RESUMEN
The aim of this study was to develop an HPLC method for simultaneous quantification of metformin (MET) and methylene blue (MB) in in vitro skin permeation/retention studies, in which retention was evaluated in the different layers of the skin [stratum corneum (SC) and the viable epidermis + dermis (VE + D)]. The method was validated considering the following parameters: specificity, linearity, quantitation limit (LOQ), recovery, precision and accuracy. Calibration curves were obtained using the following six matrices: methanol, water, methanolic extracts from the SC and VE + D spiked with the drugs and drugs extracted from the SC and VE + D. The precision, accuracy and LOQ of the method were evaluated in water and in VE + D and SC, applying the drug extraction process. The results show that the method is selective and linear for both drugs. The precision and accuracy values, independent of matrix and drug, were below the limit of 15%. The LOQ of MB was defined as 0.4 µg/ml in the VE + D and SC and 0.8 µg/ml in water. The LOQ of MET was defined as 0.8 µg/ml in the VE + D and SC and 0.4 µg/ml in the water. The recovery of the method was adequate, consistent and reproducible for the concentration range of 0.4-10 µg/ml for MB (73.3-92.1%) and 0.8-10.0 µg/mL for MET (72.4-94.4%). This method has a potential application in the development of formulation for skin delivery of MB and MET.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Metformina/análisis , Azul de Metileno/análisis , Absorción Cutánea/fisiología , Piel/química , Animales , Modelos Lineales , Metformina/farmacocinética , Azul de Metileno/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Piel/metabolismo , PorcinosRESUMEN
Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.
Asunto(s)
Analgesia/métodos , Levobupivacaína/administración & dosificación , Levobupivacaína/farmacocinética , Dolor/tratamiento farmacológico , Dolor/metabolismo , Animales , Bovinos , Pollos , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/metabolismo , Geles , Humanos , Liposomas , Masculino , Ratones , Células 3T3 NIH , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiologíaRESUMEN
Metformin hydrochloride is a traditional, FDA-approved drug used as a first-line drug of choice to treat type 2 diabetes. Research has shown metformin hydrochloride effective in injuries, including age-related maladies. The purpose of this ex vivo study was to evaluate the use of a commercial transdermal vehicle as a semisolid, liposomal vanishing cream (Pentravan) to deliver metformin hydrochloride through the human skin. The experiments were conducted as percutaneous absorption assay in Franz Diffusion Cells, coupled with freshly excised human skin and analyzed by high-performance liquid chromatography. Both methods were based on validated methods of both the United States Pharmacopeial Convention, Inc. and the International Conference on Harmonization. A 46.7% permeation percentage was found, with a drug flux of 3.91 µg cm-2 h-1 and a lag time of 0.51 h, following pseudo first-order absorption kinetics. These results showed that transdermal metformin hydrochloride can be an option for patients searching for diverse clinical effects.
Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Absorción Cutánea/fisiología , Administración Cutánea , Humanos , Metformina/administración & dosificación , PielRESUMEN
AIM: We evaluated the effects of the incorporation of zinc oxide (ZnO) nanoparticles in a mesoporous matrix, aiming to improve the textural, structural and morphological properties and verify their safety so that they can be applied in sunscreen cosmetics. MATERIALS AND METHODS: ZnO nano-particles were incorporated into an ordered mesoporous silica matrix known as Santa Barbara Amorphous-15 (SBA-15), using post-synthesis methodology. The resulting nanocomposites were characterized using X-ray diffraction, small angle X-ray scattering, N2 adsorption-desorption isotherms, Fourier transform infrared spectroscopy, scanning electron microscopy and predicted in vitro sun protector factor (SPF) estimation. Effectiveness and safety were evaluated by antimicrobial activity, in vitro cell toxicity and non-invasive multi-photon tomography with fluorescence lifetime imaging. RESULTS: The structure of the nanocomposites was similar to that of SBA-15, with little perturbation caused by ZnO incorporation. Nanocomposites had an increased in vitro SPF, reduced cytotoxic activity and favourable antimicrobial properties compared to ZnO. ZnO:SBA-15 nanocomposites exhibited no measurable toxicity when applied to human skin in vivo. CONCLUSION: Due to their suitable physicochemical properties and improved safety compared to bare ZnO nanoparticles, the ZnO:SBA-15 nanocomposites show promise for use in cosmetic applications.
