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KR-20260067998-A - Multifunctional Inhaled Microgel Composite Formed by Cross-linked Albumin Nanoparticles

KR20260067998AKR 20260067998 AKR20260067998 AKR 20260067998AKR-20260067998-A

Abstract

The present invention is an inhaled delivery system composed of albumin nanoparticles embedded in a porous microgel formed by interparticle pores, which efficiently delivers drugs deep into the lungs and enables long-term retention. Through this, simultaneous regulation of inflammatory and fibrotic signals has been confirmed to restore lung function and reduce ECM accumulation in a bleomycin-induced pulmonary fibrosis model. Therefore, the present invention can be utilized as a useful drug delivery platform for the inhaled treatment of intractable lung diseases, including pulmonary fibrosis.

Inventors

  • 윤유석
  • 이우탁

Assignees

  • 성균관대학교산학협력단

Dates

Publication Date
20260513
Application Date
20251103
Priority Date
20241105

Claims (17)

  1. It comprises a microgel formed by mutually bonding albumin nanoparticles using a reactive oxygen species (ROS) reactive linker, and Microgel composite for inhaled drug delivery, wherein drug-carrying lipid nanoparticles are encapsulated within the microgel.
  2. In claim 1, The above albumin nanoparticles are a microgel composite for inhaled drug delivery, having a uniform particle size of 50 nm to 1000 nm.
  3. In claim 2, The above microgel is a microgel composite for inhaled drug delivery, wherein the porosity can be controlled according to the interparticle pore size of albumin nanoparticles.
  4. In claim 3, Microgel composite for inhaled drug delivery, wherein the release of lipid nanoparticles or drugs loaded thereon is controlled according to the above-mentioned pore size and controlled porosity.
  5. In claim 3, Microgel composite for inhaled drug delivery, capable of controlling the lung delivery site due to different airflow dynamic characteristics depending on the above-mentioned pore size and controlled porosity.
  6. In claim 1, Microgel composite for inhaled drug delivery, wherein the above ROS-reactive linker is a polyethylene glycol-thioketal (PEG-TK) linker.
  7. In claim 1, Microgel composite for inhaled drug delivery, wherein the above-mentioned ROS-reactive linker is decomposed by active oxygen in the body to release encapsulated drug-carrying lipid nanoparticles.
  8. In claim 1, The above microgel is an inhalable drug delivery microgel composite having a size of 1 to 20 μm.
  9. In claim 1, Microgel composite for inhaled drug delivery, wherein the above drug-carrying lipid nanoparticles comprise cationic lipids or ionized lipids.
  10. In claim 1, Microgel composite for inhaled drug delivery, wherein the above drug-loaded lipid nanoparticles further comprise phospholipids, cholesterol, and PEG-lipids.
  11. In claim 1, The above drug is an inhaled drug delivery microgel complex comprising a nucleic acid therapeutic agent.
  12. In claim 11, The above nucleic acid therapeutic agent is one or more of siRNA, antisense oligonucleotides, or mRNA therapeutic agents, and is an inhaled drug delivery microgel complex.
  13. A pharmaceutical composition for the prevention or treatment of lung disease comprising a microgel complex for drug delivery according to claim 1.
  14. In claim 13, The above pharmaceutical composition is a pharmaceutical composition intended for transpulmonary inhalation administration.
  15. In claim 13, A pharmaceutical composition in which the above-mentioned microgel complex evades the phagocytic action of alveolar macrophages to extend the residence time of a drug in lung tissue.
  16. In claim 13, A pharmaceutical composition for the prevention or treatment of lung disease, wherein the lung disease is one or more of pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, pneumonia, or lung cancer.
  17. A drug delivery system comprising a microgel complex for drug delivery according to claim 1, wherein the composition is provided as a formulation for trans-lung inhalation administration.

