Transdermal synergists

The lack of significant impact of CPEs on transdermal delivery vehicles is related to the inherent nonspecific activity of CPEs in the different strata of the skin, as discussed earlier. This limitation may be overcome by utilization of mixtures of CPEs. Research has already shown that binary mixtures of CPEs provide increased permeation enhancement as well as increased safety compared to single enhancers. Such unique chemical combinations, called synergistic combinations of penetration enhancers or SCOPE formulations, offer new opportunities in transdermal drug delivery (46). 

The use of skin permeation enhancers in combination for synergistic effects has been studied in the transdermal literature (70). Such synergistic methods can be grouped in three categories (i) combination of two physical methods, e.g., ultrasound and iontophoresis (71-75) (ii) combination of a physical method with a chemical enhancer, e.g., use of ultrasound with sodium lauryl sulfate or isopropyl myristate (76-80) and (iii) combination of two chemicals, e.g., terpenes and propylene glycol (46,81-88). Numerous studies have been published on using combination of two physical methods or use of a physical method in conjunction with a chemical enhancer. Use of a physical method, by itself or in combination with another physical method, increases application cost for delivery purposes as mentioned before. In addition, there are unexplored safety and membrane recovery issues associated with these methods. A few reports have also been published on the use of a mixture of chemical enhancers for enhancing transdermal delivery. Typically, such studies use... 

Mitragotri S. Synergistic effect of enhancers for transdermal drug delivery. Pharm Res 2000 17 1354-1359. 

Jadoul and Preat [56] have also proposed a similar explanation for the lack of synergistic effects on transdermal delivery of domperidone with combined electroporation (1 pulse of 1000 V with a time constant of 4 ms) and iontophoresis (0.4 mA/cm2) despite the fact that iontophoresis was switched on within a few seconds after electroporation. Combined pulsing and iontophoresis also did not improve penetration of sodium nonivamide acetate through nude mouse skin [51], Therefore, when combing the two protocols, it should be more efficient to use a system that delivers current during or immediately after pulsing without delay. 

A recent work by Lavon et al. [74] suggests that the synergistic effect of SLS and ultrasound when applied simultaneously can also be attributed to the modification of the stratum corneum pH profile when exposed to ultrasound. The altered pH profile that results in improved SLS lipophylic solubility, together with improved SLS penetration and dispersion, can explain the synergistic enhancing effect on transdermal transport (see Figure 16.4). 

Ultrasound also exhibited a synergistic effect with electroporation [72], Ultrasound reduced the threshold voltage for electroporation as well as increased transdermal transport at a given electroporation voltage. The enhancement of transdermal transport induced by the combination of ultrasound and electroporation was higher than the sum of the enhancement induced by each enhancer alone. 

Johnson, M.E., et al. 1996. Synergistic effects of chemical enhancers and therapeutic ultrasound on transdermal drug delivery. J Pharm Sci 85 670. 

Mitragotri, S., et al. 2000. Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J Pharm Sci 89 892. 

Ultrasound may enhance transdermal transport by inducing skin alteration and active transport (forced convention) in the skin. Various other means of transport enhancement, including chemicals, iontophoresis and electroporation, may enhance transport synergis-tically with US. Thus, the evaluation of the synergistic effect of low-frequency US with chemical enhancers and surfactants for permeation of mannitol revealed that application of US or sodium lauryl sulfate (SLS) alone, both for 90 min, increased skin permeability about 8 and 3 times, respectively. However, the combined use of US and a 1% SLS solution increased the skin permeability 200 times to mannitol [129]. 

Kost, J., Pliquett, U., Mitragotri, S., Yamamoto, A., Langer, R., and Weaver, J. 1996. Synergistic effect of electric field and ultrasound on transdermal transport. Pharmaceutical Research, 13, 633-638. 

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