Asunto(s)
Composición de Medicamentos/métodos , Nanocompuestos/administración & dosificación , Dióxido de Silicio/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Protectores Solares/administración & dosificación , Óxido de Zinc/administración & dosificación , Adulto , Animales , Células 3T3 BALB , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Combinación de Medicamentos , Humanos , Ratones , Nanocompuestos/química , Dióxido de Silicio/síntesis química , Dióxido de Silicio/metabolismo , Absorción Cutánea/fisiología , Protectores Solares/síntesis química , Protectores Solares/metabolismo , Pruebas de Toxicidad Aguda/métodos , Difracción de Rayos X/métodos , Adulto Joven , Óxido de Zinc/síntesis química , Óxido de Zinc/metabolismoRESUMEN
The use of permeation enhancers such as microneedles (MNs) to increase drug penetration across intraoral mucosa has increased in recent years. Permeation studies, commonly performed using vertical diffusion cells, are a well-established way to preview formulations and enhance their performance during the development stage. However, to our knowledge, the existing intraoral mucosa barrier models do not permit permeation using MN-pretreated mucosa due to their insufficient thickness. Therefore, the objective of this study was to develop a barrier model using thick palate tissues to perform in vitro permeation studies, with physical enhancement of the permeability of intraoral mucosa by pretreatment with MNs. The adapted Franz-type cells used in the permeation experiments were validated (cell dimensions and volume, sealing effectiveness, stirring and dissolution efficiency, temperature control, and establishment of uniaxial flux). Commercially available MNs were used in the palatal mucosa. Optical images of the mucosa were acquired to analyze the microperforations created. In vitro permeation studies were conducted with the MN-pretreated mucosa. This work presents a new in vitro method for the evaluation of MNs as permeation enhancers, with the aim of improving the absorption of drug formulations topically applied within the oral cavity.
Asunto(s)
Membrana Mucosa/metabolismo , Preparaciones Farmacéuticas/metabolismo , Absorción Cutánea/fisiología , Piel/metabolismo , Administración Cutánea , Animales , Difusión , Sistemas de Liberación de Medicamentos/métodos , Técnicas In Vitro , Microinyecciones/métodos , Agujas , Permeabilidad , PorcinosRESUMEN
Soybean isoflavone-rich extracts have been considered as promising skin antiaging products due to their antioxidant activity. This study investigates the effect of soybean isoflavone forms on porcine ear skin permeation/retention from topical nanoemulsions and their potential in protecting skin against oxidative damage caused by UVA/UVB light. Soybean non-hydrolyzed (SNHE) and hydrolyzed (SHE) extracts, mainly composed of genistin and genistein, were produced. Nanoemulsions containing SNHE (NESNHE) and SHE (NESHE) were prepared by spontaneous emulsification procedure and yielded monodispersed nanoemulsions. A delay of isoflavone release was observed after extracts incorporation into nanoemulsions when compared to a propyleneglycol dispersion of pure compounds. An increase of isoflavone skin retention from nanoemulsions was also achieved. However, from extracts, a higher amount of genistin (NESNHE) and a lower amount of genistein (NESHE) were detected in the skin in comparison to pure isoflavones. Finally, the protection of porcine ear skin by formulations against UVA/UVB oxidative stress was evaluated. Extract-loaded nanoemulsions offered better skin protection than pure isoflavones. Skin lipids were similarly protected by NESHE and NESNHE, whereas skin proteins were more protected by NESNHE. Overall, nanoemulsions containing isoflavone-rich soybean extracts may be considered a better topical formulation aiming skin protection from UVA/UVB oxidative damage.
