Formulation and characterisation of oleanolic acid and mannitol dry powders for pulmonary delivery

Abstract

Pulmonary drug delivery is attractive in the treatment of both respiratory and systemic disease. Dry powder inhalers (DPIs) are highly efficient systems for pulmonary drug delivery. The present study is focusing on improving the physiochemical and biopharmaceutical performance of carrier free DPI formulation by means of formulation design and process optimization in order to enhance the therapeutic efficacy of aerosols. For respiratory disease therapy especially lung cancer, an inhalable oleanolic acid (OA) loaded hypromellose dry powder with sustained release property was successfully prepared by co-spray drying OA and hypromellose. OA was molecularly dispersed in an amorphous form in the hypromellose matrix with no covalent bonding to the polymer. The fine particle size and corrugated surface

morphology enabled high aerosolisation performance of dry powders. Comparing to raw OA, dry powders released OA in a sustained pattern, and solution-mediated phase transformation dominated the release from high drug loading powders. Furthermore, the hypromellose showed no toxicity to A549 cells and the bioactivity of OA with regards to cytotoxicity was well preserved after spray drying. For systemic disease therapy, an OA dry powder with absorption enhancer was designed to improved dissolution rate and permeability across the lung epithelium. Mannitol serving as a mucolytic agent and D-α-tocopheryl polyethylene glycol succinate TPGS1000 functioning as absorption enhancer were incorporated into the dry powder by co-spray drying with OA. Optimized dry powder formulation was screened in terms of dissolution behavior, aerosolization performance and permeability. The dry powder TPGS1% with mass ratio of OA: mannitol: TPGS1000 (50 : 49 : 1) exhibited the best overall performance. Powder particles were nearly spheroidal with rough surfaces in diameter around 2.5 μm. The dissolution rate and aerosolization performance of powders containing absorption enhancer were comparable with drug only formulation, whereas the permeability was approximately 4 times higher. To produce crystalline dry powders, an isothermal antisolvent crystallization method via batch crystallizer integrated with wet mill was proposed as a new process. This additive-free approach enabled tuning particles characteristic such as particle shape by adjusting the process parameter. The coupled wet mill improved the process efficiency through facilitating the generation of fine particles. In preparing hydrophobic drug OA, higher ratio of acetone to water in the antisolvent yielded more elongated OA particles. OA crystals obtained at ratio of acetone to water 5 : 5 in antisolvent displayed the best aerosolization performance with fine particle fraction (FPF) around 42.0 %. For hydrophilic compound mannitol, increased water to ethanol ratio in the antisolvent induced the transformation of α form into β form accompanied with formation of shorter crystals. After fully transforming into β form, further raising water content in the antisolvent produced more elongated crystals. The α form mannitol crystals with the lowest circularity represented the highest FPF 42.7%. The formulations and crystallization process developed in this work promise good potential in efficient inhalation therapy, and could be further expanded to deliver a variety of hydrophobic or hydrophilic drugs for inhalation.