Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers.
Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers.
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DOI：
10.1007/s11095-015-1808-x
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发表时间：
2016-03
影响因子：
3.7
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Ong W;Nowak P;Cu Y;Schopf L;Bourassa J;Enlow E;Moskowitz SM;Chen H
在吸入治疗期间用于延长局部作用的传统聚合物纳米颗粒制剂对粘膜-纤毛清除高度敏感。此外，由于有限的药物负载，聚合物载体通常以高剂量施用。由于毒理学原因，这些载体及其降解副产物由于潜在的肺蓄积而不适于吸入治疗，特别是长期使用。我们合成了一种新型的时间依赖性β-内酰胺美罗培南的不溶性前体药物（MRPD），并将MRPD制成粘液穿透晶体（MRPD-MPC）。在描述了它们的粘液流动性（体外）和稳定性之后，我们评估了豚鼠中气管内滴注MRPD-MPC和美罗培南溶液的肺药代动力学。与给予MRPD-MPC的豚鼠相比，接受美罗培南溶液的豚鼠肺中美罗培南水平迅速下降。在给药后9 h，接受美罗培南溶液的动物肺部药物水平降至12 ng/mL，而接受MRPD-MPC的动物在12 h内保持平均药物水平≥ 1，065 ng/mL。这项工作表明，前药化学和粘液渗透平台的组合产生了纳米颗粒，在豚鼠肺中产生持续水平的美罗培南。这种策略代表了一种新的方法，持续的局部药物输送到肺部，而不使用封装矩阵。
Traditional polymeric nanoparticle formulations for prolonged local action during inhalation therapy are highly susceptible to muco-ciliary clearance. In addition, polymeric carriers are typically administered in high doses due to finite drug loading. For toxicological reasons, these carriers and their degradation byproducts are undesirable for inhalation therapy, particularly for chronic use, due to potential lung accumulation. We synthesized a novel, insoluble prodrug (MRPD) of a time-dependent β-lactam, meropenem, and formulated MRPD into mucus-penetrating crystals (MRPD-MPCs). After characterizing their mucus mobility (in vitro) and stability, we evaluated the lung pharmacokinetics of intratracheallyinstilled MRPD-MPCs and a meropenem solution in guinea pigs. Meropenem levels rapidly declined in the lungs of guinea pigs receiving meropenem solution compared to those given MRPD-MPCs. At 9 h after dosing, drug levels in the lungs of animals that received meropenem solution dropped to 12 ng/mL, whereas those that received MRPD-MPCs maintained an average drug level of ≥1,065 ng/mL over a 12-h period. This work demonstrated that the combination of prodrug chemistry and mucus-penetrating platform created nanoparticles that produced sustained levels of meropenem in guinea pig lungs. This strategy represents a novel approach for sustained local drug delivery to the lung without using encapsulating matrices.