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在大鼠中进行 co-spray-dried 可吸入吡非尼酮微球的药代动力学和药效学研究。

pharmacokinetic and pharmacodynamic study of co-spray-dried inhalable pirfenidone microparticles in rats.

机构信息

College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.

College of Pharmacy, Wonkwang University, Iksan, Republic of Korea.

出版信息

Drug Deliv. 2022 Dec;29(1):3384-3396. doi: 10.1080/10717544.2022.2149899.

DOI:10.1080/10717544.2022.2149899
PMID:36415157
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9704105/
Abstract

Pirfenidone (PRF) is the first FDA-approved API in the treatment of idiopathic pulmonary fibrosis (IPF). However, PRF induces serious side effects, such as photophobia and gastrointestinal disorder. PRF inhalation can be expected with a lower effective dose and reduced side effects. In this study, PRF was prepared as inhalable co-spray-dried particles for dry powder inhalation. Mannitol, L-leucine (Leu), and NaCl were used as a stabilizer. The kinds and ratios of stabilizers affecting the physicochemical properties of particles were analyzed, including particle size and surface composition, because of the surface enrichment properties of Leu, the most effective stabilizer. The co-spray-dried PRF and Leu microparticle (SD-PL1:1) have the smallest size and highest aerosol performance. The bioavailability was confirmed by pharmacokinetics (PK) studies. In addition, pharmacodynamics (PD) experiments were conducted using a bleomycin-induced IPF rat model. PK experiments demonstrated that pulmonary administration of SD-PL1:1 was 4 times more effective than the oral route. Similar to the PK results, the therapeutic effect was improved when SD-PL1:1 was administered via the pulmonary route compared to the oral route.

摘要

吡非尼酮（PRF）是美国食品药品监督管理局（FDA）批准用于治疗特发性肺纤维化（IPF）的首个 API。然而，PRF 会引起严重的副作用，如畏光和胃肠道紊乱。PRF 吸入剂有望以较低的有效剂量和减少副作用。在这项研究中，PRF 被制备成可吸入的共喷雾干燥颗粒用于干粉吸入。甘露醇、L-亮氨酸（Leu）和 NaCl 被用作稳定剂。分析了影响颗粒理化性质的稳定剂的种类和比例，包括粒径和表面组成，因为 Leu 具有表面富集特性，是最有效的稳定剂。共喷雾干燥的 PRF 和 Leu 微球（SD-PL1：1）具有最小的粒径和最高的气溶胶性能。通过药代动力学（PK）研究证实了生物利用度。此外，还使用博来霉素诱导的 IPF 大鼠模型进行了药效学（PD）实验。PK 实验表明，SD-PL1：1 经肺部给药的效果是口服途径的 4 倍。与 PK 结果相似，与口服途径相比，SD-PL1：1 经肺部给药时的治疗效果得到了改善。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/96e659d83a32/IDRD_A_2149899_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/a364ea7af774/IDRD_A_2149899_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/910295f8ad24/IDRD_A_2149899_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/2d3c0304cc1a/IDRD_A_2149899_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/655037bb3fb2/IDRD_A_2149899_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/ccacd8424382/IDRD_A_2149899_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/1cadf418671c/IDRD_A_2149899_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/1f2c5c1ed050/IDRD_A_2149899_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/96e659d83a32/IDRD_A_2149899_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/a364ea7af774/IDRD_A_2149899_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/910295f8ad24/IDRD_A_2149899_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/2d3c0304cc1a/IDRD_A_2149899_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/655037bb3fb2/IDRD_A_2149899_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/ccacd8424382/IDRD_A_2149899_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/1cadf418671c/IDRD_A_2149899_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/1f2c5c1ed050/IDRD_A_2149899_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e6/9704105/96e659d83a32/IDRD_A_2149899_F0008_C.jpg

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引用本文的文献

[1]
Development of Novel Fluticasone/Salmeterol/Tiotropium-Loaded Dry Powder Inhaler and Bioequivalence Assessment to Commercial Products in Rats.

Pharmaceutics. 2025-1-14

[2]
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本文引用的文献

[1]
Effects of L-leucine on the properties of spray-dried swellable microparticles with wrinkled surfaces for inhalation therapy of pulmonary fibrosis.

Int J Pharm. 2021-12-15

[2]
Co-Spray Dried Nafamostat Mesylate with Lecithin and Mannitol as Respirable Microparticles for Targeted Pulmonary Delivery: Pharmacokinetics and Lung Distribution in Rats.

Pharmaceutics. 2021-9-19

[3]
Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis.

PLoS One. 2021

[4]
Leucine as an excipient in spray dried powder for inhalation.

Drug Discov Today. 2021-10

[5]
Butyrate Improves Skin/Lung Fibrosis and Intestinal Dysbiosis in Bleomycin-Induced Mouse Models.

Int J Mol Sci. 2021-3-9

[6]
A critical review of spray-dried amorphous pharmaceuticals: Synthesis, analysis and application.

Int J Pharm. 2021-2-1

[7]
Inhaled bosentan microparticles for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats.

J Control Release. 2021-1-10

[8]
The Effect of Particle Size and Surface Roughness of Spray-Dried Bosentan Microparticles on Aerodynamic Performance for Dry Powder Inhalation.

Pharmaceutics. 2020-8-13

[9]
Imaging Biomarkers and Pathobiological Profiling in a Rat Model of Drug-Induced Interstitial Lung Disease Induced by Bleomycin.

Front Physiol. 2020-6-19

[10]
Caveolin-1-derived peptide limits development of pulmonary fibrosis.

Sci Transl Med. 2019-12-11

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