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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

KEY WORDS

antibiotics drug delivery meropenem mucus nanoparticle prodrug 

ABBREVIATIONS

CF

Cystic fibrosis

Cmax

Peak concentration

CVM

Cervicovaginal mucus

HLMs

Human lung microsomes

HPLC

High-performance liquid chromatography

LML

Luminal mucus layer

MIC

Minimum inhibitory concentration

MPC

Mucus-penetrating crystal

mPEG

Methoxy poly(ethylene) glycol

MPP

Mucus-penetrating particle

MRPD

Meropenem prodrug

MRPD-MPC

MRPD formulated as a mucus-penetrating crystal

n

Particle population

PCL

Periciliary layer

PDI

Polydispersity index

PK

Pharmacokinetics

PS

Polystyrene

S

Solubility

Vmean

Mean ensemble velocity

Supplementary material

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ESM 1(DOCX 43 kb)
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ESM 3(DOCX 67 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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