References

Skin, the final frontier. International Journal of Pharmaceutics 2001 224(1 2) 1 18. 2. RJ Feldmann, HI Maibach. Regional variation in percutaneous penetration of 14C cortisol in man. Journal of Investigative Dermatology 1967 48(2) 181-183. 3. BW Barry. Reflections on transdermal drug delivery. Pharmaceutical Science and Technology Today 1999 2(2) 41-43. 4. VM Knepp, J Hadgraft, RH Guy. Transdermal drug delivery problems and possibilities. CRC Critical Reviews in Therapeutic Drug...

Appendix B Documentation Of Permeability Coefficient Data

This appendix contains specific documentation about the permeability coefficient data included in the FV, provisional, and excluded databases. Details are arranged alphabetically by the last name of the first author of the investigation. As stated previously, all data were evaluated with respect to the requirement that they be measured at steady state. Preferably, experimental evidence of steady state (e.g., demonstration that absorption is linear in time) was shown. Sometimes steady state was...

Topical Drug Delivery

Compared to chemical methods or other physical methods, e.g., iontophoresis and sonophoresis, which also enhance transdermal and topical drug delivery, electroporation could be a promising alternative for enhancing topical drug delivery. In contrast to these methods, skin electroporation has been shown to perme-abilize the underlying tissue, including the keratinocytes (Mir and Orlowsky, 1999, Regnier and Preat, 1999). Hence if the keratinocytes or other epidermal cells are the target cells,...

Info

A FV Fully validated database LSER Subset of FV database for which LSER parameters were available (see Table A4). b n number of data points, m number of different compounds. c The uncertainties expressed within parenthesis are reported as standard error in the coefficients. d Coefficients indicated with an asterisk (*) are not meaningfully different from zero at the 95 confidence level. a FV Fully validated database LSER Subset of FV database for which LSER parameters were available (see Table...

Epidermal Lipid Synthesis

Numerous studies have described the changes in lipid composition that accompany SC formation in murine, porcine, and human epidermis (6). These studies demonstrate the loss of phospholipids and the emergence of ceramides, cholesterol, and free fatty acids during barrier formation. Moreover, a further gradient in lipid transformation occurs during the final stages of terminal differentiation and barrier formation e.g., small amounts of glucosylceramides and phospholip- ids persist in the lower...

Comparison with the Flynn Permeability Coefficient Database

The FV database contains 170 permeability coefficient values for 127 compounds, encompassing many different organic compound structural classes. The entire FV database is broad in the sense of log Kow (-3.10 mannitol < log Kow < 4.57 decanol mean 1.66, median 1.94, standard deviation 1.75) andMW (18.0 water < MW 584.6 ouabain mean 201.9, median 160.25, standard deviation 129.11) and should be useful for predicting permeability coefficient values for a diverse set of organic compounds....

Adjustment for Ionization

Permeability coefficients have been measured for chemicals that exhibit diverse ionization behavior. Many compounds are essentially nonionized at the pH of the experiment (i.e., typically 2 < pH < 10). However, many others (e.g., aniline, caffeine, codeine, isoquinoline, ibuprofen, and nicotine among others) exist in equilibrium with a charged species (frequently protonated amines or dissociated carboxylic acid). Some compounds are always completely ionized (e.g., paraquat or...

Results And Discussion

Permeability Coefficient

Appendix A summarizes all of the permeability coefficient values collected in this study. Table A1 contains the FV database of permeability coefficients. The provisional database is contained in Table A2. Permeability coefficients that were excluded from further analysis are listed in Table A3. The adjustment of pKa values for temperature and the calculation offni and the natural pH for unbuffered solutions at known solute concentration are summarized in Table A4. Figure 2 shows the FV database...

Phonophoresis In Animal Skin A Steroids

Kost and coworker documented successful hydrocortisone phonophoresis in vitro through whole sections of hairless mouse skin (Machluf and Kost, 1993). The authors reported a duration-responsive effect when a 1 MHz pulsed beam was operated at an intensity of 3 W cm-2. While 30 minutes of sonication did not affect hydrocortisone flux, sonication for 1.5 hours or more produced significant Figure 5 Scheme illustrating how cavitation in the stratum corneum may facilitate pho-nophoresis. The scheme...

In Vivo Assessments

Clearly, the gold standard for measuring in vivo dermal or transdermal absorption is the use of living human tissue. In the case of transdermal delivery, the goal is to obtain an appropriate blood level of the active. This is usually monitored using a straightforward analysis of blood samples over the time course of the application. It is interesting to continue blood sampling after the device has been removed. Data analysis of the concentration decay from the blood can give information about...

Evaluating the Transdermal Permeability of Chemicals

Bunge Colorado School of Mines, Golden, Colorado, U.S.A. Contaminated terrestrial waters and chemically disinfected waters frequently contact human skin, and waterborne contaminants (environmental pollutants and disinfection byproducts, respectively) can be dermally absorbed. Reasonable estimates of the amount of chemical absorption by the skin is important for determining safe levels of contamination. Similarly, dermal absorption estimates are helpful in...

Saket et al 1985

This paper reports Kcwiep values for hydrocortisone, five esters of hydrocortisone (hydrocortisone acetate, hydrocortisone propionate, hydrocortisone valerate, hydrocortisone hexanoate, and hydrocortisone octanoate), cortisone and four esters of cortisone (cortisone acetate, cortisone butyrate, cortisone hexanoate, and cortisone octanoate). The Kcw,rep value for hydrocortisone at 37 C was taken from Table 1 (abdominal skin) in this reference, while the other Kcw,rep values (at 25 C for...

