Effect of accelerated stability on the physical, chemical, and mechanical properties of experimental bleaching gels containing different bioadhesive polymers.

OBJECTIVE: To evaluate the physical-chemical (weight, pH, quantification of hydrogen peroxide) and mechanical (texture profile and rheology tests) properties of the experimental bleaching gel based on the bioadhesive polymer Aristoflex® AVC, after accelerated stability testing. MATERIALS AND METHODS: A total of 300 syringes of bleaching gels were divided into 5 groups (n = 60): Whiteness Perfect® 10%-FGM (WP); carbamide peroxide 10% with aristoflex (CPa); carbamide peroxide 10% with Carbopol (CPc); aristoflex thickener (A); and Carbopol thickener (C). According to the following requirements and time, the accelerated stability test was performed: in an incubator at 40 °C and 75% humidity per 1, 3, and 6 months, and baseline (refrigerator at 5 °C and 25% humidity). The variables were analyzed following the statistical tests: Two-way ANOVA and Tukey's test were applied to pH; weight data were analyzed using a mixed model for repeated measurements over time and the Tukey-Kramer test; one-way ANOVA and Tukey's test analyzed the rheology test; generalized linear models were used to quantify the peroxide amount and texture profile data. A significance level of 5% was considered. RESULTS: The experimental bleaches CPa and CPc had the highest pH values when compared to the others in 6 months. Thickeners A and C did not change the pH, weight, and active content over the accelerated stability times (p > 0.05). Furthermore, there was weight loss after 3 months of storage for CPa and CPc (p < 0.05). In the quantification of hydrogen peroxide, the WP group showed the highest values over time (p < 0.0001), only showing a significant loss after the 3rd month. Meanwhile, CPa and CPc showed a reduction in quantification from the 1st month. CONCLUSIONS: Temperature and humidity directly influenced the active content and properties of bleaching gels. In addition, the presence of components regardless of thickeners, such as stabilizers, in the commercial gel allowed for greater stability over time. CLINICAL RELEVANCE: The development of experimental bleaching gels for clinical use requires careful testing. Therefore, accelerated stability testing represents a valuable tool in the development and evaluation of cosmetic formulations.

Altered physical-chemical properties of home bleaching gels after an accelerated stability study and their effects on tooth enamel.

OBJECTIVES: To investigate the physical-chemical properties of home bleaching gels based on Carbamide Peroxide (CP) and Hydrogen Peroxide (HP) after accelerated stability (AS) and its effects on enamel. MATERIALS AND METHODS: A total of 360 bovine teeth blocks were divided (n = 12): Control, CP10%-Whiteness Perfect, CP10%-Pola Night, HP7.5%-Pola Day, and HP7.5%-White Class Calcium. Microhardness (KHN), roughness (Ra), color (ΔE and ΔE00), hardness, compressibility, elasticity, cohesiveness, adhesiveness, weight, pH, and calcium (Ca) quantification in enamel were analyzed without storage of the bleaching gels and after AS at 1 and 3 months. Data of Ca, KHN, and Ra were analyzed through mixed models for repeated measurements and the Tukey-Kramer test. Values of weight, hardness, compressibility, and elasticity were analyzed with two-way ANOVA and Tukey's test. ΔE/ΔE00 data, cohesiveness, and adhesiveness were analyzed with Kruskal-Wallis and Dunn tests (α = 0.05). RESULTS: Groups subject to AS had lower ΔE and ΔE00 compared to those without storage. Lower KHN and higher Ra values were found after bleaching treatment in all groups compared to controls. Higher amounts of Ca were found on the first day of evaluation in the gels subject to AS for 3 months, regardless of the bleaching agent used. CONCLUSIONS: Incorrectly stored bleaching gel accentuates adverse effects on enamel. Temperature and humidity interfere directly with the chemical stability of bleaching agents, reducing their properties. CLINICAL RELEVANCE: HP is an unstable oxidizing agent when stored at high temperatures. Therefore, pH becomes more acidic and potentiates the demineralizing effect on enamel.

Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues.

Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-ß-CD), as shown by the phase solubility study. The resulting complex (HP-ß-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and 1H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.

Characterization of Articaine-Loaded Poly(ε-caprolactone) Nanocapsules and Solid Lipid Nanoparticles in Hydrogels for Topical Formulations.

