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

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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.

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Abbreviations

CF:

Cystic fibrosis

C max :

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

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ACKNOWLEDGMENTS AND DISCLOSURES

The work described was partially supported by Award Number R43HL106899 from the National Heart, Lung and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung and Blood Institute or the National Institutes of Health.

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Authors and Affiliations

  1. Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA

    Winston Ong, Pawel Nowak, Yen Cu, Lisa Schopf, James Bourassa, Elizabeth Enlow & Hongming Chen

  2. Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA

    Samuel M. Moskowitz

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  1. Winston Ong
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  2. Pawel Nowak
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  3. Yen Cu
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  4. Lisa Schopf
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  5. James Bourassa
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  6. Elizabeth Enlow
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  7. Samuel M. Moskowitz
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  8. Hongming Chen
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Correspondence to Winston Ong.

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Ong, W., Nowak, P., Cu, Y. et al. Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers. Pharm Res 33, 563–572 (2016). https://doi.org/10.1007/s11095-015-1808-x

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  • DOI: https://doi.org/10.1007/s11095-015-1808-x

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