Irinotecan-encapsulated double-reverse thermosensitive nanocarrier system for rectal administration

Abstract

Republic of Korea AbstractIntravenously administered for the treatment of rectum cancer, irinotecan produces severe side effects due to very high plasma concentrations. A novel irinotecan-encapsulated double reverse thermosensitive nanocarrier system (DRTN) for rectal administration was developed as an alternative. The DRTN was fabricated by dispersing the thermosensitive irinotecanencapsulated solid lipid nanoparticles (SLN) in the thermosensitive poloxamer solution. Its gel properties, pharmacokinetics, morphology, anticancer activity and immunohistopathology were assessed after its rectal administration to rats and tumor-bearing mice. In the DRTN, the solid form of the SLN and the liquid form of the poloxamer solution persisted at 25 C; the former melted to liquid, and the latter altered to gel at 36.5 C. The DRTN was easily administered to the anus, gelling rapidly and strongly after rectal administration. Compared to the conventional hydrogel and intravenously administered solution, it retarded dissolution and initial plasma concentration. The DRTN gave sustained release and nearly constant plasma concentrations of irinotecan at 1-3 h in rats, resulting in improved anticancer activity. It induced no damage to the rat rectum and no body weight loss in tumor-bearing mice. Thus, this irinotecan-encapsulated DRTN associated with a reduced burst effect, lack of toxicity and excellent antitumor efficacy would be strongly recommended as a rectal pharmaceutical product alternative to commercial intravenous injection in the treatment of rectum and colon cancer. KeywordsIrinotecan, double reverse thermosensitive nanocarrier, rectal administration, burst effect, toxicity, anti-tumor efficacy History

Physiological and Pharmaceutical Considerations for Rectal Drug Formulations

“…Mucoadhesive bases alone have not been evaluated for nanoparticle delivery into the rectum. Instead, the use of thermosensitive polymers in the formulation base has been more common for the rectal delivery of nanoparticles (Seo et al, 2013; Din et al, 2015; Din et al, 2017; Melo et al, 2019). These polymers create an initial liquid dosage form at room temperature that allows ease of administration and mucosal spreading, before transitioning to a gel phase at body temperature.…”

“…Similarly, Din et al (2017) developed a novel rectal formulation of irinotecan for the local treatment of rectal cancer. This nanoparticulate dosage form consisted of thermosensitive irinotecan-encapsulated SLNs (mean particle size of 190 nm) dispersed in a thermosensitive poloxamer solution to create a double-reverse thermosensitive nanocarrier system (DRTN).…”

Proniosomes derived niosomes: recent advancements in drug delivery and targeting

“…Although parenteral route of administration is the most effectual route but there is an instant decline in systemic concentrations and requires frequent administration to maintain constant therapeutic concentration of a drug that eventually results in poor patient compliance. These limitations can be avoided by utilizing biodegradable polymeric nanosystems by maintaining controlled and slow release of drug for longer durations, consequently reduces the dosing frequency and toxic effects and improve the quality of treatment (Komal et al, 2013;Din et al, 2017;Ud Din et al, 2017).…”

<p>Preparation and evaluation of tacrolimus-loaded thermosensitive solid lipid nanoparticles for improved dermal distribution</p>

“…This clearly supported the data for the particle size and polydispersity index values. The TCR-SLNs were surrounded by the hydrophilic Poloxamer aqueous solution owing to the previously described interfacial phenomenon 51,52. The excellent stability is a result of the adequate surfactant content, including Poloxamer 188 53,54.…”