Local anaesthetics are used regularly in the medical world for a variety of different procedures. Topical anaesthetics are used largely in minor skin breaking procedures, laceration repair and minor surgical procedures such as laryngoscopy, oesophagoscopy or urethroscopy (Franchi et al., 2008:186e1). The topical means of application of a local anaesthetic is non-invasive and painless that results in a good patient acceptability profile (Little et al., 2008:102). An existing commercial topical anaesthetic product contains a eutectic mixture of the amide-type local anaesthetics lidocaine hydrochloride (HCl) and prilocaine hydrochloride (HCl). This commercial product takes up to an hour to produce an anaesthetic effect. This is considered as a disadvantage in the use of topical anaesthetics, an hour waiting time is not always ideal in certain medical circumstances (Wahlgren & Quiding, 2000:584). This study compared the lag times, transdermal and topical delivery of lidocaine HCl and prilocaine HCl from four different semi-solid formulations with the inclusion of a current commercial product. One of the formulated semi-solid formulations included Pheroid™ technology, a novel skin-friendly delivery system developed by the Unit for Drug Research and Development at the North-West University, Potchefstroom Campus, South Africa. The skin is the body’s first line of defence against noxious external stimuli. It is considered the largest organ in the body with an intensive and complex structure. It consists of five layers with the first outer layer, the stratum corneum, the most impermeable (Williams, 2003:1). The stratum corneum has excellent barrier function characteristics and is the cause for the time delay in the transdermal delivery of active pharmaceutical ingredients (API) (Barry, 2007:569). Local anaesthetics need to penetrate all the epidermal skin layers in order to reach their target site, the dermis. Skin appendages as well as blood vessels and skin nerve endings are located in the dermis. Local anaesthetics have to reach the free nerve endings in the dermis in order to cause a reversible block on these nerves for a local anaesthetic effect (Richards & McConachie, 1995:41). Penetration enhancement strategies for the transdermal delivery of lidocaine and prilocaine have been investigated and include methods like liposomal entrapment (Franz-Montan et al., 2010; Müller et al., 2004), micellisation (Scherlund et al., 2000), occlusive dressing (Astra Zeneca, 2006), heating techniques (Masud et al., 2010) and iontophoresis (Brounéus et al., 2000). The Pheroid™ delivery system has improved the transdermal delivery of several compounds with its enhanced entrapment capabilities. Pheroid™ consists mainly of unsaturated essential fatty-acids, non-harmful substances that are easily recognised by the body (Grobler et al., 2008:285). The morphology and size of Pheroid™ is easily manipulated because it is a submicron emulsion type formulation which provides it with a vast flexibility profile (Grobler et al., 2008:284). Vesicular entrapment was used to entrap lidocaine HCl and prilocaine HCl in the Pheroid™ and incorporated into an emulgel formulation. An emulgel without the inclusion of Pheroid™ was formulated for comparison with the Pheroid™ emulgel as well as with a hydrogel. Pheroid™ solution was prepared and compared to a phosphate buffer solution (PBS) without Pheroid™, both containing lidocaine HCl and prilocaine HCl as APIs. Franz cell type transdermal diffusion studies were performed on the four semi-solid formulations (emulgel, Pheroid™ emulgel, hydrogel and the commercial product) and two solutions (PBS and Pheroid™). The diffusion studies were performed over a 12 h period followed by the tape stripping of the skin after each diffusion study. Caucasian female abdominal skin was obtained with consent from the donors. The skin for the diffusion cells were prepared by using a Zimmer Dermatome®. PBS (pH 7.4) was prepared as the receptor phase of the diffusion studies. The receptor phase was extracted at certain pre-determined time intervals and analysed with high performance liquid chromatography (HPLC) to determine the amount of API that had traversed the skin. Stratum corneum-epidermis samples and epidermis-dermis samples were prepared and left over night at 4 °C and analysed the next day with HPLC. This was done to determine the amount of API that accumulated in the epidermis-dermis and the amount of API that were left on the outer skin layers (stratum corneum-epidermis). The results from the Franz cell diffusion studies indicated that the emulgel formulation without Pheroid™ shortened the lag time of lidocaine HCl and that the emulgel formulated with Pheroid™ shortened the lag time of prilocaine HCl, when compared to the commercial product. Pheroid™ did not enhance the flux of lidocaine HCl and prilocaine HCl into the skin. The hydrogel formulation demonstrated a high transdermal flux of prilocaine HCl due to the hydrating effect it had on the stratum corneum. The commercial product yielded high flux values for both APIs but it did not result in a high concentration of the APIs delivered to the epidermis-dermis. Pheroid™ technology did, however, enhance the epidermal-dermal delivery of lidocaine HCl and prilocaine HCl into the skin epidermis-dermis. The stability of the emulgel formulation, Pheroid™ emulgel formulation and the hydrogel formulation was examined over a 6 month period. The formulations were stored at 25 °C/60% RH, 30 °C/60% RH and 40 °C/75% RH. The API concentration, mass, pH, zeta potential, particle size, viscosity and visual appearance for each formulation at the different storage conditions were noted and compared at month 0, 1, 2, 3 and 6 to determine if the formulations remained stable for 6 months. The results obtained from the stability study demonstrated that none of the formulations were stable for 6 months. The emulgel remained stable for the first 3 months. At 6 months, large decreases in API concentration and pH occurred which could cause a loss of anaesthetic action in the formulations. The Pheroid™ emulgel formulation did not remain stable for 6 months. