Abstract
Indocyanine green (ICG) is the most commonly used FDA-approved agent for clinical optical imaging, administered through injections only, due to its poor membrane permeability. Although ICG has vast potential for non-invasive non-radioactive imaging in patients, the clinical applications are limited by the invasive administration and short half-life in blood circulation. To expand the clinical value of ICG, non-toxic chitosan-based ICG-loaded films were designed for sublingual administration for near-infrared (NIR) and short-wave infrared (SWIR) optical imaging. Two film formulations were developed with different ICG release rates. Mold-casted self-emulsifying films rapidly released ICG (80% in 4 h) in the form of nanosized droplets, which were mostly swallowed and produced significant contrast of upper digestive tract to enable in vivo swallowing evaluations using NIR/SWIR imaging. Regular films released ICG slowly (80% in 25 h), allowing for steady absorption of ICG to systemic circulation. Inflammation in mouse feet was detected within 30 min after sublingual administration with a 1.43-fold fluorescence increase within 1 h at the inflammation sites, comparable to a 1.76-fold increase through intravenous injection. Administering ICG using sublingual films displayed notable potential for non-invasive diagnosis and monitoring of inflammatory conditions and swallowing disorders, addressing a current need for alternatives to ICG parenteral administration.
Highlights
Fluorescence imaging within the near infrared window (NIR, 700–1,000 nm) has enabled new technologies for preclinical and clinical a pplications[1]
The sublingual route has many advantages when compared with oral that can assist increasing systemic exposure of Indocyanine green (ICG): (1) Sublingual rate of absorption is higher due to thinner membrane thickness[16,17], allowing for easier and faster mass transfer; (2) low degree of keratinization[17], facilitating permeability; and most-importantly (3) molecules absorbed from the buccal cavity have direct access to the systemic circulation via jugular vein, by-passing first-pass hepatic metabolism associated with oral absorption and increasing b ioavailability[18,19]
A Quality by Design (QbD) approach was taken to investigate the impact of critical Self‐emulsifying drug delivery system (SEDDS) components on droplet size and concentration
Summary
Fluorescence imaging within the near infrared window (NIR, 700–1,000 nm) has enabled new technologies for preclinical and clinical a pplications[1]. Molecules displaying high liver extraction rates such as ICG (hepatic extraction rate in healthy humans ≈ 70%14,15) have their blood concentrations greatly reduced prior to reaching systemic circulation, and greatly reducing bioavailability In this sense, the sublingual route has many advantages when compared with oral that can assist increasing systemic exposure of ICG: (1) Sublingual rate of absorption is higher due to thinner membrane thickness[16,17], allowing for easier and faster mass transfer; (2) low degree of keratinization[17], facilitating permeability; and most-importantly (3) molecules absorbed from the buccal cavity have direct access to the systemic circulation via jugular vein, by-passing first-pass hepatic metabolism associated with oral absorption and increasing b ioavailability[18,19]. Chitosan has been selected as film-forming mucoadhesive polymer for this platform as it has been reported to be non-toxic for oral applications[23] and it is capable of fostering mucoadhesion via electrostatic interactions with negatively charged mucin proteins present in m ucus[23,24,25]
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