Sharif Shahjabeen, Muneer Saiqa, Izake Emad L, Islam Nazrul
Pharmacy Discipline, School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4000, Australia.
School of Chemistry and Physics, Science and Engineering Faculty, Queensland University of Technology, Brisbane, QLD 4000, Australia.
Pharmaceutics. 2023 Feb 16;15(2):674. doi: 10.3390/pharmaceutics15020674.
This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and TGA. Using a Twin-Stage Impinger (TSI), the in vitro aerosolization of the formulations with and without carrier lactose was studied at a flow rate of 60± 5 L/min and the IBF was determined using a validated HPLC method. The flow properties were determined by the Carr's Index (CI), Hausner Ratio (HR) and Angle of Repose (AR) of the milled IBF with 4-6.25% leucine and leucine containing formulations showed higher flow property than those of formulations without leucine. The fine particle fraction (FPF) of IBF from the prepared formulations was significantly ( = 0.000278) higher (37.1 ± 3.8%) compared to the original drug (FPF 3.7 ± 0.9%) owing to the presence of leucine, which enhanced the aerosolization of the milled IBF particles. Using quantitative phase analysis, the XPRD data revealed the crystallinity and accurate weight percentages of the milled IBF in the formulations. FTIR revealed no changes of the structural integrity of the milled IBF in presence of leucine or MgSt. The presence of 2.5% MgSt in the selected formulations produced the highest solubility (252.8 ± 0.6 µg/mL) of IBF compared to that of unmilled IBF (147.4 ± 1.6 µg/mL). The drug dissolution from all formulations containing 4-6.25% leucine showed 12.2-18.6% drug release in 2.5 min; however, 100% IBF dissolution occurred in 2 h whereas around 50% original and dry milled IBF dissolved in 2 h. The results indicated the successful preparation of inhalable IBF microparticles by the wet milling method and the developed DPI formulations with enhanced aerosolization and solubility due to the presence of leucine may be considered as future IBF formulations for inhalation.
本研究调查了亮氨酸和硬脂酸镁（MgSt）包埋的湿磨可吸入布洛芬（IBF）干粉吸入剂（DPI）制剂的开发与特性。通过湿磨均质工艺制备了IBF微粒，并通过扫描电子显微镜（SEM）、傅里叶变换红外光谱（FTIR）、差示扫描量热法（DSC）、X射线衍射（XRD）和热重分析（TGA）对其进行了表征。使用双级撞击器（TSI），在流速为60±5 L/min的条件下研究了含和不含载体乳糖的制剂的体外雾化情况，并采用经过验证的高效液相色谱（HPLC）方法测定IBF。通过卡尔指数（CI）、豪斯纳比（HR）和休止角（AR）测定了研磨后的含4 - 6.25%亮氨酸的IBF及其制剂的流动性质，含亮氨酸的制剂比不含亮氨酸的制剂表现出更高的流动性质。由于亮氨酸的存在，所制备制剂中IBF的细颗粒分数（FPF）显著更高（P = 0.000278）（37.1±3.8%），相比原料药（FPF 3.7±0.9%）有所提高，亮氨酸增强了研磨后IBF颗粒的雾化。使用定量相分析，X射线粉末衍射（XPRD）数据揭示了制剂中研磨后IBF的结晶度和准确重量百分比。FTIR显示在存在亮氨酸或MgSt的情况下，研磨后IBF的结构完整性没有变化。与未研磨的IBF（147.4±1.6 µg/mL）相比，所选制剂中2.5% MgSt的存在使IBF的溶解度最高（252.8±0.6 µg/mL）。所有含4 - 6.25%亮氨酸的制剂在2.5分钟内药物溶出显示12.2 - 18.6%的药物释放；然而，100%的IBF在2小时内溶解，而原料药和干磨IBF在2小时内约50%溶解。结果表明通过湿磨法成功制备了可吸入的IBF微粒，并且由于亮氨酸的存在而开发的具有增强雾化和溶解度的DPI制剂可被视为未来用于吸入的IBF制剂。
