Galit Levin

Passive transdermal drug delivery has been used for more than 20 years, but faces certain limitations with the type of active molecules that may delivered through this route. Very few drugs can passively diffuse across the skin barrier at therapeutically useful rates. Cell ablation using a radio-frequency (RF) alternating electrical current is a well known, proven medical technology that can be applied to drug delivery to overcome this obstacle. RF ablation is a safe, low-cost technique and a familiar concept in medical practice. When properly modified, RF cell-ablation technology may also create microchannels in the skin's surface to enable transdermal delivery of drugs.   

RF ablation is a well-known medical technology to eliminate living cells. It is widely used to cut through tissues in minimally invasive operations or to destroy small tumors in the kidney and liver (1–5). RF ablation is performed by placing a conducting wire on a body area and passing an alternating electrical current at a frequency above 100 KHz (radio frequency) through the area. The ions in the cells adjacent to the electrodes vibrate as they try to follow the change in electrical current direction. These vibrations cause heat, which results in water evaporation and cell ablation. RF microchannels are created by placing a closely spaced array of tiny electrodes with very precise dimensions against the skin (see Figure 1). The alternating electrical current is transferred through each of the microelectrodes, ablates the cells underneath each electrode, and forms microscopic passages in the stratum corneum and outer dermis (6, 7). These RF microchannels penetrate only the outer layers of the skin, where there are no blood vessels or nerve endings. This action minimizes skin trauma and unpleasant sensations. The process is performed in seconds. Immediately after formation, the microchannels fill with interstitial fluid, which is responsible for the hydrophilic nature of the microchannels. As a result, microchannels serve as aquatic channels into the inner layers of the skin. They are embedded in the surrounding of the hydrophobic stratum corneum. For drug delivery, the microchannels may last up to 24 h. At 36 h, the delivery through treated skin returns to the values of intact skin. 

A major difficulty in penetrating the skin for drug delivery is that the texture and softness of the skin change from site to site and from person to person. To address these variations, a  unique microelectrode-array design was used. This microelectrode array design adapts to these differences in skin type within and between treatment sites. This design is essential to forming RF microchannels with consistent, well-controlled depths, enabling the drug to reach the capillary bed without unnecessary trauma to the inner layers of the skin (8).  

The "ViaDerm" (TransPharma Medical Ltd., Lod, Israel) system is an example of a microelectronic system based on RF cell ablation for transdermal drug delivery. The system consists of the device, which is used to pretreat the skin and form the RF microchannels in the outer layers of the skin, and a patch containing the drug, which is placed on top of the pretreated skin (see Figure 2). 

The device consists of a handheld electronic control unit and a microelectrode array. The control unit (see Figure 2a) is battery-operated, rechargeable, and reusable for at least 1000 applications. This particular device is available in three sizes (treatment area of 1, 2.5, or 5 cm

 ), depending on the desired dose of drug to be delivered (see Figure 3). 

The microelectrode array (see Figure 2b) contains hundreds of microelectrodes. The microelectrode array is disposable, low-cost and intended for one use only. The array is based on a proprietary design and made of biocompatible materials that are well-established in medical devices. Within a few seconds, the control unit and the array create an array of RF microchannels (see Figure 4), thereby preparing the treatment site for the patch containing the drug. After application of the patch (see Figure 2c) on the pretreated area, the drug passively diffuses from the patch through the RF microchannels into the inner layers of the skin and into systemic circulation (9). 

Transdermal delivery of large proteins is a novel and exciting method (10). No commercial technology currently available incorporates proteins into transdermal patches. The unique printed-patch technology for transdermal delivery of proteins complements RF cell ablation. The manufacturing method involves dispensing very small droplets of a concentrated protein solution on a transdermal liner in a predetermined pattern (see Figure 5). The liquid is dried, leaving a dry and thin layer of formulated protein on top of the liner. The highly water-soluble proteins are dissolved by the interstitial fluid that is secreted from the skin through the RF microchannels, thus forming a highly concentrated protein solution 

. The diffusion of the dissolved molecules occurs through the RF microchannels into the viable tissues of the skin across a steep concentration gradient. This process brings about a high delivery rate and a peak-blood profile of the drug resembling that of a subcutaneous injection (9). 

A dispensing–manufacturing technology widely used in the diagnostic industry was adapted to successfully manufacture the printed patches. This manufacturing method enables complete and flexible control of the drug load on the patch, control of patch size and shape, and high manufacturing yield with minimal protein losses. In addition, this method fully retains the stability and biological activity of the protein drug. Printed patches were used in studies in which human growth hormone, insulin, and teriparatide (hPTH

) were delivered in animals (guinea pigs and pigs) and humans (11). 

