Dry Powder Inhalation of Nintedanib in Dibasic Calcium Phosphate for Targeting the Lungs in Pulmonary Fibrosis.

Abstract

We prepared three variants of nintedanib dry powder inhalations (DPIs), one with dibasic calcium phosphate dihydrate (CaHPO₄·2H₂O) and two with lactose monohydrate as the carrier. CaHPO₄ is not reported as a DPI excipient. We compared nintedanib pharmacokinetics and efficacy of the CaHPO₄ formulation against bleomycin-induced pulmonary fibrosis following oral (3.875 mg/q12h) and DPI (200 μg/12 h) dosing in rats. Blood plasma C_max, T_max, and AUC resulting from oral dosing and DPI were 780 versus 147.5 μg/mL, 2.47 versus 2.22 h, and 5562 versus 1094 μg/mL·h, respectively. Drug remaining in the lungs and airways at the end of 12 h of dosing with the DPI (2.41 ± 0.37 μg/g of tissue) was double the amount found after oral dosing (1.25 ± 0.56 μg/g). Lung fibrosis induced in rats using bleomycin was resolved equally well by the two interventions administered q12h for 14 days. We submit that the reduction in systemic exposure to nintedanib and enhanced exposure to target tissue could offer significant therapeutic and safety advantages, and CaHPO₄ can be easily developed as an excipient for DPIs.