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CN-122005459-A - Liposome nanoparticle for treating cardiomyopathy as well as preparation method and application thereof

CN122005459ACN 122005459 ACN122005459 ACN 122005459ACN-122005459-A

Abstract

The invention belongs to the technical field of biological medicines and nano medicines, and discloses liposome nano particles for treating cardiomyopathy, a preparation method and application thereof, wherein the liposome nano particles are composed of phospholipid, cholesterol, functional lipid and medicines for treating cardiomyopathy according to a specific mass ratio, wherein the mass ratio of the phospholipid, the cholesterol and the functional lipid is 60-80:10-20:5-20, and the mass ratio of the medicines to the total lipid is 1:10-1:50. The preparation method comprises the steps of lipid film formation, vacuum drying, buffer hydration, extrusion granulation, purification and sterilization, and the like, and can be further connected with a targeting molecule. According to the invention, by optimizing the lipid prescription and process, the nano particles with uniform particle size, high encapsulation efficiency and good stability are successfully prepared, and the myocardial targeted delivery and slow release of the drug can be realized.

Inventors

  • SHI JIN
  • LI XUEMEI
  • ZHAO WEIAN
  • Ying Linyan
  • JIANG JING
  • YUAN WENJING

Assignees

  • 重庆市妇幼保健院(重庆市妇产科医院、重庆市遗传与生殖研究所)

Dates

Publication Date
20260512
Application Date
20260323

Claims (10)

  1. 1. A method for preparing liposome nano-particles for treating cardiomyopathy, which is characterized by comprising the following steps: (1) Dissolving phospholipid, cholesterol, functionalized lipid and therapeutic drug together in an organic solvent to form a lipid phase solution, wherein the mass ratio of the phospholipid, the cholesterol and the functionalized lipid is 60-80:10-20:5-20, and the mass ratio of the therapeutic drug to the total lipid is 1:10-1:50; (2) Removing the organic solvent from the lipid phase solution obtained in the step (1) by rotary evaporation at 40-60 ℃ under reduced pressure, and forming a uniform lipid film on the container wall; (3) Placing the lipid film in a vacuum drying oven, and continuously drying for 4-12 hours under the conditions of minus 0.05 to minus 0.1 MPa and room temperature so as to thoroughly remove the residual organic solvent; (4) Adding phosphate buffer saline solution with a pre-heated value of C, pH to 6.5-7.5 at 50-65 degrees to hydrate the dried lipid film, wherein the adding amount of the buffer solution is that the mass volume concentration of the total lipid is in the range of 5-20 mg/mL, and hydrating for 30-90 minutes at the same temperature to obtain crude liposome suspension; (5) Extruding the crude liposome suspension at 50-65deg.C for multiple times through polycarbonate membrane with pore diameter of 0.4 μm, 0.2 μm and 0.1 μm to obtain liposome nanoparticle with uniform particle diameter and average particle diameter of 80-150 nm; (6) Purifying the liposome nanoparticle solution obtained in the step (5) to remove free drugs, then filtering and sterilizing under the aseptic condition, and filling inert gas at the temperature of 2-8 ℃ for sealing and preserving.
  2. 2. The preparation method according to claim 1, wherein the phospholipid in the step (1) is at least one of hydrogenated soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine, and the functionalized lipid is polyethylene glycol-distearoyl phosphatidylethanolamine and/or maleimide-polyethylene glycol-distearoyl phosphatidylethanolamine.
  3. 3. The method of claim 1, wherein the therapeutic agent in step (1) is an angiotensin II receptor antagonist, an aldosterone receptor antagonist or a β -adrenergic receptor blocker.
  4. 4. The method according to claim 1, further comprising the step (7) of covalently linking the liposome nanoparticle with a targeting molecule for cardiac myocytes under conditions of 4-25 ° C, pH 6.5.5-7.5, and purifying after the reaction, thereby obtaining actively targeted liposome nanoparticle.
  5. 5. A liposome nanoparticle for treating cardiomyopathy prepared by the preparation method of any one of claims 1 to 4.
  6. 6. The liposomal nanoparticle according to claim 5, characterized in that its surface is modified with targeting molecules to cardiac myocytes by covalent attachment.
  7. 7. The liposomal nanoparticle of claim 6 wherein the targeting molecule is a cyclic peptide containing an arginine-glycine-aspartic acid sequence that specifically binds integrin αvβ3 on the surface of cardiomyocytes.
  8. 8. Use of a liposome nanoparticle according to any one of claims 5-7 for the preparation of a medicament for the treatment of cardiomyopathy.
  9. 9. The use according to claim 8, wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy or ischemic cardiomyopathy.
  10. 10. A pharmaceutical formulation for the treatment of cardiomyopathy comprising the liposomal nanoparticle of any of claims 5-7 and a pharmaceutically acceptable carrier.

