Anderson et al 1989

This paper reports Kcw,IBp values for five chemicals a-(4-hydroxyphenyl) acet-amide, 4-hydroxy-benzyl alcohol, 4-hydroxyphenylacetic acid, methyl 4-hydroxyphenylacetate, and p-cresol . Because 4-hydroxyphenylacetic acid was more than 10 ionized (pH 4.0), the measurement for this compound is listed in the provisional database. The other compounds were not ionized. The time for equilibration was not specified. We assumed that partition coefficients were based on dry SC mass, because this was the...

Info

Figure 2 Rapid temporal control of transdermal transport using skin electroporation. The time profiles of calcein transdermal flux due to electroporation at different transdermal voltages are shown. 1 ms pulses were applied to human epidermis in vitro at 1 pulse per minute for 1 h, at 270 V (solid line), 135 V (dashed line), or 115 V (dotted line). (From Prausnitz et al., 1994.) Figure 2 Rapid temporal control of transdermal transport using skin electroporation. The time profiles of calcein...

Biophysical Investigation of the Stratum Corneum Structure

Different biophysical methods have been used to study the stratum corneum following application of high-voltage pulses (Jadoul et al., 1997, 1998a, 1999) (Table 3). Hydration of the stratum corneum due to pulsing was observed by ATR-FTIR and measurement of total water content. Differential thermal analysis, x-ray diffraction, and freeze fracture electron microscopy studies revealed a dramatic perturbation of the lamellar ordering. The larger the pulses, the larger the perturbations. A...

Cavitational Activity

Cavitation is defined as acoustically induced bubble activity (Apfel, 1997). It includes diverse types of behavior, ranging from the relatively gentle volumetric pulsations of gas-filled bodies (stable cavitation) to the destructive and free radical-generating formation and implosion of vapor-filled voids (transient cavita-tion). Cavitation is powered by the energy from the incident ultrasonic beam, about 10 of which may be reradiated from the bubble as an outgoing spherical wave. The remainder...

J L f

Where LVE is the (phenomenological) electroosmotic flow coefficient describing the direction and magnitude of the volume flow resulting from the driving force, -dO dx. By convention, the volume flow is positive when the membrane is negative. Pikal explains the electroosmotic effect via the electrical volume force on the ion atmosphere (electrical double layer). When a membrane pore is lined with fixed or immobile charges, there is a region, the so-called ion atmosphere or electrical double...

In Vivo Studies

Most of the studies on transdermal drug delivery using skin electroporation have been performed in vitro using standard diffusion cells. However, in vivo studies have confirmed that skin electroporation enhances and expedites transdermal drug delivery (Vanbever and Preat, 1999). A first limited study assessed transport due to skin electroporation in vivo by measuring serum concentrations of calcein (Prausnitz et al., 1993b). Fluxes at least two orders of magnitude greater than controls were...

Other Drugs

Ultrasound-promoted delivery of various other drugs has been documented in the literature reports. For instance, it was found that 3 hours of sonication with a 1 MHz, 3 W cm-2 pulsed beam almost doubled caffeine permeation through full thickness hairless mouse skin (Machluf and Kost, 1993). Additionally, an intensity-drug flux response was demonstrated for in vitro digoxin penetration through hairless mouse skin under the influence of 10 minutes 3.3 MHz c.w. ultrasound (Pinton et al., 1991...

References

A Badkar, G Betageri, G Hofmann, A Banga. Enhancement of transdermal ionto-phoretic delivery of a liposomal formulation of colchicine by electropora-tion. Drug Del 6 111-115, 1999. A Banga, ed. Electrically-assisted transdermal and topical drug delivery. Bristol, PA Taylor and Francis, 1998. A Banga, M Prausnitz. Delivery of protein and gene-based drugs by skin electro- poration. Trends Biotech 16 408-412, 1998. A Banga, S Bose, T Ghosh. Iontophoresis and electroporation comparisons and...

Peptides

The use of iontophoresis for peptide transdermal application has been extensively examined (15,16,18,19,36,40-42,59-62,76,77). Iontophoresis facilitates the delivery of these usually charged and or polar molecules through an otherwise quite impermeable skin barrier. It was soon shown that iontophoresis could provide, noninvasively, plasma levels of certain peptides comparable to those obtained after IV infusion or subcutaneous administration (11,76). Furthermore, ionto phoresis reduced the lag...

Analgesics

The iontophoresis of morphine, hydromorphone, fentanyl, and sufentanil has been studied (27,31,81). Fentanyl, of course, has already been formulated as a passive transdermal patch (Duragesic ) for the management of chronic pain. However this method of administration is not appropriate for treating acute postoperative pain as it cannot be patient controlled. The iontophoretic device, E-TRANS , on the other hand, allows an effective treatment that is patient-actuable (31). In vivo human studies...

