RESEARCH ARTICLES Synergistic Effects of Chemical Enhancers and Therapeutic Ultrasound on Transdermal Drug Delivery MARK E. JOHNSON,SAMIR MITRAGOTRI,ASHISH PATEL,DANIEL BLANKSCHTEIN X , AND ROBERT LANGER X Received February 13, 1996, from the Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 . Final revised manuscript received March 22, 1996. Accepted for publication April 24, 1996 X . Abstract 0 The effects of (i) a series of chemical enhancers and (ii) the combination of these enhancers and therapeutic ultrasound (1 MHz, 1.4 W/cm 2 , continuous) on transdermal drug transport are investigated. A series of chemical enhancer formulations, including (i) polyethylene glycol 200 dilaurate (PEG), (ii) isopropyl myristate (IM), (iii) glycerol trioleate (GT), (iv) ethanol/pH 7.4 phosphate buffered saline in a 1:1 ratio (50% EtOH), (v) 50% EtOH saturated with linoleic acid (LA/EtOH), and (vi) phosphate buffered saline (PBS), as a control, are evaluated using corticosterone as a model drug. LA/EtOH is the most effective of these enhancers, increasing the corticosterone flux by 900-fold compared to that from PBS. Therapeutic ultrasound (1 MHz, 1.4 W/cm 2 , continuous) increases the corticosterone permeability from all of the enhancers examined by up to 14-fold (LA/EtOH) and increases the corticosterone flux from the saturated solutions by up to 13000-fold (LA/EtOH), relative to that from PBS. Similar enhancements are obtained with LA/EtOH with and without ultrasound for four other model drugs, dexamethasone, estradiol, lidocaine, and testosterone. The permeability enhancements for all of these drugs resulting from the addition of linoleic acid to 50% EtOH increase with increasing drug molecular weight. Likewise, the permeability enhancement attained by ultrasound and LA/EtOH relative to passive EtOH exhibits a similar size dependence. A mechanistic explanation of this size dependence is provided. It is suggested that bilayer disordering agents, such as linoleic acid and ultrasound, transform the SC lipid bilayers into a fluid lipid bilayer phase or create a separate bulk oil phase. The difference in diffusivity of a given solute in SC bilayers and in either fluid bilayers or bulk oil is larger for larger solutes, thereby producing greater enhancements for larger solutes. I. Introduction The outermost layer of the skin, the stratum corneum (SC), is a remarkable transport barrier which effectively retards the diffusion of exogenous compounds into the body. In recent years, researchers have studied a variety of different methods for increasing the transport of drug molecules across the skin in order to develop effective transdermal delivery systems. These methods include the use of (i) chemical enhancers, 1 (ii) therapeutic 2,3 and low-frequency 4 ultrasound (sonophoresis), and (iii) electrical current (iontophoresis 5 and electropora- tion 6 ). Considerable attention has been devoted both to developing practical systems and to understanding the mech- anisms by which these methods work. For example, elec- troporation is believed to work in part by creating transient pores in the lipid bilayers of the SC, 6 while iontophoresis provides an electrical driving force. 5 Ultrasound has been shown to induce cavitation within the SC, which disorders the lipid bilayers, thus increasing drug transport. 3 Chemical enhancers have been found to increase transdermal drug transport via several different mechanisms, including in- creased solubility of the drug in the donor formulation, increased partitioning into the SC, fluidization of the lipid bilayers, and disruption of the intracellular proteins. 7-9 Since different chemical enhancers have been found to increase transdermal drug transport via different mecha- nisms, we hypothesized that the combination of two chemical enhancers which act in different manners might be most effective in increasing the overall drug transport. Specifically, ethanol has been found to increase the solubility of drugs up to 10000-fold 10 resulting in, for example, a 140-fold transder- mal flux increase of estradiol, 11 while unsaturated fatty acids in propylene glycol have been shown to increase the fluidity of SC lipid bilayers and increase the transdermal transport of certain drugs. 1,7,8,12,13 Unlike ethanol, propylene glycol is not a very effective permeation enhancer by itself. 7 Accord- ingly, a mixture of ethanol and the unsaturated fatty acid linoleic acid were combined (referred to as LA/EtOH) and examined in order to simultaneously exploit the solubility enhancement ability of ethanol solutions and the bilayer fluidity enhancement ability of linoleic acid. Linoleic acid was chosen as the model bilayer fluidizing enhancer over, for example, the commonly studied fatty acid oleic acid since linoleic acid has two double bonds in the alkyl chain, which may better fluidize the bilayers, 12 in contrast to oleic acid, which has only one. Single component enhancer formulations were also examined, including polyethylene glycol 200 dilau- rate (PEG), isopropyl myristate (IM), glycerol trioleate (GT), ethanol/pH 7.4 phosphate buffered saline in a 1:1 ratio (referred to as 50% EtOH), and PBS, as a control. Further- more, since chemical enhancers and ultrasound can each individually increase transdermal drug transport, we also hypothesized that the combination of chemical enhancers and ultrasound may result in a greater enhancement than that resulting from each enhancement method alone. In this paper, we examine the validity of these hypotheses. After describing the materials and methods in section II, the remainder of the paper is organized as follows. In section III.A, the effects of the chemical enhancers alone on the transdermal transport properties of a single model drug, corticosterone, are examined. The permeabilities, solubilities, and saturated fluxes of corticosterone with the various chemi- cal enhancers are evaluated. Section III.B examines the effects of therapeutic ultrasound combined with these chemi- cal enhancers on the transdermal transport of the model drug, corticosterone. Section III.C probes the generality of the key enhancement findings beyond corticosterone. Specifically, LA/ EtOH and ultrasound as well as LA/EtOH alone are examined for their abilities to increase the transdermal transport of four additional model drugs, dexamethasone, estradiol, lidocaine, X Abstract published in Advance ACS Abstracts, June 1, 1996. S0022-3549(96)00079-2 CCC: $12.00 670 / Journal of Pharmaceutical Sciences © 1996, American Chemical Society and Vol. 85, No. 7, July 1996 American Pharmaceutical Association