An Explanation for the Variation of the Sonophoretic Transdermal Transport Enhancement from Drug to Drug

NOTES

An Explanation for the Variation of the Sonophoretic Transdermal Transport Enhancement from Drug to Drug SAMIR MITRAGOTRI, DANIEL BLANKSCHTEINX,

AND

ROBERT LANGERX

Received December 31, 1996, from the Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. Final revised manuscript received May 15, 1997. Accepted for publication May 28, 1997X. Abstract 0 Over the last few decades, application of therapeutic ultrasound (frequency between 1 and 3 MHz and intensity between 1 and 2 W/cm2) has been attempted to enhance transdermal transport of several drugs, a method referred to as sonophoresis. The sonophoretic enhancement of transdermal drug transport was found to vary significantly from drug to drug. In certain cases, ultrasound did not induce any enhancement of transdermal drug transport. This variation in the efficacy of sonophoresis has raised a controversy regarding its applicability as a transdermal delivery enhancer. The objective of this paper is to provide a summary of the literature data on sonophoresis and an explanation for the observed variation of the sonophoretic enhancement from drug to drug. This paper also presents an equation to qualitatively predict whether therapeutic ultrasound may enhance transdermal transport of a given drug based on knowledge of the drug passive skin permeability and octanol−water partition coefficient. The systemic as well as topical delivery of drugs via the transdermal route is limited by the low skin permeability which is attributed to the stratum corneum (SC), the outermost layer of the skin.1 Application of ultrasound has been attempted to enhance transport of drugs across the SC, a method referred to as sonophoresis.2 Although a variety of ultrasound conditions have been used for sonophoresis,2-45,49,51 the most commonly used ultrasound condition corresponds to therapeutic ultrasound (frequency in the range of 1-3 MHz and intensity in the range of 1-2 W/cm2). Over the last few decades, attempts have been made to enhance transdermal delivery of more than 15 drugs by application of therapeutic ultrasound. However, a measurable sonophoretic enhancement has been reported only in certain cases.2,3,9,11-16,20-26,28,32-35,37-39,44,45 For example, ultrasound was found to enhance transdermal delivery of hydrocortisone2,3,9,11-16,20,21,23,24,26,28,32,34,35,37-39,44 and indomethacin32 but not of lidocaine4,27,43 and salicylate.10,36 This variation in the efficacy of sonophoresis from drug to drug has raised a controversy regarding its applicability as a transdermal delivery enhancer.36 In this paper, we provide a summary of the literature data on sonophoresis performed under therapeutic conditions, as well as an explanation for the observed variation of the enhancement from drug to drug. We also present an equation to quantitatively predict the sonophoretic enhancement of transdermal drug transport based on knowledge of two physicochemical properties of the drug: passive skin permeability and octanol-water partition coefficient. We have previously shown2 that the mechanism of sonophoresis under therapeutic conditions is based on ultrasoundX

Abstract published in Advance ACS Abstracts, August 1, 1997.

1190 / Journal of Pharmaceutical Sciences Vol. 86, No. 10, October 1997

induced cavitation in the stratum corneum. Specifically, cavitation disorders the SC lipid bilayers, thereby enhancing the diffusion of drugs in the SC. Based on this mechanism, we have shown that the relative sonophoretic transdermal transport enhancement, e ([sonophoretic permeability/passive permeability] - 1) can be predicted using the following equation52:

e∼

Ko/w0.75 (4 × 104)Pp

(1)

where Ko/w is the drug octanol-water partition coefficient and Pp is the passive skin permeability of the drug in the units of cm/h. Note that the units on both sides of eq 1 are balanced through appropriate conversion factors. For details, see ref 2. Pp and Ko/w values for various drugs can be found in refs 47 and 48, respectively. Equation 1, therefore, relates the sonophoretic enhancement of transdermal drug transport, e, to two fundamental physicochemical properties of the drug, the passive skin permeability, Pp, and the octanol-water partition coefficient, Ko/w, which are readily available in the literature. Table 1 provides a compilation of literature data on sonophoresis. The table lists various drugs and the corresponding experimental conditions that have been used in the past for sonophoresis. Note that two types of literature data are reported in Table 1. The first type of data comprises the first eight drugs listed in Table 1 for which the sonophoretic enhancements were reported in terms of the drug pharmacological activity in in vivo or clinical experiments (for example, induction of anesthesia in the case of lidocaine). Since an enhancement in the pharmacological activity cannot be easily related to the enhancement in permeability, this type of data offers only qualitative information regarding the drug permeability enhancements. In addition, some of these data were obtained using different animal models and hence cannot be quantitatively compared with the predictions of eq 1, which were derived for human skin. The second type of data comprises the last five drugs listed in Table 1, including estradiol, corticosterone, progesterone, testosterone, and caffeine, for which quantitative measurements of drug permeability enhancements across human skin in vitro are reported.2 Both types of data are compared to the predictions of eq 1 in Figure 1. Figure 1 shows the e values predicted using eq 1 for various drugs. Empty circles correspond to drugs for which no enhancement of transdermal delivery has been observed during sonophoresis, while filled circles correspond to drugs for which an experimentally observed enhancement has been reported (see also Table 1).2,3,9,11-16,20-26,28,32-35,37-39,44,45 Note

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Table 1sCompilation of Literature Data on Sonophoresisa No.

