Stein Stephen W, Sheth Poonam, Younis Usir S, Mogalian Erik, Myrdal Paul B
3M Drug Delivery Systems , 3M Center-Building 260-3A-05, St. Paul, Minnesota 55144, United States.
Cirrus Pharmaceuticals, Inc. , 511 Davis Drive, Suite 100, PO Box 14748, Morrisville, North Carolina 27560, United States.
Mol Pharm. 2015 Sep 8;12(9):3455-67. doi: 10.1021/acs.molpharmaceut.5b00467. Epub 2015 Aug 24.
A simulation model has been established to predict the residual aerodynamic particle size distribution (APSD) of dual-component pressurized metered dose inhalers (pMDIs). More specifically, this model estimates the APSD of pMDI formulations containing dissolved and suspended compounds for various formulations, and has been verified experimentally. Simulated and experimental data illustrate that APSDs of the dissolved and suspended components of the pMDI are influenced by concentrations of the dissolved and micronized suspended drugs, along with suspended drug size. Atomized droplets from such combination formulations may contain varying number of suspended drug particles and a representative concentration of dissolved drug. These sub-populations of atomized droplets may explain the residual APSDs. The suspended drug follows a monomodal, lognormal distribution and is more greatly impacted by the size and concentration of the suspended drug in comparison to the concentration of dissolved drug. On the other hand, dissolved drug illustrates a bimodal, lognormal residual particle size distribution both theoretically and experimentally. The smaller mode consists of residual particles made of dissolved drug only, while the larger mode consists of residual particles that contain both dissolved and suspended drugs. The model effectively predicted the size distributions of both the dissolved and suspended components of combination formulations (r(2) value of 0.914 for the comparison of simulated versus experimental MMAD values for the formulations examined). The results demonstrate that this model is a useful tool that may be able to expedite the development of combination pMDI formulation.
已建立一个模拟模型来预测双组分压力定量吸入器（pMDI）的残余空气动力学粒径分布（APSD）。更具体地说，该模型估计了各种配方中含有溶解和悬浮化合物的pMDI配方的APSD，并已通过实验验证。模拟和实验数据表明，pMDI溶解和悬浮成分的APSD受溶解和微粉化悬浮药物的浓度以及悬浮药物粒径的影响。此类复方制剂的雾化液滴可能含有数量不等的悬浮药物颗粒和具有代表性浓度的溶解药物。这些雾化液滴的亚群可以解释残余APSD。悬浮药物呈单峰对数正态分布，与溶解药物浓度相比，其受悬浮药物的粒径和浓度影响更大。另一方面，溶解药物在理论和实验上均呈现双峰对数正态残余粒径分布。较小的峰由仅由溶解药物构成的残余颗粒组成，而较大的峰由同时含有溶解和悬浮药物的残余颗粒组成。该模型有效地预测了复方制剂溶解和悬浮成分的粒径分布（在所研究配方的模拟与实验MMAD值比较中，r(2)值为0.914）。结果表明，该模型是一种有用的工具，或许能够加速复方pMDI制剂开发。
