Respiratory Technology, The Woolcock Institute for Medical Research and Discipline of Pharmacology, Sydney Medical School, University of Sydney, NSW 2006, Australia.
Chiesi Limited, Chippenham, Wiltshire, United Kingdom.
Int J Pharm. 2018 Jun 10;544(1):141-152. doi: 10.1016/j.ijpharm.2018.04.012. Epub 2018 Apr 10.
This study was performed to investigate how increasing the active pharmaceutical ingredient (API) content within a formulation affects the dispersion of particles and the aerosol performance efficiency of a carrier based dry powder inhalable (DPI) formulation, using a custom dry powder inhaler (DPI) development rig.
Five formulations with varying concentrations of API beclomethasone dipropionate (BDP) between 1% and 30% (w/w) were formulated as a multi-component carrier system containing coarse lactose and fine lactose with magnesium stearate. The morphology of the formulation and each component were investigated using scanning electron micrographs while the particle size was measured by laser diffraction. The aerosol performance, in terms of aerodynamic diameter, was assessed using the British pharmacopeia Apparatus E cascade impactor (Next generation impactor). Chemical analysis of the API was observed by high performance liquid chromatography (HPLC).
Increasing the concentration of BDP in the blend resulted in increasing numbers and size of individual agglomerates and densely packed BDP multi-layers on the surface of the lactose carrier. BDP present within the multi-layer did not disperse as individual primary particles but as dense agglomerates, which led to a decrease in aerosol performance and increased percentage of BDP deposition within the Apparatus E induction port and pre-separator.
As the BDP concentration in the blends increases, aerosol performance of the formulation decreases, in an inversely proportional manner. Concurrently, the percentage of API deposition in the induction port and pre-separator could also be linked to the amount of micronized particles (BDP and Micronized composite carrier) present in the formulation. The effect of such dose increase on the behaviour of aerosol dispersion was investigated to gain greater insight in the development and optimisation of higher dosed carrier-based formulations.
本研究旨在使用定制的干粉吸入器（DPI）开发装置，研究制剂中活性药物成分（API）含量的增加如何影响颗粒的分散以及基于载体的干粉吸入剂（DPI）制剂的气溶胶性能效率。
使用含有粗乳糖和细乳糖以及硬脂酸镁的多组分载体系统，配制了 API 倍氯米松二丙酸酯（BDP）浓度在 1%至 30%（w/w）之间的 5 种制剂。使用扫描电子显微镜研究制剂和各成分的形态，通过激光衍射测量粒径。使用英国药典装置 E 级级联撞击器（下一代撞击器）评估气溶胶性能，以空气动力学直径表示。通过高效液相色谱法（HPLC）观察 API 的化学分析。
混合物中 BDP 浓度的增加导致单个团聚体的数量和尺寸增加，并且乳糖载体表面上的 BDP 多层紧密堆积。存在于多层中的 BDP 没有分散为单个初级颗粒，而是作为密集的团聚体，这导致气溶胶性能下降，装置 E 诱导口和预分离器内的 BDP 沉积百分比增加。
随着混合物中 BDP 浓度的增加，制剂的气溶胶性能呈反比下降。同时，诱导口和预分离器中 API 沉积的百分比也可能与制剂中存在的微米化颗粒（BDP 和微米化复合载体）的量有关。研究这种剂量增加对气溶胶分散行为的影响，旨在深入了解高剂量载体制剂的开发和优化。
