SUMMARY.— The permeability of excised human skin to dimethyl sulphoxide and the effects of this solvent on water permeability are described. The results of measurements of the electrical impedance of excised human skin both before and after chemical and heat treatments are also given. Stratum corneum is shown to undergo irreversible structural changes when heated above 65°C. or incubated in aqueous media at pH < 3 or > 9. Simultaneous measurements of water permeability and electrical impedance of skin samples subjected to treatments with dimethyl sulphoxide, detergents and surfactants show that there is a good correlation (coefficient ‐ 0·78) between the two quantities. Some organic solvents including aliphatic acids, bases, and neutral compounds are shown to produce large changes in electrical impedance, and hence, it is inferred, in water permeability. It is suggested that these changes are due to solution of skin components, loosening of the skin structure, and hence swelling and hydration of the skin. The solvent induced changes in water permeability provide an explanation for the accelerating effect of the solvents on the penetration rates of topically applied drugs.
SUMMARY.— The ability of a number of liquids to increase the permeability of human skin in vitro has been assessed in terms of their power to accelerate the percutaneous penetration of tri‐n‐propyl phosphate (TPP).
The most effective “accelerants”. 8 M‐urea and dimethylsulphoxide (DMSO), increased the permeability of full thickness skin to TPP up to 190 times, they were also amongst those compounds, which produced the greatest reduction in skin impedance and the most swelling of the stratum corneum, suggesting that part of their effectiveness may be due to an ability to lower the diffusional resistance of the stratum corneum.
The acceleratns were all able to extract soluble components from the stratum corneum; DMSO extracted lipoprotein, and chloroform‐methanol extracted phospholipids, suggesting the possibility of ultrastructural modifications consistent with an increase in permeability.
For a liquid to be a good accelerant it must also release the penetrant readily to the aquesous milieu of the viable epidermis. This process could be hindered by an excessively unfavourable partition coefficient or by the extremely low water solubility of a penetrant.
1. During the 6-h occluded cutaneous application of 35S-sulphur mustard vapour to rat, most of the dose, approximately 75%, passed through the skin and was systemically-distributed. Up to 25% of the 35S was retained in the skin, up to 30% was excreted in the urine and 5-8% was present in the blood, by the end of the application. 2. 35S initially declined rapidly in skin and then more slowly with a half-life of approximately 7.4 days. Some of the early loss was as sulphur mustard vapour from a possible depot of this compound which was larger with increase in dose. There was some apparent continuing uptake from such a depot into the systemic circulation. 3. The decline of 35S in blood was much slower than that from skin. About one-fifth of the original post-exposure level in the blood still present 6 weeks later. 4. The 35S in blood was mainly in the red cell contents as reaction products of haemoglobin with sulphur mustard. Its persistence in the systemic circulation, after an initial rapid decline due to its removal from the plasma, reflected the 65 day life span of these cells. Significant levels of 35S were found in the plasma only for a few days (t1/2 = 2.4 days). 5. Uptake and subsequent distribution of 35S in rat and human blood in vitro during gradual exposure to 35S-sulphur mustard using a novel method were similar. 35S in the red cells was associated mainly with the haemoglobin protein, but slightly greater binding with human, rather than with rat, plasma components was indicated.
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