RESUMO
Conventional treatments for cutaneous leishmaniasis, a neglected vector-borne infectious disease, can frequently lead to serious adverse effects. Paromomycin (PAR), an aminoglycoside antibiotic, has been suggested for the topical treatment of disease-related lesions, but even when formulated in high drug-loading dosage forms, presents controversial efficacy. The presence of five ionizable amino groups hinder its passive cutaneous penetration but make PAR an excellent candidate for iontophoretic delivery. The objective of this study was to verify the feasibility of using iontophoresis for cutaneous PAR delivery and to propose a topical passive drug delivery system that could be applied between iontophoretic treatments. For this, in vitro iontophoretic experiments evaluated different application durations (10, 30, and 360 min), current densities (0.1, 0.25, and 0.5 mA/cm2), PAR concentrations (0.5 and 1.0 %), and skin models (intact and impaired porcine skin). In addition, 1 % PAR hydrogel had its penetration profile compared to 15 % PAR ointment in passive transport. Results showed iontophoresis could deliver suitable PAR amounts to dermal layers, even in short times and with impaired skin. Biodistribution assays showed both iontophoretic transport and the proposed hydrogel delivered higher PAR amounts to deeper skin layers than conventional ointment, even though applying 15 times less drug. To our knowledge, this is the first report of PAR drug delivery enhancement by iontophoresis. In summary, the association of iontophoresis with a topical application of PAR gel seems appropriate for improving cutaneous leishmaniasis treatment.
Assuntos
Leishmaniose Cutânea , Paromomicina , Animais , Suínos , Paromomicina/metabolismo , Paromomicina/farmacologia , Iontoforese/métodos , Distribuição Tecidual , Pomadas/metabolismo , Pele/metabolismo , Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Leishmaniose Cutânea/tratamento farmacológico , Hidrogéis/farmacologiaRESUMO
Innovative technologies have been designed to improve efficacy and safety of chemical UV filters. Encapsulation can enhance efficacy and reduce transdermal permeation and systemic exposure. The aims of this work were (i) to determine the cutaneous biodistribution of avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC) incorporated in mesoporous silica SBA-15 and (ii) to perform preclinical (in vitro) and (iii) clinical safety studies to demonstrate their innocuity and to evaluate sun protection factor (SPF) in humans. Skin penetration studies showed that deposition of OXY and AVO in porcine and human skin after application of stick formulation with incorporated filters (stick incorporated filters) was significantly lower than from a marketed (non-encapsulated) stick. Cutaneous deposition and transdermal permeation of OXY in and across human skin were 3.8-and 13.4- fold lower, respectively, after application of stick entrapped filters. Biodistribution results showed that encapsulation in SBA-15 decreased AVO and OXY penetration reaching porcine and human dermis. Greater deposition (and permeation) of OXY in porcine skin than in human skin, pointed to the role of follicular transport. Stick incorporated filters had good biocompatibility in vivo and safety profiles, even under sun-exposed conditions. Entrapment of UV filters improved the SPF by 26% and produced the same SPF profile as a marketed stick. Overall, the results showed that SBA-15 enabled safety and efficacy of UV filters to be increased.
Assuntos
Benzofenonas/farmacocinética , Cinamatos/farmacocinética , Propiofenonas/farmacocinética , Dióxido de Silício/farmacologia , Distribuição Tecidual , Administração Cutânea , Animais , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Filtros Microporos , Absorção Cutânea , Fator de Proteção Solar , Protetores Solares/farmacocinética , SuínosRESUMO
Avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC), are widely used UV filters. The aim of this study was to investigate the effect of incorporation in mesoporous silica (SBA-15) on their cutaneous deposition and permeation. Stick formulations containing "free" and "incorporated" UV filters (SF1 and SF2, respectively) were prepared and characterized with respect to their physicochemical, thermal, and functional properties. Cutaneous delivery experiments using porcine skin with quantification by UHPLC-MS/MS, demonstrated that skin deposition of AVO and OXY after application of SF2 for 6 and 12â¯h was significantly lower than that from SF1 at each time-point (Student t-test, pâ¯<â¯0.05): e.g. OXY permeation across the skin was 30-, 12- and 1.5-fold lower after 6, 12 and 24â¯h, respectively, following application of SF2. Cutaneous biodistribution profiles of AVO and OXY to 800⯵m evidenced a significant decrease in the amounts in the viable epidermis and dermis. In contrast, deposition of the more lipophilic OMC was not significantly different (pâ¯Ëâ¯0.05). In vitro photoprotective efficacy results demonstrated that adsorption/entrapment of UV filters enhanced the sun protection factor by 94%. In conclusion, SBA-15, an innovative mesoporous material, increased photoprotection by UV filters while reducing their cutaneous penetration and transdermal permeation.
