Quality by Design-driven investigation of the mechanical properties of mucoadhesive films for needleless anesthetics administration

Objectives: To systematically evaluate the effects of hydroxypropyl methyl cellulose (HPMC) type (E5LV, E15LV, and K100LV); plasticizer type (glycerol and mannitol), plasticizer loading (0.12 and 0.24% w/w); and loading of prilocaine and lidocaine hydrochlorides combined at 1:1 ratio (0 and 47 mg/cm2) in the mechanical properties of buccal films. Methods: A quality by design (QbD) approach based on a full factorial design (3 x 23) and complementarily multivariate statistical tools i.e., principal component analysis (PCA), response surface methodology (RSM), and correlation matrix were used in this pursuit. The thickness, elongation at break, tensile strength, force at break, and Young`s modulus of the anesthetic buccal films obtained by solvent casting were assessed. Results: The QbD, PCA and RSM altogether demonstrated that all studied formulation variables, mainly the drug loading, affect the mechanical properties of the films at different significance levels. The multivariate analysis yielded the modelling of elongation at break, tensile strength, and force at break, which significantly correlated with each other. The drugs exerted a synergic plasticizing effect on the films, and the use of HPMC K100 LV (with greater hydroxypropyl substitution degree and viscosity) and mannitol favored their elasticity and resistance. Furthermore, the majority of the films fulfilled the requirements for buccal administration due to their softness and mechanical resistance. Conclusion: Mannitol is suitable plasticizer for manufacturing HPMC anesthetic buccal films with improved mechanical properties. These results are a step forward in the rational development of formulations for the replacement of needles in dentistry

Effect of iontophoresis on fluoride uptake in enamel with artificial caries lesion

Abstract: Iontophoresis is a noninvasive technique, based on the application of a constant low-intensity electric current to facilitate the release of a variety of drugs, whether ionized or not, through biological membranes. The objective of this research was to evaluate the effect of iontophoresis using different electric current intensities on the uptake of fluoride in dental enamel with artificial caries lesions. In this in vitro operator-blind experiment, bovine enamel blocks (n = 10/group) with caries-like lesions and predetermined surface hardness were randomized into 6 groups: placebo gel without fluoride applied with a current of 0.8 mA (negative control), 2% NaF gel without application of any current, and 2% NaF gel applied with currents of 0.1, 0.2, 0.4 and 0.8 mA. Cathodic iontophoresis was applied for 4 min. The concentration of loosely bound fluoride (calcium fluoride) and firmly bound fluoride (fluorapatite) was determined. The results were analyzed by the nonparametric Kruskal-Wallis and Dunn tests. Iontophoresis at 0.8 mA, combined with the application of fluoridated gel (2% NaF), increased fluoride uptake in enamel with caries-like lesions, as either calcium fluoride or fluorapatite.

Physical methods for topical skin drug delivery: concepts and applications

Topical drug delivery is an interesting approach to treat skin diseases and to avoid pain and low patient compliance in cases where a systemic delivery is required. However, the stratum corneum, which is the outermost skin layer, strongly protects the body from the entrance of substances, especially those hydrophilic. In this context, different physical methods have been studied to overcome the stratum corneum barrier and facilitate penetration of drugs into or through the skin. Among them, iontophoresis, low-frequency ultrasound and microneedles have been widely employed for transdermal drug delivery. More recently, they are also studied to aid in the treatment of dermatological disorders, such as skin tumors and inflammation. Basically, iontophoresis refers to the movement of charged and non-charged hydrophilic molecules through the skin due to the application of a low constant electric current and the contributions of electromigration and electroosmosis. In low-frequency ultrasound, cavitation is the main mechanism for skin permeabilization that consists on the formation of microbubbles that disorganize the stratum corneum. Microneedles are microprojections, minimally invasive, that can be designed with different lengths, materials and geometry to increase skin permeability. In this review, concepts, mechanisms and applications of these three physical methods will be presented and discussed with focus on their use in dermatological treatments. Moreover, comparative studies using different physical methods will be presented and also some clinical perspectives will be addressed

Influence of ceramide 2 on in vitro skin permeation and retention of 5-ALA and its ester derivatives, for photodynamic therapy / Influência da ceramida 2 sobre a permeação cutânea in vitro e retenção de 5-ALA e seus derivados de ésteres, para terapia fotodinâmica

Photodynamic therapy (PDT) based on topical 5-aminolevulinic acid (5-ALA), an endogenous precursor of protoporphyrin, is an interesting approach for the treatment of skin cancer. However, 5-ALA is a hydrophilic molecule and such a characteristic limits its appropriate cutaneous penetration and retention. In this way, more lipophilic molecules, such as esterified 5-ALA derivatives, have been under investigation in order to improve the skin penetration of this molecule. Drug formulation can also alter 5-ALA skin penetration. Therefore, the aim of this work was to study the influence of ceramide 2 - the main lipid of the SC- on the cutaneous delivery of 5-ALA and its ester derivatives in vitro, using Franz diffusion cell. The skin permeation of all studied drugs was decreased in the presence of ceramide, representing a desirable characteristic in order to avoid the risk of systemic side effects. Nevertheless, the SC and [epidermis + dermis] retention after 16 h has also been decreased in the presence of ceramide, as compared to control. In conclusion, ceramide was not a good adjuvant, meaning that research of other vehicles could be useful to improve cutaneous delivery of 5-ALA.

A Terapia Fotodinâmica (TFD) tópica com um precursor das porfirinas endógenas, o ácido 5-aminolevulínico (5-ALA), constitui uma nova modalidade para o tratamento do câncer de pele. Entretanto, o 5-ALA é uma molécula hidrofílica, o que limita sua penetração e retenção cutânea apropriadas. Moléculas mais lipofílicas, tais como derivados esterificados do 5-ALA, estão sob intensa investigação para melhorar a penetração cutânea desta molécula. A formulação que contém o fármaco também pode alterar a penetração cutânea do 5-ALA. Desta forma, o objetivo deste trabalho foi estudar a influência da ceramida 2 - o principal lipídeo do EC- sobre a penetração cutânea de 5-ALA e seus derivados esterificados usando células de difusão de Franz. A permeação de todas as drogas estudadas através da pele foi diminuída na presença de ceramida, o que é desejável, evitando riscos de efeitos colaterais sistêmicos. Entretanto, a retenção no EC e [epiderme + derme] também foi diminuída na presença da ceramida, após 16 horas, comparado ao controle. Concluindo, a ceramida não foi um bom adjuvante, sendo necessária a pesquisa de outros veículos para melhorar a liberação cutânea do 5-ALA.