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Local anaesthetics are used regularly in the medical world for a variety of different procedures. Topical anaesthetics are used largely in minor skin breaking procedures, laceration repair and minor surgical procedures such as laryngoscopy, oesophagoscopy or urethroscopy (Franchi et al., 2008:186e1). The topical means of application of a local anaesthetic is non-invasive and painless that results in a good patient acceptability profile (Little et al., 2008:102). An existing commercial topical anaesthetic product contains a eutectic mixture of the amide-type local anaesthetics lidocaine hydrochloride (HCl) and prilocaine hydrochloride (HCl). This commercial product takes up to an hour to produce an anaesthetic effect. This is considered as a disadvantage in the use of topical anaesthetics, an hour waiting time is not always ideal in certain medical circumstances (Wahlgren & Quiding, 2000:584). This study compared the lag times, transdermal and topical delivery of lidocaine HCl and prilocaine HCl from four different semi-solid formulations with the inclusion of a current commercial product. One of the formulated semi-solid formulations included Pheroid™ technology, a novel skin-friendly delivery system developed by the Unit for Drug Research and Development at the North-West University, Potchefstroom Campus, South Africa. The skin is the body’s first line of defence against noxious external stimuli. It is considered the largest organ in the body with an intensive and complex structure. It consists of five layers with the first outer layer, the stratum corneum, the most impermeable (Williams, 2003:1). The stratum corneum has excellent barrier function characteristics and is the cause for the time delay in the transdermal delivery of active pharmaceutical ingredients (API) (Barry, 2007:569). Local anaesthetics need to penetrate all the epidermal skin layers in order to reach their target site, the dermis. Skin appendages as well as blood vessels and skin nerve endings are located in the dermis. Local anaesthetics have to reach the free nerve endings in the dermis in order to cause a reversible block on these nerves for a local anaesthetic effect (Richards & McConachie, 1995:41). Penetration enhancement strategies for the transdermal delivery of lidocaine and prilocaine have been investigated and include methods like liposomal entrapment (Franz-Montan et al., 2010; Müller et al., 2004), micellisation (Scherlund et al., 2000), occlusive dressing (Astra Zeneca, 2006), heating techniques (Masud et al., 2010) and iontophoresis (Brounéus et al., 2000). The Pheroid™ delivery system has improved the transdermal delivery of several compounds with its enhanced entrapment capabilities. Pheroid™ consists mainly of unsaturated essential fatty-acids, non-harmful substances that are easily recognised by the body (Grobler et al., 2008:285). The morphology and size of Pheroid™ is easily manipulated because it is a submicron emulsion type formulation which provides it with a vast flexibility profile (Grobler et al., 2008:284). Vesicular entrapment was used to entrap lidocaine HCl and prilocaine HCl in the Pheroid™ and incorporated into an emulgel formulation. An emulgel without the inclusion of Pheroid™ was formulated for comparison with the Pheroid™ emulgel as well as with a hydrogel. Pheroid™ solution was prepared and compared to a phosphate buffer solution (PBS) without Pheroid™, both containing lidocaine HCl and prilocaine HCl as APIs. Franz cell type transdermal diffusion studies were performed on the four semi-solid formulations (emulgel, Pheroid™ emulgel, hydrogel and the commercial product) and two solutions (PBS and Pheroid™). The diffusion studies were performed over a 12 h period followed by the tape stripping of the skin after each diffusion study. Caucasian female abdominal skin was obtained with consent from the donors. The skin for the diffusion cells were prepared by using a Zimmer Dermatome®. PBS (pH 7.4) was prepared as the receptor phase of the diffusion studies. The receptor phase was extracted at certain pre-determined time intervals and analysed with high performance liquid chromatography (HPLC) to determine the amount of API that had traversed the skin. Stratum corneum-epidermis samples and epidermis-dermis samples were prepared and left over night at 4 °C and analysed the next day with HPLC. This was done to determine the amount of API that accumulated in the epidermis-dermis and the amount of API that were left on the outer skin layers (stratum corneum-epidermis). The results from the Franz cell diffusion studies indicated that the emulgel formulation without Pheroid™ shortened the lag time of lidocaine HCl and that the emulgel formulated with Pheroid™ shortened the lag time of prilocaine HCl, when compared to the commercial product. Pheroid™ did not enhance the flux of lidocaine HCl and prilocaine HCl into the skin. The hydrogel formulation demonstrated a high transdermal flux of prilocaine HCl due to the hydrating effect