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.

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.

Hybrid nanofilms as topical anesthetics for pain-free procedures in dentistry.

Topical anesthetics are widely applied in order to relieve the discomfort and anxiety caused by needle insertion and other painful superficial interventions at the oral cavity. So far, there are no commercially available effective topical anesthetic formulations for that purpose, and the most of developments are related to hydrophilic and low mucoadhesive forms. Therefore, we have prepared different hybrid nanofilms composed of biopolymer matrices (chitosan, pectin, and chitosan-pectin) blended with nanostructured lipid carriers (NLC) loading the eutectic mixture of 5% lidocaine-prilocaine (LDC-PLC), in order to fulfill this gap in the market. These dual systems were processed as hybrid nanofilms by the solvent/casting method, and its mucoadhesive, structural and mechanical properties were detailed. The most appropriate hybrid nanofilm combined the advantages of both pectin (PCT) and NLC components. The resultant material presented sustained LDC-PLC release profile for more than 8 h; permeation across porcine buccal mucosa almost twice higher than control and non-cytotoxicity against 3T3 and HACAT cell lines. Then, the in vivo efficacy of PCT/NLC formulation was compared to biopolymer film and commercial drug, exhibiting the longest-lasting anesthetic effect (> 7 h), assessed by tail flick test in mice. These pectin-based hybrid nanofilms open perspectives for clinical trials and applications beyond Dentistry.

Palatal needle-free anesthesia for upper molars extraction. A randomized clinical trial.

BACKGROUND: The aim of this study was to compare the ability of liposomal and non-liposomal lidocaine and prilocaine in hydrogel formulations to promote topical anesthesia in palatal mucosa during upper molar extractions. METHODS: In this randomized, cross over, triple-blinded clinical trial, a liposomal and a non-liposomal formulation of the eutectic mixture of local anesthetics, 2.5% lidocaine and 2.5% prilocaine, were used to promote palatal anesthesia without the local anesthetic infiltration during bilateral upper molars extractions. RESULTS: From the total of 40 patients included in this study, the non-liposomal eutectic lidocaine-prilocaine formulation failed in 40% of cases, unlike the liposomal formulation, which was effective for all patients (Fisher's exact test, p < 0.0001). Furthermore, the liposomal formulation (26.75 ± 7,47 min) induced longer anesthesia duration (t-test, p < 0.0001) than the non-liposomal formulation (16.78 ± 4.75 min). No mucosal ulceration or discomfort was reported for both formulations. CONCLUSION: The liposomal formulation was able to induce adequate anesthesia in palatal mucosa during dental extraction, avoiding the local anesthetic infiltration. For the first time, a topical formulation allowed upper molars surgical removal without injection of any local anesthetic agent into palatal mucosa in adults.

Recent advances and perspectives in topical oral anesthesia.

INTRODUCTION: Topical anesthesia is widely used in dentistry to reduce pain caused by needle insertion and injection of the anesthetic. However, successful anesthesia is not always achieved using the formulations that are currently commercially available. As a result, local anesthesia is still one of the procedures that is most feared by dental patients. Drug delivery systems (DDSs) provide ways of improving the efficacy of topical agents. Areas covered: An overview of the structure and permeability of oral mucosa is given, followed by a review of DDSs designed for dental topical anesthesia and their related clinical trials. Chemical approaches to enhance permeation and anesthesia efficacy, or to promote superficial anesthesia, include nanostructured carriers (liposomes, cyclodextrins, polymeric nanoparticle systems, solid lipid nanoparticles, and nanostructured lipid carriers) and different pharmaceutical dosage forms (patches, bio- and mucoadhesive systems, and hydrogels). Physical methods include pre-cooling, vibration, iontophoresis, and microneedle arrays. Expert opinion: The combination of different chemical and physical methods is an attractive option for effective topical anesthesia in oral mucosa. This comprehensive review should provide the readers with the most relevant options currently available to assist pain-free dental anesthesia. The findings should be considered for future clinical trials.

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 and Evaluation of a Novel Mucoadhesive Film Containing Acmella oleracea Extract for Oral Mucosa Topical Anesthesia.