Introduction

Fortunately for us, the skin has evolved into an extremely efficient barrier, which prevents both excessive water loss from the body and the ingress of xenobiotics. It enables us to withstand a considerable range of environmental challenges. The reasons for this are manifold and may be summarized simply for the purposes of this chapter. The outer layer of the skin, the stratum corneum, forms the rate-controlling barrier for diffusion for almost all compounds (Fig. 1). It is composed of dead,...

Regulatory Considerations for Abbreviated New Drug Applications ANDA as TDS

The most important study for an ANDA is a bioequivalence (BE) study. A BE study should be carried out using the test product and a reference product at the highest strength, in accordance with the Guidance Bio-availability and bioequivalence studies for orally administered drug products general considerations (3). The approaches discussed in this general guidance are also applicable to non-orally administered drug products such as TDS. Generally for modified (extended or controlled) release...

P P P

Except for very lipophilic penetrants (approximately log Kow > 4), the permeability coefficient through the entire epidermis (i.e., Pw) is not different from that through the SC alone (i.e., Pcw), so that these equations are often considered to predict SC permeability coefficients. This issue was addressed more quantitatively by Vecchia (4), who collected several published experimental values of the ratio Pcw Pew, which he used to derive correlations based on log Kow. One of the equations in...

Twocompartment Model

Most of the latter observations are better explained by the unique structural and biochemical heterogeneity of the SC (2). In this so-called two-compartment model, the lipids of the SC are segregated within intercellular domains, while the lipid-depleted corneocytes act primarily as spacers, while providing protection from mechanical insults. The permeability barrier forms coincident with the secretion of lamellar body (LB) contents at the stratum granulosum (SG)-SC interface. The delivery of...

Electrical Parameters

The influence on molecular transport of the electrical parameters of the pulses, i.e., the pulse waveform and the pulse voltage, time constant, number, and rate, have been extensively examined (Prausnitz et al., 1993a, 1994 Vanbever et al., 1994, 1996a Gallo et al., 1997 Jadoul et al., 1998 Regnier and Preat, 1998). Skin electroporation experiments reported in the literature generally use generators delivering exponential-decay pulses (Prausnitz et al., 1993b Vanbever et al., 1994 Bommannan et...

The Convective Contribution Electroosmosis

In 1980, Gangarosa et al. (6) used the term iontohydrokinesis to describe the transport of water into a tissue as a result of iontophoresis, irrespective of the mechanism of transport. These early experiments demonstrated quite nicely, in vivo, the transport of solvent induced by iontophoresis. Briefly, after applying iontophoresis to mice (in which anode and cathode formulations were spiked with tritiated water) a punch biopsy was taken from the skin beneath the electrodes and analyzed for...

C

In Eq. (2) Cc,eq is the mass of solute per mass of the dried SC that is in equilibrium with Cw. Partition coefficient measurements based on the dry-mass of SC (Kcw) can be related to Kcw through the ratio of the aqueous solution density (pw) and p' defined as the mass of dry SC over hydrated skin volume as follows

Evaporation

An increase in thermodynamic activity can also be achieved by evaporation of the volatile components of a formulation. For example, a compound may be present in a formulation in a subsaturated state, but when it is applied to the skin surface, the volatile components may evaporate, resulting in a decreased solubility in the residual components on the skin surface. It is then possible that the solubility of the compound on the skin surface is reduced to the extent that a supersaturated state...

The Two Pathway Model

Until now we have essentially ignored the fact that the SC is a heterogeneous membrane composed of lipophilic domains (the intercellular lipids) and hydro-philic domains (the cellular protein). The protein and lipid domains in the SC are histologically revealed as a mosaic of cornified cells containing cross-linked keratin filaments and intercellular lipid-containing regions (19). The cellular protein is not itself a homogeneous domain, but the differences within this domain are small when...

Analysis with the LSER Model

The LSER model, Eq. (32), has been used to analyze chemicals from the FV database for which solvatochromic parameters could be found. These chemicals, identified in Table A1 with an asterisk to the left of the chemical name, represent a low MW fraction of the FV database. The solvatochromic parameters, all from Abraham et al. (28), were calculated by averaging multiple normalized solvent effects on a variety of chemical properties involving many varied types of indicators (28). Table A5...

Linear Solvation Energy Relationships Model

The theoretical foundations of linear solvation-energy relationships (LSERs) have been described elsewhere (26-28), and LSER models have been developed to interpret and predict SC permeability coefficients (29,30). Appendix C provides additional information on LSERs. Briefly, LSER models have been successful at representing free energy-dependent properties exhibited by a class of solutes in the same solvent. In this application, the parameters of the LSER model (i.e., the solvatochromic...