This work describes the development of poly-ε-caprolactone nanocapsules (PCL-NC) and solid lipid nanoparticles (SLN) aiming delivery for articaine (ATC), in order to improve its chemical stability in semi-solid preparations looking forward their use for skin delivery. The nanoparticles were characterized by size, polydispersity index, and pH. Cellular viability was evaluated using the MTT test and the in vitro release kinetics was determined using a two-compartment model. The hydrogels with nanoparticle suspensions were characterized considering their rheological aspects and in vitro permeation across artificial membranes. Colloidal stability was satisfactory, since the formulations did not present major alterations during 120 days. High ATC encapsulation was achieved (78% for PCL-NC and 65% for SLN). The release profile of PCL-NC-ATC was slower, compared to the free molecule and SLN-ATC. MTT experiments showed the nanosystems were capable to increase cellular viability compared with free ATC. The hydrogels showed good consistency, homogeneity, and stability and presented pseudoplastic behavior with thixotropy, improving drug efficacy in clinical applications. The gel based on PCL-NC showed faster onset of activity and flux of 35.68 ± 1.98 µg/cm2/h, which then continued for up to 8 h. This study opens up prospects for employment of nanoparticulate systems for modified release of ATC.

Stress-related salivary proteins affect the production of volatile sulfur compounds by oral bacteria.

OBJECTIVE: To determine whether stress-related substances and sex hormones influence the growth and in vitro production of volatile sulfur compounds (VSCs) by Solobacterium moorei and Fusobacterium nucleatum. MATERIALS AND METHODS: Bacteria growth and VSCs production were evaluated in the presence of alpha-amylase, beta-defensin-2, mucin, estradiol, and progesterone. Growth was evaluated by colony counting, and the production of the VSCs hydrogen sulfide (H2 S) and methyl mercaptan (CH3 SH) was measured using the Oral Chroma™ instrument. RESULTS: Mucin induced the production of H2 S by both bacteria, but had a slight inhibitory effect on CH3 SH production by F. nucleatum. It also increased the viability of F. nucleatum. Alpha-amylase increased H2 S production by S. moorei and CH3 SH production by F. nucleatum, but had no effect on H2 S production by F. nucleatum. No substance altered the viability of S. moorei. No effects of beta-defensin-2, estradiol, or progesterone were observed. CONCLUSION: The salivary stress-related proteins mucin and alpha-amylase altered VSCs production by F. nucleatum and S. moorei, favoring H2 S production. These findings are a step toward understanding the relation between stress and increased amounts of H2 S.

Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model.

The aim of this study was to evaluate the in vitro cytotoxicity and the in vivo analgesic effect and local toxicity of the local anesthetic butamben (BTB) encapsulated in conventional or elastic liposomes incorporated in gel formulations. The results showed that both gel formulations of liposomal BTB reduced the cytotoxicity (p < 0.001; one-way ANOVA/Tukey's test) and increased the topical analgesic effect (p < 0.05; one-way ANOVA/Tukey's test) of butamben, compared to plain BTB gel. The gel formulations presented good rheological properties, and stability assays detected no differences in physicochemical stability up to 30 d after preparation. Moreover, histological assessment revealed no morphological changes in rat skin after application of any of the gel formulations tested.

Development of egg PC/cholesterol/α-tocopherol liposomes with ionic gradients to deliver ropivacaine.

CONTEXT: Ropivacaine (RVC) is an aminoamide local anesthetic widely used in surgical procedures. Studies with RVC encapsulated in liposomes and complexed in cyclodextrins have shown good results, but in order to use RVC for lengthy procedures and during the postoperative period, a still more prolonged anesthetic effect is required. OBJECTIVE: This study therefore aimed to provide extended RVC release and increased upload using modified liposomes. MATERIALS AND METHODS: Three types of vesicles were studied: (i) large multilamellar vesicle (LMV), (ii) large multivesicular vesicle (LMVV) and (iii) large unilamellar vesicle (LUV), prepared with egg phosphatidylcholine/cholesterol/α-tocopherol (4:3:0.07 mol%) at pH 7.4. Ionic gradient liposomes (inside: pH 5.5, pH 5.5 + (NH4)2SO4 and pH 7.4 + (NH4)2SO4) were prepared and showed improved RVC loading, compared to conventional liposomes (inside: pH 7.4). RESULTS AND DISCUSSION: An high-performance liquid chromatography analytical method was validated for RVC quantification. The liposomes were characterized in terms of their size, zeta potential, polydispersion, morphology, RVC encapsulation efficiency (EE(%)) and in vitro RVC release. LMVV liposomes provided better performance than LMV or LUV. The best formulations were prepared using pH 5.5 (LMVV 5.5in) or pH 7.4 with 250 mM (NH4)2SO4 in the inner aqueous core (LMVV 7.4in + ammonium sulfate), enabling encapsulation of as much as 2% RVC, with high uptake (EE(%) ∼70%) and sustained release (∼25 h). CONCLUSION: The encapsulation of RVC in ionic gradient liposomes significantly extended the duration of release of the anesthetic, showing that this strategy could be a viable means of promoting longer-term anesthesia during surgical procedures and during the postoperative period.

Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans.

OBJECTIVE: To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. MATERIALS AND METHODS: Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). RESULTS: The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. CONCLUSION: We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.

Polymeric Nanocapsules Loaded with Lidocaine: A Promising Formulation for Topical Dental Anesthesia.

Lidocaine is the most commonly used local anesthetic worldwide, known for its rapid onset and moderate duration of anesthesia. However, it is short-lived and does not effectively promote effective topical anesthesia in the oral cavity when used alone. Our aim was to investigate whether an approximate 50% encapsulation of lidocaine in poly(ε-caprolactone) nanocapsules (LDC-Nano) would be able to increase its permeation and analgesic efficacy and reduce cytotoxicity. In this study, we characterized LDC-Nano and conducted MTT tests with HaCaT cells to assess their in vitro cytotoxicity. Additionally, in vitro permeation assays across the pig esophageal epithelium and the anesthetic efficacy of the hind paw incision model in rats were performed. Plain lidocaine (LDC) was compared with LDC-Nano and lidocaine hydrochloride plus epinephrine (LDC-Epi). The physicochemical characteristics of LDC-Nano were satisfactory (pH: 8.1 ± 0.21; polydispersity index: 0.08 ± 0.01; mean diameter (nm): 557.8 ± 22.7; and encapsulation efficiency (%): 51.8 ± 1.87) and remained stable for up to 4 months. LDC-Nano presented similar in vitro cytotoxicity to LDC but was higher than LDC-Epi (LD50: LDC = 0.48%; LDC-Nano = 0.47%; and LDC-Epi = 0.58%; p < 0.0001). Encapsulation increased the permeability coefficient about 6.6 times and about 7.5 the steady-state flux of lidocaine across the mucosal epithelium. Both encapsulation and epinephrine improved anesthesia duration, with epinephrine demonstrating superior efficacy (100% of animals were anesthetized up to 100, 30, and 20 min when LDC-Epi, LDC-nano, and LDC were used, respectively). Although LDC-Epi demonstrated superior in vivo anesthetic efficacy, the in vitro permeation and cytotoxicity of LDC-Nano indicate promising avenues for future research, particularly in exploring its potential application as a topical anesthetic in the oral cavity.

Analysis of Key Factors for Evaluating Mucosal Adhesion Using Swine Buccal Tissue.

The assessment of the mucoadhesive properties peak mucoadhesive force (Fmax) and work of mucoadhesion (Wmuc) with texture analyzers is a common in vitro method for analyzing formulation capabilities. Challenges arise in selecting and standardizing experimental conditions due to various variables influencing mucoadhesion. This complexity hampers direct product performance comparisons. In our study, we explored factors (contact force and time, probe speed and mucin in artificial saliva) impacting a model formulation's mucoadhesive capacity. Using Omcilon-A®Orabase on porcine buccal mucosa, we systematically varied experimental conditions, employing a statistical approach (Central Composite Design - CCD). Three variables (contact force, contact time, probe speed) and their interactions were assessed for their impact on Fmax and Wmuc. Results showed that contact time and force positively affected Fmax, while only contact time influenced Wmuc. In the mucin artificial saliva test, a force of 0.5 N, time of 600 s, and speed of 1 mm/s yielded optimal Fmax (0.587 N) and Wmuc (0.468 N.s). These conditions serve as a reference for comparing mucoadhesive properties of formulations for topical oral use.

Transdermal delivery of butamben using elastic and conventional liposomes.