Asunto(s)
Antioxidantes/metabolismo , Glycine max , Isoflavonas/metabolismo , Nanopartículas/metabolismo , Estrés Oxidativo/fisiología , Absorción Cutánea/fisiología , Administración Tópica , Animales , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Emulsiones , Genisteína/administración & dosificación , Genisteína/metabolismo , Isoflavonas/administración & dosificación , Isoflavonas/aislamiento & purificación , Nanopartículas/administración & dosificación , Técnicas de Cultivo de Órganos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/efectos de los fármacos , PorcinosRESUMEN
Rifampicin (RIF) and clindamycin phosphate (CDM) are the main drugs currently used in combination to treat severe infectious diseases in hair follicles. This work describes a simple, rapid and sensitive method for simultaneous analysis of RIF and CDM in the different skin layers using high performance liquid chromatography (HPLC). The efficient chromatographic separation of CDM and RIF was succeeded using a C18 column (150â¯mmâ¯xâ¯4.6â¯mm, 5⯵m) with gradient elution using a mobile phase composed of 0.01â¯M phosphoric acid and methanol at a flow rate of 1â¯mL min-1. Determinations were performed using UV-vis detector at 200â¯nm and 238â¯nm for CDM and RIF, respectively. The method was precise, accurate and linear (r2 > 0.999) with regression curve in the concentration range from 0.5 to 20.0⯵gâ¯mL-1 and recovery rates from the skin layers higher than 85%. The retention times for CDM and RIF were approximately 7.4 and 12.2â¯min, respectively. The presence of skin components did not interfere with the analysis. The validated method was therefore appropriate for quantification of both CDM and RIF and thus may be feasible to be used in skin permeation studies.
Asunto(s)
Técnicas de Química Analítica/normas , Clindamicina/análogos & derivados , Rifampin/análisis , Rifampin/metabolismo , Absorción Cutánea/fisiología , Animales , Antibacterianos/análisis , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antibióticos Antituberculosos/análisis , Antibióticos Antituberculosos/metabolismo , Antibióticos Antituberculosos/farmacología , Técnicas de Química Analítica/métodos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Clindamicina/análisis , Clindamicina/metabolismo , Clindamicina/farmacología , Técnicas de Cultivo de Órganos , Reproducibilidad de los Resultados , Rifampin/farmacología , Absorción Cutánea/efectos de los fármacos , PorcinosRESUMEN
Vitamin D3 supplementation is important to prevent and treat hypovitaminosis that is a worldwide public health issue. Most types of supplementation are by oral route or fortification foods. The alternative route must be investigated, as transdermal route, for people with fat malabsorption or other diseases that impair the absorption of vitamin D3. This study focused on verifying the feasibleness of vitamin D3 skin retention and permeation with the presence of chemical penetration enhancers (soybean lecithin, isopropyl palmitate, propylene glycol, ethoxydiglycol, and cereal alcohol) at different pharmaceutical forms (gel and cream) through a human skin. The integrity of skin was evaluated by transepidermal water loss (TEWL) during the skin retention and permeation test. The combination of chemical penetration enhancers presented in cream did not compromise the skin, different from the gel that association of cereal alcohol and propylene glycol compromised the skin in 24 h. Gel formulation showed vitamin D3 detection at stratum corneum in 4 h and at epidermis and dermis in 24 h. Vitamin D3 demonstrated an affinity with the vehicle in the cream formulation and was detected at the skin surface. No active was found at receptor fluid for both formulations. In conclusion, the vitamin D3 did not indicate feasibleness for transdermal use probably due to its physical-chemical characteristics such as high lipophilicity since it was not permeated through a human skin. Nevertheless, the transdermal route should be continuously investigated with less lipophilic derivates of vitamin D3 and with different combination of penetration enhancers.
Asunto(s)
Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/metabolismo , Colecalciferol/química , Colecalciferol/metabolismo , Absorción Cutánea/fisiología , Administración Cutánea , Conservadores de la Densidad Ósea/farmacología , Colecalciferol/farmacología , Composición de Medicamentos , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Femenino , Humanos , Técnicas de Cultivo de Órganos/métodos , Permeabilidad/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/efectos de los fármacos , Agua/metabolismoRESUMEN
The aim of this study is to describe the development of nanoemulsion-loaded hydrogels to deliver pentyl gallate (PG), a gallic acid n-alkyl ester, through the skin. PG is an antioxidant agent; however, it seems to be a promising agent for herpis labialis treatment. Aristoflex AVC® and chitosan were used as gelling agents for nanoemulsion thickening. The developed formulations presented suitable PG content (94.4-100.3% w/w), nanometric droplet sizes (162-297 nm), high zeta potentials, and a non-Newtonian pseudoplastic behavior. Both vehicles neither enhanced PG penetration nor delayed its release from the nanoemulsion. Formulations remained physically stable at 8°C during 3 months of storage.