Description

Multifunctional Inhaled Microgel Composite Formed by Cross-linked Albumin Nanoparticles The present invention relates to an inhalable drug delivery microgel composite comprising a microgel formed by mutually bonding albumin nanoparticles using an active oxygen (ROS) reactive linker, wherein drug-carrying lipid nanoparticles are encapsulated in the pores between the albumin nanoparticles within the microgel. Chronic lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and asthma are fatal respiratory diseases with high morbidity and mortality rates worldwide; in particular, pulmonary fibrosis is characterized by the irreversible destruction of alveolar structures and excessive deposition of extracellular matrix (ECM). These diseases are primarily caused by factors such as smoking, environmental pollution, recurrent infections, and genetic factors, and are clinically characterized by a gradual decline in respiratory function as tissue fibrosis progresses based on a chronic inflammatory response. To date, there is no fundamental cure for pulmonary fibrosis and chronic lung diseases, and drug treatment also shows only limited effectiveness in delaying disease progression. Although inhaled formulations are widely used as drug delivery systems for the treatment of such lung diseases, the alveolar delivery efficiency of inhaled agents is closely correlated with the median mass aerodynamic diameter (MMAD), and it is known that particles in the 1–5 μm range are delivered to the alveoli. However, existing microparticles and nanocarriers have had the problem of not being able to retain the drug sufficiently in the target tissue because they are captured in the upper airway or, even if they reach the alveoli, are rapidly removed by the mucus layer and alveolar macrophages. Consequently, limitations have been reported, such as the requirement for repeated administration to achieve the same therapeutic effect, large variability in efficacy, and a high risk of systemic side effects. In particular, for precision therapeutics such as siRNA, antifibrotics, and immunomodulators, the risk of degradation is high and intracellular delivery is difficult, so the need for a stable delivery platform that protects them and allows them to remain in lung tissue for an extended period is being further emphasized. Furthermore, due to the complex pathological characteristics of lung diseases, it is difficult to induce a sufficient therapeutic response with a single drug, and there is a demand for next-generation complex nano-delivery systems capable of delivering two or more active ingredients simultaneously or sequentially. While conducting research to overcome the low alveolar delivery rate, short residence time, removal by macrophages, and limitations of single-functional materials of existing inhaled drug delivery systems, the inventors confirmed that a microgel structure prepared by crosslinking albumin nanoparticles can serve as a platform capable of remaining in the alveolar microenvironment for a long period and simultaneously carrying multiple nanocarriers. Furthermore, the inventors completed the present invention by identifying that this microgel is airflow-dynamically suitable for inhaled formulations and can be delivered to deep parts of the lungs while avoiding macrophage phagocytosis. Figure 1 shows (A) the particle size distribution and Cryo-TEM/TEM analysis results of mannose surface modified lipid nanoparticles (siTGFβ) and albumin nanoparticles (ANP 200 , ANP 400 , ANP 800 ) encapsulated with TGFβ antagonist siRNA according to the present invention, and (B) the results of confirming the airflow dynamic characteristics of albumin nanoparticle-based microgels (ANP 0 @μGel, ANP 200 @μGel, ANP 400 @μGel, ANP 800 @μGel) by NGI analysis. Figure 2 shows the results of confirming the release of lipid nanoparticles according to the controlled pore size (porousness) of the albumin nanoparticle-based microgel according to the present invention. Figure 3 shows the results of confirming the surface structure and morphology of the albumin nanoparticle-based microgel according to the present invention through FE-SEM analysis. Figure 4 is a comparison of the particle velocity distribution and average velocity in a flow environment of an albumin nanoparticle-based microgel according to the present invention. Figure 5 shows the ROS reactivity characteristics of the albumin nanoparticle-based microgel according to the present invention as it decomposes according to the hydrogen peroxide treatment time. Figure 6 shows the endosome evasion ability of siRNA-LNP according to the present invention confirmed by confocal microscopy. Figure 7 is the result of analyzing the TGF-β gene expression levels by treatment group according to the present invention using RT-qPCR. Figure 8 is the result of analyzing the macrophage cell uptake rate of siRNA-LNP according to the present invention using FACS. Figure 9 is the r