RESUMEN
OBJECTIVE: Develop and assess a transdermal emulsion loaded with nanostructured lipid carriers for vitamin D3 supplementation. METHODS: Vitamin D3 loaded nanostructured lipid carriers, produced via high shear homogenization and ultrasonication, were assessed for their particle size, distribution, morphology, zeta potential, entrapment efficiency, and cytotoxicity. They were incorporated into a transdermal vehicle, and the stability and ex vivo permeation were evaluated. RESULTS: Spherical nanoparticles were developed with a particle size of 192.5 nm, a polydispersity index of 0.13, a zeta potential of -29.0 mV, and an entrapment efficiency of 99.75%. They were stable (particle size and distribution) for 15 days when stored in a refrigerator, and for 30 days at room temperature and 32°C. The nanoparticles decreased the drug cytotoxicity against fibroblasts, as shown by IC50 (nanoparticle: 32.48 µg mL-1 vitamin D3: 16.73 µg mL-1). The emulsion loaded with nanoparticles minimized the degradation of vitamin D3 when compared with the nanoparticle dispersion. Additionally, the emulsion provided the skin permeation of vitamin D3 following the recommended daily allowance. CONCLUSION: To the best of our knowledge, this is the first study to use nanostructured lipid carriers for transdermal delivery of vitamin D. The developed formulation is a promising strategy to overcome the vitamin D3 variable oral bioavailability. It also represents a comfortable route of administration; thus it could be beneficial for patients and clinicians. However, further studies are needed to allow the permeation of larger amounts of vitamin D3, and the combination of these nanoparticles with microneedles would be interesting.
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Nanopartículas , Nanoestructuras , Administración Cutánea , Colecalciferol/metabolismo , Portadores de Fármacos/metabolismo , Emulsiones , Humanos , Lípidos , Tamaño de la Partícula , Piel/metabolismoRESUMEN
The aim of the study was to develop a novel buccal dosage form to transport rhodamine 123 and human insulin as models for poorly water-soluble and biological drugs, using lipid-core micelles (LCMs)-loaded mucoadhesive films. LCMs were synthesized by a low-energy hot emulsification process, yielding spherically shaped, small-sized, monodispersed and negatively charged carriers with high entrapment efficiency. In vitro release studies demonstrated a higher release of insulin rather than rhodamine from LCMs in simulated physiological conditions, due to an initial burst release effect; however, both release profiles are mainly explained by a diffusion mechanism. Furthermore, LCMs-loaded mucoadhesive films were manufactured and preserved with similar mechanical properties and optimal mucoadhesive behavior compared to nonloaded films. Ex vivo permeation experiments using excised porcine buccal epithelium reveal that both rhodamine and insulin-loaded LCM films elicited a significantly enhanced permeation effect compared to LCMs in suspension and free drugs in solution as controls. Hence, LCMs-loaded mucoadhesive films are suitable as buccal dosage form for the transport and delivery of rhodamine 123 and insulin, as models for poorly water-soluble and biological drugs, respectively.
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Current oral squamous cell carcinoma chemotherapies demonstrate off-target toxicity, which could be reduced by local delivery. Curcumin acts via many cellular targets to give anti-cancer properties; however the bioavailability is hindered by its physicochemical characteristics. The incorporation of curcumin into emulgel systems could be a promising approach for its solubilization and delivery. The aim of this work was to develop emulgel systems containing curcumin for the treatment of oral cancer. The emulgels containing curcumin were prepared with poloxamer 407, acrylic acid derivatives, oil phase (sesame oil or isopropyl myristate). The more stable system was evaluated for mechanical and rheological properties, as well as, the in vitro drug release profile, permeation and cytotoxic potential to oral mucosa models. The flow-throw system evidenced that the formulations could keep 5 min over porcine oral mucosa. Emulgel showed pseudoplastic behavior and a gelation temperature of 33 °C, which ensure their higher consistency. In addition, 70% of the incorporated curcumin was released within 24 h in an in vitro drug release study and could permeate porcine oral mucosa. Monolayers cultures and tissue-engineered models showed the selectivity of the drug and systems for tumor cells. The physicochemical properties, subsequent release and permeation of curcumin to selectivity kill cancer cells could be improved by the incorporation into emulgel systems.
