WO2024040593A1 - 抗肺炎药物及其制备方法和应用 - Google Patents

抗肺炎药物及其制备方法和应用 Download PDF

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WO2024040593A1
WO2024040593A1 PCT/CN2022/115234 CN2022115234W WO2024040593A1 WO 2024040593 A1 WO2024040593 A1 WO 2024040593A1 CN 2022115234 W CN2022115234 W CN 2022115234W WO 2024040593 A1 WO2024040593 A1 WO 2024040593A1
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inhibitor
protein
pneumonia
cyclophilin
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朱棣
陆伟
陆路
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Fudan University
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  • the present invention relates to the field of medicine, and in particular to anti-pneumonia drugs and their preparation methods and applications.
  • nucleocapsid protein of the coronavirus SARS-CoV interacts with human cyclophilin A in the human body and plays an important role in virus maturation, virus replication and the formation of new virus particles.
  • the invention provides an anti-pneumonia drug and its preparation method and application to facilitate the treatment of pneumonia diseases caused by coronavirus.
  • the anti-pneumonia drug of the present invention includes a carrier loaded with an inhibitor; wherein the inhibitor is an inhibitor capable of blocking the binding of N protein and cyclophilin A; the carrier is pulmonary surfactant
  • the bionic particles can treat pneumonia caused by coronavirus by blocking the combination of N protein and cyclophilin A.
  • the mass of the carrier is 10-20 times the mass of the inhibitor.
  • the bionic particles of pulmonary surfactant include phospholipid components of pulmonary surfactant, simulated components of proteins contained in pulmonary surfactant, and cholesterol components.
  • the mass of the phospholipid component of the pulmonary surfactant is 10-20 times the mass of the cholesterol component.
  • the protein-mimicking component contained in the pulmonary surfactant has the same content as the cholesterol component.
  • the phospholipid component of the pulmonary surfactant is at least one of palmitchophospholipid and dipalmitoylphosphatidylglycerol.
  • the simulated component of the protein contained in the pulmonary surfactant is dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000.
  • the inhibitor is at least one of Debio-025, Cyclosporin A, NIM811, SCY-635, STG-175, MM284 and CPI-431-32.
  • the average particle size of the carrier is 130-140 nanometers, and the dispersion index is less than 0.2.
  • the preparation method of the anti-pneumonia drug of the present invention includes:
  • S0 Provides inhibitors that can block the binding of N protein and cyclophilin A, palmitoyl phospholipid, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol;
  • S1 Disperse the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol in an organic solvent, and then add the An inhibitor that blocks the binding of N protein and cyclophilin A is obtained to obtain a suspension containing drug-loaded particles, and the organic solvent is a good solvent for the inhibitor that can block the binding of N protein and cyclophilin A;
  • S2 Perform a liposome extrusion process on the suspension containing drug-loaded particles at 40-60 degrees Celsius to obtain a carrier loaded with the inhibitor capable of blocking the binding of N protein and cyclophilin A.
  • the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol are dispersed in an organic solvent.
  • the steps include:
  • dipalmitoylphosphatidylglycerol the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol have the same quality.
  • the anti-pneumonia drug of the present invention is used in the treatment of anti-SARS-CoV-2.
  • the anti-pneumonia drug of the present invention is administered through the nasal cavity, oral administration or injection.
  • Figure 1 is an imaging photograph of the lung organs of mice in vivo and in vitro according to an embodiment of the present invention
  • Figure 2 is a photo of immunofluorescence staining of mouse lung tissue according to an embodiment of the present invention.
  • the embodiments of the present invention provide an anti-pneumonia drug and its preparation method and application to facilitate the treatment of pneumonia caused by coronavirus.
  • Embodiment 1 provides a method for preparing an anti-pneumonia drug, including:
  • S0 Provides inhibitors that can block the binding of N protein and cyclophilin A, palmitoyl phospholipid, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol;
  • S1 Disperse the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol in an organic solvent, and then add the An inhibitor that blocks the binding of N protein and cyclophilin A is obtained to obtain a suspension containing drug-loaded particles, and the organic solvent is a good solvent for the inhibitor that can block the binding of N protein and cyclophilin A;
  • S2 Perform a liposome extrusion process on the suspension containing drug-loaded particles at 40-60 degrees Celsius to obtain a carrier loaded with the inhibitor capable of blocking the binding of N protein and cyclophilin A.
  • the inhibitor that can block the binding between N protein and cyclophilin A is cyclosporine polypeptide A.
  • the step S1 of this embodiment is specifically:
  • the temperature of the drug-loaded suspension is controlled to 50 degrees Celsius, and the drug-loaded suspension is sequentially passed through a 400 nanometer polycarbonate filter membrane and a 200 nanometer polycarbonate filter membrane to perform a liposome extrusion process to obtain cyclosporine polypeptide A-loaded Nanoparticles (abbreviated as P-CsA).
  • P-CsA cyclosporine polypeptide A-loaded Nanoparticles
  • the particle size and zeta potential of three groups of P-CsA were measured by Zetasizer, and the average particle size was 135.6 ⁇ 3.8 nanometers, the dispersion index was 0.148 ⁇ 0.056, and the zeta potential was 0.258 ⁇ 0.736mV.
  • Example 2 provides the application of P-CsA of Example 1 in anti-SARS-CoV-2 treatment, specifically:
  • CsA was administered intranasally to mice. After 24 hours, the near-infrared zone was used to image the living and isolated lung organs of the mice respectively.
  • immunofluorescence staining analysis was performed on the lung tissues of the mice, and the results shown in Figure 1 were obtained. The imaging photos of mouse lung organs in vivo and in vitro are shown, as well as the immunofluorescence staining photos of mouse lung tissue shown in Figure 2. As can be seen from Figures 1 and 2, P-CsA can reach the lungs quickly and efficiently.

