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Exploring Peyer’s Patch Uptake as a Strategy for Targeted Lung Delivery of Polymeric Rifampicin Nanoparticles SAGAR S. BACHHAV, VIKAS D. DIGHE, and Padma V. Devarajan Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00382 • Publication Date (Web): 14 Aug 2018 Downloaded from http://pubs.acs.org on August 15, 2018
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Molecular Pharmaceutics
Exploring Peyer’s Patch Uptake as a Strategy for Targeted Lung Delivery of Polymeric Rifampicin Nanoparticles
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Sagar S. Bachhav1, Vikas D. Dighe2, Padma V. Devarajan1*
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1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.
P. Marg, Matunga (E), Mumbai-400019, Maharashtra, (India). 2
National Center for Preclinical Reproductive and Genetic Toxicology, National Institute for
Research in Reproductive Health (NIRRH), ICMR, J.M. Street, Parel, Mumbai-400 012, (India)
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* Corresponding author
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Prof. Padma V. Devarajan
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Department of Pharmaceutical Sciences and Technology,
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Institute of Chemical Technology, N. P. Marg, Matunga (E),
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Mumbai, Maharashtra, India
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Email:
[email protected]
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[email protected]
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Abstract Graphic:
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Molecular Pharmaceutics
ABBREVIATIONS:
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RIF
Rifampicin
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TB
Tuberculosis
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MTB
Mycobacterium Tuberculosis
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Gz
Gantrez®AN-119
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EC
Ethyl cellulose
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GIT
Gastrointestinal tract
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SLN
Solid lipid nanoparticles
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GALT
Gut-associated lymphoid tissue
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AOT
Docusate sodium or Aerosol OT
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EE
Entrapment Efficiency
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DL
Drug Loading
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TEM
Transmission electron microscopy
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XRD
X-ray diffraction
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DSC
Differential scanning calorimetry
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RH
Relative humidity
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OCT
Optimal Cutting Temperature compound
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H/E
Hematoxylin and eosin
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HPMC
Hydroxypropyl methylcellulose
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EDTA
Ethylenediaminetetraacetic acid
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PK
Pharmacokinetics
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Cmax
The maximum (or peak) plasma concentration that a drug achieves
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Tmax
Time to achieve the maximum (or peak) plasma concentration of drug
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AUC (in PK)
Area under the curve in a plot of drug concentration in blood plasma or organ vs. time
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MIC
Minimum inhibitory concentration
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ALT
Alanine aminotransferase
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AST
Aspartate aminotransferase
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ALP
Alkaline phosphatase
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Abstract
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Uptake of nanoparticles through Peyer’s patches (PP) following oral administration could enable
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translocation through lymph to lymphatic organs like the lungs. An important consideration
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however is nanosize and particle hydrophobicity. Furthermore, as delivering the nanoparticles to
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the intestine where the PP are localized is important, their intact and rapid transit through the
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stomach into the intestine is highly desirable. We report hydrophobization of mucoadhesive
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Rifampicin- Gantrez®AN-119 nanoparticles (GzNP) using a hydrophobic polymer,
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cellulose (EC), with the objectives of augmenting PP uptake due to enhanced hydrophobicity
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and increased intestinal localization as a result of decreased mucoadhesion. RIF-Gantrez-EC
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nanoparticles (ECGzNP2) exhibited >13% RIF loading and an average particle size of 400-450
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nm which is appropriate for translation through lymph following PP uptake. Higher contact
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angle (67.3±3.5° Vs 30.3±2.1°) and lower mucoadhesion (30.7±4.8g Vs 87.0±3.0g) of
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ECGzNP2 over GzNP confirmed hydrophobization and lower mucoadhesion. Fluorescence
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photomicrographs of intraduodenally administered coumarin labeled RIF-NP in rats,
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demonstrated higher PP uptake with ECGzNP2, while the increased lung: plasma RIF ratio
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signified lymph mediated lung targeting. The gastrointestinal transit study in rats which revealed
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a significantly higher intestine-to-stomach accumulation ratio with ECGzNP2 (3.4) compared to
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GzNP (1.0) [p3 µm)
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remained confined to Peyer’s patches, nanoparticles (