The skin's low permeability limits the types of drugs that can be delivered transdermally. Many drugs with a hydrophilic character permeate the intact skin too slowly to be of therapeutic benefit (10). Under RF cell ablation, pretreating the skin allows aquatic channels to form across the stratum corneum, which provides significant enhancement in the permeability of water-soluble compounds. Drugs that exhibit insufficient solubility in water can still benefit from the technology. By increasing solubility using various formulation approaches, such as  drug-cyclodextrin complexes or dissolving the drug in a water-alcohol mixture, the drugs are also able to permeate the skin. Table I shows the 

 skin permeability of various drugs in a dynamic diffusion-cell model using full-thickness porcine skin. The results show enhanced transdermal delivery with the hydrophilic compounds—granisetron hydrogen chloride (HCl) and lidocaine HCl. Lidocaine HCl is more water-soluble than diclofenac sodium and had higher delivery rates. The effect of the compound concentration on its delivery rate was shown with testosterone (2% versus 6% in aqueous solution) and lidocaine HCl (2% versus 5% in aqueous solution). The delivery rate increased linearly with the concentration of the loaded compound. 

Effect of molecular size on delivery rate

The effect of molecular size on the delivery rate of macromolecules through the treated skin was shown in a study using fluorescein isothiocyanate-labeled dextran molecules of various sizes: 10, 40 or 70 kDa. This 

 experiment tested the delivery of these macromolecules through a full-thickness porcine skin that had been pretreated with the device. An increase in molecular size brought about a decrease in delivery rate (see Figure 6). However, it is important to note that even the largest 70-kDa molecule was successfully delivered transdermally through the RF microchannels. 

Effect of patch technology on pharmacokinetic profiles

Based on the patch technology used, two types of drug profiles are feasible using the microelectronic system (ViaDerm).  When a patch based on a dry formulation is used (

, a protein-printed patch), a peak-drug profile is observed in the blood, which resembles a profile of a subcutaneous injection. Figure 7 shows the blood profile for delivering human growth hormone in pigs. The peak 

 (maximum concentration) is affected by the patch dose (see Figure 7a) or by microchannel density (see Figure 7b). Figure 7a shows that increasing the drug load on the patch resulted in a higher delivered amount. Figure 7b shows the effect of microchannel density on the efficiency of drug delivery. Increasing the microchannel density from 150 to 300 microchannels (MCs)/cm

  resulted in a much higher delivered amount without increasing the drug load on the patch. This technique also significantly increased the bioavailability of the drug. 

It is possible to achieve a sustained drug flux for 24 h by incorporating the active material into a moist matrix such as a hydrogel that serves as an infinite reservoir. The matrix holds the drug on the skin in a soluble form, which makes it available for delivery through the aqueous microchannels. The matrix releases the drug slowly at a rate suitable for delivery, enabling the drug concentration in the blood to be maintained as long as 24 h. This effect was shown in a human study of granisetron delivery. The study measured the transdermal delivery of granisetron (a charged, water-soluble molecule) during a period of 24 h. The drug was administered through  a small patch (5.6 cm

 ) using a microelectronic system based on RF cell ablation (the ViaDerm system). This delivery method was compared with other routes, including passive transdermal delivery, oral delivery (one tablet every 12 h), and intravenous (IV) delivery. The study was conducted on six healthy adult volunteers in each test group. The results (see Figure 8) revealed differences in the plasma-drug levels and profiles between the treatments. The IV and oral deliveries displayed a peak or peak-and-valley profile corresponding to the administration regimen. In contrast, the transdermal delivery through microchannels resulted in a concentration increase up to 9 h and a constant level up to 24 h, indicating that the channels enabled drug delivery for at least 24 h. The control group (marked as "ViaDerm untreated" in Figure 8) showed very low plasma levels across the entire time period, emphasizing that the skin pretreatment used to form microchannels enabled the transdermal delivery of this water-soluble molecule. 

The variability in drug levels in the blood of subjects treated with the system using RF cell ablation was similar to that measured for oral delivery. This finding confirms that RF microchannel formation is uniform and reproducible.   

Factors influencing bioavailability and delivered dose

A large delivered dose and high bioavailability are important for any drug-delivery method, particularly for costly macromolecule active materials. If the bioavailability of the protein using a specific delivery method is low (< 10–20%), there is a significant loss of protein. Alternative delivery routes for peptides and proteins result in low bioavailability compared with subcutaneous injection (12). A microelectronic system based on RF cell ablation using  printed-protein patches resulted in very high bioavailability of up to 40% relative to subcutaneous injection. Table II shows the  bioavailability of three drug molecules. The data show that a low (

, 6%) or high (up to 40%) relative bioavailability is attainable, depending on the ratio between the amounts of active material and microchannels. 

Drug delivery through microchannels using RF cell ablation may be affected by the molecular size of the molecule delivered, water solubility, concentration, microchannel density, duration of delivery, dosage forms, drug profile, type of patches, and drug accumulation.  

. No data exist regarding the limitation of the size of drug molecules that can penetrate the microchannels. The transdermal delivery of small-molecule drugs can be increased significantly by pretreatment. In addition, macromolecules such as peptides and proteins can also be delivered systemically through the skin using this technology. 

