质预混，再一同施用。
例如，所述铋-高分子复合物可以与这些功能物质分开施用。例如，所述铋-高分子复合物可以与所述功能物质存在于不同容器中。例如，可以先施用所述铋-高分子复合物，再施用所述功能物质。例如，可以在施用所述铋-高分子复合物后1分钟、2分钟、5分钟、10分钟、15分钟、20分钟、25分钟、30分钟、40分钟、50分钟、60分钟、70分钟、80分钟、90分钟、2小时、3小时或更久后，再施用所述功能物质。例如，可以先施用所述功能物质，再施用所述铋-高分子复合物。例如，可以在施用所述功能物质后1分钟、2分钟、5分钟、10分钟、15分钟、20分钟、25分钟、30分钟、40分钟、50分钟、60分钟、70分钟、80分钟、90分钟、2小时、3小时或更久后，再施用所述铋-高分子复合物。
在某些实施方式中，所述铋-高分子复合物的施用，基本上不影响某些功能物质的功能和/或效果。
本申请还提供了试剂盒，其能够包含本申请所述的铋-高分子复合物以及其他功能物质。在本申请中，所述试剂盒还可包含一种或多种其他成分。例如，所述试剂盒还可以包含括药学上可接受的载体。例如，所述药学上可接受的载体可以选自下组：填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂和乳化剂。
在本申请中，所述试剂盒中还可包含说明书。例如，所述说明书可以提供本申请所请求保护的铋-高分子复合物可用于消化道可视化的用途。例如，所述说明书可以提示所述铋-高分子复合物可与其他成分共同施用。例如，所述说明书可以提示所述铋-高分子复合物的具体给药方案。例如，所述给药方案可以包含给药途径、给药方式、给药时机和/或给药剂量等。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的用途等，而不用于限制本申请发明的范围。
实施例
实施例1合成本申请所述的铋-高分子复合物P1
将氢氧化铋(约2.6g，10mmol)，低甲氧基果胶(约2.5g，以羧酸计10mmol)分散在山梨醇的水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进 行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后上清液转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P1(氢氧化铋-果胶复合物)，结构如图1所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例2合成本申请所述的铋-高分子复合物P2
本申请所述的铋-高分子复合物P2，也即氢氧化铋-聚丙烯酸复合物，其合成步骤如下。
将氢氧化铋(约2.6g，10mmol)，聚丙烯酸(分子量3000左右，约0.75g，以羧酸计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P2(氢氧化铋-聚丙烯酸复合物)，结构如图2所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例3合成本申请所述的铋-高分子复合物P3
本申请所述的铋-高分子复合物P3，也即氢氧化铋-海藻酸复合物，其合成步骤如下。
将氢氧化铋(约2.6g，10mmol)，海藻酸钠(分子量3000左右，约2.5～3.0g，以羧基计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P3(氢氧化铋-海藻酸复合物)，结构如图3所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例4合成本申请所述的铋-高分子复合物P4
本申请所述的铋-高分子复合物P4，也即氢氧化铋-透明质酸复合物，其合成步骤如下。
将氢氧化铋(约2.6g，10mmol)，透明质酸(分子量3000左右，约2.5～3.0g，以氨基 计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P4(氢氧化铋-透明质酸复合物)，结构如图4所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例5合成本申请所述的铋-高分子复合物P5
本申请所述的铋-高分子复合物P5，即氧化铋-聚丙烯酸复合物，其合成步骤如下。
将氧化铋(约2.35g，5mmol)，聚丙烯酸(分子量3000左右，约0.75g，以羧酸计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P5(氧化铋-聚丙烯酸复合物)，结构如图5所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例6合成本申请所述的铋-高分子复合物P6
本申请所述的铋-高分子复合物P6，即硝酸铋-聚丙烯酸复合物，其合成步骤如下。