Asunto(s)
Emulsiones/administración & dosificación , Ácido Gálico/análogos & derivados , Hidrogeles/administración & dosificación , Nanopartículas/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Administración Tópica , Animales , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Composición de Medicamentos , Emulsiones/metabolismo , Ácido Gálico/administración & dosificación , Ácido Gálico/metabolismo , Hidrogeles/metabolismo , Nanopartículas/metabolismo , Técnicas de Cultivo de Órganos , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/fisiología , PorcinosRESUMEN
This project was carried out to investigate the feasibility of using microemulsions for transdermal delivery of lapachol. From the screening of surfactants and oils, a range of microemulsions were developed using oleic acid, a mixture of Cremophor EL and Tween 20 and water. The solubility of lapachol was determined in these ingredients and in the formulated microemulsions. The microemulsions were characterised using cross-polarising light microscopy, their electrical conductivity, pH, zeta potential and rheology were analysed, and they were also investigated using small-angle X-ray scattering and differential scanning calorimetry. Ex vivo studies were performed using porcine ear skin and Franz diffusion cells to investigate the permeation and retention of lapachol. Systems containing different concentrations of Cremophor EL (8.4-41.6%), Tween 20 (5.4-41.6%) and oleic acid (12-31.9%) are able to form microemulsions. Lapachol was delivered more effectively through the skin from all of the microemulsions tested than by the control (oleic acid). These studies indicated that microemulsions incorporating lapachol were formed successfully and that these enhanced drug delivery and retention in the skin. Microemulsion systems may, therefore, provide promising vehicles for percutaneous delivery of lapachol.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/metabolismo , Naftoquinonas/administración & dosificación , Naftoquinonas/metabolismo , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Portadores de Fármacos/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos/métodos , Emulsiones , Excipientes/administración & dosificación , Excipientes/química , Excipientes/metabolismo , Naftoquinonas/química , Técnicas de Cultivo de Órganos , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/fisiología , Tensoactivos/administración & dosificación , Tensoactivos/química , Tensoactivos/metabolismo , PorcinosRESUMEN
Topical application of dermocosmetics containing antioxidant and/or the intake of antioxidants through diet or supplementation are remarkable tools in an attempt to slow down some of the harmful effects of free radicals. Rutin is a strong antioxidant compound used in food and pharmaceutical industries. It was established that rutin presents a low skin permeation rate, a property that could be considered an inconvenience to the satisfactory action for a dermocosmetic formulation to perform its antioxidant activity onto the skin. Therefore, it is indispensable to improve its delivery, aiming at increasing its antioxidant capacity in deeper layers of the epidermis, being a possibility to associate the rutin to liposomal vesicles, such as ethosomes. Thus, in this work, the pre-clinical safety of rutin-loaded ethosomes was investigated employing an in vitro method, and the clinical safety and efficacy were also assessed. Rutin-loaded ethosomes were efficaciously obtained in a nanoscale dimension with a relevant bioactive compound loading (80.2%) and provided antioxidant in vitro activity in comparison with the blank sample. Pre-clinical and clinical safety assays assured the innocuous profile of the rutin-loaded ethosomes. The ethosomes containing the bioactive compound accomplished a more functional delivery system profile, since in the tape stripping assay, the deeper layers presented higher rutin amounts than the active delivered in its free state. However, the ex vivo antioxidant efficacy test detected no positive antioxidant activity from the rutin-loaded ethosomes, even though the in vitro assay demonstrated an affirmative antioxidant action.
