Search

WO-2026095717-A1 - ACID-RESISTANT CORE-SHELL NANOCOMPLEX FOR ORAL USE AND MRCP T2-NEGATIVE CONTRAST USING SAME

WO2026095717A1WO 2026095717 A1WO2026095717 A1WO 2026095717A1WO-2026095717-A1

Abstract

The present invention relates to an orally administrable complex having an average hydrated particle diameter of 10 nm to 100 nm and comprising: a core composed of metal or metal oxide-based nanoparticle(s); and a shell disposed as an acid-resistant barrier layer on the surface of the core and coated with polysaccharide crosslinked colloidal particles which form multi-point coordination bonds with metal ions on the surface of the core and have an average hydrated particle diameter of 2 nm to 8 nm and a surface charge of -20 mV to 0 mV. The polysaccharide crosslinked colloidal particles are characterized in that, in an aqueous solvent, (i) an -OH functional group of a monosaccharide, which is a building block of a linear polysaccharide, a branched polysaccharide, or a cyclic polysaccharide, is modified using a first crosslinking agent having an epoxide group, and (a) the functional group modified by the first crosslinking agent and a spatially adjacent -OH functional group are directly crosslinked and/or (b) two spatially adjacent functional groups modified by the first crosslinking agent are crosslinked intramolecularly and/or intermolecularly via a second crosslinking agent having two or more amine groups (-NH2) to form polysaccharide crosslinked particles, and (ii) the number of crosslinking agent-derived basic amine groups exposed on the surface is modified with a -COOH functional group so that the surface charge of the polysaccharide crosslinked colloidal particles is in the range of -20 mV to 0 mV. The orally administrable complex according to the present invention is a T2 MRI contrast agent that can be used as an active ingredient of a composition for diagnostic biliary and pancreatic imaging.

Inventors

  • SHIN, TAE-HYUN
  • KIM, JI-WOOK

Assignees

  • 주식회사 인벤테라

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241031

Claims (19)