P

However, the VE is much more hydrophilic than the SC, and Kce will be similar to partitioning between lipophilic and hydrophilic solvents, such as octanol and water. Consequently, the VE resistance to chemicals with large log Kow could be similar to or even larger than the resistance presented by the SC (i.e., B > 1). These highly lipophilic compounds enter the relatively hydrophilic VE with difficulty, thereby causing the total permeability of the combined SC-VE...

Metabolic Approach to Transdermal Drug Delivery

Feingold University of California, San Francisco, San Francisco, California, U.S.A. University of California, San Francisco, San Francisco, California, U.S.A. National Cheng Kung University, Taiwan and Cellegy Pharmaceuticals, Inc., Foster City, California, U.S.A. Cellegy Pharmaceuticals, Inc., Foster City, California, U.S.A. Gopinathan Menon Avon Products, Inc., Suffern, New York, U.S.A.

M

If the transport number of the drug of interest is tD , it follows that the number of moles of drug transported is If the transport number is known, the intensity required to deliver a given dose in a fixed time T can be estimated. With this calculated intensity, the area of skin to be contacted by the driving electrode formulation can be deduced, remembering that the upper limit of current density is around 0.5 mA cm2 (26). Above this value, discomfort and pain are typically felt. It is...

Final Considerations and Recommendations

There are an ample number of Kcw measurements in the literature to make reasonable estimates for moderately lipophilic compounds. However, more measurements are needed at large and small values of Kow (i.e., log Kow > 4 and log Kow < 0, respectively). The usual procedure in partition coefficient experiments is to measure the mass of absorbed chemical in the SC (Mc). The concentration of chemical in the SC (i.e., the mass of chemical in the SC over the volume of hydrated SC) is then...

Mechanisms of Molecular Transport

During and after the physical disruption of the lipid bilayers of the stratum cor-neum, molecular transport occurs by electrophoresis, electroosmosis and or diffusion. The main driving force for transport of charged compounds during high-voltage pulses is electrophoresis (Prausnitz et al., 1993a Vanbever et al., 1994, 1996b). Evidence is the drop in transdermal transport with the wrong polarity of the electrodes in the donor solution (Prausnitz et al., 1993a Vanbever et al., 1994, 1996b Regnier...

New Aqueous Pathways

Models involving transient creation of aqueous pathways across lipid bilayers have been used to explain the dramatic and often-reversible changes in membrane properties of cells and nonliving systems (e.g., liposomes, red blood cell ghosts) associated with high-voltage pulse application, hence the term electroporation (Chang et al., 1992 Weaver, 1995 Weaver and Chizmadzhev, 1996a, b). Although electropores are plausible, there is no direct evidence for their existence. It is unlikely that...

Selection of

There are three different approaches for relating permeability coefficients for ionogenic compounds with log Kow. If only nonionized species penetrate, the best approach is to use both Pcw and Kow for the nonionized species. The next best approach is to disregard ionization effects and use the observed (for all ionized and nonionized species) permeability coefficient Pcw,obs and the observed (for all ionized and nonionized species) Kow,obs measured at the same conditions (i.e., the same pH,...

C01 001 C1 1

Figure 4 The threshold intensity for the development of transient cavitation in aqueous media, as a function of frequency. (A) represents an aerated medium and (D) represents degassed medium. (From Williams, 1983.) There is now evidence that cavitation can develop in human epidermis (Wu et al., 1998). Following sonication with c.w. 0.168 MHz ultrasound at 1.2 W cm-2, human epidermis samples were immersed in saline solutions containing a fluorescent lipid probe. Epifluorescence imaging of the...

Mw

In summary, Eqs. (16) and (19) adjust MW using LD alone (i.e., temperature in these equations only adjusts the LD value), while Eqs. (17) and (20) also adjust for temperature of the permeability coefficient measurement. Eqs. (16) through (20) require values for KT, which are not always known. If Kt(Tref - T) is small, then the following simple linear equation accurately represents the exponential expression in these equations exp -Kt (Tref - T ) 1 - Kt (Tm - T ) 1 - KT With this simplification,...

Ifw

Figure 5 Correlation of lidocaine absorption, from 4 to 6 hours after lipid synthesis inhibitors were applied to acetone-treated hairless mice for 4 hours, with the changes in TEWL (r 0.698). (Reproduced from Ref. 44, with permission.) Figure 5 Correlation of lidocaine absorption, from 4 to 6 hours after lipid synthesis inhibitors were applied to acetone-treated hairless mice for 4 hours, with the changes in TEWL (r 0.698). (Reproduced from Ref. 44, with permission.) Figure 6 Correlation of...

Regulatory Considerations for New Drug Applications NDA as TDS

TDS are regarded as new drugs and require scientific data to substantiate clinical safety and efficacy. Studies for the approval of NDA should be customized based on the critical nature of the drug, availability of marketed systemic dosage forms of the same active drug substance, medical and biopharmaceutical rationale, and literature data on a drug entity. If the drug substance is marketed in another form, than a comparative bio-availability employing known routes of administration and TDS...

