(M1230-03-18) Formulation of an Inhalable Nanoemulsion Prepared with a Deep Eutectic Solvent of Pirfenidone and Citric Acid

Purpose: The aim of this study was to prepare an inhalable nanoemulsion of Pirfenidone (PRF) using a deep eutectic solvent (DES) composed of PRF and citric acid (CA), which can have a higher concentration of PRF than the original drug. The DES is a mixture of two crystalline powders with a low melting point, which can load a higher concentration of PRF than the original drug.

Methods: DES was prepared by heating a PRF-CA mixture and NE-DES was prepared by mixing it with DW. The prepared NE-DES was evaluated for solubility and compared with the original PRF solution (raw) made by dissolving PRF in DW. In an in vivo test, ITI (NE-DES) group was administered by intratracheal instillation (ITI) using a micro-spray pump at 30 mg/kg of NE-DES to SD-rat, and Oral (raw) and ITI (raw) groups were administered at an equivalent dosage for comparison as control groups. Lungs and blood were collected from the drug-administered rats over time, and the amount of PRF accumulated in the lungs per weight (µg/g) and the concentration of the drug in plasma were obtained using HPLC.

Results: The solubility of Oral (raw) was about 19.5 µg/ml, and the solubility of ITI (NE-DES) was about 8.9 times higher than that of Oral (raw). In vivo results, Oral (raw), ITI (raw), ITI (NE-DES) groups showed Cmax of 48.14±12.03, 35.78±2.79, and 75.20±18.41 µg/g respectively, and AUC of 13.56±1.74, 17.85±4.10, and 25.30±3.78 h*µg/g, respectively. The bioavailability of the ITI (NE-DES) group was 1.4 times higher than the ITI (raw) group.

Conclusion: In conclusion, PRF was able to significantly increase solubility by preparing NE-DES with CA. In an in-vivo test, the possibility of drug delivery to liquid inhalation of PRF approved for oral pulmonary anti-fibrotic was confirmed.

Acknowledgements: this research was also supported by "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE)(2021RIS-001).

Figure 1. Formulation and properties of NE-DES

Figure 2. Solubility of Pirfenidone in Oral (raw) and ITI (NE-DES)

Figure 3. Pharmacokinetics and efficacy study