将氧化铋(约2.43g，5mmol)，聚丙烯酸(分子量3000左右，约0.75g，以羧酸计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P6(硝酸铋-聚丙烯酸复合物)，结构如图6所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例7合成本申请所述的铋-高分子复合物P7
本申请所述的铋-高分子复合物P7，即次水杨酸铋-聚丙烯酸复合物，其合成步骤如下。
将次水杨酸铋(约1.82g，5mmol)，聚丙烯酸(分子量3000左右，约0.75g，以羧酸计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10.5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P7(次水杨酸铋-聚丙烯酸复合物)，结构如图7所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
实施例8合成本申请所述的铋-高分子复合物P8
本申请所述的铋-高分子复合物P8，即枸橼酸铋-聚丙烯酸复合物，其合成步骤如下。
将枸橼酸铋(约3.52g，5mmol)，聚丙烯酸(分子量3000左右，约0.75g，以羧酸计10mmol)分散在山梨醇水溶液中(含100mL去离子水，25g山梨醇)，并在70℃油浴下搅拌6小时，形成悬浊液。使用氢氧化钾调节上述悬浊液酸碱度至pH＝10..5附近。碱度调节后对上述悬浊液进行油浴加热，并搅拌(75℃)。反应4小时后，将反应液离心(500rpm，5分钟)并将离心后底部固体去除，剩余液体转移至透析袋(Mw＝1000)中，在含有50％乙醇的水溶液中室温下透析24小时。24小时后将透析袋内固体取出并冷冻干燥，得到铋-高分子复合物P8(枸橼酸铋-聚丙烯酸复合物)，结构如图8所示。其中x为大于0的数，y为大于等于0的数。图中结构不仅限于钾盐，也可为钠盐等其他常用的阳离子盐，或者酸的形式。
同时，在铋-高分子复合物的体外测试中，选取了以及制备了一些对比例，主要为常用的可口服的生物安全性高分子，具体选用高分子与制备方法见下述(D1～D9)。
本实验中选取的高分子对比例主要为常用的可口服且具备一定肠道内黏附性的生物安全高分子，包括葡聚糖(D1)、果胶(D2)、明胶(D3)、壳聚糖(D4)、羧甲基纤维素(D5)、海藻酸钠(D6)、羟丙基甲基纤维素(D7)。将上述高分子溶解于水中配置成2％质量分数的高分子溶液备用。
此外选取了上述高分子中的一些与铋离子进行简单混合来进行对比，将硝酸铋溶解于浓硝酸溶液中制备成铋离子溶液(5mg/mL)，并将上述铋离子溶液与羧甲基纤维素溶液以及海 藻酸钠溶液混合(SA)，配置成含有1％质量分数铋离子的高分子溶液，其中羧甲基纤维素溶液与铋离子的混合称为D8，海藻酸钠与铋离子的混合称为D9。
实施例9本申请所述的铋-高分子的酸化
本申请所述的铋-高分子在发挥作用前，必须经过酸化处理才能具备相应效果。酸化处理可以为体外酸化，也可以在进入体内后，通过与例如胃酸相互作用后完成。
实验方法：将铋-高分子复合物(1g，P2)加入至去离子水中(12mL)形成悬浊液。搅拌振荡上述悬浊液1小时后，向其中加入酸溶液(1mol/L，3mL，包含但不限于盐酸，醋酸，硫酸，草酸等)，调节pH至3～4左右。
实验结果：未酸化的铋-高分子复合物悬浊液在酸化后会形成粘稠的膏状物质，如图9所示。根据上述配方，酸化后的铋-高分子复合物的水质量含量大于85％。
实施例10本申请所述的铋-高分子复合物酸化前后的形态观察
实验方法：酸化前后的铋-高分子复合物(P1)分别被水稀释至1％(m/v)浓度。将稀释后的铋-高分子复合物(酸化前与酸化后)用光学显微镜观察。
实验结果：可以观察到，酸化前的高分子复合物呈现出微凝胶颗粒状的分散状态，而酸化后的铋-高分子复合物呈现出聚集的状态，如图10所示。颗粒大小约为1～20微米。
实施例11-18本申请所述的铋-高分子复合物的飞行时间二次离子质谱仪表征
实验方法：将酸化后的铋-高分子复合物(P1-P8)分别冻干，研磨，并使用飞行时间二次离子质谱仪(time of flight-secondary ion mass spectroscopy，TOF-SIMS)进行表征。
实验结果：可以发现酸化后的铋-高分子复合物具有均在质核比257处(也即m/z＝257处，推测为碎片峰：BiO3 -)具有明显信号(intensity count>200)，具体结果如图11，表1所示。
表1：实施例11-18的具体结果
实施例19-35本申请所述的铋-高分子复合物的胃肠道粘附效果体外评价
