Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers
Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers
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DOI：
10.1208/s12249-018-1071-7
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发表时间：
2018-07-01
影响因子：
3.3
通讯作者：
Saluja, Bhawana
中科院分区：
文献类型：
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作者：
Schroeter, Jeffry D.;Sheth, Poonam;Saluja, Bhawana
加压定量吸入器（MDI）的性能受制剂和器械变量的影响，这些变量会影响递送剂量、空气动力学粒度分布，进而影响肺部沉积和治疗效果。评价了与两种市售产品-Prosthesis A（R）HFA [硫酸沙丁胺醇（AS）混悬液]和QvarA（R）[二丙酸倍氯米松（BDP）溶液]相关的特定制剂变量，以确定其对体外级联冲击研究实验测量的关键性能属性的影响。这些商用计量吸入器用作模型系统，为生产多种悬浮液和溶液计量吸入器配方的实验设计计划提供了中间点。实验结果被用作输入变量的计算剂量学模型，以预测MDI配方变量对肺沉积的影响。对于BDP溶液DoE MDI，增加表面活性剂油酸（0- 2%w/w）的浓度使肺沉积从24%增加到46%，而共溶剂乙醇（7- 9%w/w）浓度的变化对肺沉积没有影响。对于AS悬浮DoE计量吸入器，（0.005- 0.25%w/w）对肺沉积没有显著影响，而当乙醇浓度从2增加到20%w/w时，肺沉积从48%降低到26%，并且微粉化药物体积中值粒度分布的变化（X（50），1.4-2.5 μ m）使气管支气管气道中的沉积从5%增加到11%。观察到细颗粒分数和预测的肺沉积之间存在直接相关性。这些结果表明，使用剂量学模型，以进一步探讨性能变量和肺沉积之间的关系的价值。
The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-ProventilA (R) HFA [albuterol sulfate (AS) suspension] and QvarA (R) [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0-2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7-9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005-0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X (50), 1.4-2.5 mu m) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.