Glossary

A Surface area of chemical exposure a Intercept of equations in the form of Eq. (4) a, b, c, d Parameters determined by regression of model equation to experimental data b Regression coefficient multiplying log Kow in equations with the form of Eq. Cc Concentration of absorbing chemical in the SC in units of mass of chemical Cceq Concentration of absorbing chemical in the SC in equilibrium with an aqueous solution reported in units of mass of chemical per unit volume of hydrated SC C'-eq...

Extracellular Processing

During the final stages of epidermal differentiation, a sequence of membrane transitions occurs within the SC extracellular domains (Fig. 1). Extrusion of LB contents at the SG-SC interface is followed sequentially by unfurling, elongation, and processing of secreted contents into mature lamellar membrane unit structures (2,29). Since occlusion inhibits each of these steps, the entire LB secretory response therefore is linked to barrier homeostasis. The lamellar basic unit bilayer pattern...

Sg

SGDB is the average SG of the compounds in the database used to derive the conventional model equation. Strictly, SG and SGDB should be at a uniform set of conditions (e.g., for liquid state at the same convenient T such as 25 C). However, given that conventional model estimates have errors of at least 1 order of magnitude, a reasonable estimate for SGDB may be sufficient. SGdb 0.9 for the data set used to derive Eq. T6. This is probably typical for many of the...

Heating and Cooling

Saturated solubilities generally increase with increasing temperature (Fig. 2), and consequently when a fixed concentration of a solid dispersion is heated, the dispersant completely dissolves in the solvent. When the solution is cooled to a temperature below that of the saturated solubility, the solution may crystallize, or a stable supersaturated system may result. An indomethacin gel (Henmi et al., 1994) was prepared by heating a mixture of the drug with hydrogenated soybean phospholipid and...

Potential Therapeutic Applications A Transdermal Drug Delivery

All the literature data demonstrate that electroporation is an efficient method of enhancing the transdermal delivery of drugs, including macromolecules. (a) electroporation enhances transdermal transport in vitro by 1 to 4 orders of magnitude (Table 1) with a very short lag time (seconds to minutes depending on the experimental model) (b) electroporation quickly increases the plasma levels of drugs in vivo (c) electroporation enhances transdermal delivery of macromolecules up to at least 40...

Future Applicationsmicromechanical Systems For Drug Delivery And Diagnostics

With the advent of micromachining technology, new opportunities exist to marry drug delivery and diagnostics, with electronic monitoring and reporting (see Ref. 60 for review). A first step toward this goal has come from the work of Santini et al. (61) who developed a micromachined chip capable of controlled drug delivery. The device comprises multiple microreservoirs, each covered by a gold foil that is electrically connected to a microelectronically controlled power source. Timed application...

Bronaugh and Congdon 1984

This paper reports Kcw,rep values (based on dry SC volume) for o-phenylenedi-amine, 2-nitro-p-phenylenediamine, and 4-amino-2-nitrophenol in Table I. According to the authors, values were measured on the basis of SC mass and then multiplied by 1.32 g of dry SC per mL of dry SC. These Kcwiep values were adjusted to the hydrated SC volume basis by multiplying Kcw,rep by 0.19 ( 0.25 g of dry SC per mL of hydrated SC divided by 1.32 g of dry SC per mL of dry SC). Unlike the permeability coefficient...

Contributors

Bunge Chemical Engineering Department, Colorado School of Mines, Golden, Colorado, U.S.A. Adrian Davis GlaxoSmithKline Consumer Healthcare, Weybridge, England M. Bego a Delgado-Charro Centre Interuniversitaire de Recherche et d'Enseignement, Universities of Geneva and Lyon, Archamps, France, and School of Pharmacy, University of Geneva, Geneva, Switzerland James A. Down BD Technologies, Research Triangle Park, North Carolina, U.S.A. Peter M. Elias Departments of Dermatology and...

Toxicity

Major problems in developing a transdermal system are caused by irritation and sensitization. Testing for such has to be examined, therefore, at a very early stage of a development programme. To date there are no algorithms available that can predict skin toxicity on the basis of chemical structure. Cultured cells can be used to provide some guidance (74). Specific biochemical indicators of toxicity such as IL-1a can be measured however, the approach needs considerable validation before it can...

Ve

Fraction of the total chemical dose that is nonionized in the vehicle Statistic measuring the predictive power of the regression Octanol-water partition coefficient of the penetrating chemical Mineral oil-water partition coefficient of the penetrating chemical Molecular weight of the absorbing chemical Number of data points included in the regression Number of fitted parameters in the regression Steady-state permeability coefficient of the SC from water Steady-state permeability coefficient of...