实验方法：为了模拟胃肠道的粘液表面，使用粘蛋白(来自猪胃，Sigma-Aldrich公司购 买)来模拟仿真胃肠道内部的粘液层环境。将粘蛋白溶液(20μL，10mg/mL)刷在带正电荷的载玻片上并在室温下干燥。然后将候选材料(P1～P8以及其他对比用高分子材料D1～D9，对比用高分子的配置方法可见下述的具体对比例)刷涂并填充在两张上述的载玻片之间构建为夹心三明治模型(如图12所示)。为了保持相同的实验条件(也即相同重量的干物质和相同的水含量)，在上述的候选物的实验中通过添加水来调整最终的配方(保持在每次实验的载玻片中包含1mg的干物质以及50mg的水)。载玻片在20N的作用力下压缩30秒。为使粘蛋白和材料始终保持湿润(模拟肠道内的湿润环境)，单次测试应在1分钟内完成，以免发生不希望的蒸发。使用微机控制的电子万能试验机测量粘附力。将粘附的载玻片拉开的最大力量记录为候选者物质(P1～P8，D1～D9)的粘膜粘附力。拉力越大也即黏附效果越佳。
实验结果：酸化后的铋-高分子复合物(P1～P8)均表现出高于对比例(D1～D9)的粘附力。如表2，表3所示。
表2：实施例19-26的具体结果
表3：实施例27-35的具体结果
实施例36-52本申请所述的铋-高分子复合物的流动性效果评价
实验方法：为了模拟胃肠道的粘液表面，使用粘蛋白(来自猪胃，Sigma-Aldrich公司购买)来模拟仿真胃肠道内部的粘液层环境。将粘蛋白溶液(10mg/mL)刷在带细胞培养孔板上(24孔板)并在室温下干燥。然后将候选材料(P1～P8以及其他对比用高分子材料D1～D9，对比用高分子的配置方法可见下述的具体对比例，0.3mL)滴入孔中心。然后将孔板配备振动器并以1500rpm的速度涡旋。候选材料的铺展至孔板边沿的时间被记录为流动性的定量指标。铺展至边沿的时间越短则代表候选物的流动性越好。
实验结果：酸化后的铋-高分子复合物(P1～P8)均表现出优于，相当，或不明显劣于对比例(D1～D9)的流动性。具体数据结果如表4，表5所示。
表4：实施例36-43的具体结果
表5：实施例44-52的具体结果
实施例53本申请所述的铋-高分子复合物的生物安全性评价
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。实验第一天给予大鼠单剂量铋-高分子复合物(P1，酸化后3mL/100g)，连续10天记录体重。将给予PBS的大鼠设置为对照比较。给予铋-高分子24小时后，获取全血样本用于进一步的血细胞计数和血液生化测试。
为测试血液和器官的铋浓度，给予大鼠单次剂量的铋-高分子复合物(灌胃)，并在不同时间点获得全血样本。离心后，收集血清样品用于ICP-MS分析。灌胃24小时后，从大鼠中获得选定的器官用于进一步的ICP-MS分析。
实验结果：口服铋-高分子复合物的大鼠的血常规(图13)，血生化(图14-15)，均与口服饮水的对照组中的大鼠表现相当。大鼠的血清以及组织器官中的铋浓度也保持在较低水平(图16)。实验过程中未观察到大鼠出现明显毒性与副作用。具体结果如图13～16所示。
实施例54本申请所述的铋-高分子复合物包载硫酸钡造影剂的制备
实验方法：将硫酸钡粉末(钡餐，1g)与铋-高分子复合物(1g)在水(12mL)中混合并涡旋3小时。之后使用盐酸进行酸化处理。将盐酸(1mol/L，3mL)滴入涡旋下的悬浮液中。随着悬浊液pH值的降低，硫酸钡被铋-高分子复合物包裹并发生聚集，形成白褐色糊状 物。最终将pH调节至3～4，可获得15mL铋-高分子包裹的硫酸钡复合物。
实验结果：未酸化的铋-高分子复合物悬浊液在酸化后会形成粘稠的膏状物质，并在这个过程中包裹硫酸钡。如图17，18所示。根据上述配方，酸化后的包裹硫酸钡的铋-高分子复合物的水质量含量大于85％。
实施例55本申请所述的铋-高分子复合物包载碘海醇的制备
实验方法：铋-高分子复合物(1g)与碘海醇的水溶液溶液(12mL,25mg/mL)混合并涡旋3小时。之后使用盐酸进行酸化处理。将盐酸(1mol/L，3mL,其中含有25mg/mL的碘海醇)滴入涡旋下的悬浮液中。随着pH值的降低，碘海醇与铋-高分子复合物混合形成白棕色糊状物。最终将pH调节至3～4，可获得15mL铋-高分子复合物包裹的碘海醇。
实验结果：未酸化的铋-高分子复合物悬浊液在酸化后会形成粘稠的膏状物质，并在这个过程中包载碘海醇。
实施例56-63本申请所述的铋-高分子复合物包载硫酸钡后在大鼠中的X线模态下的胃肠道造影效果
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。使用数字减影血管造影(DSA)设备(German,Siemens Healthineers,Artis Q Ceiling)对大鼠进行二维X射线平扫和三维X射线断层扫描。大鼠在不同时间点灌胃口服铋-高分子复合物包载的硫酸钡(2.5mL/100g，此处灌胃口服可类似于胃部插管，复合物不会接触食管)，之后成像。使用同样剂量的硫酸钡悬浊液对另一组大鼠进行相同操作，作为对照组进行对比。在成像之前，使用阿佛丁注射液麻醉大鼠。DSA成像参数为下，球管电流：40μA(三维断层扫描)，58μA(二维平扫)；电压：70kV。总成像时间：20秒。原始图像在Siemens软件(syngo.via)上进行处理和重建。重建完毕后，在影像提供的信息基础上，在合适的时间点，对大鼠进行安乐处死，解剖胃肠道，测量铋-高分子复合物包裹的硫酸钡所覆盖的胃肠道长度，并与大鼠的胃肠道全长度相比，得到铋-高分子复合物覆盖长度与胃肠道总长的比例，确定为此灌胃剂量下的铋-高分子复合物的胃肠道覆盖比例。
