Pharmaceutical Research

, Volume 33, Issue 3, pp 563–572 | Cite as

Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers

  • Winston Ong
  • Pawel Nowak
  • Yen Cu
  • Lisa Schopf
  • James Bourassa
  • Elizabeth Enlow
  • Samuel M. Moskowitz
  • Hongming Chen
Research Paper



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 intratracheally-instilled 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.


antibiotics drug delivery meropenem mucus nanoparticle prodrug 



Cystic fibrosis


Peak concentration


Cervicovaginal mucus


Human lung microsomes


High-performance liquid chromatography


Luminal mucus layer


Minimum inhibitory concentration


Mucus-penetrating crystal


Methoxy poly(ethylene) glycol


Mucus-penetrating particle


Meropenem prodrug


MRPD formulated as a mucus-penetrating crystal


Particle population


Periciliary layer


Polydispersity index








Mean ensemble velocity

Supplementary material

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ESM 1(DOCX 43 kb)
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ESM 2(DOCX 50 kb)
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ESM 3(DOCX 67 kb)
11095_2015_1808_MOESM4_ESM.docx (13 kb)
ESM 4(DOCX 13 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Winston Ong
    • 1
  • Pawel Nowak
    • 1
  • Yen Cu
    • 1
  • Lisa Schopf
    • 1
  • James Bourassa
    • 1
  • Elizabeth Enlow
    • 1
  • Samuel M. Moskowitz
    • 2
  • Hongming Chen
    • 1
  1. 1.Kala Pharmaceuticals, Inc.WalthamUSA
  2. 2.Department of PediatricsMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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