Drug

1 2 3

Dexomethasone Fluocinolone Acetonide Hydrocortisone

4 5

Indomethacin Lidocaine

6 7 8

Phenylbutazone Physostigime Salicylate

9 10 11 12 13

Caffeine Corticosterone Estradiol Progesterone Testosterone

Experimental System

Passive Permeability Pp (cm/h)

Partition Coefficient Ko/w

Swine skin in vivo9 Human skin in vivo28 Dog skin in vivo11 Human skin in vivo20 Human skin in vivo37 Human skin in vivo13 Swine skin in vivo15 Pig skin in vivo12 Rat skin in vivo32 Human skin in vivo4 Human skin in vivo43 Human skin in vivo49 Hairless rat skin in vivo26 Human skin in vivo10 Human skin in vivo38 Human skin in vitro2 Human skin in vitro2 Human skin in vitro2 Human skin in vitro2 Human skin in vitro2

6.4 × 10-5 51 1.5 × 10-4 47

9748 30048

12 12

1.3 × 10-4 47

4048

3

1 × 10-3 a 4 × 10-3 b

120048 20048

5 0.3

3.8 × 10-3 a 4.4 × 10-4 a 1 × 10-4 31

158048 3848 0.148

2 1 0.04

1.0 × 10-4 2 3.0 × 10-4 2 3.2 × 10-3 2 1.3 × 10-2 2 2.2 × 10-3 2

148 872 70002 60002 20702

0.2 2 6 1 4

Experimentally Meausred e Value

Theoretically Predicted e Value

Significant enhancement Significant enhancement Significant enhancement Significant enhancement Significant enhancement Significant enhancement Significant enhancement Significant enhancement Significant enhancement No significant enhancement No significant enhancement Significant enhancement Significant enhancement No significant effect No significant effect 0 3 ± 0.6 12 ± 1.5 0.1 ± 0.5 4 ± 1.1

a The table lists various drugs that have been used for sonophoresis, some of their physicochemical properties (Pp and K ), the experimental conditions used for o/w sonophoresis, e values for these drugs predicted using eq 1, and experimentally observed e values which are listed as significant or no significant enhancement, based on whether a statistically significant enhancement in the corresponding pharmacological activity is reported. In cases where quantitative information on drug permeability enhancement is available, e is reported as mean ± SD. Note that eq 1 is applicable for transdermal transport of uncharged species. Charged molecules may diffuse through nonbilayer pathways and their transport may not be described by eq 1. b Predicted based upon the molecular weight, Ko/w and the equations described in ref 50 since no experimentally measured values of P are available. c Unpublished data of the authors (experimentally measured values).

ment of transdermal drug delivery by application of therapeutic ultrasound.

Acknowledgments We thank Stanley Liauw for his assistance in compiling the literature data on sonophoresis. This work was supported by the National Institute of Health (NIH grant GM44884).

Figure 1sThe figure shows e values predicted using eq 1 for various drugs that have been used in the past for sonophoresis. Drugs indicated by empty circles correspond to those for which no enhancement of transdermal delivery has been observed during sonophoresis. Drugs indicated by filled circles correspond to those for which an experimentally observed enhancement has been reported (see also Table 1).

that drugs having a predicted e value smaller than 1 exhibit no experimental sonophoretic enhancement, while all those having a predicted e value equal to or greater than 1 do exhibit experimental sonophoretic enhancement. Of particular interest are four drugs that have been commonly used for sonophoresis, that is, hydrocortisone, indomethacin, lidocaine, and salicylic acid. Equation 1 predicts that application of ultrasound should enhance transdermal delivery of hydrocortisone and indomethacin (e > 1) but not of lidocaine and salicylic acid (e < 1), a prediction that is in agreement with observations by various investigators.2-4,9-16,20,21,23,24,26,28,32,34-39,42-44 Fundamentally, this suggests that the passive diffusion of hydrocortisone and indomethacin through the SC bilayers is very low and is significantly enhanced by ultrasound-induced bilayer disordering. On the other hand, the passive diffusion of salicylic acid and lidocaine is comparable to that through the disorganized bilayer phase and is not affected by ultrasound application. In summary, the observed variation of sonophoretic enhancement from drug to drug, which has been considered so far to reflect an inconsistency of sonophoresis, is related to the physicochemical properties of drugs and can be predicted using eq 1. This not only offers an explanation for the longlasting controversy over the efficacy of sonophoresis but also provides qualitative guidelines to predict a priori the enhance-

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