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Abstract

本发明提供了一种抗肺炎药物及其制备方法和应用。本发明的所述抗肺炎药物包括负载有抑制剂的载体；其中，所述抑制剂为能够阻断N蛋白和亲环素A结合的抑制剂；所述载体为肺表面活性物质的仿生颗粒，能够通过阻断N蛋白和亲环素A的结合治疗冠状病毒引起的肺炎疾病。

Description

抗肺炎药物及其制备方法和应用 技术领域
本发明涉及医药领域，尤其涉及抗肺炎药物及其制备方法和应用。
技术背景
有研究发现，冠状病毒SARS-CoV的核衣壳蛋白与人体中的人亲环素A有相互作用，对病毒的成熟、病毒的复制和新病毒颗粒的形成起重要作用。
因此，有必要开发新型的抗肺炎药物来治疗CoV感染。
发明概要
本发明提供了一种抗肺炎药物及其制备方法和应用，以利于治疗冠状病毒引起的肺炎疾病。
为实现上述目的，本发明的所述抗肺炎药物包括负载有抑制剂的载体；其中，所述抑制剂为能够阻断N蛋白和亲环素A结合的抑制剂；所述载体为肺表面活性物质的仿生颗粒，能够通过阻断N蛋白和亲环素A的结合治疗冠状病毒引起的肺炎疾病。
优选的，所述载体的质量为所述抑制剂质量的10-20倍。
优选的，所述肺表面活性物质的仿生颗粒包括肺表面活性物质的磷脂成分、肺表面活性物质中所含蛋白质的模拟成分和胆固醇成分。
优选的，所述肺表面活性物质的磷脂成分的质量为所述胆固醇成分质量的10-20倍。
优选的，所述肺表面活性物质中所含蛋白质的模拟成分与所述胆固醇成分具有相同的含量。
优选的，所述肺表面活性物质的磷脂成分为棕榈胆磷和二棕榈酰磷脂酰甘油的至少一种。
优选的，所述肺表面活性物质中所含蛋白质的模拟成分为二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000。
优选的，所述抑制剂为Debio-025、环孢多肽A、NIM811、SCY-635、STG-175、MM284和CPI-431-32中的至少一种。
优选的，所述载体的平均粒径为130-140纳米，分散性指数小于0.2。
本发明所述抗肺炎药物的制备方法包括：
S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇；
S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；
S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。
优选的，所述步骤S1中，将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中的步骤包括：
控制所述棕榈胆磷的质量为所述二棕榈酰磷脂酰甘油质量的10-20倍；
控制所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇具有相同的质量。
本发明的所述抗肺炎药物应用于抗SARS-CoV-2的治疗。
本发明所述抗肺炎药物经鼻腔给药、口服给药或注射给药。
附图说明
图1为本发明实施例的小鼠活体和离体肺部器官的成像照片；
图2为本发明实施例的小鼠肺部组织免疫荧光染色照片。
发明内容
本发明实施例提供了一种抗肺炎药物及其制备方法和应用，以利于治疗冠状病毒引起的肺炎疾病。
实施例1
实施例1提供了一种抗肺炎药物的制备方法，包括：
S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇；
S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；
S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。
本实施例的所述步骤S0中，能够阻断N蛋白和亲环素A结合的抑制剂为环孢多肽A。
本实施例的所述步骤S1具体为：
控制棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇的质量比为10：1：1：1，将棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇分散在氯仿中，再加入环孢多肽A直至溶解，得到载药悬液。其中，控制加入的环孢多肽A的质量与加入的二棕榈酰磷脂酰甘油的质量相当。
将载药悬液温度控制为50摄氏度，使载药悬液顺次通过400纳米聚碳酸酯滤膜和200纳米聚碳酸酯滤膜以进行脂质体挤出工艺，得到负载环孢多肽A的纳米颗粒(简记为P-CsA)。所述脂质体挤出工艺的具体操作步骤为本领域技术人员的常规技术手段。
本实施例通过Zetasizer测量得到的三组P-CsA的粒径和ζ电势，得到平均 粒径为135.6±3.8纳米，分散性指数为0.148±0.056,ζ电势为0.258±0.736mV.
实施例2
实施例2提供了实施例1的P-CsA在抗SARS-CoV-2治疗方面的应用，具体为：
采用近红外II区荧光探针BPBBT(Ex/Em＝808nm/1050nm)和红光荧光探针DiD(Ex/Em＝644nm/665nm)标记P-CsA得到共同标记P-CsA，将共同标记P-CsA经小鼠鼻腔内滴入给药，24小时后使用近红外二区分别对小鼠活体和离体肺部器官进行成像，此外对小鼠肺部组织进行免疫荧光染色分析，得到图1所示的小鼠活体和离体肺部器官的成像照片，以及图2所示的小鼠肺部组织免疫荧光染色照片。从图1和图2可以看到，P-CsA能够迅速高效地到达肺部。

