Skin penetrating property of drugs dissolved in dimethylsulfoxide (DMSO) and other vehicles

doi:10.1016/0024-3205(64)90079-7

Life Sciences

Volume 3, Issue 12, December 1964, Pages 1389-1395

https://doi.org/10.1016/0024-3205(64)90079-7 Get rights and content

Abstract

The recent studies of Jacob $et al$ . (1, 2, 3) on dimethylsulfoxide (DMSO) indicate this solvent to be a penetrant of biological membranes, including the human skin, and a possible carrier of various chemical agents. Employing a bladder perfusion technique the above authors demonstrated that drugs such as heparin, sulfadiazine, salicylic acid, trypan blue and insulin, when dissolved in a DMSO-buffer solution, were absorbed into the circulation in much greater quantities than when buffer alone was employed as the solvent. While this method permits determination of drug penetration through a biological membrane, it requires a number of relatively laborious steps when larger numbers of drugs are to be assayed.

As a possible approach to determining whether DMSO would enhance drug absorption through a biological membrane, we employed a simple test of immersing the tails of mice and rats into solutions of drugs dissolved in DMSO. We employed primarily psychoactive drugs since it would be possible to observe grossly any change in behavior, if, in fact, such did occur. This paper deals with the results of such a study and of a comparison of the ability of different solvents to permit passage of drugs across the skin barrier.

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DMSO is routinely used as a mild oxidant during various synthetic reactions and is widely used in the study of carbanion chemistry. DMSO has been also shown to possess the unique characteristic of transporting small molecules through various barriers leading to its extensive use in various laboratory applications and clinical applications (Horita and Weber, 1964). In a laboratory setting, DMSO can be used to dissolve organic agents in water for various experimental purposes (Santos et al., 1997).
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The medical applications of DMSO originate from its anti-inflammatory, antioxidant and analgesic activities [10]. Above all, however, DMSO penetrates membranes and therefore it is often used as a carrier for pharmaceuticals into cells [11]. Triphenylphosphonium (TPPH+), on the other hand, penetrates the mitochondrial membrane due to its lipophilicity and its stable cationic charge [12].
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This work investigated the simultaneous permeation of ketoprofen and propylene glycol (PG) across pig ear skin from simple gel formulations administered under simulated in-use conditions. The aims were to quantify rates of permeation of both solvent and active, probe the effects of formulation drying and gain insight into drag/complexation interactions. Simple 3-component gels were formulated using a fixed amount of ketoprofen and hydroxypropyl cellulose thickener with decreasing content of solvent propylene glycol. Multiple finite (5 mg × 15 mg) doses were massaged over 24 h into full thickness pig ear skin in vertical Franz-type diffusion cells. The permeation of ketoprofen was inversely proportional to the content of PG, whereas the permeation of PG was directly proportional, although the amount of PG permeated was always greater than ketoprofen, even from the driest gel practically achievable. In this state, the molar ratio of PG/ketoprofen was ∼12, suggesting that this number of PG molecules constitutes the solvation cage of ketoprofen. Dragging/pulling effect extends throughout the skin and into the receptor compartment and probably the system, in an in vivo situation. Although PG may represent a worse case scenario given its well-documented skin permeation enhancement properties, it is probable that other solvents exert a similar effect on solutes across skin. A drying film will behave in different ways depending on the nature of both the thickener and solvent, where the outcomes are not readily predictable. It is important to account for the fate of all species administered from a topical formulation.
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Considerable advances in our understanding of the mechanisms by which drugs permeate the skin barrier have been made over the past 60 years. The key publications, which have influenced the field of skin permeation research are highlighted in the present review. The methodologies commonly employed for estimation of skin permeability are discussed as are the mechanisms proposed for skin permeation. The principal findings from the commonly employed in vitro and in vivo models are considered as well as the applications of enhancers and surfactants for optimization of skin delivery. As these studies presaged the emergence of transdermal drug delivery research in the 1970s, early approaches to model and predict dermal and transdermal absorption are also outlined. The published work on skin permeability in this period embodies the fundamental literature sources for consultation by scientists new to and currently engaged in transdermal drug delivery.
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Skin penetrating property of drugs dissolved in dimethylsulfoxide (DMSO) and other vehicles

Abstract

J. Invest. Dermat.

Curr. Therap. Res.

Northwest Med.