Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

Repeated applications of a transdermal patch: analytical solution and optimal control of the delivery rate

The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.     

Effects of epidermal turnover on the dynamics of percutaneous drug absorption

A method was proposed to evaluate the effect of desquamation on the time to reach steady-state drug delivery rate and concentration in the skin layers. Evaluation of the effective time constant, in terms of key physicochemical properties of the system, does not require solving the fundamental equations. Laplace transforms and the residue theorem were applied to monitor the evolution of the medicament in the skin layers and subsequent uptake into the systemic circulation. The equilibrium flux and the effective time constant declined with increasing stratum corneum turnover velocity and were not affected by the speed at which cells in the viable epidermis moved toward the surface of the skin. Ninety eight percent of the equilibrium penetration rate was reached after four time constants. This dynamic metric helped measure the extent to which high lipophilicity or molecular weight delayed percutaneous drug absorption.     

In vitro indentation to determine the mechanical properties of epidermis

The lack of understanding of the mechanical behavior of the human skin layers makes the development of drug delivery using microneedles or microjets a challenging task. In particular, the key mechanical properties of the epidermis composed of stratum corneum and viable epidermis should be better understood. Micro-indentation experiments were applied, using a spherical tip with a large diameter to the sample thickness ratio. The Young's moduli were derived via an analytical and a numerical method. The tests showed that the analytical method was not appropriate to assess the Young's moduli. That is why a numerical model was used to obtain the correct stiffness. When loaded perpendicularly, the stiffness of both the epidermis and stratum corneum vary between 1 and 2MPa. No significant differences in stiffness between the stratum corneum and viable epidermis were observed.     

Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum

We have previously presented evidence that two human kallikrein-related peptidases, KLK5 (hK5, stratum corneum tryptic enzyme, SCTE) and KLK7 (hK7, stratum corneum chymotryptic enzyme, SCCE), which are abundant in the stratum corneum, may be involved in desquamation. Since we had noted that not all trypsin-like activity in the plantar stratum corneum could be ascribed to KLK5, we set out to identify other skin proteases with similar primary substrate specificity. Here we describe purification of a protease identified as KLK14 from plantar stratum corneum, and show that this enzyme may be responsible for as much as 50% of the total trypsin-like activity in this tissue, measured as activity towards a chromogenic substrate cleaved by a wide variety of enzymes with trypsin-like specificity. This was in spite of very low levels of KLK14 protein compared to KLK5 and KLK7. KLK14 could be detected by immunoblotting in normal superficial stratum corneum of all individuals examined. The majority of KLK14 in the plantar stratum corneum is present in its catalytically active form. KLK14 could be immunohistochemically detected in sweat ducts, preferentially in the intraepidermal parts (the acrosyringium), and in sweat glands. The role played by this very efficient protease under normal and disease conditions in the skin remains to be elucidated.     

The effects of layer properties on shear disturbance propagation in skin

The effects of the stratum corneum and dermis on shear wave propagation along the skin surface was investigated using a mathematical model. The skin was modeled as two distinct viscoelastic layers, one representing the stratum corneum and the other representing the dermis. The layers were supported by a semi-infinite visco-elastic half-space representing the subcutaneous fat. Physical and mechanical properties of the materials in the model were determined from the literature and from our own experimental measurements. Although the stratum corneum is very thin (12-15 microns), results showed that it could have a strong effect on the wave propagation due to its high stiffness relative to the dermis. Results of the analysis are discussed with respect to an experimental procedure used to determine age-related changes in mechanical properties of skin.     

Determination of molecular conformation and permeation in skin via IR spectroscopy, microscopy, and imaging

Skin tissue, in addition to its specific use in dermal research, provides an excellent model for developing the techniques of vibrational microscopy and imaging for biomedical applications. In addition to permitting characterization of various regions of skin, the relative paucity of major biological constituents in the stratum corneum (the outermost layer of skin), permits us to image, with microscopic resolution, conformational alterations and concentration variations in both the lipid and protein components. Thus we are able to monitor the effects of exogenous materials such as models for drug delivery agents (liposomes) and permeation enhancers (DMSO) on stratum corneum lipid organization and protein structure. In addition, we are able to monitor protein conformational changes in single corneocytes. The current article demonstrates these procedures, ranging from direct univariate measures of lipid chain conformational disorder, to factor analysis which permits us to image conformational differences between liposomes that have permeated through the stratum corneum from those which have remained on the surface in a reservoir outside the skin.     