Asunto(s)
Antioxidantes/administración & dosificación , Portadores de Fármacos/administración & dosificación , Rutina/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Antioxidantes/metabolismo , Pollos , Portadores de Fármacos/metabolismo , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Humanos , Liposomas , Tamaño de la Partícula , Rutina/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/fisiologíaRESUMEN
Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.
Asunto(s)
Celecoxib/química , Glicéridos/química , Cristales Líquidos/química , Piel/metabolismo , Administración Cutánea , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Celecoxib/farmacología , Química Farmacéutica/métodos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/efectos de los fármacos , Edema/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Masculino , Ácido Oléico/química , Permeabilidad/efectos de los fármacos , Propilenglicol/química , Ratas , Ratas Wistar , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiología , Solubilidad/efectos de los fármacos , Agua/químicaRESUMEN
OBJECTIVES: This work aimed to evaluate semisolid formulations containing topotecan (TPT) loaded nanostructured lipid carriers (NLC) for topical treatment of skin cancers, as TPT is effective against a variety of tumours. A formulation which increases TPT skin permeation would be extremely desirable. METHODS: TPT-NLC were prepared and incorporated in hydrogels with hydroxyethyl cellulose and chitosan (TPT-NLC-HEC and TPT-NLC-Ch, respectively). Control formulations were obtained by dispersing TPT in HEC and Ch hydrogels (TPT-HEC and TPT-Ch). KEY FINDINGS: TPT-NLC-HEC and TPT-NLC-Ch showed to maintain the drug and nanoparticle dispersions stable for up to 30 days. When nanoparticles were incorporated into gels, TPT release was significantly decreased (P < 0.05). Still, TPT-NLC-HEC increased 2.37 times permeation compared with TPT-HEC (11.9 and 5.0 µg/cm2 , respectively). Cell culture experiments with B16F10 melanoma demonstrated that nanoencapsulation significantly increased TPT cytotoxicity (P < 0.05). TPT-NLC was more toxic than free TPT, with IC50 value of 5.74 µg/ml, whereas free TPT had an IC50 > 20 µg/ml. As skin permeated values of TPT from developed formulation (TPT-NLC) were superior to melanoma IC50, it can be extrapolated that chemotherapeutic permeated amounts may be sufficient for a therapeutic effect. CONCLUSIONS: TPT-NLC-HEC may be a valuable tool for the topical treatment of skin cancers.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Melanoma Experimental/tratamiento farmacológico , Nanopartículas/administración & dosificación , Absorción Cutánea/fisiología , Neoplasias Cutáneas/tratamiento farmacológico , Topotecan/administración & dosificación , Administración Tópica , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/metabolismo , Hidrogeles/administración & dosificación , Hidrogeles/metabolismo , Lípidos/administración & dosificación , Melanoma Experimental/metabolismo , Ratones , Nanopartículas/metabolismo , Técnicas de Cultivo de Órganos , Absorción Cutánea/efectos de los fármacos , Neoplasias Cutáneas/metabolismo , Porcinos , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/metabolismo , Topotecan/metabolismo , Resultado del TratamientoRESUMEN
Hypericin (Hyp) is a natural photoactive pigment utilized in the treatment of different types of cancer and antimicrobial inactivation using photodynamic therapy (PDT). Hyp is poorly soluble in water leading to problems of administration, getting close contact with the site, and bio-availability. Therefore, this study aimed to develop bioadhesive thermoresponsive system containing Hyp for local PDT. Carbomer 934P, poloxamer 407, and Hyp were used to prepare the thermoresponsive bioadhesive formulations. They were characterized for sol-gel transition temperature, mechanical, mucoadhesive, rheological (continuous flow and oscillatory) and dielectric properties, syringeability, in vitro Hyp release kinetics, ex vivo permeability, and photodynamic activity. The formulations displayed suitable gelation temperature and rheological characteristics. The compressional, mechanical and mucoadhesive properties, as well the syringeability showed the easiness of administration and the permanence of the system adhered to the mucosa or skin. The dielectric analysis helped to understand the Hyp availability, and its release presented an anomalous behavior. The system did not permeate the pig skin nor rat intestine and showed good biological photodynamic activity. Therefore, data obtained from the bioadhesive system indicate a potentially useful role as a platform for local hypericin delivery in PDT, suggesting it is worthy of in vivo evaluation.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Resinas Acrílicas/química , Animales , Antracenos , Liberación de Fármacos , Geles/química , Absorción Intestinal/fisiología , Fenómenos Mecánicos , Perileno/administración & dosificación , Perileno/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Poloxámero/química , Ratas , Reología , Absorción Cutánea/fisiología , Porcinos , Adherencias TisularesRESUMEN