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Carcinoma de Células Escamosas , Curcumina , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Mucosa Bucal , Neoplasias de la Boca/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , PorcinosRESUMEN
BACKGROUND: Transdermal delivery is an alternative route for the administration of drugs. However, it requires the development of vehicles that allow the drugs to cross the layers of the skin and reach the systemic circulation. OBJECTIVE: In this study, a new transdermal vehicle was evaluated using progesterone, estradiol, estradiol + estriol (Biest) and ketoprofen administered as model drugs. METHODS: To evaluate the ex vivo permeation of the drugs, the Franz vertical diffusion cell with human skin was used. RESULTS: After 24 h, the vehicle was able to deliver 18.32 µg/cm2 of progesterone and 92.07 µg/cm2 of ketoprofen through the skin to the receptor medium. The permeation percentages were 91%, 78.8%, 48.5%, 73.2%, and 63.6%, respectively, for estradiol, estradiol (Biest), estriol (Biest), progesterone and ketoprofen. For all drugs, sufficient amounts were delivered to achieve a systemic effect, and it was also possible to decrease the amount of emulsion applied. CONCLUSION: Thus, the vehicle demonstrated a high performance and the possibility of it being used for drugs that present difficulties in regards to administration by the transdermal route.
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Sistemas de Liberación de Medicamentos , Absorción Cutánea , Piel/metabolismo , Administración Cutánea , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Combinación de Medicamentos , Estradiol/administración & dosificación , Estriol/administración & dosificación , Femenino , Humanos , Técnicas In Vitro , Cetoprofeno/administración & dosificación , Progesterona/administración & dosificaciónRESUMEN
Oral therapy with 8-methoxypsoralen (8-MOP) may cause major side effects, whereas the topical treatment might not be much effective due to the low penetration induced by typical formulations. Therefore, the objectives of this work are the development and characterization of a nanoemulsion (NE) containing 8-MOP together with an ex vivo permeation study, monitored by a validated HPLC-Fluo method, to determine the amount of drug retained in viable skin (epidermis (E) and dermis (D)) and in stratum corneum (SC). The optimized conditions for NE formulation were achieved by full factorial designs (25 and 32): 60â¯s and 60% of ultrasound time and potency, respectively; 10â¯mL of final volume; 2% v/v of oil phase (clove essential oil); and 10% m/v of Poloxamer 407. The NE showed mean droplet diameter of 24.98⯱â¯0.49â¯nm, polydispersity index (PDI) of 0.091⯱â¯0.23, pH values of 6.54⯱â¯0.06, refractive index of 1.3525⯱â¯0.0001 and apparent viscosity of 51.15⯱â¯3.66â¯mPa at 20⯰C. Droplets with nanospherical diameters were also observed by transmission electron microscopy (TEM). Ex vivo permeation study showed that 8.5% of the applied 8-MOP dose permeated through the biological membranes, with flux (J) of 1.35⯵gâ¯cm-2â¯h-1. The drug retention in Eâ¯+â¯D and in SC was 10.15⯱â¯1.36 and 1.95⯱â¯0.71⯵gâ¯cm-2, respectively. Retention in viable skin induced by the NE was almost two-fold higher than a compounded cream (5.04⯱â¯0.30⯵gâ¯cm-2). These results suggested that the developed NE is a promising alternative for 8-MOP topical therapy when compared to commercial formulations.
