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Physicochemical and Pharmacokinetic Evaluation of Spray-Dried Coformulation of Salvia miltiorrhiza Polyphenolic Acid and L-Leucine with Improved Bioavailability.

Abstract：

: Background: Salvia miltiorrhiza polyphenolic acid (SMPA) is effective in the treatment of cardiovascular diseases and currently it is administered orally or intravenously. However, SMPA is poorly absorbed orally and quickly eliminated in vivo. A long-term frequent intravenous administration leads to poor patient compliance. Therefore, it is urgently demanded to find a new alternative route of noninjection drug delivery system for SMPA. Methods: Two dry powder inhalation (DPI) formulations of spray-dried SMPA formulation (P1) and spray-dried SMPA-L-leucine formulation (P2) were prepared by spray drying method and their physicochemical properties were assessed by thermogravimetric analysis, X-ray diffraction, scanning electron microscopy, particle size distribution analysis, and in vitro aerodynamic analysis. Moreover, In vitro cytotoxicity of SMPA and P2 was conducted with NR8383 cells. In vivo pharmacokinetics were carried out by Penn-Century endotracheal intubation technique to deliver P2 to the lungs of rats. Results and Conclusions: The moisture content of P1 and P2 were 5.81% ± 0.005%, and 4.08% ± 0.002%, respectively. P1 and P2 were in an amorphous state. Moreover, P1 had slightly corrugated surfaces, whereas P2 exhibited severely corrugated surfaces with invagination due to the presence of L-leucine. In addition, there were more hollow particles with smooth surface in P1 than that in P2. Compared with P1, P2 has shown optimal physical particle size and aerosolization behavior with D (v, 50) of 2.64 ± 0.01 μm and fine particle fraction of 37.55% ± 2.63%. The findings of in vitro cytotoxicity showed that P2 did not inhibit cell viability and could be safe for pulmonary administration. The absolute bioavailability of salvianolic acid B (Sal B) for pulmonary administration was 19.15% ± 7.44%, which is significantly higher than the oral bioavailability of Sal B (<5.56%). In this study, we have shown the feasibleness of pulmonary administration of SMPA in the form of DPIs for systemic delivery to treat cardiovascular diseases.

journal_name

J Aerosol Med Pulm Drug Deliv

journal_title

Journal of aerosol medicine and pulmonary drug delivery

authors

Lu P,Xing Y,Peng H,Liu Z,Zhou QT,Xue Z,Ma Z,Kebebe D,Zhang B,Liu H

doi

10.1089/jamp.2019.1538

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

73-82

issue

eissn

1941-2711

issn

1941-2703

journal_volume

pub_type

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Physicochemical and Pharmacokinetic Evaluation of Spray-Dried Coformulation of Salvia miltiorrhiza Polyphenolic Acid and L-Leucine with Improved Bioavailability.