  1. A core composed of metal or metal oxide-based nanoparticle(s); and An oral administration complex having a hydration average particle size of 10 nm to 100 nm, comprising a shell coated with polysaccharide cross-linked colloidal particles having a hydration average particle size of 2 nm to 8 nm and a surface charge of -20 mV to 0 mV, which are disposed as an acid-resistant barrier layer on the surface of the core and form multi-point coordination bonds with metal ions on the core surface. A polysaccharide crosslinked colloidal particle for oral administration characterized in that, in an aqueous solvent, (i) the -OH functional group of a monosaccharide, which is a building block of a linear polysaccharide, branched polysaccharide, or cyclic polysaccharide, is modified by a first crosslinking agent having an epoxide group, (a) the functional group modified by the first crosslinking agent is directly and/or (b) two spatially adjacent functional groups modified by the first crosslinking agent are crosslinked intramolecularly and/or intermolecularly through a second crosslinking agent having two or more amine groups ( -NH2 ), thereby forming a polysaccharide crosslinked particle, and (ii) the surface charge of the polysaccharide crosslinked colloidal particle is within the range of -20 mV to 0 mV through modification of the number of crosslinking agent-derived basic amine groups exposed on the surface to -COOH functional groups.
  2. An oral administration complex according to claim 1, characterized in that it is a mononuclear core-shell structure or a multinuclear (bridged) core-shell structure that behaves as a single hydrated particle in a dynamic fluid environment, wherein some of the polysaccharide cross-linked colloidal particles coordinately bond to one or more cores to cross-link (share) between adjacent cores, so that the number of cores of the final oral administration complex is one or more, preferably four or more, and the hydrated average particle size is 10 nm to 100 nm.
  3. An orally administered complex according to claim 1, characterized in that the polysaccharide crosslinked colloidal particles having a hydration average particle size of 2 nm to 8 nm, which coat the core surface through coordination bonding with metal ions of metal or metal oxide-based nanoparticles, simultaneously act as chelators of metal ions through (i) hydroxyl groups and/or (ii) amine functional groups and/or -COOH functional groups derived from the crosslinking agent exposed on the surface where metal ions are not coordinately bonded.
  4. An orally administered complex according to claim 1, characterized in that dispersion stability is maintained without aggregation or precipitation during a gastric retention of 30 to 120 minutes.
  5. The oral administration complex according to claim 1, characterized in that when the solution containing the oral administration complex is administered orally, it stimulates the secretion of digestive fluid from the gallbladder.
  6. An oral administration complex according to claim 1, characterized in that the surface charge of the oral administration complex is -20 mV to 0 mV due to polysaccharide cross-linked colloid particles having a surface charge of -20 mV to 0 mV coated on the core surface.
  7. The oral administration structure according to claim 1, characterized in that the polysaccharide cross-linked colloid particles coated on the core surface of the oral administration complex are not hydrolyzed by carbohydrases.
  8. An orally administered complex according to any one of claims 1 to 7, characterized in that 60% or more, 70% or more, 90% or more, or 95% or more of the total number of monosaccharides, which are the building blocks of polysaccharides, are modified by a crosslinking agent so as not to be hydrolyzed by enzymes in the body and so as to reduce or minimize immunostimulatory activity against immune cells.
  9. An orally administered complex according to any one of claims 1 to 7, characterized in that the polysaccharide cross-linked colloidal particles are not hydrolyzed by enzymes in the body, as at least one -OH functional group in at least one of two consecutive monosaccharides within the polysaccharide chain is mostly modified by a cross-linking agent.
  10. A core composed of metal or metal oxide-based nanoparticle(s); and A nanocomposite having a hydration average particle size of 10 nm to 100 nm comprising a shell coated with polysaccharide cross-linked colloidal particles having a hydration average particle size of 2 nm to 8 nm and a surface charge of -20 mV to 0 mV, which form multi-point coordination bonds with metal ions on the core surface, Polysaccharide crosslinked colloidal particles are formed in an aqueous solvent by (i) modifying the -OH functional group of a monosaccharide, which is a building block of a linear polysaccharide, branched polysaccharide, or cyclic polysaccharide, with a first crosslinking agent having an epoxide group, (a) directly between the functional group modified by the first crosslinking agent and a spatially adjacent -OH functional group, and/or (b) intramolecularly and/or intermolecularly crosslinking between two spatially adjacent functional groups modified by the first crosslinking agent through a second crosslinking agent having two or more amine groups (-NH2), thereby forming polysaccharide crosslinked particles, and (ii) modifying the number of crosslinking agent-derived basic amine groups exposed on the surface to -COOH functional groups so that the surface charge of the polysaccharide crosslinked colloidal particles is within the range of -20 mV to 0 mV. Acid-resistant nanocomposites designed so that polysaccharide cross-linked colloidal particles simultaneously perform the functions of strongly bonded anchor ligands, acid-resistant barrier layers, aggregation inhibition, and precipitation inhibition.
  11. An acid-resistant nanocomposite according to claim 10, characterized in that it is a mononuclear core-shell structure or a multinuclear (bridged) core-shell structure that behaves as a single hydrated particle in a dynamic fluid environment, wherein some of the polysaccharide cross-linked colloidal particles coordinate with two cores simultaneously to cross-link (share) between adjacent cores, so that the number of cores of the final nanocomposite is one or more, preferably four or more, and the hydrated average particle size is 10 nm to 100 nm.
  12. An MRI contrast agent pharmaceutical composition comprising the acid-resistant nanocomposite of claim 10 or 11.
  13. A composition for diagnosing biliary and pancreatic duct imaging containing an oral administration complex of any one of claims 1 to 9 as a contrast agent.
  14. A composition for biliary and pancreatic duct imaging diagnosis according to claim 13, characterized in that the orally administered complex acts as a T2 contrast agent when it remains in the stomach during T2-weighted imaging.
  15. A composition for diagnosing biliary and pancreatic duct imaging according to claim 13, characterized by confirming cancer, inflammation, gallstones, pancreatic stones, bile duct stenosis, or pancreatic duct stenosis through biliary and pancreatic duct imaging during T2-weighted imaging.
  16. A composition for diagnosing biliary and pancreatic duct imaging according to claim 13, characterized in that the orally administered complex acts as a T2 contrast agent when residing in the stomach and/or duodenum, thereby further increasing the signal of the biliary and pancreatic duct relative to the signal of the stomach during T2-weighted imaging to identify cancer, inflammation, gallstones, pancreatic stones, and biliary and pancreatic duct stenosis, and to diagnose the cause of biliary and pancreatic duct disease.
  17. A method for imaging the bile duct or pancreatic duct, wherein an oral administration complex of any one of claims 1 to 9 is orally administered to a subject, and while the oral administration complex remains in the stomach or duodenum, T₂-weighted MRI or MRCP is performed to reduce gastrointestinal signals, thereby imaging the bile duct or pancreatic duct in high contrast.
  18. Step of preparing a metal or metal oxide nanoparticle core suspension; A step of preparing a polysaccharide cross-linked colloid particle colloid solution by modifying the -OH groups of a polysaccharide in an aqueous solvent with a first cross-linking agent having an epoxide group and forming intramolecular/intermolecular cross-linking particles with a second cross-linking agent of a divalent or higher polyamine, and then partially modifying the amine groups on the surface of the polysaccharide cross-linked colloid particles with -COOH to adjust the zeta potential to -20 mV to 0 mV; and A step of mixing the above metal or metal oxide nanoparticle core suspension and the above polysaccharide cross-linked colloidal particle solution having a zeta potential of -20 mV to 0 mV. A method for manufacturing an acid-resistant nanocomposite of claim 10 or 11, comprising
  19. A use for the preparation of an orally administered stabilizing modifier that induces the formation of an acid-resistant barrier, inhibition of inter-particle aggregation, and inhibition of precipitation in the gastrointestinal tract under pH 1 to 2 conditions, wherein (i) the -OH functional group of a monosaccharide, which is a building block of a linear polysaccharide, branched polysaccharide, or cyclic polysaccharide, is modified in an aqueous solvent by (i) modifying the -OH functional group of a monosaccharide, which is a building block of a linear polysaccharide, branched polysaccharide, or cyclic polysaccharide, with a first crosslinking agent having an epoxide group, and (a) intramolecular and/or intermolecular crosslinking between the functional group modified by the first crosslinking agent and the spatially adjacent -OH functional group, and (b) two spatially adjacent functional groups modified by the first crosslinking agent through a second crosslinking agent having two or more amine groups (-NH2), to form polysaccharide crosslinked particles (hydrated average particle size 2 to 8 nm), and (ii) the surface charge of the polysaccharide crosslinked colloidal particles, which is controlled to a range of -20 mV to 0 mV by modifying the number of crosslinking agent-derived basic amine groups exposed on the surface to -COOH functional groups.