Description

Liposome nanoparticle for treating cardiomyopathy as well as preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines and nano-medicines, and in particular relates to liposome nano-particles for treating cardiomyopathy, a preparation method thereof and application thereof in preparing medicines for treating cardiomyopathy. Background Cardiomyopathy is a group of myocardial mechanical and/or electrical activity dysfunction diseases caused by different causes, and mainly comprises dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy and the like. Such diseases ultimately often lead to heart failure and malignant arrhythmias, which are one of the leading causes of mortality in cardiovascular diseases. Currently, the drug treatment of cardiomyopathy mainly relies on oral drugs such as angiotensin converting enzyme inhibitors, beta-receptor blockers, aldosterone antagonists, and the like, which act by systemic administration. However, existing conventional drug treatment regimens have significant limitations. Firstly, the medicine is lack of specificity in vivo, only a very small amount of medicine can be enriched in diseased myocardial tissues, and in order to achieve effective treatment concentration, large-dose administration is often required, which not only increases treatment cost, but also causes serious systemic toxic and side effects, such as hypotension, bradycardia, renal function injury and the like, and limits the clinical curative effect and application thereof. Secondly, many potentially effective therapeutic agents suffer from poor water solubility, low chemical stability, or rapid clearance in vivo, and the like, and have extremely low bioavailability, and it is difficult to maintain effective concentrations at focal sites for long periods of time, thereby affecting therapeutic efficacy. In recent years, nanotechnology has provided new ideas for drug delivery. Liposomes have been widely studied as a classical nanocarrier due to their good biocompatibility and ability to entrap drugs of different nature. However, conventional liposomes still suffer from insufficient targeting in vivo, they are more easily captured and cleared by mononuclear phagocyte systems such as liver, spleen, etc., and are difficult to actively and efficiently enrich in the deep organ of the heart. In addition, how to realize precise control of the particle size of liposome nanoparticles and stability of large-scale preparation thereof is a challenge which is not well solved in the prior art. In the prior art, targeted modification of liposomes to improve cardiac delivery has also been investigated. For example, there are reports of the use of antibodies or peptide ligands targeting to cardiac myocyte surface antigens (e.g., connexin 43, integrins, etc.). Among them, RGD peptide containing arginine-glycine-aspartic acid sequence can specifically recognize and bind to integrin alpha v beta 3 highly expressed in cardiac muscle cells, vascular endothelial cells and pathologic (such as fibrosis and ischemia) cardiac muscle region, and is a targeting molecule with great potential. However, combining these targeting strategies with liposome preparation processes that are high in encapsulation efficiency, high in stability and suitable for industrialization remains a technical problem to be solved in the art. Disclosure of Invention To solve the above problems, the present invention provides an innovative liposome nanoparticle delivery system. The system can realize passive targeting by utilizing nano-size effect through carefully designed lipid composition, particle size control and optional targeting modification, and can be efficiently enriched in diseased myocardial tissues under the guidance of active targeting function. The lipid bilayer structure can effectively encapsulate and protect the hydrophobic drug, and can realize the controlled release of the drug at the focus part by enhancing permeation and retention effects or specific ligand-receptor combination while reducing the systemic exposure of the drug, thereby remarkably improving the treatment efficiency and relieving the toxic and side effects. Another object of the present invention is to provide a method for preparing the above liposome nanoparticle. The method has the characteristics of clear technological parameters, good reproducibility, easy realization of large-scale production, and capability of ensuring that the prepared nano particles have uniform particle size, high encapsulation efficiency and excellent stability. The invention also aims to provide application of the liposome nanoparticle in preparing medicaments for treating cardiomyopathy, in particular to application in treating dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy and the like, and finally provides a brand new solution for realizing accurate, efficient and low-toxic