Routes of Transport

Transdermal transport by high-voltage pulses has been shown to occur through highly localized transport regions (LTRs), distributed over human stratum cor-neum (Pliquett et al., 1996b Prausnitz et al., 1996a). These LTRs are not located Figure 4 Cumulative mannitol transported across hairless rat skin in vitro following highvoltage pulse application at time 0. Mannitol was present in the donor compartment only during pulsing (O), only after pulsing (O), or both during and after pulsing ( )....

Formulation of the Drug Reservoir

Increasing the drug concentration of the donor solution enhances drug transport proportionally (Vanbever et al., 1995 Regnier et al., 1998a). Hence the choice of drug concentration allows control of drug delivery. Increasing the co-ion concentration decreased drug transport because of competition in electrophoretic transport (Vanbever et al., 1994, 1996b). Drug transport decreased with increasing viscosity of the solution as well (Vanbever and Preat, 1995). These data point out that careful...

Skin Electrical Properties

As the stratum corneum has a much higher electrical resistance than the other parts of the skin, an electric field applied to the skin will concentrate in the stratum corneum. In contrast, the field will be much lower in the viable tissues. Skin resistance drops by orders of magnitude during high-voltage pulses and recovers either partially or fully to prepulse values. The recovery takes a few ms or up to several hours depending on pulse magnitude, length, number, rate (Pliquett et al., 1995a),...

Sato et al 1989

The Kcw,rep value (based on dry SC mass) is reported in Table 4 of this reference. The skin was plantar callus, which probably has more proteinaceous material than abdominal, thigh, or dorsal stratum corneum, and consequently may have more hydrophilic partitioning properties. Twenty-four hours were allowed for the partitioning process to equilibrate. Nicorandil was not ionized at the basic pH attained by the 0.05 (w v) solution used in these studies. The partition coefficient is listed in the...

Metabolic Basis For Enhancement Of Transdermal Drug Delivery

Several approaches and strategies to overcome the barrier have been devised to enhance transdermal drug delivery, with varying degrees of success. Briefly, these have been classified as physical (mechanical), chemical, and metabolic approaches. Combinations of these strategies can also be employed either to further increase efficacy (44,45) or to extend the time available for transdermal delivery. These techniques vary from straightforward approaches (e.g., occlusion, tape stripping) to highly...

Modifying Agents

The addition of substances into the donor solution can cause an altered rate of transport by skin electroporation. This has been exemplified in vitro with the presence of charged macromolecular compounds or reducing agents in the donor solution (Weaver et al., 1997 Vanbever et al., 1997 Zewert et al., 1999 Ilic et al., 1999). Heparin, a linear, highly charged macromolecule, significantly altered the transport of two fluorescent dyes during pulsing, and it prolonged the lifetime of aqueous...

Preparation Of Supersaturated Solutions And Their Application To Percutaneous Absorption

A number of methods can be used to prepare supersaturated systems (Khamskii, 1969) 2. The removal of a solvent, i.e., evaporation 3. The reaction of two or more solutes to produce a new compound that is less soluble in solution than the original starting solutes 4. Addition of a substance to a solution that reduces the solubility of the solute, for example biphasic mixing The following review of the application of supersaturated systems to topical and transdermal delivery is divided into the...

Analysis with the Lipophilic Hydrophilic Domain Model

Some investigators have theorized that the existence of multiple domains within the stratum corneum should present regions with different polarities. In the simplest theory, the SC consists of polar and nonpolar regions. Hydrophilic chemicals should partition primarily in the polar region, while lipophilic chemicals should partition to the nonpolar regions. Partitioning between the nonpolar regions and water would be expected to increase with a measure of lipophilic character such as log Kow....

Transdermal Iontophoresis A A Basic Circuit of Iontophoresis

Iontophoresis is the application of a low electrical potential gradient across the skin so as to enhance the penetration of molecules. Its appeal resides on the direct relation that can be established, via the transport number, between the flux of any ion present in the circuit, on either side of the skin, and the current passed (1,9-12) where , t, and z are, respectively, the flux, transport number, and valence of the ion i. It follows that the sensible way of performing iontophoresis in drug...

Microstreaming

When a structure within an ultrasonic field experiences an unequal distribution of radiation pressure forces across its length, it is subjected to a force known as the acoustic torque. In a liquid or semiliquid medium, the torque can produce microscopic currents known as acoustic microstreaming. At a frequency of 0.025 MHz, the dimensions of the streaming patterns are determined by the boundary layer thickness, the size of which is estimated to be approximately 3.6 m in water. These small...

Structural Basis For The Stratum Corneum Barrier

A decrease in the concentrations of any of three critical lipid species affects the barrier integrity (19). Several excellent papers and reviews on the biophysical aspects of barrier lipids have been published (20,21), which have contributed to our current understanding of the mechanics of barrier function. One recent model of barrier lipid organization is the domain-mosaic model (22), which considers the SC lipid matrix as a two-phase system with a discontinuous lamellar-crystalline structure...