Description

Oral acid-resistant core-shell nanocomposite and MRCP T2-negative contrast using the same The present invention relates to an oral T2 contrast agent that improves biliary-pancreatic duct (MRCP) contrast by treating the gastrointestinal lumen as a negative contrast in magnetic resonance imaging (MRI). Specifically, the invention relates to a core-shell type orally administered complex comprising a core made of metal or metal oxide-based nanoparticle(s) (e.g., SPION) and a shell made of polysaccharide cross-linked colloidal particles that form multivalent coordination bonds through metal ions on the core surface and multiple functional groups present on the surface. The polysaccharide cross-linked colloidal particles are designed such that their hydration average particle size is 2 nm to 8 nm and their surface charge is controlled to be -20 mV to 0 mV, and the final complex, which is coated with these particles on a core made of metal or metal oxide-based nanoparticle(s) (e.g., SPION), has a hydration average particle size in the range of 10 nm to 100 nm. This orally administered complex reduces or nulls the water signal of the stomach and/or duodenum, thereby inducing negative contrast in T2-weighted images; therefore, it can be used as an active ingredient in a composition for biliary and pancreatic duct imaging diagnostics for high-contrast imaging of the bile ducts and pancreatic ducts. The present invention relates to a metal or metal oxide nanoparticle-based composition that can be orally administered for in vivo imaging diagnostics such as MRI or for location tracking, and to a core-shell oral formulation designed to provide a homogeneous and reproducible signal by simultaneously suppressing dissolution, aggregation, and precipitation in a highly acidic environment such as gastric juice. Magnetic Resonance Imaging (MRI) is a technology that generates images by utilizing the magnetic properties of hydrogen protons within the human body. When radio frequency (RF) pulses are applied to protons aligned under a strong, uniform magnetic field, their alignment is disrupted; upon removal of the pulses, they return to their original state while releasing energy. Since the rate of realignment and the emitted energy vary depending on differences in the chemical environment surrounding the protons, signal differences are formed between tissues, allowing for a certain level of contrast to be obtained even without the use of contrast agents. Nevertheless, administering a contrast agent modulates the relaxation characteristics of protons within the microenvironment where the agent is distributed, further enhancing contrast between tissues. In T2-weighted images, structures with high free water content appear relatively bright, so water signals in the lumen of the gastrointestinal tract (especially the stomach and duodenum) often interfere with the visibility of fluid columns such as the bile ducts and pancreatic ducts (Fig. 1a). Therefore, by using an orally administered negative contrast agent to reduce water signals in the lumen of the gastrointestinal tract, the anatomical structures of the bile ducts and pancreatic ducts can be visualized more clearly (Fig. 1b). Iron oxide-based nanoparticles (e.g., SPION) can provide a negative contrast effect by inducing local magnetic sensitivity differences through superparamagnetism, thereby promoting spin phase dephasing and shortening the T2 (or T2*) time. Although SPIO agents such as Ferumoxide (Feridex) were commercialized in the past, their clinical application was limited due to rapid removal by the reticuloendothelial system and accumulation in specific organs. For example, superparamagnetic iron oxide (SPIO) agents with a diameter of approximately 50–200 nm are phagocytosed relatively quickly by the reticuloendothelial system and removed from the blood within a short time, and preferentially distributed to Kupffer cells in the liver, thereby reducing the signal intensity of normal liver parenchyma in T2 and T2*-weighted images. The bile ducts and pancreatic ducts serve as pathways for digestive fluids, and cancer, inflammation, gallstones, pancreatic stones, and strictures are known to be major causes of biliary and pancreatic duct diseases. Imaging diagnostic methods for these diseases include endoscopic retrograde cholangiopancreatography (ERCP), ultrasound, and magnetic resonance cholangiopancreatography (MRCP). MRCP utilizes T2-weighted sequences to non-invasively visualize the bile and pancreatic duct systems, and bile columns with relatively long T2 relaxation times exhibit higher signal intensity than surrounding soft tissues. Sequences widely used in clinical practice include RARE (Rapid Acquisition with Relaxation Enhancement), FRFSE (Fast Recovery Fast Spin Echo), and HASTE (Half-Fourier Acquisition Single-Shot Turbo Spin Echo). MRCP is essential for the evaluation of various pancreatobiliary diseases, such as cholangiolithiasis, neoplasms of the biliary an