实验结果：铋-高分子复合物(P1-P8)包载的硫酸钡在大鼠体内实现了长时间，大面积的胃肠道造影。铋-高分子复合物包载的硫酸钡在大鼠体内达到了大于50％的胃肠道覆盖比例，且可保持大约2小时的覆盖时间。而仅灌胃硫酸钡(钡餐)悬浊液的大鼠，并未表现出大面积，长时间的胃肠道覆盖。仅有部分胃部，出现了较为清晰的成像。具体数据结果如表6所示。
表6：铋-高分子复合物包载的硫酸钡在大鼠体内达到的胃肠道覆盖比例
实施例64-71本申请所述的铋-高分子复合物包载碘海醇后在大鼠中的X线模态下的胃肠道造影效果
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。使用数字减影血管造影(DSA)设备(German,Siemens Healthineers,Artis Q Ceiling)对大鼠进行二维X射线平扫和三维X射线断层扫描。大鼠在不同时间点灌胃口服包载了碘海醇的铋-高分子复合物(2.5mL/100g)，之后成像。使用同样剂量的碘海醇对另两组大鼠进行对比，一组为灌胃处理，一组为尾静脉注射处理。在成像之前，使用阿佛丁注射液麻醉大鼠。DSA成像参数为下，球管电流：40μA(三维断层扫描)，58μA(二维平扫)；电压：70kV。总成像时间：20秒。原始图像在Siemens软件(syngo.via)上进行处理和重建。重建完毕后，在影像提供的信息基础上，在合适的时间点，对大鼠进行安乐处死，解剖胃肠道，测量包载了碘海醇的铋-高分子复合物所覆盖的胃肠道长度，并与大鼠的胃肠道全长度相比，得到包载了碘海醇的铋-高分子复合物的胃肠道覆盖长度与胃肠道总长的比例，确定为此灌胃剂量下的包载了碘海醇的铋-高分子复合物的胃肠道覆盖比例。
实验结果：铋-高分子复合物(P1-P8)包载的碘海醇在大鼠体内实现了长时间，大面积的胃肠道造影。包载了碘海醇的铋-高分子复合物在大鼠体内达到了大于60％的胃肠道覆盖比例，且可保持大约2小时以上的覆盖时间(图21所示)。而仅灌胃硫碘海醇水溶液或仅注射碘海醇的大鼠，并未表现出大面积，长时间的胃肠道覆盖(图22，23所示)。仅有部分小肠，在灌胃处理组表现出了较为清晰的成像。静脉注射组未观察到胃肠道的影响(图22，23所示)。具体数据结果如表7所示。
表7：铋-高分子复合物包载的碘海醇在大鼠体内达到的胃肠道覆盖比例

实施例72-79本申请所述的铋-高分子复合物包载的硫酸钡用于大鼠中的X线模态下的食管造影效果
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。使用数字减影血管造影(DSA)设备(German,Siemens Healthineers,Artis Q Ceiling)对大鼠进行二维X射线平扫和三维X射线断层扫描。大鼠在不同时间点经嘴部口服铋-高分子复合物包载的硫酸钡(2.5mL/100g，酸化后经口腔咽服，此处为食管接触型口服，会接触食管并对食管造影)，之后成像。在成像之前，使用阿佛丁注射液麻醉大鼠。DSA成像参数为下，球管电流：40μA(三维断层扫描)，58μA(二维平扫)；电压：70kV。总成像时间：20秒。原始图像在Siemens软件(syngo.via)上进行处理和重建。使用软件重建时，清除肋骨影像，展示出食管成像的效果(如图25所示)。
实验结果：铋-高分子复合物包载的硫酸钡在大鼠的食管内体内实现了大面积的食管内造影(图24所示)。铋-高分子复合物包载的硫酸钡在大鼠体内达到了大于80％的食管覆盖比例。具体数据结果如表8所示。
表8：铋-高分子复合物包载的硫酸钡在大鼠体内达到的食管覆盖比例
实施例80本申请所述的铋-高分子复合物包载硫酸钡后在猪中的X线模态下的胃肠道造影效果
实验方法：雌性约克夏白猪(体重为30～45kg)适应性饲养一周。猪的二维X射线平扫和三维X射线断层扫描成像是在计算机断层扫描(CT)设备(美国、GE医疗、revolution ACT)上进行的。简而言之，给猪口服铋-高分子复合物包载的硫酸钡或硫酸钡悬浮液，约8mL/kg，酸化后插管灌胃)，然后在不同时间点成像。使用同样剂量的硫酸钡悬浊液对另一组猪进行相同操作，作为对照组进行对比。在成像之前，使用Telazol(tiletamine/zolazepam)肌肉注射， 对猪进行麻醉，之后使用异氟醚维持麻醉。在成像过程中监测心率和血压以确保猪的安全。CT的成像参数为下，球管电流：20μA(二维平扫)，85μA(三维断层扫描)；电压：120kV。原始图像在DICOM文件阅读器上进行处理和重建。
