Influence of stabilizer type and concentration on the lung deposition and retention of resveratrol nanosuspension-in-microparticles

摘要

The purpose of this study was to explore the influence of stabilizer type and concentration on the properties of spray dried nanosuspension-in-microparticles (NS-in-MPs) for inhalation. Taking resveratrol (RES) as a Biopharmaceutical Classification System II (BCS II) model drug, the RES containing nanosuspensions were fabricated by high pressure homogenization method with different stabilizers including sodium dodecyl sulphate (SDS), sodium alginate (SA), chitosan (CS) and polyvinyl alcohol (PVA). Then, the nanosuspensions were spray dried with mannitol to obtain inhalable NS-in-MPs. The particle size, morphology, drug existing state, in vitro aerodynamic performance, in vitro release behavior, lung retention and pharmacokinetic behaviors were characterized. It was found that the morphology, lung deposition as well as in vitro drug release from the microparticles were significantly influenced by stabilizer type, with 1% PVA as stabilizer presenting the highest fine particle fraction (FPF). Meanwhile, taking PVA as an example, it was found stabilizer concentration could alter morphology and flowability of the microparticles, and the FPF value decreased with the increase of stabilizer concentration. Further drug retention and in vivo pharmacokinetic studies demonstrated that the positively charged stabilizer CS could facilitate drug retention and minimize drug expose to the systemic circulation. In conclusion, the deposition and lung retention behavior of NS-in-MPs could be well tuned by selecting different type or concentration of stabilizers, which could facilitate local lung diseases therapy.