Mucoadhesive Fenretinide Patches for Site-Specific Chemoprevention of Oral Cancer: Enhancement of Oral Mucosal Permeation of Fenretinide by Coincorporation of Propylene Glycol and Menthol

Abstract

The objective of this study was to enhance oral mucosal permeation of fenretinide by co-incorporation of propylene glycol (PG) and menthol in fenretinide/Eudragit® RL PO mucoadhesive patches. Fenretinide is an extremely hydrophobic chemopreventive compound with poor tissue permeability. Co-incorporation of 5-10 wt% PG (mean Js = 16-23 μg cm−2 h−1; 158-171 μg fenretinide/g tissue) or 1-10 wt% PG + 5 wt% menthol (mean Js = 18-40 μg cm−2 h−1; 172-241 μg fenretinide/g tissue) in fenretinide/Eudragit® RL PO patches led to significant ex vivo fenretinide permeation enhancement (p < 0.001). Addition of PG above 2.5 wt% in the patch resulted in significant cellular swelling in the buccal mucosal tissues. These alterations were ameliorated by combining both enhancers and reducing PG level. After buccal administration of patches in rabbits, in vivo permeation of fenretinide across the oral mucosa was greater (~43 μg fenretinide/g tissue) from patches that contained optimized permeation enhancer content (2.5 wt% PG + 5 wt% menthol) relative to permeation obtained from enhancer-free patch (~ 17 μg fenretinide/g tissue) (p < 0.001). In vitro and in vivo release of fenretinide from patch was not significantly increased by co-incorporation of permeation enhancers, indicating that mass transfer across the tissue, and not the patch, largely determined the permeation rate control in vivo. As a result of its improved permeation and its lack of deleterious local effects, the mucoadhesive fenretinide patch co-incorporated with 2.5 wt% PG + 5 wt% menthol represents an important step in the further preclinical evaluation of oral site-specific chemoprevention strategies with fenretinide.

Chemopreventive Potential of Flavonoids in Oral Squamous Cell Carcinoma in Human Studies

“…Buccal and sublingual delivery systems use mouthwashes, aerosol sprays, chewing gums, bioadhesive tablets, gels and patches to locally treat conditions such as gingivitis, oral candidosis, oral lesions, dental caries and xerostomia [48,49]. Although many drugs have been formulated for transmucosal oral delivery in order to treat both local and systemic conditions, only very few studies have been carried out on flavonoid and oral cancer [50,51]. …”

Polymeric drug delivery systems for intraoral site‐specific chemoprevention of oral cancer

“…A variety of polymeric local drug delivery systems (Figure ) have been developed and evaluated for their potential against OSCC . The delivery of chemopreventive agents directly into the affected site of the mouth provides multiple therapeutic advantages . The main advantage is that drug exposure is limited to the tumor region or mouth with no or very minimal systemic drug exposure .…”

“…The main advantage is that drug exposure is limited to the tumor region or mouth with no or very minimal systemic drug exposure . Importantly, intraoral site‐specific drug delivery has been shown to prevent the progression of recognized premalignant lesions of oral epithelial dysplasia to overt OSCC and to inhibit local tumor recurrence and the development of new, second primary tumors . Intraoral therapy has emerged as a strong alternative to systemic chemotherapy for effective and improved oral cancer chemoprevention without any significant side effects/toxicity .…”

Transmucosal delivery of Docetaxel by mucoadhesive polymeric nanofibers

“…Several attempts have been made for local drug delivery via the mucous membranes lining of oral cavity to improve the therapeutics potential of the drugs and reduce their systemic side eff ects. Wu et al investigated the therapeutic potential of Fenretinide mucoadhesive patch along with propylene glycol and menthol as permeation enhancer for oral cancer (Wu et al 2012). Mallery et al studied the anti-cancer activity of mucoadhesive gel of freeze dried black raspberries.…”