it had on the stratum corneum. The commercial product yielded high flux values for both APIs but it did not result in a high concentration of the APIs delivered to the epidermis-dermis. Pheroid™ technology did, however, enhance the epidermal-dermal delivery of lidocaine HCl and prilocaine HCl into the skin epidermis-dermis. The stability of the emulgel formulation, Pheroid™ emulgel formulation and the hydrogel formulation was examined over a 6 month period. The formulations were stored at 25 °C/60% RH, 30 °C/60% RH and 40 °C/75% RH. The API concentration, mass, pH, zeta potential, particle size, viscosity and visual appearance for each formulation at the different storage conditions were noted and compared at month 0, 1, 2, 3 and 6 to determine if the formulations remained stable for 6 months. The results obtained from the stability study demonstrated that none of the formulations were stable for 6 months. The emulgel remained stable for the first 3 months. At 6 months, large decreases in API concentration and pH occurred which could cause a loss of anaesthetic action in the formulations. The Pheroid™ emulgel formulation did not remain stable for 6 months. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2004. / Härtill 6 uppsatser.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Objective: Systematic review and meta-analysis to assess the effects of uterine or paracervical lidocaine application on pain control during IUD insertion. Methods: PubMed and five other electronic research databases were searched through 15 November 2017 for RCTs comparing lidocaine treatment vs. a control (placebo or no-intervention) to prevent pain during IUD insertion. Searched terms included ‘IUD insertion’, ‘lidocaine’ and ‘randomised controlled trial’. RCTs evaluating lidocaine treatment before IUD insertion without restriction of language, age and IUD type. Pain measured by visual pain scales at tenaculum placement, IUD insertion and immediate post-IUD insertion. Results of random effects meta-analyses were reported as mean differences (MDs) of visual pain scale (VPS) scores and their 95% confidence intervals (CIs). Results: Eleven RCTs (n = 1458 women) reporting paracervical lidocaine block or uterine mucosa lidocaine application before IUD insertion. Lidocaine produced lower VPS scores during tenaculum placement (MD −0.99, 95% CI: −1.73 to −0.26), IUD insertion (MD −1.26, 95% CI: −2.23 to −0.29) and immediate post-IUD insertion period (MD −1.25, 95% CI: −2.17 to −0.33). Conclusion: Lidocaine treatment was associated with modest reduction of pain during tenaculum placement and after IUD insertion. / Revisión por pares

A anestesia local da cavidade bucal é uma etapa fundamental na maioria dos procedimentos odontológicos. A administração não-invasiva efetiva de anestésicos locais na cavidade bucal visando substituir as doloridas injeções, possibilitaria o aprimoramento de procedimentos rotineiros e cirúrgicos. No entanto, a anestesia profunda e pelo tempo adequado de regiões estratégicas da mucosa bucal requer a penetração do anestésico em quantidades efetivas. A combinação dos cloridratos de lidocaína (LCL) e prilocaína (PCL) é uma estratégia interessante do ponto de vista farmacocinético, visto que a lidocaína inicia sua ação mais rapidamente, porém a prilocaína apresenta uma potência maior. A velocidade de liberação e permeação dos fármacos pode ser aumentada e modulada através da aplicação da iontoforese. O objetivo deste trabalho foi avaliar in vitro a influência da iontoforese na permeação de PCL e LCL através de mucosa esofageal suína a partir de uma formulação semi-sólida mucoadesiva. Para tanto, um hidrogel à base de hidroxipropilmetilcelulose foi desenvolvido e o efeito do pH (5,8 e 7,0) avaliado em função da iontoforese (1 mA/cm2 por 60 minutos). Um método analítico de cromatografia líquida de alta eficiência foi validado para quantificação simultânea dos fármacos, apresentando satisfatória seletividade, linearidade no intervalo de 0,25 a 10 ?g/mL, sensibilidade, precisão, exatidão e robustez. A recuperação dos fármacos a partir da mucosa esofageal suína forneceu níveis adequados conforme preconizado pela literatura. A formulação desenvolvida apresentou uniformidade de conteúdo e propriedades mecânicas e mucoadesivas adequadas para a aplicação bucal. A combinação dos fármacos na formulação não ocasionou a formação de uma mistura eutética, porém promoveu mudanças nos coeficientes de distribuição mucosa/formulação do PCL, tendo maior caráter hidrofílico em pH 7,0 e maior caráter hidrofóbico em pH 5,8. Nos estudos de permeação in vitro através de mucosa esofageal suína, a iontoforese a partir da formulação pH 7,0 foi capaz de aumentar as quantidades de PCL permeada e recuperada da mucosa quando isolada e combinada na formulação. Porém, as quantidades de LCL foram aumentadas por iontoforese apenas na mucosa quando combinada ao PCL. A iontoforese a partir da formulação contendo os fármacos isolados em pH 5,8, com o intuito de promover maior ionização dos fármacos, aumentou o fluxo do PCL e do LCL. No entanto, o fluxo passivo foi menor em pH 5,8 e o maior aumento de fluxo proporcionado pela iontoforese neste pH não acarretou em maiores quantidades de fármaco permeadas. O pré-tratamento da mucosa com LCL aumentou ligeiramente o fluxo passivo do PCL, porém quando a iontoforese foi aplicada, tanto o fluxo quanto o acúmulo do PCL na mucosa diminuíram após o pré-tratamento. Assim, para a anestesia não invasiva em procedimentos odontológicos, é recomendável aplicar a iontoforese diretamente na formulação que contém a combinação de PCL e