Nanohybrid hydrogels designed for transbuccal anesthesia

International Journal of Nanomedicine Dovepress open access to scientific and medical research O r i g in a l R e s e a r c h International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 110.9.250.155 on 31-May-2020 For personal use only. Open Access Full Text Article Nanohybrid hydrogels designed for transbuccal anesthesia This article was published in the following Dove Press journal: International Journal of Nanomedicine Lígia Nunes de Morais Ribeiro 1 Michelle Franz-Montan 2 Márcia Cristina Breitkreitz 3 Gustavo Henrique Rodrigues da Silva 1 Simone Ramos de Castro 1 Viviane Aparecida Guilherme 1 Daniele Ribeiro de Araújo 4 Eneida de Paula 1 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil; 2Department of Physiological Sciences, Piracicaba Dental School, Unicamp, Piracicaba, São Paulo, Brazil; 3 Department of Analytical Chemistry, Institute of Chemistry, Unicamp, Campinas, São Paulo, Brazil; 4Human and Natural Science Center, ABC Federal University, Santo André, São Paulo, Brazil 1 Background: Local anesthesia in dentistry is by far the most terrifying procedure for patients, causing treatment interruption. None of the commercially available topical formulations is effective in eliminating the pain and phobia associated to the needle insertion and injection. Materials and methods: In this work we prepared a nanostructured lipid-biopolymer hydrogel for the sustained delivery of lidocaine–prilocaine (LDC-PLC) for transbuccal preanesthesia. The lipid was composed of optimized nanostructured lipid carriers (NLC) loaded with 5% LDC-PLC (NLC/LDC-PLC). The biopolymer counterpart was selected among alginate, xanthan (XAN), and chitosan matrices. The XAN-NLC hydrogel presented the most uniform aspect and pseudoplastic rheological profile, as required for topical use; therefore, it was selected for subsequent analyses. Accelerated stability tests under critical conditions (40°C; 75% relative humidity) were conducted for 6 months, in terms of drug content (mg/g), weight loss (%), and pH. Results: In vitro LDC-PLC release profile through Franz diffusion cells revealed a bimodal kinetics with a burst effect followed by the sustained release of both anesthetics, for 24 hours. Structural analyses (fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy) gave details on the molecular organization of the hybrid hydrogel, confirming the synergic interaction between the components. Safety and efficacy were evaluated through in vitro cell viability (3T3, HaCat, and VERO cells) and in vivo antinociceptive (tail-flick, in mice) tests, respectively. In comparison to a control hydrogel and the eutectic mixture of 5% LDC-PLC cream (EMLA®), the XAN-NLC/LDC-PLC hybrid hydrogel doubled and quadrupled the anesthetic effect (8 hours), respectively. Conclusion: Considering such exciting results, this multifaceted nanohybrid system is now ready to be further tested in clinical trials. Keywords: hybrid hydrogel, NLC, xanthan, lidocaine–prilocaine, topical buccal anesthesia, dentistry Introduction Correspondence: Lígia Nunes de Morais Ribeiro Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Rua Monteiro Lobato, 255, 13083-862, Campinas, São Paulo, Brazil Tel +55 19 3521 6144 Email 6453 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2018:13 6453–6463 Dovepress © 2018 Ribeiro et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJN.S180080 Powered by TCPDF (www.tcpdf.org) One of the most expected innovations in dentistry is the development of an effective topical anesthetic formulation. This is a relevant concern due to the patient fear to the injection and local anesthetic (LA) administration. Currently, “needle phobia” is the cause of treatment nonadherence, aggravating the dental problems. Moreover, there is a lack of efficient noninvasive pain relief formulations.1 The most desirable marketed topical anesthetic cream is composed of the eutectic mixture of lidocaine and prilocaine (LDC-PLC) 5% w/w (EMLA®). However, this formulation has been designed for dermatological purposes, and it causes ulceration when applied at the oral mucosa and does not minimize the palatal anesthesia pain, in humans.2,3 Furthermore, systemic toxicity symptoms, such as fever after the eutectic mixture of LDC-PLC cream buccal application, were also reported.4 Dovepress International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 110.9.250.155 on 31-May-2020 For personal use only. Ribeiro et al The nanoencapsulation of LA is a versatile approach, which has been successfully found in protecting the drug against degradation, providing nanostructured drug delivery systems (DDS) with physicochemical stability, biocompatibility, and optimized efficacy.5 Nanostructured lipid carriers (NLC) are a DDS formed by a lipid blend inner core coated with surfactants, and they provide efficient loading of hydrophobic molecules.6 In an attempt to develop an efficient pre-anesthetic for transbuccal application, we have previously described an optimized NLC/LDC-PLC (5%) formulation, selected from factorial design, with excellent structural properties, stability, and in vitro sustained release profile for both LAs.7 Despite the excellent properties of that DDS, the fluidness and low adhesion8 inherent to most of the colloidal formulations prevented its application as a pre-anesthetic in dentistry. Hydrogels are macroscopic and water-soluble pharmaceutical forms formed by a tridimensional polymeric network, widely used for topical administration of several classes of drugs.9 Hydrogels can be processed from synthetic or natural polymers.10,11 Processing hydrogels from biopolymeric matrices is especially interesting due to their biocompatibility and biodegradability properties, abundance, low cost, and absence of organic solvents or weak acids in most of the preparation methods.12 Xanthan gum (XAN) is an anionic biopolymer synthesized from strains of Xanthomonas campestris that is broadly used in pharmaceutical and food industries.13 Its interest for use as hydrogel matrices for oral mucosa is also given by the free carboxylic acid available groups, which form hydr (...truncated)