Stratum corneum permeability coefficient

Confining their study to monofunctional molecules, Roberts et al. [38] compared seven different models for predicting human stratum corneum permeability coefficients. The performance of the models was assessed by the adjusted coefficient of determination r2dj and the Akaike Information Criterion (AIC) [39], Both r2dj and AIC allow for comparing models with different numbers of variables (degrees of freedom). Exclusion of polyfunctional molecules led to a comparatively small set of only 24 molecules. The previously reported... 

In an early, quite elaborate model for the diffusion through the stratum corneum, Michaels et al. derived an equation for diffusion through a two-dimensional brick-and-mortar structure [50], In this model, stratum corneum permeability for a given compound depended only on two parameters one was the product of the partition coefficient between the protein and the donor phase /fprot/donor and the diffusion coefficient in the protein phase >Prot the other was the product of the partition coefficient between the lipid and protein phases Aip/prot and the ratio of the diffusion coefficients in the two phases... 

The dermal penetration coefficient Kp in this simplest case depends on both the partitioning of the chemical from its vehicle (usually water) into the stratum corneum, and its diffusion through the stratum corneum. Both of these quantities can be estimated from a chemical s properties or structure. Partitioning from water into the stratum corneum can be estimated from a chemical s octanol-water partition coefficient, Kow Diffusion through the stratum corneum is dependent on the molecular volume of the chemical, which is in turn a function of its molecular weight (MW). Perhaps the most widely used expression of the dependence of stratum corneum permeability on readily available physicochemical properties is the Potts-Guy equation ... 

To illustrate the above point, take the set of largest values given for the diffusion coefficients found in Table 8, that is, 10-9 cm2/s for the stratum corneum, 10-7 cm2/s for sebum, and 10-6 cm2/s for the viable tissue, and convert them to cm2/h. Conversion of these from reciprocal seconds to reciprocal hours eventually leads to permeability coefficients that are more easily compared with literature values (P in units of cm/h) When these values are substituted into Eq. (7) along with... 

Roberts et al. criticized the attempts to predict permeabilities since permeability is the result of two processes, partitioning and diffusion [40], Therefore, instead of following the approach of Potts and Guy, Roberts et al. tried to find a predictive model for each of these processes separately. For the partitioning step they found a Collander-type linear relationship (Eq. 11) between the logarithms of the stratum corneum-water and the octanol-water partition coefficients with a high correlation coefficient (r2 = 0.839) ... 

To determine the molecular properties influencing the diffusion process they investigated the relationship between experimental stratum corneum-water partition coefficients and permeability data for 45 compounds. Rearrangement of the logarithmic form of Eq. 4 led to... 

Substituting hx = 3.6 cm and K ip/w = K - into Eq. 28 Johnson et al. calculated solute lateral diffusion coefficients in stratum corneum bilayers from macroscopic permeability coefficients. Measurements with highly ionized or very hydrophilic compounds were not performed because of the possible transport along a nonlipoidal pathway. Comparison of the computed Aat values with experimentally determined data for fluorescent probes in extracted stratum corneum lipids [47] showed a highly similar curve shape. The diffusion coefficient for the lateral transport showed a bifunctional size dependence with a weaker size dependence for larger, lipophilic compounds (> 350 Da), than... 

Combining the equation for the diffusion coefficient with a Collander-type expression for the lipid-water partition coefficient resulted in an expression for calculating the permeability across the stratum corneum ... 

In order to increase the number of drugs which can be administered transdermally, the barrier function of the skin must be reduced. The kinetic model can be used to assess the role of a penetration enhancer as a function of the physicochemical properties of the drug. In its simplest form a penetration enhancer may be considered to act in one of two ways. Firstly it may increase the permeability of the skin and, secondly, it may additionally modify the partitioning characteristics at the stratum corneum-viable tissue interface. For illustration, two enhancers have been arbitrarily chosen, the first PE1 increases the permeability by a factor of 10, i.e. k- is increased ten fold. The second, PE2, increases k- by a factor of 10 and decreases kg by a similar amount. Thus PE2 additionally reduces the partition coefficient by a factor of 10. The relative effects can be seen by considering two model drug... 

A new theoretical model will now be described aimed at attempting to provide a possible explanation for the deviations observed in Figure 3. The model assumes that significant porosity prevails in the hairless mouse stratum corneum when ethanol is present. Although it can be assumed, that at low ethanol concentrations (below 50%) ethanol fluidizes lipid bilayers, there is evidence, that ethanol at high concentration (over 50%) may induce significant pore formations in hairless mouse stratum corneum as measured by the substantial increase of tetraethylammonium bromide permeabilities (10). The permeability coefficient P of a solute across a membrane or stratum corneum under steady state conditions may be described by ... 