实验结果：铋-高分子复合物(P1)包载的硫酸钡在猪体内实现了长时间，大面积的胃肠道造影(如图25所示)。铋-高分子复合物包载的硫酸钡在猪体内达到了大于50％的胃肠道覆盖比例，且可保持大约2小时的覆盖时间。而仅灌胃硫酸钡(钡餐)悬浊液的猪，并未表现出大面积，长时间的胃肠道覆盖。仅有部分胃部，出现了部分成像(图26所示)。
实施例81本申请所述的铋-高分子复合物用于大鼠中的X线模态下的胃肠道造影效果
由于铋本身作为一种高序数元素，也具有较好的X射线成像效果。本实施例是为了说明，当酸化后的铋-高分子复合物膏体中铋的含量较高时，也具备较好的胃肠道X射线成像效果。
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。使用数字减影血管造影(DSA)设备(German,Siemens Healthineers,Artis Q Ceiling)对大鼠进行二维X射线平扫和三维X射线断层扫描。大鼠在不同时间点口服铋-高分子复合物(2.5mL/100g，酸化后口服，调节酸化过程中的水含量，使铋所占最终酸化后铋-高分子复合物中的质量分数提高，配置过程见下述)，之后成像。在成像之前，使用阿佛丁注射液麻醉大鼠。DSA成像参数为下，球管电流：40μA(三维断层扫描)，58μA(二维平扫)；电压：70kV。总成像时间：20秒。原始图像在Siemens软件(syngo.via)上进行处理和重建。
为了配置铋含量较高的铋-高分子复合物膏体。将铋-高分子复合物(1g，P2)加入至去离子水中(5mL)形成悬浊液。搅拌振荡上述悬浊液1小时后，向其中加入酸溶液(1mol/L，包含但不限于盐酸，醋酸，硫酸，草酸等)，调节pH至3～4左右。未酸化的铋-高分子复合物悬浊液形成粘稠的膏状物质。
实验结果：铋-高分子复合物在大鼠体内实现了长时间，大面积的胃肠道造影。铋-高分子复合在大鼠体内达到了大于60％的胃肠道覆盖比例(图27所示)。
实施例82本申请所述的铋-高分子复合物用于大鼠中的MR模态下的胃肠道造影效果
酸化后的铋-高分子复合物膏体具有较高的含水量，可以作为一种很好的MR模态下的胃肠道造影剂
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。大鼠的成像在MRI设备(German,Siemens Healthineers,Aera)上进行。简而言之，大鼠在口服铋-高分子复合物后 (2.5mL/100g，酸化后口服)4小时进行成像。使用同样剂量的甘露醇水溶液(2.5mg/mL，2.5mL/100g)对另一组大鼠进行相同操作，作为对照组进行对比。在成像之前，使用阿佛丁注射液麻醉大鼠。MR成像参数如下，回波时间：5.21s；重复时间：11s；切片厚度：1毫米；磁场强度：1.5T；序列：t1_fl3d_sag_iso；发射线圈名称：TxRx_Knee_15；原始图像在Siemens软件(syngo.MR E11)上进行处理和重建。
实验结果：铋-高分子复合物在大鼠体内实现了长时间，大面积的MR模态下的胃肠道造影效果(图28所示)。仅灌胃同等剂量的甘露醇的大鼠，并未表现出清晰的胃肠道MR影像(图29所示)。
实施例83本申请所述的铋-高分子复合物用于大鼠中的X线/MR融合模态下的胃肠道造影效果
实验方法：雌性SD大鼠(体重为200～300g)适应性饲养一周。大鼠的成像在MRI设备(German,Siemens Healthineers,Aera)上进行。简而言之，大鼠在口服铋-高分子复合物包载的硫酸钡(2.5mL/100g，酸化后口服)4小时进行成像。使用同样剂量的甘露醇水溶液以及硫酸钡悬浊液(2.5mg/mL，2.5mL/100g)对另两组大鼠进行相同操作，作为对照组进行对比。在成像之前，使用阿佛丁注射液麻醉大鼠。MR成像后，立即在DSA下对大鼠进行X线模态下的成像，以进行进一步的图像融合。MR成像参数如下，回波时间：5.21s；重复时间：11s；切片厚度：1毫米；磁场强度：1.5T；序列：t1_fl3d_sag_iso；发射线圈名称：TxRx_Knee_15；DSA成像参数为下，球管电流：40μA(三维断层扫描)，电压：70kV。总成像时间：20秒。原始图像在软件(syngo.MR E11)上进行处理和重建。将获得的DSA和MR成像原始数据在软件(syngo.via)上融合。
实验结果：铋-高分子复合物(P2)包载的硫酸钡在大鼠体内实现了长时间，大面积的MR/X线胃肠道融合造影(图30所示)。而仅灌胃硫酸钡(钡餐)悬浊液或者甘露醇水溶液的大鼠，并未表现出大面积，长时间的胃肠道融合影像(图31-32所示)。
实施例84本申请所述的铋-高分子复合物包载硫酸钡后用于大鼠的全腹部辐照模型的放射毒性缓解
实验方法：SD大鼠(4～6周龄，雌性)分为4组(n＝4只大鼠/组)并适应1周后纳入研究。第1组用PBS处理，不做任何照射作为空白对照组。第2组口服PBS并接受8Gy X线辐照。第3组口服铋-高分子复合物并接受8Gy X线辐照。第4组口服包裹硫酸钡的铋-高分子复合物并接受8Gy X线辐照。X线照射前8小时和4小时给药，以实现全长小肠和大肠 覆盖(每次剂量2.5mL/100g；通过X射线扫描确认GI分布)。第5天，用FITC-Dextran(FITC-葡聚糖，300mg/kg，口服)处理大鼠，3小时后通过眼眶收集全血用于进一步测试。在最后一天，用二氧化碳对大鼠实施安乐死。分离胃肠道用于进一步的载玻片和染色。