LCL, em pH 7,0. Desta forma, alia-se início de ação mais rápido (LCL) e potência (PCL) e alcançam-se maiores quantidades permeadas e retidas na mucosa para ambos os fármacos. / Local anesthesia of the oral cavity is a key step in most dental procedures. The effective non-invasive administration of local anesthetics in the oral cavity, in order to replace the painful injections, would enable the improvement of routine and surgical procedures. However, deep anesthesia for a suitable period of time of strategic regions of the oral mucosa requires penetration of the anesthetic in effective amounts. The combination of lidocaine hydrochloride (LCL) and prilocaine (PCL) is an interesting strategy, since lidocaine begins to act more quickly, but prilocaine has a higher potency. The rate of release and permeation of drugs can be enhanced and modulated by the application of iontophoresis. The objective of this study was to evaluate in vitro the influence of iontophoresis on the permeation of PCL and LCL through porcine esophageal mucosa from a mucoadhesive semisolid formulation. Thus, a hydroxypropyl methylcellulose hydrogel was developed and the effect of pH (5.8 and 7.0) evaluated in function of iontophoresis (1 mA/cm2 for 60 minutes). An analytical method of high performance liquid chromatography was validated for the simultaneous quantification of drugs with satisfactory selectivity, linearity in the range 0.25 to 10 ?g/mL, sensitivity, precision, accuracy and robustness. The recovery of the drugs from the porcine esophageal mucosa provided adequate levels, as related in the literature. The formulation developed had uniformity of content and mechanical and mucoadhesive properties suitable for buccal application. The combination of the drugs at the formulation did not cause the formation of an eutectic mixture, but provided changes in the distribution coefficients (mucosa/formulation) of PCL, having greater hydrophilicity at pH 7.0 and higher hydrophobic character at pH 5.8. Regarding the in vitro permeation studies across porcine esophageal mucosa, iontophoresis from the formulation at pH 7.0 was able to increase the amounts of PCL permeated and recovered when isolated and combined at the formulation. For LCL, the amount was enhanced by iontophoresis only at the mucosa when the drug was associated with PCL. Iontophoresis from the formulation at pH 5.8, in order to promote higher ionization of the drugs, increased the flow of PCL and the LCL. However, the passive flux was lower at pH 5.8 and the greater increase of flow provided by iontophoresis at this pH did not result in higher amounts of total permeated drug. Pretreatment of the mucosa with LCL slightly increased passive flux of PCL, but when the iontophoresis was applied, both the flow and the amount of PCL recovered from the mucosa decreased after pretreatment. Thus, for a non-invasive anesthesia for dental procedures, it is recommended to apply iontophoresis directly at the formulation containing the combination of PCL and LCL, at pH 7.0. Therefore, it combines a faster onset of action (LCL) and higher potency (PCL), providing larger amounts permeated and recovered from the mucosa for both drugs.

Orientador: Leonardo Fernandes Fraceto / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T03:20:07Z (GMT). No. of bitstreams: 1 Baratelli_Diego_M.pdf: 5417308 bytes, checksum: 04980cc029526e213ff664b425962296 (MD5) Previous issue date: 2014 / Resumo: O controle da dor em diferentes procedimentos clínicos é de extrema importância, logo a descoberta dos anestésicos locais (ALs), caracterizados pela capacidade de diminuir a dor sem a perda da consciência representou um grande avanço para a clínica médica. O anestésico local ideal deve apresentar ação anestésica duradoura e baixa toxicidade. Devido aos avanços da nanotecnologia, gerou-se a possibilidade de associar os ALs com sistemas nanoparticulados poliméricos (SNPs), que agem como transportadores, aumentando assim a eficácia terapêutica daqueles. O presente trabalho teve como objetivo o desenvolvimento de nanocápsulas poliméricas como sistema carreador conjunto para dois ALs amplamente usados na clínica, a prilocaína (PLC) e a lidocaína (LDC) visando melhorar as propriedades terapêuticas destes ALs, pela liberação sustentada, de forma a diminuir os efeitos indesejáveis como a alergenicidade e toxicidade. Desta forma, no presente estudo foram preparadas nanocápsulas (NC) compostas por três diferentes polímeros (PCL) poli-epsilon-caprolactona, (PLGA) poli-lactídeo-co-glicolídeo e (PHBV) poli-hidroxibutirato-co-hidroxivalerato, baseadas na metodologia de emulsificação/evaporação do solvente. A caracterização destes sistemas foi feita através da medida de diâmetro médio das partículas, polidispersão, potencial zeta, pH, eficiência de encapsulação e avaliação do perfil de liberação. Os resultados mostraram que as nanopartículas apresentaram diâmetro médio de 375 a 580 nm com valores de polidispersão abaixo de 0,25; o potencial zeta variou de - 5,4 a - 25,1 mV e o pH entre 3,5 e 8,5. A eficiência de encapsulação dos ALs foi superior a 50% para a PLC e 75% para a LDC. Os ensaios de liberação in vitro mostraram que em todas as formulações a PLC é liberada mais rapidamente que a LDC. Os resultados para os diferentes polímeros mostraram que o perfil de liberação (horas) para a PLC de ~ 2,0; 4,0; 4,5; 5,5 e para LDC de 4,5; 6,0; 8,0; 9,5 seguindo a ordem PLGA>PCL>PCLmistura>PHBV, devido às diferentes características dos polímeros e interações intermoleculares entre os ALs e a matriz polimérica. A análise matemática dos perfis de liberação