Differential scanning calorimetric and infrared spectroscopic investigations of intact stratum corneum, extracted lipids and keratinized protein residue sheets suggested the thermal transitions occurring within the 30 to 70°C region were associated with increased molecular mobility of the lipids. The permeability coefficients of lipophilic molecules through hairless mouse skin increased by several orders of magnitude over the same temperature... 

For example, the permeability coefficients of intact stratum corneum for lipophilic compounds such as corticosterone are in the order of 2 x lO cm/sec in an aqueous system. The aqueous solubility of corticosterone is approximately 0.3mg/mL.f A simple calculation using Eqs. (1) and (2) show why only potent drug of a required dose less than 1 mg per day can utilize the transdermal route via passive delivery. Physical and chemical transdermal enhancers are required for most drugs. Table 1 provides a list of transdermal enhancement methods and companies involved in the development of technologies related to these methods. The readers are encouraged to view the company websites listed in the table, but caution must be taken because the information and claims provided in a company website are subjective and not peer-reviewed. 

For compounds that have either a very low diffusion coefficient or a very low lipid-water partition coefficient, the lipid barrier of the stratum corneum is a formidable impediment to penetration through the skin. However, for such compounds it has been observed that there is no longer a correlation between skin permeation and lipid solubility further, there also appears to be little dependence on molecular weight. It has therefore been hypothesized that such compounds make use of an alternative, low-permeability, and essentially aqueous pathway through the stratum corneum. Although direct physical evidence for such pores is lacking, the notion of a... 

Skin-snake-model percutaneous absorption Relationships between the in vitro permeability of basic compounds through shed-snake skin as a suitable model membrane for human stratum corneum and their physio-chemical properties were investigated. Compounds with low pKa values were selected to compare the permeabilities of the nonionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physico-chemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the MWs and the partition coefficients of basic compounds. 

Three major variables account for differences in the rate at which different compounds permeate the skin the concentration of permeant applied, the partition coefficient of the permeant between the stratum corneum lipids and the vehicle and the diffusivity of the compound within the stratum corneum. For a homologous series of chemicals, such as the alkanols, in which lipid/water partition coefficients increase exponentially with increasing alkyl chain length (Flynn and Yalkowski 1972) and for permeation through a lipid membrane of fixed or normalized thickness, the permeability coefficients will directly reflect partitioning... 

Figure 14.1 Effect of permeant lipophilicity on the rate of skin permeation. Average permeability coefficient data for aqueous alcohol solutions through human stratum corneum as a function of alcohol chain length (data from Scheuplein and Blank 1973],...

If the drug stratum corneum/product partition coefficient K is defined as Csc(o)/C)>, CJc is assumed to be much less than Csc(o), and the permeability coefficient (kp) is KD/h, equation 4 is equivalent to equation 3. The lag time is normally defined by Fick s law as h2/6D. The importance of equation 4 is well illustrated by the work of Rougier and Lotte (1993) in which it was shown that the in vivo percutaneous absorption (= Js) of a series of compounds was directly related to their concentration in stripped stratum corneum, irrespective of their structure, concentration or site of application. In theory, drug transport could go via a polar pathway, with a permeability coefficient kp pojar, as well as through the intercellular lipid pathway, with a permeability coefficient kp iipi(1, although the existence of a polar pathway remains controversial. As indicated previously, for lipophilic drugs, an aqueous boundary layer is likely to be present at the stratum corneum-viable epidermis interface... 

Figure 14.5 Influence of Azone and analogues on the permeation rate [expressed as the permeability coefficient) of 9-desglycin-amide-8-arginine vasopressin through human stratum corneum in vitro [data from Hoogstraate et al. 1991).

Stereoselectivity in the metabolism and percutaneous permeation, related to skin enzymatic activity, was reported for several compounds [23-28]. Stereoselectivity in permeation and cutaneous hydrolysis of several ester prodrugs of propranolol through hairless mouse skin was investigated [23]. The authors reported the stereoselective hydrolysis of propranolol prodrugs that is notably biased towards the R-isomer, which resulted in the enantioselective permeation. The lipophilicity of prodrugs, expressed as the partition coefficients, was found to affect the apparent skin permeability coefficients. The more lipophilic prodrugs readily entered into the stratum corneum, but their clearance into hydrophilic deeper strata (epidermis and dermis), where drug hydrolysis takes place, was much less effective. Unlike S-isomers, the R-isomers of propranolol esters were entirely hydrolyzed in epidermis and freely crossed the dermis strata. 

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