Claims (10)

  1. 一种抗肺炎药物，其特征在于，包括负载有抑制剂的载体；
    所述抑制剂为能够阻断N蛋白和亲环素A结合的抑制剂；
    所述载体为肺表面活性物质的仿生颗粒。
  2. 根据权利要求1所述的抗肺炎药物，其特征在于，所述载体的质量为所述抑制剂质量的10-20倍。
  3. 根据权利要求1所述的抗肺炎药物，其特征在于，所述肺表面活性物质的仿生颗粒包括肺表面活性物质的磷脂成分、肺表面活性物质中所含蛋白质的模拟成分和胆固醇成分；
    所述肺表面活性物质的磷脂成分的质量为所述胆固醇成分质量的10-20倍；
    所述肺表面活性物质中所含蛋白质的模拟成分与所述胆固醇成分具有相同的含量。
  4. 根据权利要求3所述的抗肺炎药物，其特征在于，所述肺表面活性物质的磷脂成分为棕榈胆磷和二棕榈酰磷脂酰甘油的至少一种，所述肺表面活性物质中所含蛋白质的模拟成分为二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000。
  5. 根据权利要求1所述的抗肺炎药物，其特征在于，所述抑制剂为Debio-025、环孢多肽A、NIM811、SCY-635、STG-175、MM284和CPI-431-32中的至少一种。
  6. 根据权利要求1所述的抗肺炎药物，其特征在于，所述载体的平均粒径为130-140纳米，分散性指数小于0.2。
  7. 一种抗肺炎药物的制备方法，其特征在于，包括：
    S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固 醇；
    S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；
    S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。
  8. 根据权利要求7所述的抗肺炎药物的制备方法，其特征在于，所述步骤S1中，将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中的步骤包括：
    控制所述棕榈胆磷的质量为所述二棕榈酰磷脂酰甘油质量的10-20倍；
    控制所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇具有相同的质量。
  9. 根据权利要求8所述的抗肺炎药物的制备方法，其特征在于，所述步骤S1中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂的步骤包括：
    控制所述能够阻断N蛋白和亲环素A结合的抑制剂的质量与所述二棕榈酰磷脂酰甘油的质量相当。
  10. 一种抗肺炎药物的应用，其特征在于，应用于抗SARS-CoV-2的治疗。
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Publication number Priority date Publication date Assignee Title
CN101053660A (zh) * 2006-04-13 2007-10-17 复旦大学 一种蛋白多肽类药物载体及其制备方法和应用
US20160082074A1 (en) * 2014-03-11 2016-03-24 Ludwig-Maximilians-Universitaet Muenchen Compositions and methods for treating coronavirus infection
CN111074572A (zh) * 2019-12-27 2020-04-28 上海纳米技术及应用国家工程研究中心有限公司 一种抗呼吸系统病毒性疾病纤维的制备方法
CN112472791A (zh) * 2020-11-16 2021-03-12 复旦大学 CsA脂质体在制备抗SARS-CoV-2药物中的应用
CN113663073A (zh) * 2021-08-19 2021-11-19 山东大学 一种靶向s蛋白棕榈酰化的多肽在制备广谱抗冠状病毒药物中的应用

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CN101053660A (zh) * 2006-04-13 2007-10-17 复旦大学 一种蛋白多肽类药物载体及其制备方法和应用
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