KR-20260067317-A - An Inhaled drug delivery system for long-term treatment of lung diseases based on a porous PLGA matrix loaded with liposomes and lipid nanoparticles

KR20260067317AKR 20260067317 AKR20260067317 AKR 20260067317AKR-20260067317-A

Abstract

The present invention relates to a nano-microparticle composite for inhaled drug delivery comprising a biodegradable polymer matrix adsorbed with liposomes and lipid nanoparticles, and a method for preparing the same. Furthermore, the present invention relates to a pharmaceutical composition for treating lung diseases comprising the nano-microparticle composite. The present invention utilizes low-density porous PLGA microparticles to effectively protect drug-loaded nanoparticles and achieves excellent alveolar delivery efficiency and therapeutic effects by evading the airflow-dynamic barrier of the lungs and the phagocytosis of macrophages. Furthermore, local lung delivery reduces gastrointestinal side effects associated with high-dose oral administration, while continuous drug release and long-term retention minimize systemic side effects. Therefore, the present invention can be utilized as a drug delivery platform for the long-term and effective treatment of various lung diseases, including pulmonary fibrosis and chronic obstructive pulmonary disease (COPD).

Inventors

윤유석
정유진

Assignees

성균관대학교산학협력단

Dates

Publication Date: 20260512
Application Date: 20251023
Priority Date: 20241105

Claims (17)

Nano-microparticle composite for inhaled drug delivery comprising a biodegradable polymer matrix adsorbed with liposomes and lipid nanoparticles.
In Article 1, A composite characterized in that the above-mentioned biodegradable polymer matrix is one or more selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), and polycaprolactone (PCL).
In Article 1, A composite characterized in that the above-degradable polymer matrix has a porous structure and an aerodynamic mass average diameter (MMAD) of 1 μm to 5 μm.
In Article 1, The liposomes, lipid nanoparticles, and biodegradable polymer matrix each contain a drug, and A complex characterized by having one or more drugs selected from the group consisting of antifibrotic agents, immunomodulators, gene therapy agents, or pharmaceutically acceptable salts thereof.
In Article 4, A complex characterized by the above antifibrotic agent being one or more selected from the group consisting of nintedanib and pirfenidone.
In Article 4, A complex characterized in that the above-mentioned immunomodulator is a TLR7 agonist.
In Article 4, The above gene therapy complex is characterized by being one or more selected from the group consisting of siRNA, miRNA, and derivatives thereof.
As a method for manufacturing the composite of claim 1, (a) a step of preparing porous polymer microparticles by mixing and stirring a mixture of an oil phase containing a biodegradable polymer, a first drug, and an organic solvent, and an aqueous phase containing a porous agent and distilled water with a stabilizer; (b) a step of preparing a liposome containing a second drug; (c) a step of preparing lipid nanoparticles containing a third drug; and (d) a step of forming a nano-microparticle complex by adsorbing the liposomes and lipid nanoparticles onto the surface of the porous polymer microparticles; A method including
In Article 8, A method characterized in that the above-mentioned biodegradable polymer is one or more selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), and polycaprolactone (PCL).
In Article 8, A method characterized in that the first drug, the second drug, and the third drug are each one or more selected from the group consisting of antifibrotic agents, immunomodulators, gene therapy agents, or pharmaceutically acceptable salts thereof.
In Article 10, The first drug is one or more selected from the group consisting of nintedanib and pirfenidone, and The second drug mentioned above is a TLR7 agonist, and A method characterized in that the third drug is one or more selected from the group consisting of siRNA, miRNA and derivatives thereof.
In Article 8, The above organic solvent is methylene chloride, and The above porous agent is ammonium bicarbonate, and A method characterized in that the above-mentioned stabilizer is polyvinyl alcohol.
In Article 8, A method characterized in that the above stirring is performed at a temperature of 30 ℃ to 40 ℃.
In Article 8, A method characterized in that the above-described porous polymer microparticles are in the form of a double emulsion (W₁/O/W₂).
A pharmaceutical composition for the prevention or treatment of lung disease comprising the complex of claim 1 as an active ingredient.
In Article 15, A pharmaceutical composition characterized in that the above lung disease is one or more selected from the group consisting of pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and acute respiratory distress syndrome (ARDS).
In Article 15, A pharmaceutical composition characterized by the above composition being for inhalation.