mostrou que os ALs são liberados por transporte do tipo caso II (difusão e relaxamento da cadeia polimérica). Os resultados obtidos neste trabalho indicou que sistemas carreadores poliméricos de PLC e LDC constituem uma alternativa promissora para futuras aplicações no tratamento da dor / Abstract: In different clinical procedures pain control is of extreme important, so that the discovery of local anesthetics (LAs), characterized by the ability to reduce pain without loss of consciousness represented a major breakthrough in medicine. An ideal local anesthetic agent should have long duration and low toxicity. Advances in nanotechnology allowed the combined use of Las with polymeric nanoparticle systems (SNPs), which act as carriers to increase the therapeutic efficacy of anesthetics. This study aimed the development of polymeric nanocapsules as carrier systems for two LAs widely used in the clinics: prilocaine (PLC) and lidocaine (LDC). To improve these LAs, we wanted to prolong their release profile to reduce side effects, such as allergenicity and toxicity. Thus, in this study were have prepared nanocapsules (NC) using three different kind of polymers: poly-epsilon-caprolactone (PCL), poly-lactide-co-glycolide (PLGA) and polyhydroxybutyrate-co-hydroxyvalerate (PHBV) based on the emulsification/solvent evaporation methodology, The characterization of these systems was considerate by measuring the diameter, polydispersion, zeta potential, pH, encapsulation efficiency of the LAs and investigation of the in release profile. Results demonstrated that the nanoparticles had a mean diameter of 375 to 580 nm with values of polydispersity below 0.25; the zeta potential ranged from - 5.4 to - 25.1 mV and the pH between 3.5 and 8.5. The encapsulation efficiency of LAs were above 50% for PLC and 75% for the LDC. The in vitro release assays showed that PLC was released faster than LDC. in all formulations The results for the different polymers showed the following release profile order PLGA>PCL>PHBV, due to the differences in the polymers proprieties and intermolecular interactions of LAs and the polymeric matrixes. Mathematical analysis of the release profiles showed that LAs are released by type II transport. The results obtained in this work indicated polymeric carrier systems of PLC and LDC could be a promising alternative for future applications in the treatment of pain / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

Syftet med denna randomiserade kliniska studie var att jämföra anestesieffekten mellan 2 % lidocain med 1:200,000 adrenalin och 3 % prilocain med 0,03 i.u./ml felypressin vid en blockad av Nervus alveolaris inferior för behandling av patienter med symtomatisk pulpit i en underkäksmolar eller –premolar.Materialet utgjordes av 5 patienter som uppsökt Tandvårdshögskolans jourmottagning för akuta besvär. Patienterna fick upp till 3,6 ml av antingen 2% lidocain (n=4) eller 3% prilocain (n=1). Det valda medlet var okänt för både patient och behandlare under hela behandlingen. Behandling (pulpotomi) påbörjades först när patienten erhållit bedövad läpp. Information om smärta före och under behandling, intag av analgetika och oro inför behandling noterades. Lyckad anestesi ansågs vara ingen eller endast mild smärta under behandling (<54 mm av 170 mm på en visuell analog skala).Lyckandefrekvensen för lidocain var 50 % och för prilocain 100 %. Det insamlade materialet var för litet för möjliggöra statistisk analys.De patienter som inkluderades i denna pilotstudie var för få för att visa eventuella skillnader i anestesieffekt mellan lidocain och prilocain vid en blockad av Nervus alveolaris inferior för behandling av patienter med symtomatisk pulpit i en underkäksmolar eller –premolar. Ett större underlag krävs för att kunna dra slutsatser om något av de testade bedövningsmedlen är överlägset. Ett stickprov på 57 deltagare i varje grupp krävs för att upptäcka en skillnad i lyckandefrekvens på 25 % (power 80 %). Protokollet har nu testats och visat sig vara lämpligt att använda i en större studie. / The aim of this randomized clinical trial was to compare the anesthetic efficacy of 2% lidocaine with 1:200,000 epinephrine and 3% prilocaine with 0,03 i.u./ml felypressin used for the inferior alveolar nerve block (IANB) in endodontic treatment of adult patients with symptomatic pulpitis in posterior mandibular teeth.5 patients visiting the emergency clinic of the Faculty of Odontology, Malmö University participated in the study. They randomly received, in a double-blind manner, up to 3,6 ml of either 2% lidocaine (n=4) or 3% prilocaine (n=1) in a conventional IANB. Treatment (pulpotomy) was only initiated after profound lip numbness was obtained. Pre- and perioperative pain, intake of analgesics and anxiety was recorded. Anesthetic success was defined as no or only mild pain (a rating of <54mm on a 170mm Visual Analogue Scale) during treatment.The success rate for IANB using lidocaine was 50% and for prilocaine 100%. The material size was insufficient to enable statistical analysis.The few patients selected for this pilot study were insufficient to assess any difference in anesthetic efficacy between lidocaine and prilocaine for IANB in endodontic treatment of adult patients with symptomatic pulpitis in a posterior mandibular tooth. Further data collection is needed to make conclusions about possible superiority of any of the tested substances. A sample size of 57 test subjects in each group would give a power of 80% to detect a difference of 25% in success rate. The protocol appears to be suitable for use in a larger-scale study.

