Preparation of 18β-Glycyrrhetinic Acid Liposome and Its Therapeutic Effect on Pulmonary Arterial Hypertension

Yanmin Pei,1,* Meidong Si,1,* Xuemei Ma,1 Siyun Liu,1 Fang Zhao,2 Ru Zhou1,3,4 1School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Pediatric Intensive Care Unit, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 3NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 4Ningxia Characteristic Traditional Chinese Medicine Modernization Engineering Technology Research Center, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Zhao, Pediatric Intensive Care Unit, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China, Tel/Fax +86 951 409 1488, Email [email protected] Ru Zhou, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China, Tel/Fax +86 951 698 0192, Email [email protected]: 18β-Glycyrrhetinic acid liposomes (18β-GA-Lips) were developed to enhance lung-specific drug delivery and optimize the therapeutic management of pulmonary arterial hypertension (PAH).Methods: 18β-GA-Lips of varying particle sizes were formulated using the film-dispersion method and the thin-film dispersion-probe ultrasonic technique. Their characteristics, pharmacokinetics, and tissue distribution were thoroughly investigated, followed by an inhalation subacute toxicological analysis. Anti-PAH effects were assessed through hemodynamic measurements, right ventricular hypertrophy evaluation, echocardiography, histomorphometric, and morphological analyses.Results: The 18β-GA-Lips, with varying particle sizes, exhibited a uniform spherical morphology, achieved entrapment efficiencies exceeding 80%, and had average particle sizes ranging from 150 to 1183 nanometers. These were categorized into four distinct size groups. The drug release profile demonstrated favorable sustained-release characteristics in vitro, and the formulation remained stable for up to 15 days when stored at 4°C. Pharmacokinetic analyses revealed that, compared with the 18β-GA-solution group, the AUC(0→ 48), MRT(0→ 48), t1/2, tmax, and clearance rate of 18β-GA-Lips in each group were 4.42, 3.27, 4.28, 5.07, 2.10, 3.41, 1.73, 1.46, 1.53, 1.32, 1.79, 1.67, 0.61, 2.11, 0.71, 1.71, 1.15, 0.62, 0.96, and 0.90 times higher, respectively. Tissue distribution studies revealed that B-18β-GA-Lips exhibited the highest lung-targeting efficiency, with a Te value of 54.13%. No apparent signs of toxicity were observed. In vivo data demonstrate that rats treated with 18β-GA in different formulations (solution and liposomal) and with NO exhibited significantly lower mPAP and RVSP compared to the SuHx group, with no statistically significant differences observed among the treatment groups. Notably, 18β-GA-Lips exhibited a more pronounced reduction in RVHI compared to oral solutions and significantly attenuated pulmonary vascular remodeling. Furthermore, pharmacodynamic evaluations indicated that 18β-GA-Lips exhibited superior inhibitory effects on PAH in rats compared to both atomized and intragastric 18β-GA solutions.Conclusion: These findings confirm that 18β-GA-Lips exhibit outstanding lung-targeting capabilities and lack inhalation toxicity, thereby significantly enhancing the therapeutic efficacy of treatments for PAH.Keywords: 18β-glycyrrhetinic acid, liposomes, pharmacokinetics, lung targeting, pulmonary arterial hypertension