Gel formulations containing the local anesthetic butamben (BTB) encapsulated in either conventional (BTBLUV) or elastic (BTBLUV-EL) liposomes were prepared and characterized, and then evaluated in terms of their skin permeability. Parameters measured included vesicle size and surface charge, BTB fluorescence anisotropy, encapsulation efficiency, partition coefficient and liposomal membrane organization. Encapsulation efficiencies and membrane/water partition coefficients were determined using a phase separation. The partition coefficients of the elastic and conventional formulations were 2025 ± 234 and 1136 ± 241, respectively. The sizes of the elastic and conventional liposomes did not change significantly (p > 0.05) following incorporation of the anesthetic. As expected, the elastic liposomes presented order parameters that were lower than those of the conventional liposomes, as determined by electron paramagnetic resonance with a 5-stearic acid nitroxide probe incorporated into the bilayer. After 8 h, the fluxes into the receiving solution (µg/cm(2)/h) were 6.95 ± 1.60 (10% BTB), 23.17 ± 6.09 (10% BTBLUV) and 29.93 ± 6.54 (10% BTBLUV-EL). The corresponding time lags (h) were 1.90 ± 0.48, 1.23 ± 0.28 and 1.57 ± 0.38, respectively. The permeability coefficients (10(-3 )cm/h) were 1.02 ± 0.23, 2.96 ± 0.77 and 4.14 ± 0.9, for 10% BTB, 10% BTBLUV and 10% BTBLUV-EL, respectively. The results demonstrate that anesthetic access through the skin can be considerably enhanced using liposomal gel formulations, compared to plain gel formulations.

Liposomal-benzocaine gel formulation: correlation between in vitro assays and in vivo topical anesthesia in volunteers.

The aim of the present study was to characterize a liposome-based benzocaine (BZC) formulation designed for topical use on the oral mucosa and to evaluate its in vitro retention and permeation using the Franz-type diffusion cells through pig esophagus mucosa. To predict the effectiveness of new designed formulations during preclinical studies, a correlation between in vitro assays and in vivo efficacy was performed. Liposomal BZC was characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and morphology. Liposomal BZC (BL10) was incorporated into gel formulation and its performances were compared to plain BZC gel (B10) and the commercially available BZC gel (B20). BL10 and B10 presented higher flux and retention on pig esophagus mucosa with a shorter lag time, when compared to B20. BZC flux was strongly correlated with in vivo anesthetic efficacy, but not with topical anesthesia duration. The retention studies did not correlate with any of the in vivo efficacy parameters. Thus, in vitro permeation study can be useful to predict anesthetic efficacy during preclinical tests, because a correlation between flux and anesthetic efficacy was observed. Therefore, in vitro assays, followed by in vivo efficacy, are necessary to confirm anesthetic performance.

Effect of articaine on mental nerve anterior portion: histological analysis in rats.

OBJECTIVES: The aim of this study was to evaluate the possible toxic effects of articaine and lidocaine on mental nerve, due to the increasing number of paresthesia cases after nerve blocks. MATERIALS AND METHODS: The drugs were injected in the anterior portion of mental nerve of 24 rats, divided into three groups: G1--4% articaine with 1:100,000 epinephrine; G2--2% lidocaine with 1:100,000 epinephrine and G3--plain 1:100,000 epinephrine solution. These solutions were injected in the right side of the rat's mandible and the left side was used as control (0.9% saline solution). Previously to the injections, the animals were anesthetized with thiopental and, 24 h after the injections, their jaws were removed and submitted to routine histological techniques. A histopathological analysis was performed by optical microscopy. RESULTS: An inflammatory infiltration was found around mental nerve, classified as intense for G3, moderate for G1 and light for both G2 and control groups. No injuries were found in nervous structure, despite the inflammatory reaction observed around it. CONCLUSION: The results suggest that articaine is not toxic to the nervous structure and further studies are necessary to explain the possible relation between articaine injection and paresthesia.

Microneedles for oral mucosal delivery - Current trends and perspective on future directions.

INTRODUCTION: Oral cavity drug and vaccine delivery has the potential for local targeting, dose reduction, minimization of systemic side effects, and generation of mucosal immunity. To overcome current limitations of delivery into the oral cavity mucosa, microneedles (MNs) have emerged as a promising technology. AREAS COVERED: We reviewed the literature on MN application in the oral cavity, including in vitro studies, in vivo animal studies, and human clinical trials. EXPERT OPINION: MNs are sufficiently robust to cross the oral cavity epithelium and nearly painless when applied to different parts of the human oral mucosa including the lip, cheek, tongue, and palate. In recent years, MNs have been evaluated for different applications, including vaccination, topical anesthetic delivery, and treatment of local oral pathologies such as oral lesions or carcinomas. MNs are attractive because they have the potential to produce a better treatment outcome with reduced side effects. Over the coming years, we project a significant increase in research related to the development of MNs for use in dentistry and other medical conditions of the mouth.

Local neurotoxicity and myotoxicity evaluation of cyclodextrin complexes of bupivacaine and ropivacaine.