Determination of molecular conformation and permeation in skin via IR spectroscopy, microscopy, and imaging

Skin tissue, in addition to its specific use in dermal research, provides an excellent model for developing the techniques of vibrational microscopy and imaging for biomedical applications. In addition to permitting characterization of various regions of skin, the relative paucity of major biological constituents in the stratum corneum (the outermost layer of skin), permits us to image, with microscopic resolution, conformational alterations and concentration variations in both the lipid and protein components. Thus we are able to monitor the effects of exogenous materials such as models for drug delivery agents (liposomes) and permeation enhancers (DMSO) on stratum corneum lipid organization and protein structure. In addition, we are able to monitor protein conformational changes in single corneocytes. The current article demonstrates these procedures, ranging from direct univariate measures of lipid chain conformational disorder, to factor analysis which permits us to image conformational differences between liposomes that have permeated through the stratum corneum from those which have remained on the surface in a reservoir outside the skin.     

Using the method of homogenization to calculate the effective diffusivity of the stratum corneum with permeable corneocytes

The stratum corneum is the outermost layer of the skin, which acts as a barrier membrane against the penetration of molecules into and out of the body. It has a biphasic structure consisting of keratinized cells (corneocytes) that are embedded in a lipid matrix. The macroscopic transport properties of the stratum corneum are functions of its microstructure and the transport properties of the corneocytes and the lipid matrix, and are of considerable interest in the context of transdermal drug delivery and quantifying exposure to toxins, as well as for determining the relation of skin disorders to disruption of the stratum corneum barrier. Due to the complexity of the tissue and the difference in length scales involved in its microstructure, a direct analysis of the mass transport properties of the stratum corneum is not feasible. In this study, we undertake an approach where the macroscopic diffusion tensor of the stratum corneum is obtained through homogenization using the method of asymptotic expansions. The biphasic structure of the stratum corneum is fully accounted for by allowing the corneocytes to be permeable and considering the partitioning between the corneocytes and the lipid phases. By systematically exploring the effect of permeable corneocytes on the macroscopic transport properties of the stratum corneum, we show that solute properties such as lipophilicity and relative permeabilities in the two phases have large effects on its transdermal diffusion behavior.     

Structure of the skin barrier and its modulation by vesicular formulations

The natural function of the skin is to protect the body from unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. Since the lipids regions in the stratum corneum form the only continuous structure, substances applied onto the skin always have to pass these regions. For this reason the organization in the lipid domains is considered to be very important for the skin barrier function. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid phase behavior is different from that of other biological membranes. In stratum corneum crystalline phases are predominantly present, but most probably a subpopulation of lipids forms a liquid phase. Both the crystalline nature and the presence of a 13 nm lamellar phase are considered to be crucial for the skin barrier function. Since it is impossible to selectively extract individual lipid classes from the stratum corneum, the lipid organization has been studied in vitro using isolated lipid mixtures. These studies revealed that mixtures prepared with isolated stratum corneum lipids mimic to a high extent stratum corneum lipid phase behavior. This indicates that proteins do not play an important role in the stratum corneum lipid phase behavior. Furthermore, it was noticed that mixtures prepared only with ceramides and cholesterol already form the 13 nm lamellar phase. In the presence of free fatty acids the lattice density of the structure increases. In stratum corneum the ceramide fraction consists of various ceramide subclasses and the formation of the 13 nm lamellar phase is also affected by the ceramide composition. Particularly the presence of ceramide 1 is crucial. Based on these findings a molecular model has recently been proposed for the organization of the 13 nm lamellar phase, referred to as "the sandwich model", in which crystalline and liquid domains coexist. The major problem for topical drug delivery is the low diffusion rate of drugs across the stratum corneum. Therefore, several methods have been assessed to increase the permeation rate of drugs temporarily and locally. One of the approaches is the application of drugs in formulations containing vesicles. In order to unravel the mechanisms involved in increasing the drug transport across the skin, information on the effect of vesicles on drug permeation rate, the permeation pathway and perturbations of the skin ultrastructure is of importance. In the second part of this paper the possible interactions between vesicles and skin are described, focusing on differences between the effects of gel-state vesicles, liquid-state vesicles and elastic vesicles.     

