# Preparation of aspirin inhalable powder by ultrasound-intensified anti-solvent crystallization for pulmonary drug delivery

## TL;DR

This study develops an aspirin inhalable powder using ultrasound to improve drug delivery to the lungs, reducing side effects and increasing effectiveness.

## Contribution

The novel use of ultrasound-intensified anti-solvent crystallization and machine learning to optimize aspirin inhalable powder for pulmonary delivery.

## Key findings

- Adding L150 and L-leucine improved powder flowability and increased fine particle fraction from 10.40% to 45.86%.
- Aspirin inhalable powder showed high permeability in lung epithelial tissue and no significant cytotoxicity.
- Inhalation delivered aspirin faster and with higher bioavailability compared to oral administration in rats.

## Abstract

Aspirin is an antiplatelet agglutinating drug used clinically for the prevention and treatment of angina pectoris, myocardial infarction, and cerebral thrombosis. In this study, aspirin inhalable powder was prepared by ultrasound-intensified anti-solvent crystallization (UIAC) and developed for rapid antiplatelet aggregation, which could reduce the dose and gastrointestinal irritation. The particle size distribution, morphology, density, fluidity, and in vitro aerodynamic performance of the as-prepared powders were systematically evaluated. Meanwhile, machine learning methodology, specifically utilizing the Decision Tree Regressor in conjunction with Shapley Value analysis, was applied to elucidate the influence of critical process parameters within the production process. The powder flowability could be improved by the addition of excipients L150 and L-leucine (Leu). The value of fine particle fraction (FPF) increased from 10.40 % to 45.86 % when adding L150 (60 %, w/w) and Leu (5 %, w/w). The cytotoxicity study of aspirin inhalable powder was performed at cellular level, and demonstrated aspirin powder had no significant toxic effect. The Calu-3 cell monolayer interfaced to simulate lung epithelial tissue, demonstrated the high permeability of inhalable powder in lung. Pharmacokinetics were investigated in healthy rats, compared with oral administration, the Tmax of inhale administration (10 min) was significantly shorter than oral administration (30 min), and the AUC was 1.91 times higher than that of the oral administration, demonstrating that pulmonary drug delivery accelerated the absorption and increased the bioavailability of aspirin.