A dry powder inhalable formulation of salvianolic acids for the treatment of pulmonary fibrosis: safety, lung deposition
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ORIGINAL ARTICLE
A dry powder inhalable formulation of salvianolic acids for the treatment of pulmonary fibrosis: safety, lung deposition, and pharmacokinetic study Linxia Jiang 1 & Yijun Li 1 & Jiaqi Yu 1 & Jianhong Wang 1 & Jiarui Ju 1 & Jundong Dai 1 Accepted: 16 September 2020 # Controlled Release Society 2020
Abstract Salvianolic acids (SAL), the main bioactive component extracted from Salvia miltiorrhiza, is a natural product with a reported anti-pulmonary fibrosis (PF) effect. SAL is commonly administrated orally; however, it has a low oral bioavailability (less than 5%). The objective of this work was to develop a new dry powder inhalable formulation intended to facilitate the access of SAL to the target place. We prepared the new SAL powder formulation containing L-arginine and 2% of lecithin using the ball milling technique. L-arginine was used to regulate the strong acidity of the SAL solution, and lecithin was added to disperse the powder and improve the flowability. The resulting powder had a content in salvianolic acid B (SALB, the main active principle of SAL) of 66.67%, a particle size of less than 5 μm and a good flowability. In vivo fluorescence imaging showed that the powder could be successfully aerosolized and delivered to the lung. The acute lung irritation study proved that the presence of L-arginine improved the biocompatibility of the powder. Finally, according to the pharmacokinetic study, the new SAL powder formulation was found to significantly increase drug concentration in the lung and the bioavailability. In conclusion, the new dry powder inhalable formulation of SAL developed in this study could be a strategy to enhance the performance of SAL at the lung level. Keywords Salvianolic acids . Dry powder inhaler . Pulmonary fibrosis . Safety . Bioavailability
Introduction Pulmonary fibrosis (PF) is a fatal disease characterized by diffuse pulmonary inflammation and progressive fibrosis, which eventually leads to respiratory failure and loss of lung function [1]. Its pathological manifestations are excessive deposition of extracellular matrix and hyperproliferation of myofibroblasts [2]. According to the pathogenesis, PF can be further divided into secondary pulmonary fibrosis (SPF) and idiopathic pulmonary fibrosis (IPF) [3]. The cause of SPF is clear, including dust, gas, viruses, bacteria, and drugs. However, IPF is unknown etiology and may be related to environmental exposure, smoking, and chronic viral infection
Linxia Jiang and Yijun Li contributed equally to this work. * Jundong Dai [email protected] 1
Department of Chinese Medicinal Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fangshan District, Beijing 102488, China
[4]. Some studies have proven that the incidence and mortality of PF are on the rise in many countries [5, 6]. Between 1991 and 2003, the incidence of IPF in the UK increased by 11% annually [5]. Meanwhile, there was an overall 2–3% annual increase in mortality of IPF by analyzing data from 1999 to
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