实验结果：口服包裹了硫酸钡的铋-高分子复合物的大鼠，在接受辐照后表现出更低的损伤，与更快的恢复。受到了包裹了硫酸钡的铋-高分子复合物保护的大鼠，展现出更快的体重增长(图33所示)，更低的腹泻表现(图34所示)，更快的食欲恢复(图35所示)，更低的肠道损伤(图36所示)。肠道切片中也展示出了更好的保护效果(图37所示)。
实施例85-86本申请所述的铋-高分子复合物包载药物后用于大鼠肠道内药物缓释
实验方法：铋-高分子复合物(1g)与地塞米松的水溶液(12mL,1mg/mL)混合并涡旋3小时。之后使用盐酸进行酸化处理。将盐酸(1mol/L，3mL,其中含有1mg/mL的地塞米松)滴入涡旋下的悬浮液中。随着pH值的降低，地塞米松与铋-高分子复合物混合形成白棕色糊状物。最终将pH调节至3～4，可获得15mL铋-高分子复合物包裹的地塞米松。SD大鼠(4～6周龄，雌性)分为2组(n＝4只大鼠/组)并适应1周后纳入研究。第1组用单纯口服地塞米松。第2组口服包载了地塞米松的铋-高分子复合物。口服之后在不同时间点用二氧化碳对大鼠实施安乐死。分离肠道用于并分析肠道组织内地塞米松的药物浓度。
实验结果：口服包裹了地塞米松的铋-高分子复合物的大鼠，展示出了更高的肠道内药物浓度，与更长的缓释时间。增加了肠道内局部药物浓度。具体数据如表9，表10所示。
表9：铋-高分子复合物包载的地塞米松在大鼠肠道达到的药物浓度
表10：地塞米松在大鼠肠道达到的药物浓度

Claims (59)

  1. 铋-高分子复合物在制备用于消化道可视化的试剂中的用途。
  2. 铋-高分子复合物在制备功能物质消化道递送载体中的用途。
  3. 根据权利要求1-2中任一项所述的用途，其中所述铋-高分子复合物为铋化物与高分子之间通过相互作用复合而成。
  4. 根据权利要求1-3中任一项所述的用途，其中所述铋-高分子复合物为铋化物与高分子之间通过络合键、共价键和/或非共价的相互作用复合而成。
  5. 根据权利要求3-4中任一项所述的用途，其中所述铋化物选自下组中的一种或多种：氢氧化铋，氧化铋，碳酸铋，碱式碳酸铋，硝酸铋，没食子酸铋，铝酸铋，次水杨酸铋，碱式水杨酸铋，水杨酸铋，醋酸铋，草酸铋，柠檬酸铋，氯化铋和硫化铋。
  6. 根据权利要求1-5中任一项所述的用途，其中所述高分子中存在至少一个游离羧酸或游离羧酸盐。
  7. 根据权利要求1-6中任一项所述的用途，其中所述高分子选自下组中的一种或多种：果胶，低甲氧基果胶，聚丙烯酸，海藻酸，透明酯酸。
  8. 根据权利要求1-7中任一项所述的用途，其中所述铋-高分子复合物经过TOF-SIMS测试，具有以下碎片峰：BiO3-。
  9. 根据权利要求8所述的用途，其中所述BiO3-的碎片峰的出峰范围在约m/z＝256.5～257.5之间。
  10. 根据权利要求1-9中任一项所述的用途，其中所述铋-高分子复合物的结构如式Ⅰ所示：
    其中，x为大于等于1的数字，
    y,z,m,n分别独立地为大于等于0的数字，
    当y不等于0时，x：y＝1：(0.000001～99)，
    当z不等于0时，x：y＝1：(0.000001～99)；
    其中，R1，R2分别独立地选自以下任一(p为大于等于0的数字)：
    其中，R’选自以下任一结构：
    其中，R3选自以下任一结构：
    R4，R5分别独立地选自以下任一结构(p为大于等于0的数字)：
    R6，R7分别独立地选自以下任一结构(R为任意基团)：
    或R6，R7组合为以下任一结构：
  11. 根据权利要求1-10中任一项所述的用途，其中对所述铋-高分子复合物使用红外光谱测试，在1550～1700cm-1处显示特征峰。
  12. 根据权利要求1-11中任一项所述的用途，其中所述铋-高分子复合物中铋元素的质量含量在0.5％～70％之间。
  13. 根据权利要求1-12中任一项所述的用途，其中所述铋-高分子复合物包含氢氧化铋-果胶复合物、氢氧化铋-聚丙烯酸复合物、氢氧化铋-海藻酸复合物、氢氧化铋-透明质酸复合物、氧化铋-聚丙烯酸复合物、硝酸铋-聚丙烯酸复合物、次水杨酸铋-聚丙烯酸复合物和/或枸橼酸铋-聚丙烯酸复合物。
  14. 根据权利要求1-13中任一项所述的用途，其中所述铋-高分子复合物经酸化处理。
  15. 根据权利要求14所述的用途，其中所述酸化处理包括使用酸性物质与所述铋-高分子复合物混合。
  16. 根据权利要求15所述的用途，其中所述酸性物质为固体或液体。
  17. 根据权利要求15-16中任一项所述的用途，其中所述酸性物质选自下组中的一种或多种：盐酸、磷酸、草酸、乳酸、柠檬酸、丁二酸、甲磺酸、酒石酸、苯甲酸、苹果酸、对甲苯磺酸、丙酸、富马酸、果酸、水杨酸、甲酸和醋酸。