Os anestésicos locais têm sido utilizados na clínica médica e odontológica com o objetivo de atenuar a dor nos procedimentos cirúrgicos. Tais fármacos são administrados usualmente por meio do uso de agulhas, o que pode diminuir o número de pacientes nos consultórios dentários, afugentados pelo medo desses dispositivos invasivos. Comprimidos mucoadesivos de dissolução rápida podem ser promissores em incorporar esses anestésicos e assim liberá-los topicamente com a finalidade de promover a anestesia de forma não invasiva. Neste intuito, comprimidos de dissolução rápida contendo os anestésicos locais cloridratos de prilocaína (PCL) e lidocaína (LDC) foram desenvolvidos por três métodos: i) compressão direta; ii) compressão após pré-processamento dos adjuvantes em secagem por atomização e iii) liofilização. Estes foram comparados em relação ao tempo de hidratação e desintegração para a escolha de uma plataforma para estudos de liberação, permeação e mucoadesão in vitro. Filme polimérico oclusivo com Eudragit S100 foi moldável e flexível para a finalidade de revestimento parcial. A massa total de desintegrantes nos comprimidos modularam sua hidratação e desintegração. Os comprimidos obtidos por liofilização apresentaram menores valores de tempo de hidratação e desintegração. Os efeitos de diluente (manitol), desintegrante (glicolato sódico de amido), promotores químicos de permeação (ácido oleico, Tween® 80 e propilenoglicol) e polímeros mucoadesivos (HPMC e pullulan) sobre liberação em éster de celulose e permeação em esôfago suíno foram avaliados. Os comprimidos apresentaram rápida liberação em uma hora. A liberação obedeceu a cinética de primeira ordem e o mecanismo de liberação foi governado pelo transporte não fickiano. A proporção de manitol e tipo de polímero mucoadesivo não teve influência significativa nos estudos de liberação. A quantidade de fármacos liberada diminuiu em comprimidos com desintegrantes e promotores químicos de permeação. Um significante efeito sinérgico entre polímero mucoadesivo e promotores químicos no coeficiente de permeabilidade, fluxo e retenção de fármacos na mucosa foi observado. Quando comparado com comprimidos de HPMC com promotores químicos, o pullulam melhorou a permeação de fármacos através da mucosa. Mucoadesão dos comprimidos com diferentes polímeros foi avaliado. HPMC e pullulan melhoraram as propriedades mucoadesivas. Todos os comprimidos se mantiveram aderidos na região do epitélio durante uma hora. A nova plataforma de liberação de fármacos obtida pela combinação de tecnologias farmacêuticas de comprimidos por liofilização, com adição de promotores de permeação e pullulan como polímero mucoadesivo mostrou uma estratégia efetiva para o desenvolvimento de um sistema transbucal para LDC e PRC que pode ser usada para melhorar anestésica sem uso de agulhas / Local anesthetics have been used in medical and dental practice aiming at to become less painful some surgical procedures. Such drugs are typically administered through needles along surgical procedures, which decrease the number of patients in the dental offices, once many people are afraid of these invasive devices. Fast dissolving and mucoadhesive tablets could be promising for incorporating these anesthetics and thus releasing them topically in order to improve noninvasive anesthesia. Herein, it were developed fast dissolving tablets containing the local anesthetic drugs prilocaine (PRC) and lidocaine (LDC) hydrochloride. Three methods were used: a) direct compression of the mixture of components; b) pre-processing by spray drying adjuvants and c) freeze drying and these tablets. The tablets were compared in terms of wetting and disintegration time for the choice of a platform for further in vitro release, permeation and mucoadhesion studies. An occlusive polymeric film of Eudragit S100 showed suitable flexibility and plasticity according to purpose of coating the tablets. The total mass of disintegrants in formulations affected the wetting and disintegration of the tablets. Freeze dryed tablets had lower wetting and disintegration time values as compared to the others. The effects of diluent (mannitol), disintegrant (sodium starch glycolate), chemical enhancers (oleic acid, Tween® 80 and propylene glycol) and mucoadhesive polymers (hydroxypropyl methylcellulose and pullulan) on the drug release from cellulose ester membrane and drug permeation through porcine esophageal mucosa were evaluated. Dissolution test showed fast release on one hour. The drug release data fit well to the First order expression and the release mechanism was non-Fickian transport. No significant influence of proportion of mannitol and type of mucoadhesive polymer on release studies was observed. Release of drugs decreased in tablets with disintegrant and chemical enhancers. A significant synergic effect between the mucoadhesive polymer and chemical enhancers on the permeability coefficient, flux and retention of drugs on mucosa was observed. As compared to HPMC for tablets containing chemical enhancers, pullulan improved the drug permeation through the mucosa. Mucoadhesion to tablets with different polymers was evaluated. HPMC and pullulan improve mucoadhesive properties. All tablets maintained in the attachment site of the epithelium for at least one hour. It conclusion, the novel drug delivery platform achieved by combining the pharmaceutical technologies of freeze-dryed tablets comprising chemical enhancers and pullulan as mucoadhesive polymer displayed an effective strategy for the development of a transbuccal system for LDC and PRC that can be used to improve needle-free buccal anesthesia.

