Distribution of Anthocyanins Delivered from a Bioadhesive Black Raspberry Gel Following Topical Intraoral Application in Normal Healthy Volunteers

Abstract

Purpose-Results from our oral cavity chemoprevention trial demonstrated appreciable interpatient variations regarding chemopreventive efficacy of a freeze dried black raspberry (FBR) gel. We speculated these data reflected individual patient-related differences in absorption, target tissue uptake and local compound metabolism of key FBR compounds (anthocyanins). Accordingly, this study assessed the distribution of anthocyanins from the 10% (w/w) FBR gel in saliva, oral tissues and plasma.Methods-Human subject participation entailed collection of: (1) saliva, tissue and plasma (5 min following gel application, keratinized tissues), (2) saliva and plasma (5 min after sublingual gel application), (3) saliva and plasma at 1, 2, and 4 h post gel application (keratinized tissues), and (4) saliva (cyanidin 3-rutinoside incubations). Levels of FBR anthocyanins in the respective samples were analyzed by LC/MS/MS.Results-Our data show: significantly higher anthocyanin levels in saliva and oral tissues relative to matched plasma samples, marked donor-specific variations in anthocyanin uptake, sustainability of anthocyanins at the target site, pH affects anthocyanin penetration and intraoral anthocyanin decomposition and/or metabolism.Conclusions-No previous oral cavity chemoprevention trials evaluated compound distribution at the treatment site. Our data, which demonstrate a local delivery-derived pharmacologic advantage, provide insights which could advance oral cavity chemoprevention strategies.

Effects of Human Oral Mucosal Tissue, Saliva, and Oral Microflora on Intraoral Metabolism and Bioactivation of Black Raspberry Anthocyanins

“…Previous studies have confirmed that saliva is the intraoral compartment that retains the highest BRB anthocyanin levels following topical intraoral gel application (3). Gel to BRB rinse comparisons of salivary levels of cyanidin 3-rutinoside (most prevalent BRB anthocyanin) and total anthocyanins (collective chemopreventive compounds) were therefore performed at all shared saliva collection time points (5, 60, 120 and 240 minutes).…”

“…Rinses were prepared with the same amount of BRB (10% w/w) that was used in our gel formulation (See Table 1). (1–3). Rinse II also included chlorhexidine gluconate (0.12% final concentration).…”

“…which rinse provided the highest intra-donor levels of the parent anthocyanin at time points was determined by the Friedman Two-Way Analysis of Variance by Ranks. A two tailed Mann Whitney U test was used to compare rinse salivary levels of BRB anthocyanins relative to saliva levels obtained from the 10% BRB gel (3). The Repeated Measures Analysis of Variance, followed by the Bonferroni Multiple Comparisons Test, was used to evaluate salivary retention of PCA.…”

“…target tissue absorption, metabolic bioactivation, and local retention of the BRB constituents affected chemopreventive responsiveness. Subsequent BRB gel pharmacokinetic analyses conducted in volunteers with healthy oral mucosa, which revealed extensive inter-participant differences with regard to gel absorption, distribution and local BRB compound retention, support this premise (3). Identification of the pharmacokinetic and metabolic parameters that modulate BRB gel effectiveness could help to optimize chemopreventive strategies.…”

Advanced Drug Delivery Systems for Local Treatment of the Oral Cavity

“…Several other researchers are exploring the use of mucoadhesive drug delivery systems for chemoprevention of oral cancer [87,88]. Cid et al [89] explored chitosan gels for buccal delivery of the highly lipophilic celecoxib, a COX-2 inhibitor, for oral cancer chemoprevention.…”