Improvement of Resveratrol Permeation through Sublingual Mucosa: Chemical Permeation Enhancers versus Spray Drying Technique to Obtain Fast-Disintegrating Sublingual Mini-Tablets

Resveratrol (RSV) is a natural polyphenol with several interesting broad-spectrum pharmacological properties. However, it is characterized by poor oral bioavailability, extensive first-pass effect metabolism and low stability. Indeed, RSV could benefit from the advantage of the sublingual route of administration. In this view, RSV attitudes to crossing the porcine sublingual mucosa were evaluated and promoted both by six different chemical permeation enhancers (CPEs) as well as by preparing four innovative fast-disintegrating sublingual mini-tablets by spray drying followed by direct compression. Since RSV by itself exhibits a low permeation aptitude, this could be significantly enhanced by the use of CPEs as well as by embedding RSV in a spray-dried powder to be compressed in order to prepare fast-disintegrating mini-tablets. The most promising observed CPEs (menthol, lysine and urea) were then inserted into the most promising spray-dried excipients’ compositions (RSV-B and RSV-C), thus preparing CPE-loaded mini-tablets. However, this procedure leads to unsatisfactory results which preclude the possibility of merging the two proposed approaches. Finally, the best spray-dried composition (RSV-B) was further evaluated by SEM, FTIR, XRD and disintegration as well as dissolution behavior to prove its effectiveness as a sublingual fast-disintegrating formulation.

Spider Angioma of the Nasal Mucosa

Spider angioma is a benign vascular lesion reminiscent of a spider’s body characterized by peculiar dilatation of end vasculature. The lesion is characterized by a central spot and extensions which radiate outward like a spider’s body. Spider angiomas may appear as a solitary or multiple lesion that arises on the skin surface of the face, neck, chest, and arms; these lesions have been rarely observed in the sublingual mucosa and in the gut, and to date, they have never been reported in the nasal mucosa. In this article, we report a spider angioma of the nasal cavity found as an occasional finding during a narrow band imaging nasopharyngeal endoscopy in a 70-year-old male patient with hepatitis C virus-related liver cirrhosis and a history of total laryngectomy in 2013 due to laryngeal squamous cell carcinoma. The lesion was located in the mucosa of the pavement of the posterior portion of the left nostril; it was painless and asymptomatic.

Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting

The sublingual mucosa (SLM) in the oral cavity is utilized as the site for sublingual immunotherapy to induce tolerance against allergens. We previously reported that CD206+ round-type macrophage-like cells were induced in the SLM after repeated antigen (e.g. cedar pollen or fluorescein isothiocyanate (FITC))-painting. In this study, we examined the phenotypic and functional properties of CD206+ cells induced by repeated FITC-painting on the SLM. CD206+ cells after the repeated FITC-painting possessed a macrophage-like CD11b+Ly6C+ F4/80+CD64+ phenotype and expressed TIM-4, which was expressed in tolerogenic tissue-resident macrophages, at a high level. SLM CD206+ cells preferentially expressed molecules related to endocytosis and homeostatic processes, including the novel B7 family of immune checkpoint molecules, as assessed by microarray analyses. SLM CD206+ cells showed preferential expression of M2-related genes such as Fizz1, Aldh1a1 and Aldh1a2 but not Ym-1 and Arginase-1. A CD206+ cell-rich status inhibited OVA-specific CD4+ T-cell responses but reciprocally enhanced the proportion of both IL-10+CD4+ cells and Foxp3+ regulatory T-cells in regional lymph nodes. Co-culture of CD206+ cells with dendritic cells (DCs) showed that IL-12 production was suppressed in DCs concurrent with the decline of the MHC class IIhiCD86+ population, which was restored by neutralization of IL-10. These results demonstrate SLM CD206+ cells show the feature of tolerogenic macrophages and down-regulate the antigen-presenting cell function of mature DCs resulting in the inhibition of CD4+ T-cell responses.

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

BackgroundRecently, sublingual immunotherapy (SLIT) has been used as a safe and efficient method for the treatment of and immunization against asthma and various allergies. However, the routes of antigen uptake through the mucosa of the oral cavity remain incompletely understood, as do the roles of sex and age in the process. For this purpose, to elucidate the mechanism and efficacy of SLIT among different sexes and ages microbeads were dripped into the sublingual region to mimic antigen uptake by the sublingual mucosa.MethodsTwenty microliters of either phosphate buffered saline (PBS) or fluorescently labelled microbeads (latex and silica beads) were placed under the tongue of both male and female C57BL/6 mice at young (3 months) and old (6 months) ages. The lower jaw was examined 30 min after administration, and beads were detected with a fluorescence stereomicroscope. Morphological observations of the mucosa of the fluorescent areas were made with scanning electron microscopy (SEM) and an all-in-one light fluorescence microscope (LM). Fluorescence intensity was compared between both sexes and ages.ResultsStereomicroscopic observation revealed fluorescent illuminations in three compartments of the sublingual mucosa: the sublingual caruncles (SC), the oral rostral mucosa (OR) and the buccal mucosa (BM). Interestingly, the fluorescence intensity tended to be higher among females than among males in the SC region in particular. However, there were no significant age-related differences. SEM and LM revealed beads in the lumina of both mandibular ducts and sublingual ducts (Sd). Additionally, the apical cytoplasm of some Sd cells contained silica beads. However, there were no specification in the OR mucosa or BM.ConclusionsThis study reveals the major role Sd play in local immunity via the antigen uptake mechanisms. Furthermore, our data suggest that the efficacy of SLIT in humans could be affected by sex.

Oral Mucosal Immunotherapy for Allergic Rhinitis: A Pilot Study

Background The sublingual mucosa has been used for many years to apply allergenic extracts for the purpose of specific immunotherapy (IT). Although sublingual IT (SLIT) is both safe and efficacious, the density of antigen-presenting cells is higher in other regions of the oral cavity and vestibule, which make them a potentially desirable target for IT. Objective To present the concept of oral mucosal IT (OMIT) and to provide pilot data for this extended application of SLIT. Methods An open-label, 12-month, prospective study was undertaken as a preliminary step before a full-scale clinical investigation. Twenty-four individuals with allergic rhinitis received IT by applying allergenic extracts daily to either the oral vestibule plus oral cavity mucosa by using a glycerin-based toothpaste or to the sublingual mucosa by using 50% glycerin liquid drops. Adverse events, adherence rates, total combined scores, rhinoconjunctivitis quality-of-life questionnaire scores, changes in skin reactivity, and changes in serum antibody levels were measured for each participant. Results No severe adverse events occurred in either group. The adherence rate was 80% for the OMIT group and 62% for the SLIT group (p = 0.61). Decreased total combined scores were demonstrated for both the OMIT group (15.6%) and the SLIT group (223%), although this decrease did not reach statistical significance in either group. Both groups achieved a meaningful clinical improvement of at least 0.5 points on rhinoconjunctivitis quality-of-life questionnaire. A statistically significant rise in specific immunoglobulin G4 (IgG4) was seen in both groups over the first 6 months of treatment. Conclusion OMIT and SLIT demonstrated similar safety profiles and adherence rates. Measurements of clinical efficacy improved for both groups, but only changes in IgG4 achieved statistical significance. These pilot data provide enough evidence to proceed with a full-scale investigation to explore the role of OMIT in the long-term management of allergic rhinitis.