A anestesia local normalmente precede a maioria dos procedimentos odontológicos. Porém, por ser realizada por processo invasivo (injetável), muitas vezes afugentam o paciente do consultório. Portanto, a substituição do processo invasivo por não invasivo, além de inovador traria diversas vantagens a odontologia i.e., possibilitaria o aprimoramento de procedimentos rotineiros e cirúrgicos devido à provável redução de custos, submissão do paciente, facilidade de aplicação e menores riscos de contaminação e intoxicações. Neste intuito, filmes poliméricos hidrofílicos mono ou trilaminados, compostos pelo polímero mucoadesivo HPMC K100 LV, glicerol ou PEG 400 como plastificantes, e contendo os anestésicos locais cloridratos de prilocaína (PCL) e lidocaína (LCL) em diferentes proporções foram desenvolvidos. Os filmes apresentaram flexibilidade e moldabilidade adequadas, além de uniformidade de massa e teor. Tanto a massa total de fármaco nos filmes (11 - 55 mg/0,64cm2), quanto suas contribuições relativas nas misturas (0 - 100% m.m-1) modularam seus perfis e cinéticas de liberação e permeação, além das quantidades retidas no epitélio esofageal suíno. Quantidades menores dos fármacos conduziram aos maiores coeficientes de permeabilidade do LCL. O filme contendo mistura dos fármacos na proporção 1:1 (PCL:LCL) apresentou a melhor relação custo/benefício e foi escolhida para a continuidade dos estudos. O aumento na massa total de fármaco nos filmes de 12,5 para 25 mg aumentou significativamente sua força e trabalho de mucoadesão, mas reduziu sua resistência à tração e módulo de elasticidade. Os filmes apresentaram propriedades mecânicas e de mucoadesão adequadas para a finalidade proposta. A adição de camadas oclusiva (composta por Eudragit® S100 e trietil citrato como plastificante) e mucoadesiva (composta por HPMC K100 LV e policarbofil na proporção 3:1 m.m-1 e PEG 400 como plastificante) aos filmes reduziu significativamente as quantidades dos fármacos liberadas, permeadas e retidas no epitélio e, portanto, a composição e arquitetura dos patches trilaminados deve ser aprimorada de modo a favorecer a hidratação da camada de liberação. Pela primeira vez foi demonstrada a eficiência da técnica de iontoforese (1 mA.cm-2) na promoção da permeação destes fármacos em associação a partir de filmes poliméricos. Para que possa substituir a anestesia injetável (solução a 2%, equivalente a 36 mg de fármaco), a permeação dos fármacos a partir do filme mais promissor (12,5 mg de PCL:LCL 1:1, 3% m.m-1 HPMC K100LV e 30% PEG400 em função da massa de polímero mucoadesivo) deve ser aumentada em pelo menos 30 vezes. / Local anesthesia typically precedes the majority of dental procedures. However, due to be performed using an invasive process (injection), often it scares the patient out from the dentist office. Accordingly, besides its innovative character, the replacement of the painful injection by a noninvasive process might bring several advantages to the dentistry field. It might enable the improvement of routinely and surgical procedures as a function of cost saving, patient compliance, ease of application and lowering the risk of contamination and intoxication. In this pursuit, we developed hydrophilic polymeric films comprised by one or three layers, comprised by the mucoadhesive polymer HPMC K100 LV, glycerol or PEG 400 as plasticizers, and containing the local anesthetic drugs prilocaine (PCL) and lidocaine (LCL) hydrochloride in different proportions. The films showed suitable flexibility and plasticity, besides uniformities of mass and content. Both the total mass of drugs in the films (11 - 55 mg/0.64 cm2), and their relative contribution in the mixtures (0 - 100% w.w-1) have modulated their profiles and kinetics of both delivery and permeation, as well as their amount retained in the porcine esophageal epithelium. Lower drug loadings lead to an increase on the permeability coefficient of LCL. The film containing the drugs blended on a 1:1 (PCL:LCL) proportion has presented the most acceptable cost/benefit ratio. Hence, it was chosen for further investigations. Increasing the total amount of drug in the film from 12.5 to 25 mg significantly raised their force and work of mucoadhesion. On the other hand, it have decreased their tensile strength and elastic modulus. The films presented suitable mechanical e mucoadhesive properties for our purposes. Adding the mucoadhesive (comprised by HPMC K100 LV and polycarbophil at 3:1 w.w-1 and PEG400 as plasticizer) and occlusive (Eudragit® S100 and triethyl citrate as plasticizer) layers on the delivery layer has significantly decreased the amount of drug released, permeated and retained on the epithelium from the films. Thereby, both composition and architecture of the patches must be refined in order to improve the hydration of the delivery layer. For the first time it was presented the efficiency of iontophoresis (1 mA.cm-2) on the permeation enhancement of these drug in association from polymeric films. To reach the replacement of infiltrative anesthesia (2% solution, equivalent to 36 mg of drug), the amount of drug permeated from the most promising film (12.5 mg of PCL:LCL 1:1, 3% w.w-1 HPMC K100LV and 30% PEG400 as a function of the mass of mucoadhesive polymer) must be improved in at least 30 folds.

