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J Control Release. 2015 Jul 10;209:280-7. doi: 10.1016/j.jconrel.2015.04.040. Epub 2015 Apr 30.

Enema ion compositions for enhancing colorectal drug delivery.

Author information

1
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205 USA.
2
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA.
3
Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; ReProtect, Inc, 703 Stags Head Road, Baltimore, MD 21286 USA.
4
Department of Clinical Pharmacology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
5
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA.
6
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Center for Cancer Nanotechnology Excellence, the Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: lensign@jhmi.edu.
7
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Center for Cancer Nanotechnology Excellence, the Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA; Departments of Neurosurgery, Oncology, and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA. Electronic address: hanes@jhmi.edu.

Abstract

Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350 mOsm) compared to blood (~300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations.

KEYWORDS:

Colon; Gastrointestinal tract; Microbicide; Pre-exposure prophylaxis

PMID:
25937321
PMCID:
PMC4458383
DOI:
10.1016/j.jconrel.2015.04.040
[Indexed for MEDLINE]
Free PMC Article

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