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Aim: To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Methods: Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 mu g). Results: Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse events included nausea (9%) and peripheral edema (9%). Conclusion: FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850

In vitro dissolution, release and permeation testing is a common practice during drug product research and development. These in vitro tests, if predictive, are referred to as biorelevant tests and can play diverse roles to facilitate and expedite product development in a cost effective manner. Oral transmucosal products (OTPs) are currently tested using compendial and modified in vitro tests which may or may not be good predictors of in vivo performance due to a lack of biorelevance. A critical need for a broadly applicable and biorelevant in vitro system for OTPs has been expressed in the literature and the goal of this research was the development and validation of a biorelevant in vitro method that can facilitate accurate prediction of the in vivo behavior of OTPs. A combined strategy of appropriate apparatus design and relevant physiological and in vitro variable adjustment was investigated to incorporate biorelevance into evaluation of OTPs. A novel in vitro device, the bidirectional transmucosal apparatus (BTA), was designed and fabricated which allowed simulation of the oral cavity and its physiological variables to evaluate OTPs in a more realistic fashion. The BTA was tested using snus (a type of smokeless tobacco) as the OTP product. A simple and selective high performance liquid chromatographic (HPLC) method with photodiode array (PDA) detection was developed and validated to assess in vitro nicotine release and permeation (Linearity: 0.5 – 32 μg/mL; calibration curve accuracy (%recovery, n=5 ): 97.98-103.20%; calibration curve precision (%RSD, n=5): 0.15-3.14%). The performance of BTA was compared with the modified USP IV flow through apparatus (USP IV) and a commercially available vertical diffusion cell (VDC). The observed in vitro in vivo relationship (IVIVR) slopes with the USP IV, VDC and BTA were 0.27, 2.01 and 2.11 respectively. The BTA was selected over the VDC and USP IV devices because of better simulation and adjustment of variables to incorporate biorelevance in the test of OTPs. Additionally, the BTA allows study of permeation and release simultaneously unlike VDC and USP IV apparatuses. Further, the different BTA parameters were sequentially screened for their impact on in vitro rate of nicotine permeation that can be employed for the optimization of IVIVR for snus. Based on the results, stimulated saliva swallowing rate (SSSR) and media temperature were considered as significant factors affecting in vitro permeation of nicotine and used to further optimize IVIVR for snus. A 32 multifactorial experimental design integrating SSSR (0.32, 1.66 and 3 mL/min) and media temperature (25, 37 and 45 °C) was employed. Based on the response surface analysis, 0.55 mL/min SSSR and 43 °C media temperature were identified as optimal BTA conditions that would give perfect IVIVR (i.e. IVIVR slope close to one) for snus. The experimental value of IVIVR slope (0.92) at these optimal conditions indicated that the BTA is a valid in vitro system for evaluation of OTPs in a biorelevant manner. The applicability of BTA for predicting nicotine permeation from ‘Stonewall’, a dissolvable compressed tobacco was also evaluated. However, comparable in vitro nicotine permeation and in vivo nicotine absorption profiles were not obtained (ratio of in vitro permeation to in vivo absorption rate ranged from 0.04 to 0.14 at different in vitro conditions) either due to the unavailability of reliable clinical data or due to inherently different in vivo behavior of Stonewall compared to snus that would require further modification in the BTA. In conclusion, this research demonstrated the potential of the novel in vitro device to be a valuable tool for the prediction of in vivo performance of snus. The application of the novel bidirectional transmucosal apparatus for other types of OTPs will be an interesting subject for further investigation.