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Metoxaleno/administración & dosificación , Nanopartículas/administración & dosificación , Fármacos Fotosensibilizantes/administración & dosificación , Piel/metabolismo , Administración Cutánea , Animales , Aceite de Clavo/administración & dosificación , Aceite de Clavo/química , Aceite de Clavo/farmacocinética , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Emulsiones , Metoxaleno/química , Metoxaleno/farmacocinética , Nanopartículas/química , Permeabilidad , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Poloxámero/administración & dosificación , Poloxámero/química , Poloxámero/farmacocinética , Absorción Cutánea , Solubilidad , PorcinosRESUMEN
BACKGROUND: Taxifolin (TAX) is a flavonoid that has numerous pharmacological properties, including an antioxidant ability superior to that of other flavonoids due to its particular structure. Nevertheless, it has low oral bioavailability, which limits its therapeutic application. In this context, potentially important approaches for systemic drug delivery could be by alternative routes such as skin and vaginal mucosa, once both routes have a variety of advantages compared with the oral route, including the ability to bypass both first-pass hepatic metabolism and the consequent degradation in the gastrointestinal tract. Vaginal delivery could also account for a local effect, or an effect on circumvent microregion. OBJECTIVE: The major objective of this study was to develop and validate a high-performance liquid chromatography (HPLC) method for the determination of TAX in a semisolid dosage forms and then to evaluate ex vivo permeations across porcine vaginal mucosa and human skin. METHODS: TAX was incorporated into an oil-in-water emulsion developed previously by our group. Method for quantification was developed and validated using HPLC. Permeation through human skin and vaginal porcine mucosa were conducted in Franz-type cells. RESULTS: The method was precise (CV < 5%), accurate (recovery between 98% and 102%), linear (R2> 0.99), specific, and robust. Permeation experiments through porcine vaginal mucosa and human skin presented permeated percentages equal to 87.43% and 48.09% (per dose), respectively. CONCLUSION: The results suggest that, in the matrixes studied, TAX may be able to exert its biological activities systemically when applied by these routes. Furthermore, it exhibits greater permeability potential when administered by intravaginal route.
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Antiinflamatorios no Esteroideos/administración & dosificación , Membrana Mucosa/metabolismo , Quercetina/análogos & derivados , Crema para la Piel/administración & dosificación , Piel/metabolismo , Administración Tópica , Adulto , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Emulsiones , Femenino , Humanos , Técnicas In Vitro , Permeabilidad , Quercetina/administración & dosificación , Quercetina/farmacocinética , Absorción Cutánea , Crema para la Piel/farmacocinética , Porcinos , VaginaRESUMEN
The present study was aimed at preparation of transdermal patches of tizanidine HCl, evaluation of the effect of polymers on in vitro release pattern of the drug, and the effect of permeation enhancers on the penetration of the drug through the rabbit skin. Various proportions of hydrophilic (HPMC) and hydrophobic (Eudragit L-100) polymers were used with PEG 400 as film-forming agent, and Span 20 or DMSO as permeation enhancer. The formulations were assessed for physicochemical characteristics and in vitro drug release studies using USP paddle over disc method in phosphate buffered saline (pH 7.4) at 32.0±1°C. On the basis of in vitro studies and physicochemical evaluations, S03-A and S04-A were selected at Eudragit : HPMC ratios of 8 : 2 and 7 : 3, respectively, for further ex vivo analysis. The effects of different concentrations of Span 20 and DMSO were evaluated on excised rabbit skin using Franz diffusion cell. Cumulative drug permeation, flux, permeability coefficient, target flux, and enhancement ratio were calculated and compared with the control formulations. Kinetic models and Tukey's multiple comparison test were applied to evaluate the drug release patterns. Formulation SB03-PE containing Eudragit L-100:HPMC (7:3) with Span 20 (15% w/w) produced the highest enhancement in drug permeation, and followed zero order kinetic model with super case-II drug release mechanism.
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Animales , Conejos , Parche Transdérmico/clasificación , Parche Transdérmico/provisión & distribución , Técnicas In Vitro , Preparaciones Farmacéuticas/análisis , Interacciones Hidrofóbicas e Hidrofílicas , Liberación de Fármacos/efectos de los fármacosRESUMEN
Hydrochlorothiazide (HCT) is a diuretic used to treat hypertension. In order to study its intestinal permeation behavior applying an ex vivo methodology, a rapid, sensitive and selective reversed-phase liquid chromatography (RP-HPLC) method coupled with UV detection (RP-HPLC UV) was developed for the analysis of HCT in TC199 culture medium used as mucosal and serosal solutions in the everted rat intestinal sac model. Also, analytical procedures for the quantification of HCT by RP-HPLC with UV detection required a sample preparation step by solid-phase extraction. The method was validated in the concentration range of 8.05 × 10-7 to 3.22 × 10-5 m for HCT. Chromatographic parameters, namely carry-over, lower limit of quantification (1.4491 × 10-7 m), limit of detection (3.8325 × 10-8 m), selectivity, inter- and intraday precision and extraction recovery, were determined and found to be adequate for the intended purposes. The validated method was successfully used for permeability assays across rat intestinal epithelium applying the ex vivo everted rat gut sac methodology to study the permeation behavior of HCT.