Analysis with the Conventional Model

Equation T1 in Table 1 is the regression of permeability data in the FV database to Eq. (12). This equation is based on almost twice as many measurements as are contained in the Flynn database, with roughly half again as many new compounds. Equation T1 accounts for approximately 55 of the variability in the 170 permeability measurements by variation in log Kow and MW. Equation T1 should reasonably estimate the skin permeability coefficient for a wide range of organic compounds. One test of...

Surber et al 1992

This paper examines Kcw,rep values for 22 compounds. Six of these compounds (acetamidophenol, cyanophenol, DTT, iodophenol, PCB, and pentyloxyphenol) were reported originally in Surber et al. (47), and seven others (acitretin, caffeine, diazepam, estradiol, hydrocortisone, progesterone, and testosterone) were originally reported in Surber et al. (20). Data for nine compounds (atrazine, benzo a -pyrene, chloramphenicol, cyclosporin-A, 5-fluorouracil, ibuprofen, indometh-azine, lauric acid, and...

Application Of Supersaturation To Achieve Synergistic Methods Of Drug Delivery

Pellett et al. (1998) studied the synergistic effects on the enhancement of flurbiprofen permeation across human skin using supersaturated solutions and oleic acid (OA). Oleic acid is thought to exhibit an enhancing effect by increasing the diffusivity of a drug in the stratum corneum (Mak et al., 1990), whereas supersaturated systems increase the concentration in the vehicle. Therefore increasing both these parameters would be expected to result in a multiplicative effect on flux. Such a...

Analysis with the Two Pathway Model

Several authors have argued that hydrophilic chemicals may penetrate skin by a different mechanism than more lipophilic chemicals. Specifically, based on data like those shown in Fig. 2, they have hypothesized that permeability coefficient values for hydrophilic chemicals depend less strongly on Kow than permeability coefficient values for more lipophilic chemicals. Here we statistically analyze the data in Fig. 2 to determine if a two-mechanism model is supported by the data. This analysis...

Surber et al 1990

This paper reported Kcw,rep values (based on dry SC mass) for six chemicals (4-acetamidophenol, 4-cyanophenol, 4-iodophenol, 4-pentyloxyphenol, PCB, and DDT). Since all six were essentially nonionized even at the most dilute concentra tions, measurements made at different concentrations could legitimately be combined, and Kcw,rep values were taken directly from Table 6. Six to 24 hours were allowed for equilibration. The measurement for PCB is listed in the excluded database because it was...

Tofa

Figure 4 Effects of applications of HMGCoA reductase inhibitors on lamellar body contents (A lovastatin B fluvastatin C vehicle). (A) Note that most organelle contents are empty (solid arrow). (B) Note focal abnormalities at stratum granulosum (SG)-stratum corneum (SC) interface (open arrows). (C) Replete, compact secreted contents in vehicle-treated control. B and C, ruthenium tetroxide postfixation. (A) X85,000 (B) X125,000 (C) X 105,000. Figure 4 Effects of applications of HMGCoA reductase...

Conclusions

A set of data validation criteria, based upon physicochemical influences on the SC-water partition coefficient, was used to improve predictive estimates of Kcw data. The goal was to develop the most mechanistically relevant predictive model that could be supported by the assembled data. We found that the data are consistent with simple models in terms of log Kow but do not support more complicated models such as those based on LSER parameters or two mechanisms of partitioning. Values of Kcw can...

Drug Applications

TDS are regarded as new drugs and therefore have to be approved based on clinical safety and efficacy studies. If the toxicity and safety of the drug substance are established during the approval of a different dosage form, then the study need not be repeated for the approval of the TDS dosage form. Most of the TDS Table 1 List of TDS Products in US Market

Mathematical Modeling

As explained in previous chapters, Fick's first law of diffusion describes the steady-state transport of a compound across a membrane where J is the flux, A is the area of diffusion, K is the membrane-vehicle partition coefficient, D is the diffusion coefficient, Cv is the drug concentration in the vehicle, Cr is the concentration in the receptor phase, and h is the diffusional pathlength. Cr is usually very small, and under sink conditions, (Cv - Cr) is generally approximated to Cv. The flux...

In Vitro Testing

In vitro testing of TDS is considered important in two key areas, (1) defining skin permeation kinetic studies using a diffusion cell system and cadaver skin during the drug development process, and (2) in vitro drug release kinetics, to be used for batch-to-batch release and as a compendial test. TDS are marketed in varying strengths, sizes, and shapes and contain significantly different amounts of drug for a given rate of drug delivery. TDS contain much larger amounts of drug than the amount...

Liquid Density LD Corrections and LDTemperature Corrections

According to free-volume theory Eq. (11) , the SC diffusion coefficient is influenced by the MV of the penetrating compound. As already described, MV is often replaced by MW. Since the MW of most hydrocarbons are related similarly to MV, this is a reasonable assumption for a group of hydrocarbons (i.e., o MV MW is approximately constant). However, this assumption will introduce systematic errors if the database includes chemicals composed of heavy elements such as halogens, for which o is...

