With enhanced skin permeability

Transdermal Drug Delivery System with Enhanced Skin Permeability... 

Rhee GJ, Woo JS, Flwang S-J, Lee YW, Lee CH. Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability. Drug Development and Industrial Pharmacy. 1999 25(6) 717-726. 

It is likely that one of the major mechanistic requirements for a good enhancer is the ability to induce some sort of motional freedom in the alkyl-chain region of lipid bilayers. Azone appears to be capable of this. These lipid-chain molecular motions may lead to the easier formation of gauche conformers and thus create a greater number of lipid free volumes. Creation of such free volumes has already been associated with greater skin permeability (Potts et al., 1991), and the positive relationship between molecular size of penetrant and rate of permeation is well established. The action of OA may occur in a similar manner but, because of its longer chain, which impedes adjacent lipid chain motion, to a lesser extent. It is likely that the large kink in the OA molecule created by its cis double bond is an important structural feature in its ability to act in this manner (stearic acid seems to condense DPPC monolayers). 

Permeation of a model solute across skin in presence of an enhancer is dependent not only on the inherent capacity of the enhancer to permeabi-lize skin but also on the physicochemical interactions of the enhancer with the model solute. An end point used to characterize the effect of an enhancer on skin permeability should be able to decouple these two effects. This assures the generality of the results. 

INSIGHT uses the fundamental correlation between the electrical and permeability properties of skin. Skin permeability shows a strong correlation with skin impedance, as shown in Figure 4B. Figure 4B shows 150 independent and simultaneous measurements of mannitol skin permeability and skin impedance for six different enhancer formulations. The relationship between skin impedance and permeability to hydrophilic solutes confirms that the former can be used as a surrogate measure for the later. Skin conductance is quick and easy to obtain and does not require additional sample handling and analysis. 

The skin permeability of drugs has been reportedly improved by treating the stratum corneum surface with an appropriate skin permeation enhancer. Representatives of potential skin permeation enhancers are listed in Chart I. 

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]. 

A variety of chemical penetration enhancers with or without protease inhibitors or colloidal vehicles (liposomes) have been investigated for their potential to enhance the skin permeability of peptides and pro-teins, but these approaches have only been limited to animal models or in vitro or in vivo models of human skin and have not progressed to human clinical studies. A notable exception is the use of so-called Transferosomes , ultraflexible liposomes, containing a mixture of soybean phosphatidylcholine and sodium... 

In a recent systematic study of the dependence of 20 kHz sonophoresis on ultrasound parameters, Mitragotri et al. showed that the enhancement of skin permeability varies linearly with ultrasound intensity and ultrasound on-time (for pulsed ultrasound, ultrasound on-time equals the product of total ultrasound application time and duty cycle), while is independent of the ultrasound duty cycle. Based on those findings, fhe authors reported that there is a threshold energy dose for ultrasound induced transdermal drug transport. Once the threshold value is crossed, the enhancement of skin permeability varies linearly with the ultrasound energy dose (J/cm ), which is calculated as the product of ultrasound intensity and ultrasound on-time. This result indicates that ultrasound energy dose can be used as a predictor of the effect of 20 kHz sonophoresis. The authors also indicated that it is important to determine the threshold energy dose for each individual sonophoresis system, for example, the real in vivo situation, because it may vary from system to system. Specifically, it may vary between different skin models, as well as with the ultrasound frequency and the distance of the transducer from the skin surface, etc. 

Another argument that counters the claim that lower concentrations are more effective is that the application technique for a TCA mask involves degreasing the skin and applying glycolic acid or tretinoin beforehand. This makes the skin far more permeable and enhances the penetration of the TCA, " which means being very careful about how long the paste remains in contact with the skin. 

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