Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA.
J Pharm Sci. 2010 Jul;99(7):3150-65. doi: 10.1002/jps.22091.
The challenges in forming stable drug suspensions in hydrofluoroalkane (HFA) propellants have limited drug dosages and efficiency of drug delivery with pressurized metered dose inhalers (pMDI). Herein, stable suspensions of weakly flocculated particles, in the shape of thin plates or needles, of a poorly water-soluble drug, itraconazole (Itz), are efficiently delivered by pMDI at high doses, up to 2.4 mg/actuation. These anisotropic particles pack inefficiently and form low-density flocs that stack upon each other to prevent settling. In contrast, spherical particles formed dense aggregates that settled within minutes. Upon actuation of the pMDI, atomized propellant droplets shear apart and thus template the highly friable flocs. Evaporation of the HFA compacts the flocs to yield porous particles with optimal aerodynamic properties. High fine particle fractions (49-64%) were achieved with the stable suspensions for drug loadings up to 50 mg/mL. Furthermore, the micron-sized particles, ideal for pulmonary delivery, are composed of nanoparticles that dissociate and facilitate rapid dissolution of poorly water-soluble drugs. Pulmonary delivery of stable suspensions of templated, open flocs is broadly applicable to a range of anisotropic particle morphologies for poorly water-soluble drugs and proteins for efficient delivery of high doses, up to several milligrams, using minimal amounts of excipients.
在全氟烷烃（HFA）推进剂中形成稳定药物混悬液的挑战限制了药物剂量和压力定量吸入器（pMDI）的药物输送效率。本文中，以较差水溶性药物伊曲康唑（Itz）为模型药物，制备了具有各向异性的、弱絮凝聚并呈薄片状或针状的、在 HFA 推进剂中能够高效输送的稳定混悬液，其药物剂量高达 2.4mg/吸。这些各向异性的片状或针状颗粒的堆积效率低，形成低密度絮体，相互堆积以防止沉降。相比之下，球形颗粒形成了密集的聚集体，在几分钟内就沉降了。在 pMDI 启动时，雾化的推进剂液滴会将其剪切开，从而形成高度易碎的絮体。HFA 的蒸发会使絮体压实，得到具有最佳空气动力学性能的多孔颗粒。对于药物载量高达 50mg/mL 的稳定混悬液，可实现 49-64%的高微细粒子分数。此外，对于肺部给药而言，这些微米级的颗粒是由纳米颗粒组成的，其易于解离并促进较差水溶性药物的快速溶解。采用模板化开放絮体的稳定混悬液进行肺部给药，广泛适用于各种各向异性的较差水溶性药物和蛋白质的纳米颗粒形态，可实现高效输送高剂量药物（高达数毫克），同时仅使用少量辅料。
