The experimental evaluation and molecular dynamics simulation of a heat-enhanced transdermal delivery system

Abstract

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.

Fig. 1

The various layers incorporated to produce the transdermal patch. Components are not drawn to scale

Fig. 2

The experimental setup for the Franz-type diffusion cells

Fig. 3

Structures of a ketoprofen and b poloxamer 407 (n = 101; m = 56)

Fig. 4

An excerpt of the trajectory output of the particles in the gel in 833 ps steps (for illustration) at a 833, b 1,666, c 2,499, d 3,332, e 4,165, and f 4,998 ps. Water molecules are shown as small purple dots, ketoprofen molecules are shown in white (size exaggerated to enhance visibility), and the polymer subunits are shown as long chain structures (green and blue)

Fig. 5

The temperature versus heat profile as measured from the plastic container that was filled with the reaction mixture. The inset shows the first 15 min of the reaction

Fig. 6

The effect of heat generated by the patch on the temperature and conductance of the forearm skin of volunteers (n = 3)

Fig. 7

a The release profiles of ketoprofen from the Pluronic® F127 gel in the enhancer system as a function of temperature of the dissolution medium (n = 6). b Increase in the drug flux from the gels with an increase in the temperature of the dissolution medium (n = 6)

Fig. 8

The release profiles of a ketoprofen, b diclofenac, and c lidocaine from the patch without the heating reagents (orange symbols) and the patch containing the heating element (green symbols)

Fig. 9

a The double-logarithmic plot of MSD versus t for water at 315 K. The exponent of the regression equation is nearly unity; therefore the free diffusion regime is reached. b shows the linear increase in MSD versus t for the data region selected according to the double-logarithmic plot. The slope of (b) is determined and used to calculate the diffusion coefficient (Eq. 3). c, d Similar evaluations for ketoprofen at 315 K