A anestesia local normalmente precede a maioria dos procedimentos odontológicos. Porém, por ser realizada por processo invasivo (injetável), muitas vezes afugentam o paciente do consultório. Portanto, a substituição do processo invasivo por não invasivo, além de inovador traria diversas vantagens a odontologia i.e., possibilitaria o aprimoramento de procedimentos rotineiros e cirúrgicos devido à provável redução de custos, submissão do paciente, facilidade de aplicação e menores riscos de contaminação e intoxicações. Neste intuito, filmes poliméricos hidrofílicos mono ou trilaminados, compostos pelo polímero mucoadesivo HPMC K100 LV, glicerol ou PEG 400 como plastificantes, e contendo os anestésicos locais cloridratos de prilocaína (PCL) e lidocaína (LCL) em diferentes proporções foram desenvolvidos. Os filmes apresentaram flexibilidade e moldabilidade adequadas, além de uniformidade de massa e teor. Tanto a massa total de fármaco nos filmes (11 - 55 mg/0,64cm2), quanto suas contribuições relativas nas misturas (0 - 100% m.m-1) modularam seus perfis e cinéticas de liberação e permeação, além das quantidades retidas no epitélio esofageal suíno. Quantidades menores dos fármacos conduziram aos maiores coeficientes de permeabilidade do LCL. O filme contendo mistura dos fármacos na proporção 1:1 (PCL:LCL) apresentou a melhor relação custo/benefício e foi escolhida para a continuidade dos estudos. O aumento na massa total de fármaco nos filmes de 12,5 para 25 mg aumentou significativamente sua força e trabalho de mucoadesão, mas reduziu sua resistência à tração e módulo de elasticidade. Os filmes apresentaram propriedades mecânicas e de mucoadesão adequadas para a finalidade proposta. A adição de camadas oclusiva (composta por Eudragit® S100 e trietil citrato como plastificante) e mucoadesiva (composta por HPMC K100 LV e policarbofil na proporção 3:1 m.m-1 e PEG 400 como plastificante) aos filmes reduziu significativamente as quantidades dos fármacos liberadas, permeadas e retidas no epitélio e, portanto, a composição e arquitetura dos patches trilaminados deve ser aprimorada de modo a favorecer a hidratação da camada de liberação. Pela primeira vez foi demonstrada a eficiência da técnica de iontoforese (1 mA.cm-2) na promoção da permeação destes fármacos em associação a partir de filmes poliméricos. Para que possa substituir a anestesia injetável (solução a 2%, equivalente a 36 mg de fármaco), a permeação dos fármacos a partir do filme mais promissor (12,5 mg de PCL:LCL 1:1, 3% m.m-1 HPMC K100LV e 30% PEG400 em função da massa de polímero mucoadesivo) deve ser aumentada em pelo menos 30 vezes. / Local anesthesia typically precedes the majority of dental procedures. However, due to be performed using an invasive process (injection), often it scares the patient out from the dentist office. Accordingly, besides its innovative character, the replacement of the painful injection by a noninvasive process might bring several advantages to the dentistry field. It might enable the improvement of routinely and surgical procedures as a function of cost saving, patient compliance, ease of application and lowering the risk of contamination and intoxication. In this pursuit, we developed hydrophilic polymeric films comprised by one or three layers, comprised by the mucoadhesive polymer HPMC K100 LV, glycerol or PEG 400 as plasticizers, and containing the local anesthetic drugs prilocaine (PCL) and lidocaine (LCL) hydrochloride in different proportions. The films showed suitable flexibility and plasticity, besides uniformities of mass and content. Both the total mass of drugs in the films (11 - 55 mg/0.64 cm2), and their relative contribution in the mixtures (0 - 100% w.w-1) have modulated their profiles and kinetics of both delivery and permeation, as well as their amount retained in the porcine esophageal epithelium. Lower drug loadings lead to an increase on the permeability coefficient of LCL. The film containing the drugs blended on a 1:1 (PCL:LCL) proportion has presented the most acceptable cost/benefit ratio. Hence, it was chosen for further investigations. Increasing the total amount of drug in the film from 12.5 to 25 mg significantly raised their force and work of mucoadhesion. On the other hand, it have decreased their tensile strength and elastic modulus. The films presented suitable mechanical e mucoadhesive properties for our purposes. Adding the mucoadhesive (comprised by HPMC K100 LV and polycarbophil at 3:1 w.w-1 and PEG400 as plasticizer) and occlusive (Eudragit® S100 and triethyl citrate as plasticizer) layers on the delivery layer has significantly decreased the amount of drug released, permeated and retained on the epithelium from the films. Thereby, both composition and architecture of the patches must be refined in order to improve the hydration of the delivery layer. For the first time it was presented the efficiency of iontophoresis (1 mA.cm-2) on the permeation enhancement of these drug in association from polymeric films. To reach the replacement of infiltrative anesthesia (2% solution, equivalent to 36 mg of drug), the amount of drug permeated from the most promising film (12.5 mg of PCL:LCL 1:1, 3% w.w-1 HPMC K100LV and 30% PEG400 as a function of the mass of mucoadhesive polymer) must be improved in at least 30 folds.