Assuntos
Derme/metabolismo , Epiderme/metabolismo , Dióxido de Silício/sangue , Absorção Cutânea/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Administração Cutânea , Animais , Benzofenonas/química , Cromatografia Líquida de Alta Pressão/métodos , Cinamatos/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Propiofenonas/química , Dióxido de Silício/química , Fator de Proteção Solar/métodos , Protetores Solares/administração & dosagem , Protetores Solares/química , Suínos , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual/fisiologiaRESUMO
INTRODUCTION: Iontophoresis is an active non-invasive drug delivery technique that can increase the transport of charged and neutral molecules into and across biological membranes. Most research to-date has focused on (per)cutaneous iontophoretic drug delivery. However, recent studies illustrate its potential for drug delivery to the eye: corneal iontophoresis may enable targeted topical therapy of intracorneal diseases, whereas transscleral iontophoresis may enable non-invasive intraocular drug delivery. Areas covered: We describe iontophoretic principles in the context of ocular delivery before providing a summary of recent preclinical studies involving transcorneal and transscleral iontophoresis in vitro and in vivo. Subsequently, an overview of clinical applications with special focus on the transcorneal iontophoresis of riboflavin for corneal cross-linking and transscleral iontophoresis of corticosteroids for the treatment of posterior segment diseases is provided. Expert opinion: The feasibility of using iontophoresis for ocular drug delivery has been demonstrated. Drug formulation development and the ability to design iontophoretic applicators will now determine its success in the clinic. The specificities of the ocular globe must be taken into account; in particular, its unique morphology, and the smaller surface area available for drug diffusion and the fact that it is more susceptible to irritation and less robust than the skin.
Assuntos
Córnea/metabolismo , Sistemas de Liberação de Medicamentos , Iontoforese , Esclera/metabolismo , Animais , HumanosRESUMO
The objective of the study was to investigate the iontophoretic delivery kinetics of ketorolac (KT), a highly potent NSAID and peripherally-acting analgesic that is currently indicated to treat moderate to severe acute pain. It was envisaged that, depending on the amounts delivered, transdermal iontophoretic administration might have two distinct therapeutic applications: (i) more effective and faster local therapy with shorter onset times (e.g. to treat trauma-related pain/inflammation in muscle) or (ii) a non-parenteral, gastrointestinal tract sparing approach for systemic pain relief. The first part of the study investigated the effect of experimental conditions on KT iontophoresis using porcine and human skin in vitro. These results demonstrated that KT electrotransport was linearly dependent on current density - from 0.1875 to 0.5mA/cm(2) - (r(2)>0.99) and drug concentration - from 5 to 20mg/ml (r(2)>0.99). Iontophoretic permeation of KT from a 2% hydroxymethyl cellulose gel was comparable to that from an aqueous solution with equivalent drug loading (584.59±114.67 and 462.05±66.56µg/cm(2), respectively). Cumulative permeation (462.05±66.56 and 416.28±95.71µg/cm(2)) and steady state flux (106.72±11.70 and 94.28±15.47µg/cm(2)h), across porcine and human skin, were statistically equivalent confirming the validity of the model. Based on the results in vitro, it was decided to focus on topical rather than systemic applications of KT iontophoresis in vivo. Subsequent experiments, in male Wistar rats, investigated the local enhancement of KT delivery to muscle by iontophoresis. Drug biodistribution was assessed in skin, in the biceps femoris muscle beneath the site of iontophoresis ('treated muscle'; TM), in the contralateral muscle ('non-treated muscle'; NTM) and in plasma (P). Passive topical delivery and oral administration served as negative and positive controls, respectively. Iontophoretic administration for 30min was superior to passive topical delivery for 1h and resulted in statistically significant increases in KT levels in the skin (91.04±15.48 vs. 20.16±8.58µg/cm(2)), in the biceps femoris at the treatment site (TM; 6.74±3.80 vs. Assuntos
Cetorolaco/administração & dosagem
, Cetorolaco/metabolismo
, Músculos/efeitos dos fármacos
, Músculos/metabolismo
, Administração Cutânea
, Animais
, Sistemas de Liberação de Medicamentos/métodos
, Humanos
, Iontoforese/métodos
, Cinética
, Masculino
, Dor/tratamento farmacológico
, Permeabilidade
, Ratos
, Ratos Wistar
, Pele/efeitos dos fármacos
, Pele/metabolismo
, Absorção Cutânea
, Suínos
, Distribuição Tecidual
RESUMO
The number of drug molecules approved by the regulatory authorities for transdermal administration is relatively modest - less than two dozen. Many other therapies might benefit from the advantages offered by the transdermal route. That they have not already done so is due to the exceptional efficacy of the stratum corneum as a diffusional barrier and its remarkable ability to restrict molecular transport. As a result only extremely potent therapeutics possessing the necessary physicochemical properties can be delivered by passive diffusion across intact skin at pharmacologically relevent rates. This has led to the development of several delivery technologies that might be used to expand the range of medicinal agents that can be administered transdermally with the requisite delivery kinetics. There are essentially two approaches: (i) provide an improved driving force to increase the rate of transport (i.e., act on the molecule) or (ii) modify the properties of the microenvironment through which diffusion must occur (i.e., act on the stratum corneum). The challenge for the latter approach is to compromise the barrier in a reversible and relatively painless manner that minimises irritation, is practical for chronic conditions and has minimal risk of infection. Here, we review some of the physical methods that have been used to either transiently perturb the skin barrier or to provide additional driving forces to facilitate molecular transport with a particular focus on technologies that have either led to marketed products or have at least reached the clinical development stage.