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Preclinical and Clinical Safety Assessment of Transdermal and Topical Dermatological Products
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Lindsey C. Yeh, Howard I. Maibach
A simple mathematical model of transepidermal diffusion can be expressed using Fick’s law of diffusion. Fick’s law postulates that the magnitude of diffusion of a molecule across a membrane is directly proportional to the concentration gradient moving from an area of high concentration to an area of low concentration and to the surface area of the membrane through which diffusion is taking place. Rate of diffusion is inversely related to membrane thickness. J is representative of diffusion flux through a set area for a set time interval (amount of substance per unit area per unit time, mol/m2⋅s). Dm is the diffusion coefficient, a constant characteristic of the inherent mobility of a molecule. L is the length of the diffusion pathway, which is the thickness of the membrane in percutaneous absorbability testing. The partition coefficient (Km) is the velocity of drug passage through membrane in μg/cm2/h and must be considered when calculating flux for molecules other than water. The higher the Km for a solute, the easier it is for the molecule to diffuse and leave solvent. Cs is the concentration gradient (Cdonor – Creceptor) between donor and receptor chambers.
Imaging of Intracellular Targets
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Diffusion is one of the several transport phenomena that occur in nature and, according to Fick’s laws, the diffusion flux is reversely proportional to the gradient of concentrations (Philibert 2005). The rate at which a molecule diffuses across a membrane depends on its size and its degree of hydrophobicity. As a result, only low-molecular-weight molecules that are lipophilic can slip between the lipids in the bilayer and cross from one side to the other easily whilst this is not the case for larger and/or polar molecules, unless they are very small and uncharged (e.g., water and ethanol). All in all, relatively few endogenous molecules are capable to cross membranes by diffusion, and one should keep in mind that this process is not target specific. In other words, diffusion of a lipophilic imaging probe will take place through membranes of all cells, including those we do not want to image. As a result, high background levels can be expected. Because of the high ionic strength of blood, these compounds also tend to stick to serum proteins such as albumin, prolonging their circulation times, which will again contribute to higher background levels.
Aspects of Bilirubin Transport
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
Jules A. T. P. Meuwissen, Karel P.M. Heirwegh
Jm is the net diffusion flux inside the membrane, ∆Cf is the concentration difference of the unbound diffusing species in the aqueous phases at both sides of the membrane, ∆x is the membrane width, Dm is the perpendicular diffusion coefficient in the membrane, and Kp is the partition coefficient. Much larger concentration gradients can therefore become established in the phospholipid bilayer than would be possible if the gradient were to be set up directly between the concentrations of unbound pigment at both sides of the membrane. The way partition could increase the flux through the lipid phase of a membrane is depicted in Figure 8.
Phase transition of a microemulsion upon addition of cyclodextrin – applications in drug delivery
Published in Pharmaceutical Development and Technology, 2018
Sachin S. Thakur, Jared Solloway, Anneloes Stikkelman, Ali Seyfoddin, Ilva D. Rupenthal
While this is not a common phenomenon, CD complexation with drug may seldom contribute to slowing its release (Stella et al. 1999). Moreover, in spite of being highly water soluble, PHCl is known to complex with many CD including αCD (Keipert et al. 1996) and as such, we evaluated if this phenomenon impacted its release rate. Free and αCD-complexed PHCl solutions showed no apparent differences in their in vitro release profiles (data not shown). Given the low log P of PHCl and negligible solubility in the nonaqueous ME constituents, it may be concluded that the sustained release characteristics were primarily the result of the system adopting a more viscous liquid crystalline conformation. These observations follow Fick’s first law wherein the diffusion flux of a molecule from a medium is inversely proportional to its viscosity.
Touch-actuated microneedle array patch for closed-loop transdermal drug delivery
Published in Drug Delivery, 2018
Jingbo Yang, Zhipeng Chen, Rui Ye, Jiyu Li, Yinyan Lin, Jie Gao, Lei Ren, Bin Liu, Lelun Jiang
Numerical simulation models were built by COMSOL Multiphysics to explain the transdermal drug delivery mechanism of TMAP. The transdermal insulin delivery model of TMAP and its mesh model of viable skin are shown in Figure S4. The specific parameters of the simulations are listed in Table S2. All simulation models were built based on the physical size of MA and drug reservoirs. The radius shrinkage rate of the microchannel in the skin was fitted with Equation (S1) based on the TEWL test results. The drug permeability curves of the microchannels administered with various approaches are shown in Figure S5. Detailed descriptions of simulations are presented in the Supporting Information section. The diffusion of insulin and its concentration distribution in the skin during the delivery process was calculated based on Fick's laws of diffusion. The diffusion flux and total diffusion amount of insulin into the skin were calculated accordingly.
The Effect of Systemic Hyperoxia and Hypoxia on Scotopic Thresholds in People with Early and Intermediate Age-related Macular Degeneration
Published in Current Eye Research, 2020
Tamsin Callaghan, Tom H. Margrain, Alison M. Binns
The pathogenesis of AMD remains elusive but oxidative stress,3,4 inflammation,5 and hypoxia6,7 have all been implicated. Morphological changes to the retina and associated structures implicate hypoxia in the disease process. For example, changes to the choroid seen in AMD include a decreased choroidal blood flow,8 choriocapillaris drop out,9 and changes in choroidal vascularity index.10 A reduced choroidal blood supply might be associated with a reduced oxygen supply to the outer retina, especially in view of animal studies suggesting that the oxygen supply is only just sufficient to meet the needs of the photoreceptors under dark adapted conditions.11 In addition, age related thickening of Bruch’s membrane12 and the formation of basal linear deposits associated with AMD,13,14 increase the distance over which oxygen must diffuse to reach the retina from the choroidal circulation. According to Fick’s law, this results in a reduction in the diffusion flux,7 which may also impact on oxygen availability at the outer retina. Immunohistochemical studies have found increased levels of VEGF in early AMD,15 lending support to the notion that hypoxia is a feature of early AMD. However, it should be noted that a range of other factors may also lead to elevated levels of VEGF, including inflammation, acidosis, and other growth factors, such as TGF-α,TGF-β, insulin-like growth factor-1, FGF and platelet-derived growth factor.16,17 VEGF up-regulation alone is not, therefore, a strong indicator of the presence of hypoxia.