Description

An inhaled drug delivery system for long-term treatment of lung diseases based on a porous PLGA matrix loaded with liposomes and lipid nanoparticles The present invention relates to a nano-microparticle composite for inhaled drug delivery comprising a biodegradable polymer matrix adsorbed with liposomes and lipid nanoparticles, and a method for preparing the same. Furthermore, the present invention relates to a pharmaceutical composition for treating lung diseases comprising the nano-microparticle composite. Pulmonary fibrosis is an intractable disease in which the structure of alveoli is destroyed due to inflammatory responses and excessive proliferation of fibroblasts, leading to a decrease in lung elasticity and impaired gas exchange function. Antifibrotic drugs used to treat pulmonary fibrosis, such as nintedanib, are primarily administered orally, which has the limitation of requiring high doses to deliver the drug systemically. This results in various side effects, such as hepatotoxicity and gastrointestinal disorders, and the concentration of the drug reaching actual lung tissue is limited, leading to reduced therapeutic efficacy. Accordingly, there is an urgent need for the development of non-oral drug delivery formulations that can minimize systemic side effects while maintaining the efficacy of pulmonary fibrosis treatment drugs. Although the application of nanoparticle-based inhalants via parenteral administration is being attempted, there is a problem in that the retention time of the drug in the lungs is shortened due to the rapid removal of drug particles caused by airflow-dynamic barriers resulting from the structural characteristics of the lungs and the phagocytosis of macrophages. Particularly in diseases such as pulmonary fibrosis, where lesions are localized and the disease progression is chronic and progressive, it is difficult to maximize therapeutic efficacy unless direct and continuous drug delivery to the affected area is achieved. As such, conventional technologies have faced limitations in securing clinical efficacy due to issues such as side effects associated with high-dose oral administration of antifibrotic drugs and the low lung target delivery efficiency of nanoparticle inhalers. Therefore, there is a need for a new type of drug delivery system that enables sustained drug release and selective delivery to lesion sites while improving the efficiency of drug delivery within the lungs. Accordingly, in order to solve these problems, the inventors of the present invention have researched the present invention, which can extend the residence time of the drug in the lungs, minimize side effects, and maximize the therapeutic effect on pulmonary fibrosis by providing a nano-microparticle-based lung-targeted drug delivery system that combines the advantages of nanoparticles and microparticles by utilizing porous PLGA microparticles as a nanoparticle carrier. Figure 1 is a diagram showing the overall manufacturing process and final formulation of porous PLGA microparticles. Figure 2 is a diagram showing the optimized manufacturing design process of porous PLGA microparticles. Figure 3 is a diagram showing the manufacturing process and characteristics of a TLR7 agonist 3-loaded liposome (TLR7-3-Lip). Figure 4 is a diagram showing the manufacturing process and characteristics of siRNA-loaded lipid nanoparticles (siRNA-LNP). Figure 5 is a diagram showing the results of confocal microscopy analysis of the final formulation in which liposomes and lipid nanoparticles are evenly adsorbed onto PLGA microparticles. Figure 6 is a diagram showing the mass median aerodynamic mass average diameter (MMAD) of non-porous-PLGA, porous-PLGA, and nintedanib-encapsulated porous-PLGA microparticles. Figure 7 is a diagram showing the release characteristics of a porous PLGA microparticle formulation adsorbed with liposomes and lipid nanoparticles. Figure 8 is a diagram showing porous PLGA microparticles loaded with liposomes and lipid nanoparticles to overcome the airflow-dynamic barrier of the lungs and evade the phagocytosis of macrophages for the improvement of pulmonary fibrosis treatment. The present invention will be described in more detail below. However, this is presented as an example and is not intended to limit the present invention, and the present invention is defined only by the scope of the claims set forth below. The present invention relates to a nano-microparticle complex for inhaled drug delivery. The composite of the present invention comprises a biodegradable polymer matrix adsorbed with liposomes and lipid nanoparticles. The above-mentioned biodegradable polymer matrix is a polymer that naturally decomposes and disappears in the body after a certain period of time. For example, it may be one or more selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), and polycaprolactone (PCL), and preferably may be polyl