RESUMEN
To estimate strength of a scopolamine transdermal delivery system (TDS) in vivo, using residual drug vs. pharmacokinetic analyses with the goal of scientifically supporting a single and robust method for use across the dosage form and ultimately facilitate the development of more consistent and clinically meaningful labeling. A two-arm, open-label, crossover pharmacokinetic study was completed in 26 volunteers. Serum samples were collected and residual scopolamine was extracted from worn TDS. Delivery extent and rate were estimated by (1) numeric deconvolution and (2) steady-state serum concentration determined from graphical and non-compartmental analyses. In residual drug analyses, mean ± SD scopolamine release rate was 0.015 ± 0.002 mg/h (11% RSD), vs. 0.016 ± 0.006 mg/h (35% RSD) from numeric deconvolution, 0.015 ± 0.005 mg/h (34% RSD) from graphical analysis, and 0.015 ± 0.007 mg/h (44% RSD) from non-compartmental analysis. In residual drug analyses, total drug released was 1.09 ± 0.11 mg (10% RSD), vs. 1.12 ± 0.40 mg (35% RSD) from numeric deconvolution, 1.07 ± 0.35 mg (33% RSD) from graphical analysis, and 1.07 ± 0.45 (42% RSD) from non-compartmental analysis. Extent and rate of scopolamine release were comparable by both approaches, but pharmacokinetic analysis demonstrated greater inter-subject variability.
Asunto(s)
Sistemas de Liberación de Medicamentos , Escopolamina/administración & dosificación , Administración Cutánea , Adolescente , Adulto , Estudios Cruzados , Liberación de Fármacos , Femenino , Humanos , Masculino , Escopolamina/química , Escopolamina/farmacocinética , Adulto JovenRESUMEN
Topical beta-blocker formulations are commonly used to treat infantile hemangiomas (IHs); however, the skin concentrations and drug permeation through the skin have not been quantified. Microneedles (MNs) may increase local skin concentrations, which could further enhance lesion clearance and improve dosing regimens. The objective of this study was to quantify skin concentrations and drug permeation of two beta-blockers, propranolol and timolol, in vitro after application to intact skin and skin pretreated with solid MNs of two lengths. Propranolol skin concentrations and drug permeation were significantly higher than timolol skin concentrations for all study conditions, which is likely due to the lipophilic nature of propranolol compared to the hydrophilicity of timolol. Propranolol skin concentrations were significantly influenced by dosing regimen, as skin concentrations increased with increasing drug application. Pretreatment of the skin with solid 250 µm and 500 µm length MNs increased local skin concentrations of timolol; propranolol skin concentrations did not significantly increase after MN pretreatment. Propranolol and timolol permeation through the skin increased after MN pretreatment with both MN lengths for both compounds. Taken together, solid MN pretreatment prior to application of topical timolol may be beneficial for deep or mixed IHs upon further optimization of the MN treatment paradigm.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/metabolismo , Microtecnología/instrumentación , Agujas , Piel/metabolismo , Administración Tópica , Difusión , Relación Dosis-Respuesta a Droga , PermeabilidadRESUMEN
PURPOSE: Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin. METHODS: Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution. RESULTS: Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions. CONCLUSIONS: Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Antihipertensivos/farmacocinética , Portadores de Fármacos/química , Emulsiones/química , Propranolol/farmacocinética , Absorción Cutánea , Administración Cutánea , Antagonistas Adrenérgicos beta/administración & dosificación , Animales , Antihipertensivos/administración & dosificación , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Agujas , Tamaño de la Partícula , Propranolol/administración & dosificación , Piel/metabolismo , Solubilidad , Electricidad Estática , PorcinosRESUMEN
Application of exogenous products, such as creams, to the skin can result in subclinical changes in selected epidermal functions such as transepidermal water loss (TEWL), hydration, redness, and pH; these changes may lead to or contribute to irritation. Changes in skin surface inflammatory factors may provide further insight into this potential for irritation. The objective of this study was to evaluate the changes in epidermal properties and inflammatory mediators after 4 days of topical application of 2 different polymers formulated in cosmetic creams. Ten healthy volunteers (mean age ± SD: 20.0 ± 2.4 years) completed the study. TEWL, color, and pH were not significantly different after repeated application of these polymers. Hydration was significantly lower at sites treated with polymer A after 5 days. Significant increases in IL-1α, IL-1RA, and IL-1ß were observed after cream application at sites treated with polymer A. This is the first study to apply noninvasive measurements to quantify subclinical changes in epidermal properties and inflammatory mediator expression before and after the application of a cosmetic product, which will allow for a more enhanced safety profile to be achieved.
Asunto(s)
Cosméticos/farmacología , Epidermis/efectos de los fármacos , Polímeros/farmacología , Crema para la Piel/farmacología , Adolescente , Adulto , Citocinas/metabolismo , Epidermis/química , Epidermis/metabolismo , Eritema/inducido químicamente , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Proyectos Piloto , Agua/metabolismo , Adulto JovenRESUMEN
Transdermal delivery is an advantageous method of drug administration, particularly for an elderly population. Microneedles (MNs) allow transdermal delivery of otherwise skin-impermeable drugs by creating transient micropores that bypass the barrier function of the skin. The response of aging skin to MNs has not been explored, and we report for the first time that micropore closure is delayed in elderly subjects in a manner that is dependent upon MN length, number, and occlusion of the micropores. Twelve control subjects (25.6±2.8years) and 16 elderly subjects (77.3±6.8years) completed the study. Subjects were treated with MNs of 500µm or 750µm length, in arrays containing 10 or 50 MNs. Impedance measurements made at baseline, post-MN insertion, and at predetermined time points demonstrated that restoration of the skin barrier is significantly slower in elderly subjects under both occluded and non-occluded conditions. This was confirmed via calculation of the total permeable area created by the micropores (which would approximate the area available for drug delivery), as well as calculation of the micropore half-life. This pilot study demonstrates that longer timeframes are required to restore the barrier function of aged skin following MN insertion, suggesting that drug delivery windows could be longer following one treatment with a MN array.
Asunto(s)
Envejecimiento/fisiología , Sistemas de Liberación de Medicamentos , Microinyecciones , Agujas , Piel/anatomía & histología , Administración Cutánea , Adulto , Anciano , Anciano de 80 o más Años , Impedancia Eléctrica , Femenino , Humanos , Masculino , Porosidad , Adulto JovenRESUMEN
PURPOSE: The objective of this study was to optimize a reproducible impedance spectroscopy method in elderly subjects as a means to evaluate the effects of microneedles on aging skin. METHODS: Human volunteers were treated with microneedles at six sites on the upper arm. Repeated impedance measurements were taken pre- and post-microneedle insertion. Two electrode types were evaluated (dry vs. gel), using either light or direct pressure to maintain contact between the electrode and skin surface. Transepidermal water loss (TEWL) was measured as a complementary technique. RESULTS: Five control subjects and nine elderly subjects completed the study. Microneedle insertion produced a significant decrease in impedance from baseline in all subjects (p < 0.05, regardless of electrode type or pressure application), confirming micropore formation. This was supported by a complementary significant increase in TEWL (p < 0.05). The gel*direct condition produced the lowest variability between measurements, as demonstrated by a coefficient of variation of 3.8% and 3.5% (control and elderly subjects, respectively). This was lower than variation between TEWL measurements at the same sites: 19.8% and 21.6% (control and elderly subjects, respectively). CONCLUSIONS: Impedance spectroscopy reproducibly measures micropore formation in elderly subjects, which will be essential for future studies describing microneedle-assisted transdermal delivery in aging populations.