PURPOSE: To develop an anesthetic mucoadhesive film containing Acmella oleracea (jambu) extract for topical use on oral mucosa. METHODS: Ethanolic extracts from aerial parts of jambu were prepared by maceration. Pigment removal was obtained by adsorption with activated carbon. Three mucoadhesive films were developed using a film casting method: 10 or 20% of crude jambu extract (10% JB and 20% JB), and 10% of crude jambu extract treated with activated carbon (10% JBC). The mucoadhesive films were characterized regarding their uniformity, thickness, pH, and spilanthol content, and their stability was evaluated during 120 days. Gas chromatography was used to quantify the amount of spilanthol. In vitro tests determined the permeation of spilanthol across pig esophageal epithelium mucosa in Franz diffusion cells. Topical anesthetic efficacy was assessed in vivo using a tail flick test in mice. RESULTS: The three mucoadhesive films showed physical stability and visual appearances suitable for use on oral mucosa. The permeation study revealed that the spilanthol from 10% JBC presented higher flux and permeability coefficient values, compared to 10% or 20% JB (p < 0.001). Moreover, 10% JBC showed better topical anesthetic efficacy than the other films (p < 0.01). CONCLUSION: Mucoadhesive film containing crude extract of jambu treated with activated carbon is a potential alternative for oral, topical use, encouraging future clinical studies.

Evaluation of different pig oral mucosa sites as permeability barrier models for drug permeation studies.

The objective of the present study was to investigate the influence of preparation and storage conditions on the histology and permeability of different parts of porcine oral mucosa used for in vitro studies of transbuccal formulations. Fresh and frozen (-20°C and -80°C, with or without cryoprotectant) epithelia of porcine palatal, gingival, dorsum of the tongue, and buccal mucosa were submitted for histological analyses to determine the effects of storage conditions on barrier integrity. Permeation of lidocaine hydrochloride (used as a hydrophilic model drug) across fresh and previously frozen oral epithelium was measured in order to evaluate the barrier function. Histological evaluation demonstrated that the oral epithelium was successfully separated from the connective tissue, except for gingival mucosa. After storage under different conditions, all tissues presented desquamation of superficial layers and spherical spaces induced by the freezing process. The permeability of lidocaine hydrochloride varied among the fresh oral mucosa and generally increased after freezing. In conclusion, fresh epithelium from the buccal and dorsum of the tongue mucosa should be used for in vitro studies investigating hydrophilic drug transport when these are the desired clinical application sites. However, when the palate is the target site, both fresh and frozen (for up to 4weeks, without addition of cryoprotectant) samples could be used. The addition of glycerol as a cryoprotectant should be avoided due to increased lidocaine hydrochloride permeability.

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.

Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches.

INTRODUCTION: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions. AREAS COVERED: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches. EXPERT OPINION: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia.

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.

Micro and nanosystems for delivering local anesthetics.

INTRODUCTION: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent. AREAS COVERED: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry. EXPERT OPINION: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.

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.

Liposomal encapsulation improves the duration of soft tissue anesthesia but does not induce pulpal anesthesia.

STUDY OBJECTIVE: To compare the topical and the pulpal anesthesia efficacy of liposomal and plain benzocaine formulations. DESIGN: Double-blinded, randomized crossover study. SETTING: University ambulatory dental center. PATIENTS: 30 ASA physical status I volunteers. INTERVENTIONS: Volunteers received, in three different sessions, topical application of liposome-encapsulated 10% benzocaine (LB10), 10% benzocaine gel (B10), and 20% benzocaine gel (B20) in the right maxillary canine mucobuccal fold. MEASUREMENTS: Pain associated with the needle insertion was rated by visual analog scale (VAS) and the duration of topical anesthesia was recorded. Pulpal anesthesia was evaluated using an electric pulp tester. MAIN RESULTS: VAS values (median, 1st - 3rd quartiles) were 17 cm (11 - 25), 14 cm (3 - 22), and 21 cm (9 - 21) for B10, LB10, and B20, respectively. No differences were noted among the groups (Friedman test; P = 0.58). Soft tissue anesthesia was also not different. The LB10 [10 (8 - 12) min] showed longer soft tissue anesthesia (Friedman test; P < 0.01) than the other agents [B10 = 8 (5 - 10) min, and B20 = 7 (6 - 9) min]. None of the topical benzocaine formulations tested induced pulpal anesthesia. CONCLUSIONS: The encapsulation of benzocaine into liposome increased the duration of soft tissue anesthesia. However, it did not induce pulpal anesthesia.