Dekker

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. The first edition was published as Transdermal Drug Delivery Developmental Issues and Research Initiatives, edited by Jonathan Hadgraft and Richard H. Guy. This book is printed on acid-free paper. 270 Madison Avenue, New York, NY 10016 tel 212-696-9000 fax 212-685-4540 Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel 41-61-260-6300 fax 41-61-260-6333 The publisher...

Sato et al 1991

The Kcw,rep value (based on dry SC mass) for nicorandil into human plantar callus is shown in Fig. 3 of this reference. The digitized value of Kcw,rep from this figure is not meaningfully different from the value reported in a previous publication (59) and probably is the same measurement reported again. The authors do not indicate that this is a new measurement. Indeed, the skin source and experimental procedure are identical to those of the previous study (59). For this reason, we have...

Lamellar Body Secretion

As noted above, the unique two-compartment organization of the SC is attributable to the secretion of lamellar body (LB)-derived lipids and colocalized hydrolases at the SG-SC interface (2). Epidermal LB bodies first appear in the spinous layers as 0.2 to 0.5 micrometer ovoid structures that contain parallel arrays of lipid-enriched disks enclosed by a trilaminar membrane. In near-perfect cross sections, each lamella shows a major electron-dense band that is shared by electron-lucent material...

Increase In Molecular Transport A Range of Compounds

Application of high-voltage electric field pulses has been shown to increase transport across and or into skin for compounds ranging in size from small ions (Pli-quett et al., 1996b) to moderate-sized molecules, e.g., calcein (Prausnitz et al., 1993a) (Fig. 1) to macromolecules, e.g., LHRH, heparin, oligonucleotides, and FITC-dextran (up to 40 kDa) (Bommannan et al., 1994 Prausnitz et al., 1995 Zewert et al., 1995 Regnier et al., 1998a Lombry et al., 2000) (Table 1). Electroporation of skin can...

Permeability Coefficient Models

The steady-state permeability across the SC from an aqueous vehicle (Pcw) into an infinite sink depends on the effective diffusivity of the chemical in the SC (Dc), the SC thickness (Lc), and the equilibrium partition coefficient between the SC and the water vehicle (Kcw) as given below (12) where Kcw is defined as the concentration of chemical in the SC (mass volume of SC at absorbing conditions) divided by the equilibrium concentration in the vehicle (mass volume) (13). As defined here, Dc is...

Data Validation Criteria

SC-water partition coefficients are determined in relatively simple experiments. Most Kcw have been determined by equilibrating an accurately weighed sample of SC (often desiccated) with an aqueous solution of the absorbing compound, which is labeled with 14C or 3H. After sufficient time, the solute concentration in the aqueous solution and in the SC (frequently determined by liquid scintillation counting of radioactivity of the solubilized SC) are determined. The partition coefficient is...

Design Of Transdermal Drugs

The majority of the drugs that have been considered for transdermal delivery have been designed with another route of administration in mind. Their properties are therefore not optimum for passage across the skin. That is, the ideal characteristics for gastrointestinal absorption are not necessarily the same as those that promote skin penetration. There are, however, some guidelines that can be used to select transdermal candidates with optimum properties. As discussed above, the molecules...

Wester et al 1987

The Kcw,IBp values for sieved powdered human stratum corneum (PHSC) from plantar callus were reported in Table 2 of this reference. One of the authors confirmed that measurements were based on dry SC mass (63). Benzene and PCB (54 chlorine) were nonionized, but 4-nitroaniline, at a concentration of 4.9 g mL, was partially ionized at its natural pH. The equilibration time was only 30 min. It may be that PHSC reaches equilibrium more rapidly than SC in a membrane form, but the authors did not...

Enhancement Strategies

Mathematical modeling, whether used simply to estimate the permeability coefficient or to develop a more complex compartmental model, should indicate the feasibility of delivering enough drug through the skin. If the estimates are less than a factor of 10 to 100 of the desired value, enhancement strategies will need to be considered. There are a number of approaches that can be used, but it is very difficult to predict the exact degree of enhancement that can be achieved. There are chemicals...

Contents

Feasibility Assessment in Topical and Transdermal Delivery Mathematical Models and In Vitro Studies Jonathan Hadgraft and Richard H. Guy 2. Evaluating the Transdermal Permeability of Chemicals Brent E. Vecchia and Annette L. Bunge 3. Skin Absorption Databases and Predictive Equations Brent E. Vecchia and Annette L. Bunge 4. Partitioning of Chemicals into Skin Results and Predictions Brent E. Vecchia and Annette L. Bunge 5. Iontophoresis Applications in Drug Delivery and Noninvasive Monitoring...