BACKGROUND: Bupivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures. In previous studies, inclusion complexes of BVC or RVC in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) increased differential nervous blockade, compared to the plain anesthetic solutions. In this study we evaluated the local neural and muscular toxicity of these new formulations containing 0.5% BVC or RVC complexed with HP-ß-CD (BVC(HP-ß-CD) and RVC(HP-ß-CD)). METHODS: Schwann cell viability was assessed by determination of mitochondrial dehydrogenase activity, and histopathological evaluation of the rat sciatic nerve was used to identify local neurotoxic effects (48 hours and 7 days after the treatments). Evaluations of serum creatine kinase levels and the histopathology of rat gastrocnemius muscle (48 hours after treatment) were also performed. RESULTS: Schwann cell toxicity evaluations revealed no significant differences between complexed and plain local anesthetic formulations. However, use of the complexed local anesthetics reduced serum creatine kinase levels 5.5-fold, relative to the plain formulations. The differences were significant at P < 0.05 (BVC) and P < 0.01 (RVC). The histopathological muscle evaluation showed that differences between groups treated with local anesthetics (BVC or RVC) and their respective complexed formulations (BVC(HP-ß-CD) or RVC(HP-ß-CD)) were significant (P < 0.05). CONCLUSIONS: We concluded that the new formulations presented a lower myotoxicity and a similar cytotoxic effect when compared to plain local anesthetic solutions.

Polymeric Biomaterials for Topical Drug Delivery in the Oral Cavity: Advances on Devices and Manufacturing Technologies.

There are several routes of drug administration, and each one has advantages and limitations. In the case of the topical application in the oral cavity, comprising the buccal, sublingual, palatal, and gingival regions, the advantage is that it is painless, non-invasive, allows easy application of the formulation, and it is capable of avoiding the need of drug swallowing by the patient, a matter of relevance for children and the elderly. Another advantage is the high permeability of the oral mucosa, which may deliver very high amounts of medication rapidly to the bloodstream without significant damage to the stomach. This route also allows the local treatment of lesions that affect the oral cavity, as an alternative to systemic approaches involving injection-based methods and oral medications that require drug swallowing. Thus, this drug delivery route has been arousing great interest in the pharmaceutical industry. This review aims to condense information on the types of biomaterials and polymers used for this functionality, as well as on production methods and market perspectives of this topical drug delivery route.

Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers.

This blinded crossover study evaluated the efficacy and pain sensitivity evoked by a previously reported liposome-encapsulated mepivacaine formulation (Araujo et al., 2004). Thirty healthy volunteers received an intraoral injection (1.8 mL), at four different sessions, of the following formulations: 2% mepivacaine with 1:100,000 epinephrine (MVC(2%EPI)), 3% mepivacaine (MVC(3%)), and 2 and 3% liposome-encapsulated mepivacaine (MVC(2%LUV) and MVC(3%LUV)). Latency period and duration of anesthesia were assessed by an electrical pulp tester and injection discomfort by a visual analog scale (VAS). Data were analyzed with Tukey-Kramer and Friedman tests (P < 0.05). No significant difference was found regarding latency period (in minutes) among the formulations (P > 0.05). The duration of anesthesia after the injection of MVC(3%LUV) was higher than the one obtained after the infiltration of MVC(2%LUV) and of MVC(3%) (P < 0.05). However, the duration of anesthesia obtained with MVC(3%) did not differ from the one obtained with MVC(2%LUV) (P > 0.05). MVC(3%LUV) showed lower VAS median values than MVC(2%EPI) (P < 0.05), and there were no significant differences among the others formulations. Liposome-encapsulated 3% mepivacaine showed longer duration of anesthesia, in comparison to the commercial formulation of MVC(3%). MVC(2%LUV) was able to produce a similar duration of anesthesia as the 3% commercial formulation, despite the 50% decrease in the anesthetic concentration. Thus, the encapsulation of mepivacaine increased the duration of anesthesia and reduced the injection discomfort caused by vasoconstrictor-associated formulations in healthy volunteers.

Innovative Mucoadhesive Precursor of Liquid Crystalline System Loading Anti-Gellatinolytic Peptide for Topical Treatment of Oral Cancer.

