Enhancer transdermal application

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... 

In general, increased tissue wetness promotes transdermal delivery of both hydrophilic and lipophilic permeants. However, Bucks and Maibach [3] cautioned against too wide a generalization, stating that occlusion does not necessarily increase percutaneous absorption and may not always enhance transdermal delivery of hydrophilic compounds. Further, they warned that occlusion could irritate skin with clear implications for the design and clinical application of transdermal and topical preparations. 

Transdermal iontophoresis involves the application of an electric field across the skin to facilitate (primarily) ionic transport across the membrane. Iontophoresis, it is important to point out, is differentiated from electroporation [14], another electrical approach to enhance transdermal transport, by the low fields employed. Whereas iontophoresis has achieved commercialization, there is (to our knowledge) no active development in progress of a transdermal delivery system employing electroporation. 

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]. 

Mitragotri, S. Blankschtein, D. Langer, R. Sonophoresis enhanced transdermal drug delivery by application of ultrasound. In Encyclopedia of Pharmaceutical Tech- 112. nology, 1st Ed. Swarbrick, J., Boylan, J.C., Eds. Marcel Dekker, Inc. New York, 1996 14, 103-122. 

The most commonly used technique of sonophoresis in these studies was to apply hydrocortisone in the form of an ointment on the skin and then apply ultrasound by keeping the transducer in contact with the ointment. In some cases, the transducer was moved in circular patterns to avoid a continuous exposure of a certain part of the skin to ultrasound. Although these studies were performed using different animal models, application techniques, hydrocortisone concentrations in the ointment, and exposure time, a measurable enhancement of hydrocortisone transport was reported in almost all cases. In contrast, most of the attempts to enhance transdermal transport of lidocaine and salicylates have been less successful. In the case of lidocaine, the sonophoretic enhancement was measured in terms of reduction of onset time for anesthesia or prolonging duration of anesthesia. In most cases, no significant effect of ultrasound application on either induction time or duration of anesthesia has been reported. Similarly sonophoresis of salicylates from ointments has not been found to induce any significant increase in plasma salicylate levels. ... 

Since cavitational effects in fluids vary inversely with ultrasound frequency, it is likely that cavitational effects should play an even more important role in low-frequency sonophoresis. Tachibana et al. hypothesized that application of low-frequency ultrasound results into acoustic streaming in the hair follicles and sweat ducts of the skin, thus leading to enhanced transdermal transport. Mitragotri et al. hypohesized that transdermal transport during low-frequency sonophoresis occurs across the keratinocytes rather than hair follicles. They provided the following hypothesis for the higher efficacy of low-frequency sonophoresis. 

Application of ultrasound enhances transdermal drug transport, a phenomenon referred to as sonophoresis. Proper choice of ultrasound parameters including ultrasound energy dose, frequency, intensity, pulse length, and distance of transducer from the skin is... 

The utility of scopolamine in preventing motion sickness was enhanced with the development of the transdermal system that increased patient satisfaction and decreased untoward side effects. The efficacy of transdermal scopolamine, oral meclizine, and placebo in protection against motion sickness was compared in a double-blind crossover study in 36 healthy subjects. Transdermal applications were made and tablets were taken at least 12 and 2 hours before exposure to three 90-minute periods in a ship-motion simulator. Transdermal scopolamine provided better protection than placebo or meclizine, with dryness of mouth more frequently reported in the transdermal scopolamine subjects. ... 

It may be said that recent developments in cyclodextrin (CD) applications in drug formulations are concerned with stabilization enhancement of solubility novel preparative methods of inclusion complexes enhancement of bioavailability reduction of topical or hemolytic side effects on administration absorption enhancement in transdermal application. 

They are concerned with (a) preparative methods of CD inclusion complexes (9) (b) effects of CDs on bioavailability and drug disposition (10) and (c) absorption enhancement by CD derivatives in transdermal application (11). 

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