Pomegranate peel and seeds have demonstrated to possess antioxidant compounds with potential application to protect the skin against the ultraviolet radiation damage. However, the photoprotection activity is dependent on the amount of these compounds that reach the viable skin layers. In this paper, we describe the in vitro skin permeation and retention of the major pomegranate peel polyphenols using Franz diffusion cells, after entrapping a ethyl acetate fraction (EAF) from Punica granatum peel extract into nanoemulsions (NEs) prepared with pomegranate seed oil (PSO) or medium chain triglyceride oil (MCT). The in vitro skin permeation of gallic acid (GA), ellagic acid (EA), and punicalagin (PC) was evaluated using a HPLC-DAD validated method. After 8 h of skin permeation, all polyphenol compounds were mostly retained in the skin and did not reach the receptor compartment. However, a 2.2-fold enhancement of the retained amount of gallic acid in the stratum corneum was verified after EAF-loaded NEs are applied, when compared with the free EAF. GA and EA were delivered to the viable epidermis and dermis only when nanoemulsions were applied onto the skin. The mean retained amounts of GA and EA in the EP and DE after applying the EAF-loaded PSO-NE were 1.78 and 1.36 µg cm-2 and 1.10 and 0.97 µg cm-2, respectively. Similar values were obtained after applying the EAF-loaded MCT-NE. The skin permeation results were supported by the confocal microscopy images. These results evidenced the promising application of nanoemulsions to deliver the pomegranate polyphenols into the deeper skin layers.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Lythraceae , Nanopartículas/metabolismo , Extractos Vegetales/metabolismo , Polifenoles/metabolismo , Absorción Cutánea/fisiología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Antioxidantes/metabolismo , Emulsiones , Humanos , Nanopartículas/administración & dosificación , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Polifenoles/administración & dosificación , Polifenoles/aislamiento & purificación , Semillas , Absorción Cutánea/efectos de los fármacos , PorcinosRESUMEN
Combined therapy with corticosteroids and immunosuppressant-loaded nanostructured lipid carriers (NLC) could be useful in the treatment of skin diseases. To circumvent NLC loading capacity problems, loaded drugs should have different physicochemical characteristics, such as tacrolimus (TAC) and clobetasol (CLO). Therefore, in the present study, TAC and CLO were encapsulated in NLC (TAC-NLC, CLO-NLC and TAC+CLO-NLC), coated or otherwise with chitosan. Electron paramagnetic resonance (EPR) spectroscopy of different spin labels was used to investigate the impact of drug and oil incorporation on the lipid dynamic behavior of the lipid matrices. In addition, the impact of co-encapsulation on drug release and skin permeation was evaluated. Entrapment efficiency was greater than 90% for both drugs, even when the maximum drug loading achieved for TAC-NLC and CLO-NLC was kept at TAC+CLO-NLC, because TAC is more soluble in the solid lipid and CLO in the liquid lipid. EPR data indicated that both drugs reduced the lipid fluidity near the polar surface of the lipid matrix, which suggests their presence in this region. In addition, EPR data showed that liquid lipid is also present in more superficial regions of the nanoparticle matrix. CLO was released faster than TAC from TAC+CLO-NLC, probably because it is more soluble in the liquid lipid. TAC skin penetration was affected by CLO. A 5-fold increase in TAC penetration was observed from TAC+CLO-NLC when compared to TAC-NLC formulations. Coating also increased TAC and CLO permeation to deeper skin layers (1.8-fold and 1.6-fold, respectively). TAC+CLO-NLC seems to be an effective strategy for topical delivery of TAC and CLO, and thus constitutes promising formulations for the treatment of skin diseases.