  18. 根据权利要求14-17中任一项所述的用途，其中所述铋-高分子复合物经酸化后，pH值为约0.1～4.5。
  19. 根据权利要求14-18中任一项所述的用途，其中所述铋-高分子复合物经酸化后的微观形态为凝胶颗粒。
  20. 根据权利要求19所述的用途，其中所述凝胶颗粒的粒径范围为约50nm～1000μm。
  21. 根据权利要求19-20中任一项所述的用途，其中所述凝胶颗粒的水含量(质量分数)大于或等于60％。
  22. 根据权利要求1-21中任一项所述的用途，其中所述铋-高分子复合物的施用方式为经口腔或经肛门施用。
  23. 根据权利要求1-22中任一项所述的用途，其中所述铋-高分子复合物的施用方式为肠道插管。
  24. 根据权利要求1-23中任一项所述的用途，其中所述用于消化道可视化的试剂还包括其他功能物质。
  25. 根据权利要求24所述的用途，其中所述功能物质包括难溶或不溶颗粒。
  26. 根据权利要求24-25中任一项所述的用途，其中所述功能物质包括生物活性物质。
  27. 根据权利要求24-26中任一项所述的用途，其中所述功能物质包括造影剂。
  28. 根据权利要求27所述的用途，其中所述造影剂包括X射线造影剂和/或MR造影剂。
  29. 根据权利要求28所述的用途，其中所述X射线造影剂选自：硫酸钡，碘普罗胺，碘海醇，碘克沙醇，碘佛醇，泛影葡胺，泛影酸钠和碘化油。
  30. 根据权利要求28-29中任一项所述的用途，其中所述MR造影剂选自：水，以及钆螯合物。
  31. 根据权利要求26-30中任一项所述的用途，其中所述生物活性物质包括药物、蛋白、多肽、核酸、糖类、细菌、真菌或由至少其中一种组成的复合物。
  32. 根据权利要求31所述的用途，其中所述核酸包括DNA和/或RNA。
  33. 根据权利要求25-32中任一项所述的用途，其中所述难溶或不溶颗粒物包括：硅氧化物、金属氧化物、金属硫化物、金属氮化物、金属盐，或包含其中一种组成的复合物。
  34. 根据权利要求25-33中任一项所述的用途，其中所述难溶或不溶颗粒物的溶解度小于约10mg/mL。
  35. 根据权利要求25-34中任一项所述的用途，其中所述难溶或不溶颗粒物的粒径为约0.5nm～1mm。
  36. 根据权利要求24-35中任一项所述的用途，其中所述功能物质包括射线衰减材料。
  37. 根据权利要求36所述的用途，其中所述射线衰减材料包括金属物质。
  38. 根据权利要求37所述的用途，其中所述金属物质包括钡、铅和/或银。
  39. 根据权利要求36-38中任一项所述的用途，其中所述射线衰减材料包括金属盐。
  40. 根据权利要求39所述的用途，其中所述金属盐包括硫酸钡和/或氯化银。
  41. 根据权利要求37-40中任一项所述的用途，其中所述金属物质或金属盐中金属元素的原子序数大于50。
  42. 根据权利要求24-41中任一项所述的用途，其中所述功能物质包括辐射保护药物。
  43. 根据权利要求42所述的用途，其中所述辐射保护药物包括：氨磷汀、乙酰半胱氨酸、GSH、GC4419和/或超氧歧化酶类似物。
  44. 根据权利要求1-43中任一项所述的用途，其中所述消化道可视化的方式包括X射线成像。
  45. 根据权利要求1-44中任一项所述的用途，其中所述消化道可视化的方式包括MR成像。
  46. 根据权利要求1-45中任一项所述的用途，其中所述消化道可视化的方式包括：DF、DR、CT、MRI、DSA、PET-CT、PET-MRI和/或SPECT-CT。
  47. 根据权利要求1-46中任一项所述的用途，其中所述消化道可视化的方式包括放疗设备中的CT、MRI、PET-CT、PET-MRI和/或SPECT-CT功能。
  48. 根据权利要求1-47中任一项所述的用途，其包括：消化道疾病的诊断、消化道疾病的评估、放疗前模拟、图像引导的放疗、实时放疗、术中影像引导中所需的消化道影像和/或消化道的辐射保护。
  49. 根据权利要求48所述的用途，其中所述消化道疾病包括：消化道癌症、消化道转移癌、消化道炎性疾病和/或消化道损伤。
  50. 根据权利要求1-49中任一项所述的用途，其中所述消化道包括食管、胃肠道和/或肛门。
  51. 根据权利要求1-50中任一项所述的用途，其中所述铋-高分子复合物包载所述其他功能物质。
  52. 根据权利要求51所述的用途，其中所述包载包括选自下组的作用方式：非共价作用，共价作用，络合作用，离子作用和氢键作用。
  53. 根据权利要求1-52中任一项所述的用途，其中所述用于消化道可视化的试剂还包括药学上可接受的载剂。
  54. 一种实现消化道可视化的方法，其包括施用权利要求1-53中任一项所述的用途中所述的铋-高分子复合物。
  55. 一种放疗模拟的方法，其包括施用权利要求1-53中任一项所述的用途中所述的铋-高分子复合物。