 The microchannels are filled with interstitial fluid. Water-soluble molecules, therefore, can be easily delivered through the microchannels of the inner layers of the skin and by systemic circulation. Water-insoluble drugs can be delivered transdermally using RF cell ablation by increasing the water solubility through a suitable formulation.  

 As in any passive delivery, the rate of delivery depends on the concentration gradient. Increasing the drug concentration on the skin in the vicinity of the microchannels will result in a higher delivery rate. 

 By increasing the microchannel density (MCs/cm

 ), a higher amount of drug can be delivered. This higher amount results in a more efficient delivery process or enables the delivery of a higher one-time dose. 

 The duration in which enhanced drug delivery can be observed is up to 24 h, after which the delivery rate will not be significantly higher compared with delivery using intact skin. The maximum patch application time should be 24 h.  

 A patch is the most convenient dosage form to use with the microelectrode system. A patch has a drug area size matching the size of the electrode array. Simpler dosage forms such as gels or creams, however, can also be used. Also, the delivery of the drug in semisolid-dosage forms on treated skin can be increased significantly compared with delivery on intact skin.  

. The result of the transdermal delivery using  RF cell ablation can be a peak-plasma profile or a constant blood level, depending on the type of patch technology used. 

 A reservoir patch, usually a water-based hydrogel, can be used to incorporate small or large molecules and apply them on the skin. A hydrogel patch maintains the skin in a hydrated state, and therefore enables drug delivery at a constant level for up to 24 h. For proteins, the use of a printed patch is advisable for stability purposes. The resulting blood profile is in a peak shape that resembles that of an injection. The use of printed patches also results in efficient and cost-effective delivery. 

 One of the most disturbing issues regarding passive delivery is the accumulation of drug in the stratum corneum because of the affinity between hydrophobic drugs and this lipidic tissue. A drug in the reservoir continues to be released into circulation long after the treatment stops, thereby decreasing the effectiveness of the treatment. The microelectronic system based on RF cell ablation used in this study delivered water-soluble drugs that cannot be accumulated in the lipidic stratum corneum. No issue of reservoir formation exists.  

Other transdermal drug delivery technologies 

Drug delivery using a microelectronic system based on RF  cell ablation offers a convenient, painless, and less invasive alternative to injection, a common method for administering large proteins and peptides. This system also allows for less costly manufacturing that may not require sterility or expensive processes such as lyophilization. In instances where multiple daily administrations are needed, the one-a-day application based on RF cell ablation avoids the need for multiple injections or continuous infusion.  

Although injection is the primary delivery method for large-molecule drugs, small molecules may also be delivered orally or through passive transdermal methods. Oral drug delivery methods suffer from low gastrointestinal (GI) absorption and high first-pass effect, which may lead to low oral bioavailability and potential adverse GI effects. A transdermal alternative overcomes these limitations and offers the benefit of immediate cessation of drug administration in case of an adverse effect or overdose. Transdermal delivery also enables verification if a drug were taken or not, thereby improving compliance and monitoring in dependent populations such as dementia patients. 

Although passive transdermal delivery methods provide these benefits, they do not allow for the delivery of water-soluble drugs, a capability inherent in RF cell ablation. As earlier discussed, passive transdermal delivery often leads to the formation of a drug reservoir in the stratum corneum because of  the affinity of the lipophilic active drug to the stratum corneum. The buildup of this reservoir results in a long lag time before therapeutic concentrations in circulation are reached, a problematic titration process, as well as a long elimination process in treatment termination. RF cell ablation overcomes this problem because of the hydrophilic nature of the drugs it is able to deliver. 

 Iontophoresis is another transdermal delivery option. This approach uses an electrical repulsion of a relatively low voltage to drive molecules through the intact skin. Iontophoresis is successful only with drug molecules of up to 1000 Da. Because delivery through the intact skin requires formulations of certain pH levels, the target drug needs to be ionized for successful delivery. Iontophoresis can only be applied for short periods of time because of possible skin irritation caused by the electrical current. Only drugs with short-delivery duration, therefore, can be used with this technology. Delivery by RF cell ablation is not limited by these factors. There is no molecular size limitation, no molecular electrical charge requirement, and no specific formulation pH constraint.  

 Microneedles represent another transdermal delivery option. Microneedles create a matrix of holes in the skin using an array of ultra-sharp microscopic needles; however, they too suffer from significant limitations. The amount of drug that can be coated on microneedles is limited, so only very potent drugs are suitable for this technology. In addition, a complex formulation is needed to enable the drug to be efficiently coated onto the microneedles. Delivery through microneedles results in a sharp peak profile, compared with the more extended release the delivery system based on RF-cell ablation.   

Articles

A microelectronic system based on radio-frequency (RF) cell ablation addresses limitations of other transdermal drug-delivery methods. This system expands the transdermal spectrum to include the delivery of water-soluble molecules, peptides, proteins, and other macromolecules.