School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College Dublin, Dublin 2, Ireland.
Mol Pharm. 2011 Oct 3;8(5):1887-98. doi: 10.1021/mp200231c. Epub 2011 Sep 15.
For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPβCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPβCD were co-spray dried. Based on the particle properties, the best PEG:HPβCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPβCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 μg/kg was 2.3 times greater than for the nebulized sCT solution.
对于治疗性肽，肺部是一种有吸引力的、非侵入性的进入血液的途径。为了达到最佳的生物利用度并控制其快速吸收速度，可以通过与聚合物（如聚乙二醇（PEG））共加工来保护肽。在这里，我们使用线性或支化 PEG（L-PEG 或 B-PEG）和羟丙基-β-环糊精（HPβCD）来制备和表征鲑鱼降钙素（sCT）负载的微粒，并用于肺部给药。sCT、L-PEG 或 B-PEG 和 HPβCD 的混合物被共喷雾干燥。根据颗粒特性，对于两种 PEG，最佳的 PEG:HPβCD 比为 1:1w:w。在负载 sCT 的颗粒中，L-PEG 比 B-PEG 更具结晶性。因此，基于 L-PEG 的颗粒具有比基于 B-PEG 的颗粒更低的表面自由能和更好的空气动力学行为。然而，基于 B-PEG 的颗粒能更好地保护 sCT 免受化学降解。当 PEG 和 HPβCD 的浓度均为 1.6wt%时，穿过 Calu-3 支气管上皮单层测量的 sCT 渗透性会降低。这归因于两种赋形剂引起的缓冲液粘度增加。在静脉注射或肺部吹入后，通过 2 室模型评估 Wistar 大鼠中的 sCT 药代动力学曲线。在 sCT 溶液雾化后 3 分钟内达到 sCT 最大血浆浓度。基于 L-PEG 和 B-PEG 的微粒分别能够将 T(max)延长至 20±1min 和 18±8min。此外，基于 L-PEG 的微粒气溶胶化后 sCT 的绝对生物利用度在 100μg/kg 时是雾化 sCT 溶液的 2.3 倍。
