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2.
Prediction of drug disposition kinetics in skin and plasma following topical administration 总被引:1,自引:0,他引:1
The development of a physically based pharmacokinetic model for percutaneous absorption is described. The simulation includes four first-order rate constants assigned the following significance: (a) absorption across the stratum corneum; (b) diffusion through the viable tissue; (c) a retardation process which retains penetrant in the stratum corneum (and hence provides a means to mathematically produce a "reservoir" effect, for example); and (d) uptake from the skin into the systemic circulation and subsequent elimination from the body. The kinetic equations of the model are solved and expressions are obtained for the concentration of penetrant within the stratum corneum (and available to subsequently partition into the viable epidermis) and the plasma concentration of the administered substance, as a function of time. Using example values for the four rate parameters, disposition profiles for the penetrant in skin and plasma were derived. The cases considered cover slow and fast stratum corneum penetrants, substances which are excreted rapidly or slowly from the body, and absorbing molecules with a variety of relative stratum corneum-viable tissue affinities. The results suggest a framework for the prediction of pharmaceutically and clinically relevant information following the topical administration of therapeutic agents for local or systemic effect. 相似文献
3.
Paddy C. Dempsey Nyssa T. Hadgraft Elisabeth A. H. Winkler Bronwyn K. Clark Matthew P. Buman Paul A. Gardiner Neville Owen Brigid M. Lynch David W. Dunstan 《The international journal of behavioral nutrition and physical activity》2018,15(1):114
Background
High volumes of sitting time are associated with an elevated risk of type 2 diabetes and cardiovascular disease, and with adverse cardiometabolic risk profiles. However, previous studies have predominately evaluated only total sitting or television (TV) viewing time, limiting inferences about the specific cardiometabolic health impacts of sitting accumulated in different contexts. We examined associations of sitting time in four contexts with cardiometabolic risk biomarkers in Australian adults.Methods
Participants (n?=?3429; mean?±?SD age 58?±?10 years) were adults without clinically diagnosed diabetes or cardiovascular disease from the 2011–2012 Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Multiple linear regressions examined associations of self-reported context-specific sitting time (occupational, transportation, TV-viewing and leisure-time computer use) with a clustered cardiometabolic risk score (CMR) and with individual cardiometabolic risk biomarkers (waist circumference, BMI, resting blood pressure, triglycerides, HDL- and LDL-cholesterol, and fasting and 2-h post-load plasma glucose).Results
Higher CMR was significantly associated with greater TV-viewing and computer sitting time (b [95%CI]?=?0.07 [0.04, 0.09] and 0.06 [0.03, 0.09]), and tended to be associated with higher occupational and transport sitting time (0.01 [??0.01, 0.03] and 0.03 [??0.00, 0.06]), after adjustment for potential confounders. Furthermore, keeping total sitting time constant, accruing sitting via TV-viewing and computer use was associated with significantly higher CMR (0.05 [0.02, 0.08] and 0.04 [0.01, 0.06]), accruing sitting in an occupational context was associated with significantly lower CMR (??0.03 [??0.05, ??0.01]), while no significant association was seen for transport sitting (0.00 [??0.03, 0.04]). Results varied somewhat between the respective biomarkers; however, higher sitting time in each domain tended to be associated detrimentally with individual biomarkers except for fasting glucose (non-significant associations) and systolic blood pressure (a beneficial association was observed). Overall, associations were stronger for TV-viewing and computer use, and weaker for occupational sitting.Conclusions
Higher context-specific sitting times tended to be detrimentally associated, albeit modestly, with CMR and several cardiometabolic risk biomarkers. There was some evidence suggesting that the context in which people sit is relevant above and beyond total sitting time. Methodological issues notwithstanding, these findings may assist in identifying priorities for sitting-reduction initiatives, in order to achieve optimal cardiometabolic health benefits.4.
5.
Stobadine is a model drug with pyridoindole structure with cardioprotective and antioxidant properties. Permeation properties of its acyl derivatives were studied to find a proper prodrug form. The experimental study of transdermal delivery of derivatives was combined with the theoretical approach in which the partition coefficients of substances were estimated by means of fragmentation or quantum chemical calculations. All modes applied showed differences in the transport properties of derivative S1 (N-acetyl stobadine). The experimental results obtained for the flux of S1 were higher by one order of magnitude than for the other derivatives and the parent drug. The results are discussed from the point of view of physicochemical properties of derivatives. We concluded that the exceptional permeation value of S1 derivative results from the concurrence of partitioning coefficient, dissociation constant, and arrangement of permeation set. 相似文献
6.
Harrison Julian E. Watkinson Adam C. Green Darren M. Hadgraft Jonathan Brain Keith 《Pharmaceutical research》1996,13(4):542-546
Purpose. The purpose of this work was to analyse the mechanism of the enhancement of percutaneous penetration demonstrated by the known enhancers Azone® and Transcutol®.
Methods. Enhancer induced changes in the diffusivity and solubility of a model permeant (4-cyanophenol) in human stratum corneum were monitored (in-vitro) using Attenuated total reflectance Fourier transform infra-red (ATR-FTIR) spectroscopy and compared to the gross effects of the enhancers on flux as measured using simple Franz-type diffusion cells.
Results. It has been shown by both the well-established Franz diffusion cell technique and the use of ATR-FTIR spectroscopy that the enhancers studied both increase the flux of cyanophenol across human skin in-vitro by a factor of approximately two. Furthermore, it has been demonstrated by ATR-FTIR that these enhancers are likely to exert their effects by different mechanisms. It is probable that Azone reduces the diffusional resistance of the stratum corneum and that Transcutol increases the solubility of the penetrant in this barrier.
Conclusions. There is increasing interest in the apparently synergistic nature in which certain enhancers appear to work. The exact nature of these multiplicative and/or additive effects is not known although there are numerous suggestions in the current literature. The application of ATR-FTIR spectroscopy to such enhancing systems will allow the mechanisms of the observed enhancements to be probed in greater depth. 相似文献
7.
The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery. 相似文献
8.
Permeation enhancement of ibuprofen from supersaturated solutions formed using the cosolvent technique was investigated using silicone as a model membrane. Hydroxpropyl methyl cellulose and hydroxpropyl-beta-cyclodextrin were used to stabilise the supersaturated states. Physical stability studies showed best results for low drug concentrations in a 40:60 propylene glycol/water cosolvent system. Variations in flux across model silicone membranes from saturated solutions were observed as the PG content was increased. The flux of IBU increased with the degree of saturation for solutions prepared in a 40:60 PG/water cosolvent mixture. HPMC and CD were found to be effective in enhancing the stability of supersaturated solutions of IBU. The mechanisms of action are different for the two additives and are discussed. 相似文献
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10.
Skin, the final frontier 总被引:3,自引:0,他引:3
Hadgraft J 《International journal of pharmaceutics》2001,224(1-2):1-18