Trends in the FV Database

Permeability measurements in the FV database but not in the Flynn database, and those in both the validated Flynn database and the FV database, are compared with predictions using Eq. T1 in Fig. 3 plotted as a function of log Kow. The log Kow values in Table A1, which were only different from the log Kow reported by Flynn (21) for a few chemicals (see Table A in the Appendix to Chapter 2 for details), were used to make this plot. Measurements appearing above the upper dashed line are...

Advantages and Limitations

As a starting point, transdermal iontophoresis retains all the advantages of the transdermal route avoidance of first-pass effect and or GI metabolism degradation, improved patient acceptance and compliance, easy access, etc. On the contrary, due to the efficient degree of enhancement achieved, iontophoresis enlarges the range of drug candidates for transdermal administration, in particular including polar and or charged drugs whose passive skin permeation is severely restricted (5). Further...

P

Permeability Coefficient

- 0.179 VMW Ppol 1.52 X 10-4 VMW Pao 2.5 VMW * Equations for Models 7 and 11 are corrections from those listed in Table 6.2 of reference (25). a General description of chemicals n the total number of data points the number of different chemicals may be fewer. b Although not directly specified, there is some indication that this data is largely composed of the alkanols, alkanoic acids, and alkanediols of (17) and the phenols reported by (8). c The Bronaugh and Barton correlation (Model 3) is...

The Physics Of Ultrasound Propagation

Ultrasound is an acoustic vibration propagating in the form of longtitudinal compression waves at frequencies beyond the human auditory range, i.e., 0.02 MHz. The intensity parameter, measured in W cm-2, defines the quantity of energy conveyed by an ultrasonic wave as it passes through any given site, and this parameter is used to establish exposure. Therapeutic ultrasound is normally generated by a transducer that converts electricity to ultrasound by utilizing the piezoelectric principle....

Estimation of the Stratum Corneum Diffusion Coefficient

The ratio of the SC diffusion coefficient to SC thickness is another useful combination of parameters that appears in dermal absorption models (29). We estimate this ratio using principles that apply to membranes and models developed for predicting Kcw and the SC permeability coefficient. As discussed in Chapter 3, penetration through the SC membrane is frequently modeled as a solution-diffusion process (e.g., Ref. 29 and many others). In this case, the steady-state permeability coefficient for...

Energy Induced Transdermal Delivery Systems

Laser-Assisted Transdermal Delivery Studies of laser-assisted drug delivery across skin have investigated two distinctly different processes. The first is ablative. The high energy of the laser is imparted into the skin to form pores that permit the transit of drug through the stratum corneum from, for example, a topically applied patch or gel. The other process entails the formation of a laser-induced stress wave (5) which transiently increases the permeability of the stratum corneum to drugs....

Model Development

Equations are developed in this section that will be used for later analysis of the Kcw database. First, we develop a simple model that has been used commonly to represent Kcw data (i.e., the conventional model). Later we analyze the database with a model that allows for potentially different mechanisms for partitioning into the hydrophilic and lipophilic domains of the SC and with a linear solvation-energy relationship (LSER) model. These last two models are mechanistically based, allowing...

Antinucleant Polymers

The precise mechanism of nucleation and subsequent crystal growth is not fully understood. Frank 1949 suggests that if a molecule diffuses to the flat surface of a crystal it only has one binding surface, but if it arrives at a kink or step, it has more than one binding surface with which to anchor itself to the crystal. With screw dislocations, the crystal can continue to grow in a spiral staircase manner. Four models predicting crystal growth of theophylline monohydrate were presented by...

Comparing the Database with Other Published Models

Table 2 lists eighteen equations presented in the literature for estimating the Kcw for human skin. Also listed are the chemical classes upon which each equation was trained, a reference to the training data, and the range of MW and log Kow of the training data. The equations from Brown and Hattis Model 1 , McKone Model 7 , McKone and Howd Model 8 , Raykar et al. Model 9 , and Hui et al. Model 18 were not developed in the conventional form. Except for Brown and Hattis 31 , these references can...

Oligonucleotides

The transdermal route has been considered for antisense therapy 90 . In an early study, the iontophoresis of bases, nucleosides, and nucleotides was studied in vitro through hairless mouse and human skin. The transport of charged and uncharged species was significantly enhanced in a concentration-dependent manner. ATP and GTP were significantly metabolized, while imidoGTP was more resistant to enzymatic attack 20 . There have been several attempts to deliver oligonucleotides iontophoreti-cally...

Estimation Of Permeability Coefficient From Simple Physicochemical Parameters

Over the years, a database of skin permeability values has been consolidated e.g., Ref. 5 . To avoid confusion and to simplify interpretation, permeabilities from aqueous solutions alone are considered. The use of skin permeabilities from other vehicles is complicated in that most other solvents are capable of altering the barrier function of skin. Analysis of the existing database enabled Potts and Guy to formulate an empirical relationship between kp and two simple characteristics of the...

Radiation Pressure Force

Any structure that absorbs a component of a beam of energy is subjected to a force, termed the radiation pressure force, which tends to push that object in the Figure 3 The magnitude of the hyperemic response in human skin as a function of temperature. From Williams, 1983. Figure 3 The magnitude of the hyperemic response in human skin as a function of temperature. From Williams, 1983. direction of wave propagation Williams, 1983 . One hypothesis is that an induced radiation pressure, acting on...