Oral delivery of insulin used for the management of Type 1 Diabetes could be referred to as one of the major long term goals of diabetes research. However, the bioavailability of orally administered insulin is significantly compromised by enzymatic degradation in the GI tract and poor enteral absorption of the protein due to its macromolecular size and hydrophilicity. Nano-sized polymer-protein polyelectrolyte complexes (PECS) formed by electrostatic interactions between insulin and Polyallylamine-based polymers at pH 7.4 have been adapted to facilitate oral insulin delivery. Polyallylamine (15kDa) was quaternised by methylation of its primary amines using methyl iodide to yield quaternised Paa (QPaa). Average level of polymer quaternisation was determined by elemental analysis and was found to be 72 ± 2mol%. Subsequent thiolation of Paa and QPaa using two different thiolation procedures involving carbodiimide mediated conjugation to N-acetylcysteine (NAC) and modification of the polymers using 2-iminothiolane hydrochloride yielded their respective NAC and 4-thiobutylamidine (TBA) conjugates: Paa-NAC/QPaa-NAC and Paa-TBA/QPaa-TBA. Estimation of the free thiol content of these thiomers by iodometric titration showed that both Paa-NAC and QPaa-NAC displayed 60 ± 1.2 and 60 ± 4.3ìmol free thiol groups per gram polymer, while Paa-TBA and QPaa-TBA conjugates displayed 490 ± 18 and 440 ± 21ìmol free thiol groups per gram polymer respectively. Mixing optimal mass ratios of each polymer and insulin in Tris buffer at pH 7.4 resulted in the formation of soluble nanocomplexes. Complexes were characterised by transmittance measurements, particle size analysis, zeta potential, complexation efficiency, and transmission electron microscopy (TEM). Stable polymer-insulin complexes were observed to have hydrodynamic sizes between 50-200nm, positively charged zeta potential values ranging between 20-40mV and high insulin complexation efficiency (> 90%). Complexation of insulin with TBA conjugates however appeared to alter insulin conformation affecting the detection of complexed insulin by HPLC. TEM analysis revealed the formation of bilayered nanovessicles as well as conventional single-layered nanoparticles on complexation of insulin with QPaa and thiolated Paa/QPaa derivatives. In-vitro assessments of enzyme-protective effect of QPaa, Paa-NAC and QPaa-NAC insulin complexes showed that when compared to a free insulin control, all the aforementioned complexes could protect insulin from degradation by trypsin and á-chymotrypsin, but not from pepsin. In-vitro mucin adsorption assays showed that all polymers exhibited a similar mucoadhesive profile with their corresponding insulin PEC, with thiolated Paa derivatives adsorbing >20% more mucin than Paa. Thiolation of QPaa did not result in a noticeable improvement in its mucoadhesive capacity indicating that polymer-mucin thiol-disulphide interactions may be hindered by the presence of quaternary groups. The IC50 of each polymer was determined by MTT assays carried out on Caco-2 cells with or without the inclusion of a 24-hour cell recovery period. An MTT assay conducted without a recovery period indicated that quaternisation of Paa was associated with a 6-fold improvement in its IC50; also cells subjected to a 24-hour recovery period following treatment with QPaa (0.001-4mgml-1) showed no signs of toxicity. Thiolation of Paa resulted in slight (≤ 2 fold) improvements in IC50, while thiolation of QPaa resulted in a decrease in IC50 values obtained both with and without a cell recovery period. Each polymer was subsequently labelled with rhodamine B isothiocyanate (RBITC) and complexed with fluorescein isothiocyanate (FITC)-insulin. Monitoring uptake of these complexes by Caco-2 cells using fluorescence microscopy with DAPI staining indicated that uptake of QPaa and QPaa-TBA complexes was mainly intracellular being localised within the perinuclear area of cells highlighted by DAPI. Hence, intracellular uptake of PECS by Caco-2 cells was enhanced by Paa quaternisation and TBA-based thiolation of QPaa.

Le maintien des tissus péri-implantaires sains à un niveau le plus coronaire possible conditionne le succès à long terme des réhabilitations implanto-portées. Dès lors, la mise en place d'une barrière muqueuse protectrice et la préservation de l'os marginal au cours des premières semaines de cicatrisation est indispensable. Le design implantaire influence les remodelages tissulaires intervenant au niveau du col de l'implant lors des phases initiales de cicatrisation. L'objet de ce travail est d'analyser histologiquement chez le Beagle l'influence de deux systèmes implantaires innovants sur les caractéristiques de la muqueuse et la position de l'os marginal après 3 et 12 semaines de cicatrisation. Les résultats de cette étude, mis en relation avec les données de la littérature indiquent que les implants « deux-parts » présentant une connectique cône morse pourraient favoriser la mise en place d'un espace biologique court et limiter la perte osseuse marginale péri-implantaire. Les implants « une part » à col transmuqueux concave seraient quant à eux associés à des valeurs réduites d'espace biologique et autoriseraient une apposition osseuse sur l'épaule de l'implant. Dans la première partie de ce mémoire, nous établissons une synthèse des données histologiques actuelles concernant les caractéristiques et les processus de cicatrisation des tissus péri-implantaires, et l'influence de la conception implantaire sur les remodelages tissulaires marginaux intervenant au cours de la cicatrisation. Nous avons rédigé deux publications internationales que nous présentons en deuxième partie. Une réflexion analytique autour de ce travail est présentée dans la troisième partie / Aesthetic and functional long-term success of implant-supported rehabilitations relies on the preservation of peri-implant tissue levels in the most coronal position. Therefore, the achievement of an efficient protective mucosal seal, and the preservation of the peri-implant marginal bone during the first weeks of healing are essential to prevent long term implant failures. The characteristics of an implant transmucosal design (connections, platforms, surface properties) are related to biological width dimensions, marginal peri-implant bone levels, and the amount of inflammation within the peri-implant soft tissues. The aim of the research work presented in this manuscript was to investigate the effect of two innovative implant systems on peri-implant mucosa maturation, dimensions, collagen fiber organization, and marginal bone levels after 3 and 12 weeks of healing in the beagle dog. The results, compared with previous data, show that platform-switched twopiece implants exhibit reduced values of biological width and marginal bone loss, and that a concave transmucosal design in one-piece implants is associated with a short vertical value of biological width, and promote a mechanical interlocking of the implant body at the connective tissue and marginal bone levels. In the first part of this report, an overview of the current knowledge concerning the characteristics and healing patterns of peri-implant tissues, and the influence of implant design on the early peri-implant tissue remodeling is established. We have written two international publications which are presented in the second part. An analytical reflection about this work is presented in the third part