Use of phytotherapy in dentistry.

Over the past decade, interest in drugs derived from medicinal plants has markedly increased. This study was aimed at a literature review focusing on studies investigating herbal drugs and other natural products, as well as their therapeutic application, side effects and possible drug interactions. Few studies were found to support their rational use in dentistry. Since there is an increasing use of phytotherapeutic agents in dentistry, further studies are needed to evaluate their safety and effectiveness for clinical use.

Efficacy of 1% ropivacaine gel for topical anesthesia of human oral mucosa.

OBJECTIVE: To evaluate the efficacy of 1% ropivacaine for topical anesthesia in dentistry. METHOD AND MATERIALS: Thirty healthy volunteers randomly (blind crossover) received the following treatments: 20 mg of 1% ropivacaine gel (ropivacaine-20), 60 mg of 1% ropivacaine gel (ropivacaine-60), 20 mg of the eutectic mixture of local anesthetics 2.5% lidocaine and 2.5% prilocaine (EMLA cream, AstraZeneca; EMLA-20), 60 mg of EMLA (EMLA-60), 20 mg of 20% benzocaine gel (Benzotop, DFL; benzocaine-20), and 60 mg of 20% benzocaine gel (benzocaine-60), applied on the maxillary buccal fold of the right canine at different sessions. Pain was assessed by visual analog scale (VAS) and 11-point box scale (BS-11) after the insertion of 30-gauge needles. Soft tissue anesthesia was measured by pinprick test. Data were analyzed by Friedman and Pearson correlation tests. RESULTS: All the topical anesthetics evaluated showed similar performance in relation to the pain perceived after needle insertion (P >.05), and there were no significant differences among groups considering VAS or BS-11 (P = .177 and P = .179, respectively). The duration of soft tissue anesthesia was not statistically significantly different for ropivacaine-20, EMLA-20, benzocaine-20, ropivacaine-60, EMLA-60, and benzocaine-60, but EMLA-60 showed significantly longer duration than the other agents (P <.05). CONCLUSION: All topical anesthetics were similar in reducing pain to needle insertion. EMLA-60 promoted longer duration of soft tissue anesthesia.

Liposome-encapsulated ropivacaine for topical anesthesia of human oral mucosa.

BACKGROUND: The elimination of pain caused by needle insertion for local anesthesia would be a significant advance in dentistry. METHODS: In this blinded cross-over study we evaluated the efficacy of liposome-encapsulated ropivacaine for topical anesthesia. Thirty healthy volunteers received 60 mg topical anesthetics: Liposome-encapsulated 1% ropivacaine, 1% plain ropivacaine, 2.5% lidocaine and 2.5% prilocaine mixture (EMLA), and 20% benzocaine gel, in the buccal fold of the upper-right canine for 2 min in different sessions. After insertion of 30-G needles, pain was rated on a visual analog scale (VAS). A pinprick test was used to measure the duration of topical anesthesia. The pulpar response was assessed by an electric pulp tester. RESULTS: VAS median and interquartile range (in cm) were 0.8 (0.4-1.5), 1.6 (0.8-2.6), 1.1 (0.3-2.7), 2.2 (0.9-2.9) for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. The liposome-encapsulated ropivacaine group showed lower VAS mean values when compared with the benzocaine group (P = 0.0205). The median values and interquartile range for the duration of soft tissue anesthesia were 11 (7-14), 6.5 (4-11), 14 (11-16), and 7 (6-9) min for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. EMLA and liposome-encapsulated ropivacaine were just as efficient for reducing pain, and showed longer soft tissue anesthesia when compared to the other local anesthetics (P = 0.0001). CONCLUSION: Liposomal-encapsulated 1% ropivacaine gel was equivalent to EMLA for reducing pain during needle insertion and for the duration of soft tissue anesthesia. None of the topical anesthetics was effective for inducing pulpal anesthesia.