In vitro measurement of the mechanical properties of skin by nano/microindentation methods

The elastic behaviors of stratum corneum, viable epidermis, dermis, and whole skin were investigated by nano/microindentation techniques. Insignificant differences in reduced elastic modulus of skin samples obtained from three different porcine breeds revealed breed type independent measurements. The reduced elastic modulus of stratum corneum is shown to be about three orders of magnitude higher than that of dermis. As a result, for relatively shallow and deep indentations, skin elasticity is controlled by that of stratum corneum and dermis, respectively. Skin deformation is interpreted in the context of a layered structure model consisting of a stiff and hard surface layer on a compliant and soft substrate, supported by microscopy observations and indentation measurements.     

Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.     

综述——纳米材料与药物输递：经皮给药中纳米制剂与皮肤的质构效关系

皮肤是人体最大的器官,也为药物的递送提供了重要途径。经皮给药是药物以皮肤为媒介,透过皮肤吸收的途径。因此,皮肤角质层是经皮给药的最大限速障碍。纳米经皮给药系统,具有提高透皮效率、缓释性、避免药物肝首过效应、减少副作用等优点,是通过纳米制剂与皮肤组织之间的相互作用实现的。其中,纳米制剂的结构和组分与其发挥皮肤促渗效用密切相关。对纳米制剂与皮肤质构效关系深入透彻的了解,有助于新型透皮纳米制剂的设计,并利用综合手段构建安全、高效、实用的经皮给药系统。     

Recovery of Skin Barrier After Stratum Corneum Removal by Microdermabrasion

Microdermabrasion is widely used as a non-invasive cosmetic technique that has recently been adapted to selectively remove stratum corneum to increase skin permeability for transdermal drug delivery. This study measured the kinetics of skin barrier recovery after stratum corneum removal using microdermabrasion in hairless guinea pigs. The skin was abraded at two sites on each animal, one of which was allowed to recover under occlusion while the other remained non-occluded. Histological measurements showed that skin barrier properties to sulforhodamine B largely recovered within 12 h, and the stratum corneum appeared largely reformed within 24 h for both occluded and non-occluded skin. Skin electrical resistance measurements showed significant recovery of the skin barrier within 24 h. We conclude that transdermal drug delivery may occur for up to 12 h after microdermabrasion in guinea pigs; however, humans will probably have a longer recovery time due to expected slower skin healing rates.     

The kinetics of transdermal ethanol exchange.

The kinetics of ethanol transport from the blood to the skin surface are incompletely understood. We present a mathematical model to predict the transient exchange of ethanol across the skin while it is being absorbed from the gut and eliminated from the body. The model simulates the behavior of a commercial device that is used to estimate the blood alcohol concentration (BAC). During the elimination phase, the stratum corneum of the skin has a higher ethanol concentration than the blood. We studied the effect of varying the maximum BAC and the absorption rate from the gut on the relationship between BAC and equivalent concentration in the gas phase above the skin. The results showed that the ethanol concentration in the gas compartment always took longer to reach its maximum, had a lower maximum, and had a slower apparent elimination rate than the BAC. These effects increased as the maximum BAC increased. Our model's predictions are consistent with experimental data from the literature. We performed a sensitivity analysis (using Latin hypercube sampling) to identify and rank the importance of parameters. The analysis showed that outputs were sensitive to solubility and diffusivity within the stratum corneum, to stratum corneum thickness, and to the volume of gas in the sampling chamber above the skin. We conclude that ethanol transport through the skin is primarily governed by the washin and washout of ethanol through the stratum corneum. The dynamics can be highly variable from subject to subject because of variability in the physical properties of the stratum corneum.     

Comparison of rat epidermal keratinocyte organotypic culture (ROC) with intact human skin: lipid composition and thermal phase behavior of the stratum corneum.