Anderson et al 1976

This paper reports Kcw,rep values (based on hydrated SC mass) for various phenolic compounds in Table 3. Mean values were based on measurements in up to four SC samples. Measurements at other temperatures (12.6-34.5 C) were reported but were not incorporated into the database, since variation of temperature (over this range) appeared to have little effect on SC-water partitioning. The concentration used was low (frequently about 1 w v or 1 g 100 mL) but not reported. We assumed a concentration...

Nicotinate Esters

Hadgraft and colleagues (Benson et al., 1991) investigated the influence of 5 minutes of 1 W cm-2, 3 MHz c.w. ultrasound on the percutaneous absorption of ethyl nicotinate, methyl nicotinate, and hexyl nicotinate across human forearm skin. The group used laser Doppler velocimetry in order to quantify the nico-tinate absorption. All three nicotinate esters were found to undergo ultrasound-enhanced delivery, though for hexyl nicotinate the difference was not statistically significant. In another...

Thermal Effects

In addition to the extensive and instantaneous creation of new aqueous pathways by the electric field, local heating of the stratum corneum due to passage of current also contributes to the phenomenon of skin electroporation (Pliquett, 1999). Assuming uniform passage of current through the entire skin surface area, temperature rise during a pulse was estimated insignificant (Prausnitz, 1996). However, during electroporation, the permeability of the stratum corneum becomes spatially...

Visual Evaluation

Visual evaluation of skin after high-voltage pulse exposure has been carried out in in vivo related studies, i.e., transdermal drug delivery, electrochemotherapy, and gene therapy (Prausnitz et al., 1993b Vanbever et al., 1998b Okino et al., 1992 Titomirov et al., 1991). These studies generally reported mild, transient erythema and or edema over the area of electrical contact with the skin. No burn Table 3 Summary of the Effects of Electroporation on the Skin Table 3 Summary of the Effects of...

Local Delivery Photodynamic Therapy Psoriasis Local Anesthesia and Anti Inflammatory Effect

One of the first suggested applications of iontophoresis was the treatment of herpes labialis and keratitis in surface tissues (82,83) in fact, iontophoresis of idox-uridine has been shown to be effective against herpes simplex viral lesions on the lip. More recently, iontophoresis has also effectively increased acyclovir skin permeation in vitro (67,84). The distribution of this antiviral agent after iontophoresis in human skin in vitro is more homogeneous than that obtained after passive...

In Vivo Noninvasive Investigation of the Skin

The alterations of skin functions following the application of high-voltage pulses have been evaluated directly in vivo in hairless rat using noninvasive bioengineering methods (Vanbever et al., 1998b) (Fig. 7). In agreement with the visual evaluation, mild but transient erythema was measured by laser Doppler flowmetry and Figure 7 (A) Laser Doppler flowmetry measurement of skin blood flow. (B) Transepi-dermal water loss (TEWL) following electroporation (15 pulses of 100 V, voltage applied at...

Antimigraine Antiemetic and Anti Parkinson Drugs

The gastrointestinal absorption of the antimigraine drug alnitidan can be difficult during an acute attack due to nausea, vomiting, and gastric stasis (22). The in vitro (through hairless rats) and in vivo (in humans) iontophoretic administration of this drug has been studied (22). The in vitro data established the time, pH, and current dependencies of alnitidan transport. In vivo, the plasma levels obtained after 30 minutes of iontophoresis were equivalent to those observed after a...

Data Regression Analysis

Table 1 summarizes the results of linear regressions of the permeability coefficient data to the various model equations developed above. These regressions were performed by standard procedures using JMP (39). Uncertainties in the coefficients of the input parameters, given as the standard errors of the coefficients, are listed in parentheses. Table 1 also lists regression statistics r2, r , RMSE, and the f-ratio. The ri dj statistic is analogous to r2 but allows for more relevant comparisons...

Pw Permeability

The value of p' is not known precisely, although several investigations provide information for making a reasonable estimate. The most decisive measurements come from the study by Raykar and colleagues (3), who measured the water uptake of dry SC over a period of 48 to 72 hours. Raykar and colleagues found that an average of 2.91 g of water was absorbed per g of dry SC over a period of 48 to 72 hours when the temperature was maintained at 37 C. This result is based on 73 measurements of water...

Mechanisms Of Iontophoretic Transport A Electromigration

The electromigration (electrorepulsion) contribution to iontophoretic transport is a direct result of current application. Electron fluxes are transformed into ionic fluxes via the electrode reactions. Ionic transport proceeds through the skin so as to maintain electroneutrality (1,9,10). Faraday's law applies to steady-state transport and relates the number of ions crossing the membrane to the electric current, the time of current passage, and the charge per ion (1,9) where Ml is the number of...

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,...

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

Coefficient Permeability

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

Skin Drug Transport

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...

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...