  56. 一种诊断消化道疾病的方法，其包括施用权利要求1-53中任一项所述的用途中所述的铋-高分子复合物。
  57. 一种胃肠道辐射保护的方法，其包括施用权利要求1-53中任一项所述的用途中所述的铋-高分子复合物。
  58. 药物组合，其包括权利要求1-53中任一项所述的用途中所述的铋-高分子复合物和权利要求24-53中任一项所述的用途中所述的功能物质。
  59. 试剂盒，其包括权利要求1-53中任一项所述的用途中所述的铋-高分子复合物和权利要求24-53中任一项所述的用途中所述的功能物质。
PCT/CN2023/109604 2022-07-29 2023-07-27 铋-高分子复合物在消化道可视化中的用途 WO2024022447A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001457A1 (en) * 1990-07-20 1992-02-06 Slagel, David Products and processes for the treatment of the alimentary canal
CN1088437A (zh) * 1992-12-23 1994-06-29 大同市药物研究所 胶态果胶铋药物
CN1765937A (zh) * 2005-12-02 2006-05-03 凌沛学 透明质酸铋钾及其制备方法和应用
CN102558383A (zh) * 2012-01-10 2012-07-11 中国科学院海洋研究所 一种海藻酸铋及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001457A1 (en) * 1990-07-20 1992-02-06 Slagel, David Products and processes for the treatment of the alimentary canal
CN1088437A (zh) * 1992-12-23 1994-06-29 大同市药物研究所 胶态果胶铋药物
CN1765937A (zh) * 2005-12-02 2006-05-03 凌沛学 透明质酸铋钾及其制备方法和应用
CN102558383A (zh) * 2012-01-10 2012-07-11 中国科学院海洋研究所 一种海藻酸铋及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HONG-XING LIU, ZHAO FENG; MA YIN-LING; ZHANG SHU-ZHEN; TANG ZE-AO: "Research Progress of Nanometer Contrast Agent in Tumor Diagnosis Chinese Full Text ; Chinese Pharmaceutical Journal", CHINESE PHARMACEUTICAL JOURNAL, vol. 56, no. 18, 22 September 2021 (2021-09-22), pages 1466 - 1475, XP093132570, DOI: 10.11669/cpj.2021.18.005 *
JIANG WEN-XIN, QI JUN-RU, LIAO JIN-SONG, WAN ZHI-LI, LIANG WAN-LING, HUANG JIA-YI, CAO YONG, XIAO JIE, YANG XIAO-QUAN: "Structural characterization of pectin-bismuth complexes and their aggregation in acidic conditions", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, ELSEVIER BV, NL, vol. 154, 1 July 2020 (2020-07-01), NL , pages 788 - 794, XP093132568, ISSN: 0141-8130, DOI: 10.1016/j.ijbiomac.2020.03.143 *
YING LIN, YIN DING, XIQUN JIANG, : "Preparation and Theranostic Applications of Polymer-Inorganic Hybrid Nanospheres", PROGRESS IN CHEMISTRY, vol. 26, no. 2/3, 15 March 2014 (2014-03-15), pages 450 - 457, XP093132569 *

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