The present report is a part of our continuing efforts to explore the utility of the rat epidermal keratinocyte organotypic culture (ROC) as an alternative model to human skin in transdermal drug delivery and skin irritation studies of new chemical entities and formulations. The aim of the present study was to compare the stratum corneum lipid content of ROC with the corresponding material from human skin. The lipid composition was determined by thin-layer chromatography (TLC) and mass-spectrometry, and the thermal phase transitions of stratum corneum were studied by differential scanning calorimetry (DSC). All major lipid classes of the stratum corneum were present in ROC in a similar ratio as found in human stratum corneum. Compared to human skin, the level of non-hydroxyacid-sphingosine ceramide (NS) was increased in ROC, while alpha-hydroxyacid-phytosphingosine ceramide (AP) and non-hydroxyacid-phytosphingosine ceramides (NP) were absent. Also some alterations in fatty acid profiles of ROC ceramides were noted, e.g., esterified omega-hydroxyacid-sphingosine contained increased levels of oleic acid instead of linoleic acid. The fraction of lipids covalently bound to corneocyte proteins was distinctly lower in ROC compared to human skin, in agreement with the results from DSC. ROC underwent a lipid lamellar order to disorder transition (T2) at a slightly lower temperature (68 degrees C) than human skin (74 degrees C). These differences in stratum corneum lipid composition and the thermal phase transitions may explain the minor differences previously observed in drug permeation between ROC and human skin.     

A propagating heat wave model of skin electroporation

The main barrier to transdermal drug delivery in human skin is the stratum corneum. Pulsed electric fields (PEFs) of sufficient amplitude can create new aqueous pathways across this barrier and enhance drug delivery through the skin. Here, we describe a model of pore formation between adjacent corneocytes that predicts the following sequence of events: (1) the PEF rapidly charges the stratum corneum near the electrode until the transepidermal potential difference is large enough to drive water into a small region of the stratum corneum, creating new aqueous pathways. (2) PEFs then drive a high current density through this newly created electropore to generate Joule heating that warms the pore perimeter. (3) This temperature rise at the perimeter increases the probability of further electroporation there as the local sphingolipids reach their phase transition temperature. (4) This heat-generated wave of further electroporation propagates outward until the surface area of the pore becomes so large that the reduced current density no longer generates sufficient heat to reach the phase transition temperature of the sphingolipids. (5) Cooling and partial recovery occurs after the field pulse.This process yields large, high permeability regions in the stratum corneum at which molecules can more readily cross this skin barrier. We present a model for this process that predicts that the initial radius of the first aqueous pathway is approximately 5 nm for a transdermal voltage of 60 V at room temperature.     

The matrix representation of pharmacokinetic models.

An equation is developed from the matrix of rate constants which describes the behaviour of linear pharmacokinetic models for any initial condition as a function of time. This general matrix equation is then used to derive analogous expressions for drug distribution after a period of infusion, at the steady state, or during a multiple constant-dosage regimen. Matrix expressions are also derived for areas under drug concentration curves for any compartment after single doses or during multiple dosing. General matrix equations are shown to yield loading dosage schedules to achieve plateau concentrations throughout any open system.It is suggested that matrix methods have advantages over previously used mathematical techniques in pharmacokinetics in the simplicity of the algebraic expressions, and their ease of manipulation. An algebraic example of an open two-compartment model is worked to indicate the applicability of the general expressions.     

Local temperature rises influence in vivo electroporation pore development: a numerical stratum corneum lipid phase transition model

Electroporation is an approach used to enhance transdermal transport of large molecules in which the skin is exposed to a series of electric pulses. Electroporation temporarily destabilizes the structure of the outer skin layer, the stratum corneum, by creating microscopic pores through which agents, ordinarily unable to pass into the skin, are able to pass through this outer barrier. Long duration electroporation pulses can cause localized temperature rises, which result in thermotropic phase transitions within the lipid bilayer matrix of the stratum corneum. This paper focuses on electroporation pore development resulting from localized Joule heating. This study presents a theoretical model of electroporation, which incorporates stratum corneum lipid melting with electrical and thermal energy equations. A transient finite volume model is developed representing electroporation of in vivo human skin, in which stratum corneum lipid phase transitions are modeled as a series of melting processes. The results confirm that applied voltage to the skin results in high current densities within the less resistive regions of the stratum corneum. The model captures highly localized Joule heating within the stratum corneum and subsequent temperature rises, which propagate radially outward. Electroporation pore development resulting from the decrease in resistance associated with lipid melting is captured by the lipid phase transition model. As the effective pore radius grows, current density and subsequent Joule heating values decrease.