Asunto(s)
Clobetasol/metabolismo , Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Absorción Cutánea/fisiología , Tacrolimus/metabolismo , Administración Cutánea , Animales , Clobetasol/administración & dosificación , Clobetasol/síntesis química , Cámaras de Difusión de Cultivos , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Espectroscopía de Resonancia por Spin del Electrón/métodos , Lípidos/administración & dosificación , Lípidos/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Absorción Cutánea/efectos de los fármacos , Porcinos , Tacrolimus/administración & dosificación , Tacrolimus/síntesis químicaRESUMEN
In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, α-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Absorción Cutánea/efectos de los fármacos , Tensoactivos/administración & dosificación , Administración Cutánea , Administración Tópica , Animales , Carotenoides/administración & dosificación , Carotenoides/metabolismo , Emulsiones/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/fisiología , Lípidos/administración & dosificación , Licopeno , Propilenglicol/administración & dosificación , Propilenglicol/metabolismo , Piel/metabolismo , Absorción Cutánea/fisiología , Tensoactivos/metabolismo , Porcinos , Viscosidad , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/metabolismoRESUMEN
Currently marketed minoxidil formulations present inconveniences that range from a grease hard aspect they leave on the hair to more serious adverse reactions as scalp dryness and irritation. In this paper we propose a novel approach for minoxidil sulphate (MXS) delivery based on a solid effervescent formulation. The aim was to investigate whether the particle mechanical movement triggered by effervescence would lead to higher follicle accumulation. Preformulation studies using thermal, spectroscopic and morphological analysis demonstrated the compatibility between effervescent salts and the drug. The effervescent formulation demonstrated a 2.7-fold increase on MXS accumulation into hair follicles casts compared to the MXS solution (22.0±9.7µg/cm2 versus 8.3±4.0µg/cm2) and a significant drug increase (around 4-fold) in remaining skin (97.1±29.2µg/cm2) compared to the drug solution (23.5±6.1µg/cm2). The effervescent formulations demonstrated a prominent increase of drug permeation highly dependent on the effervescent mixture concentration in the formulation, confirming the hypothesis of effervescent reaction favoring drug penetration. Clinically, therapy effectiveness could be improved, increasing the administration interval, hence, patient compliance. More studies to investigate the follicular targeting potential and safety of new formulations are needed.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Minoxidil/administración & dosificación , Minoxidil/metabolismo , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Química Farmacéutica , Folículo Piloso/efectos de los fármacos , Folículo Piloso/metabolismo , Minoxidil/química , Técnicas de Cultivo de Órganos , Absorción Cutánea/fisiología , PorcinosRESUMEN
The aim of this study was to compare the biopharmaceutical characteristics and irritation potentials of microemulsions (MEs) and conventional systems (CSs) containing oil from Syagrus cearensis for topical delivery of Amphotericin B (AmB). Pseudo-ternary phase diagrams were constructed using a water titration method to develop the MEs, and the CSs were prepared according to the classical technique of phase inversion. In the skin permeation and retention study, dermatomed pig skin without stratum corneum was used as an alternative disturbed skin model. The irritation potential was evaluated using three different methods, chorioallantoic membrane assays (HET-CAM and CAM-TBS), and bovine corneal opacity and permeability (BCOP) test. The optimized formulation (ME1) consisting of 0.1% (w/w) Amphotericin B, 9.1% (w/w) catolé oil, 81% (w/w) Smix (1:1, Tween 20 and Kolliphor EL) possessed droplet size of 31.02 ± 0.9 nm, zeta potential of -23.4 mV, and viscosity 0.63 ± 0.1 Pa.s. ME1 exhibited greater retention of AmB in to skin layers (84.79 ± 2.08 µg cm-2) than all the others formulations. In general, MEs showed higher drug release and retention than CSs and all of the formulations showed greater retentivity than permeability. Only MEs developed using Labrasol/Plurol Oleique (L/PO) as the surfactant and co-surfactant exhibited a moderate irritation potential; all other MEs and CSs were classified as non-irritants or slight irritants. The results indicate that formulations containing oil from S. cearensis are promising alternatives for the delivery of AmB targeting the treatment of cutaneous leishmaniasis.