Current researches report an actual benefit of a treatment for oral cancer via inhibition of proteolytic matrix metallopro-teinases (MPP) with a peptide drug, called CTT1. However, peptides present poor oral bioavailability. Topical administration on oral mucosa avoids its passage through the gastrointestinal tract and the first-pass liver metabolism, but the barrier function of the oral mucosa can impair the permeation and retention of CTT1. The objective of this study is to incorporate CTT1 into a mucoadhesive precursor of liquid crystalline system (PLCS) as an interesting strategy for the topical treatment of oral cancer. PLCS consisting of oleic acid, ethoxylated 20 and propoxylated cetyl alcohol 5, polyethyleneimine (P)-associated chitosan (C) dispersion and CTT1 (FPC-CTT1) was developed and characterized by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). In vitro permeation and retention across esophageal mucosa, In vitro cytotoxicity towards tongue squamous cell carcinoma cells, and in vivo evaluation of vascular changes using the chick embryo chorioallantoic membrane (CAM) model were performed. PLM and SAXS showed that FPC-CTT1acted as PLCS, because it formed a lamellar liquid crystalline system after the addition of artificial saliva. FPC-CTT1increased approximately 2-fold the flux of permeation and 3-fold the retention of CTT1 on the porcine esophageal mucosa. CTT1 does not affect cell viability. CAM tests showed that FPC preserved the blood vessels and it can be a safe formulation. These findings encourage the use of the FPC-CTT1 for topical treatment of oral cancer.

Resistivity Technique for the Evaluation of the Integrity of Buccal and Esophageal Epithelium Mucosa for In Vitro Permeation Studies: Swine Buccal and Esophageal Mucosa Barrier Models.

Permeation assays are important for the development of topical formulations applied on buccal mucosa. Swine buccal and esophageal epithelia are usually used as barriers for these assays, while frozen epithelia have been used to optimize the experimental setup. However, there is no consensus on these methods. In transdermal studies, barrier integrity has been evaluated by measuring electrical resistance (ER) across the skin, which has been demonstrated to be a simple, fast, safe, and cost-effective method. Therefore, the aims here were to investigate whether ER might also be an effective method to evaluate buccal and esophageal epithelium mucosa integrity for in vitro permeation studies, and to establish a cut-off ER value for each epithelium mucosa model. We further investigated whether buccal epithelium could be substituted by esophageal epithelium in transbuccal permeation studies, and whether their permeability and integrity were affected by freezing at -20 °C for 3 weeks. Fresh and frozen swine buccal and esophageal epithelia were mounted in Franz diffusion cells and were then submitted to ER measurement. Permeation assays were performed using lidocaine hydrochloride as a hydrophilic drug model. ER was shown to be a reliable method for evaluating esophageal and buccal epithelia. The esophageal epithelium presented higher permeability compared to the buccal epithelium. For both epithelia, freezing and storage led to decreased electrical resistivity and increased permeability. We conclude that ER may be safely used to confirm tissue integrity when it is equal to or above 3 kΩ for fresh esophageal mucosa, but not for buccal epithelium mucosa. However, the use of esophageal epithelium in in vitro transmucosal studies could overestimate the absorption of hydrophilic drugs. In addition, fresh samples are recommended for these experiments, especially when hydrophilic drugs are involved.

Promising potential of articaine-loaded poly(epsilon-caprolactone) nanocapules for intraoral topical anesthesia.

To determine whether the permeation capacity and analgesic efficacy of articaine (ATC) could be increased and cytotoxicity decreased by encapsulation in poly(ɛ-caprolactone) nanocapsules (ATCnano), aiming at local or topical anesthesia in dentistry. Cellular viability was evaluated (using the MTT test and fluorescence microscopy) after 1 h and 24 h exposure of HaCaT cells to ATC, ATCnano, ATC with epinephrine (ATCepi), and ATC in nanocapsules with epinephrine (ATCnanoepi). The profiles of permeation of 2% ATC and 2% ATCnano across swine esophageal epithelium were determined using Franz-type vertical diffusion cells. Analgesic efficacy was evaluated with a von Frey anesthesiometer in a postoperative pain model in rats, comparing the 2% ATC, 2% ATCnano, 2% ATCepi, and 2% ATCnanoepi formulations to 4% ATCepi (a commercially available formulation). We show that use of the nanocapsules decreased the toxicity of articaine (P<0.0001) and increased its flux (P = 0.0007). The 2% ATCepi and 4% ATCepi formulations provided higher analgesia success and duration (P<0.05), compared to 2% ATC, 2% ATCnano, and 2% ATCnanoepi. Articaine-loaded poly(ɛ-caprolactone) nanocapsules constitute a promising formulation for intraoral topical anesthesia (prior to local anesthetic injection), although it is not effective when injected in inflamed tissues for pain control, such as irreversible pulpitis.