Expert consensus of the Chinese Association for the Study of Pain on pain treatment with the transdermal patch

Chronic pain lasting more than 3 mo, or even several years can lead to disability. Treating chronic pain safely and effectively is a critical challenge faced by clinicians. Because administration of analgesics through oral, intravenous or intramuscular routes is not satisfactory, research toward percutaneous delivery has gained interest. The transdermal patch is one such percutaneous delivery system that can deliver drugs through the skin and capillaries at a certain rate to achieve a systemic or local therapeutic effect in the affected area. It has many advantages including ease of administration and hepatic first pass metabolism avoidance as well as controlling drug delivery, which reduces the dose frequency and side effects. If not required, then the patch can be removed from the skin immediately. The scopolamine patch was the first transdermal patch to be approved for the treatment of motion sickness by the Food and Drug Administration in 1979. From then on, the transdermal patch has been widely used to treat many diseases. To date, no guidelines or consensus are available on the use of analgesic drugs through transdermal delivery. The pain branch of the Chinese Medical Association, after meeting and discussing with experts and based on clinical evidence, developed a consensus for promoting and regulating standard use of transdermal patches containing analgesic drugs.     

Transdermal drug delivery using iontophoresis and phonophoresis

Introducing medicines into the human body by way of the skin is an ancient practice, and transdermal delivery has long been a standard for administering medications such as nitroglycerin and scopalamine. Phoresis, another method of transdermal drug delivery, is now being ordered for an increasing number of orthopaedic patients who suffer from inflammation, strains, or sprains. In phoretic drug delivery, enhancers such as electricity or ultrasound are used to stimulate drug absorption in the treatment area. To guide their patients to explore a variety of treatment options, orthopaedic nurses need a greater understanding of these phoretic modalities.     

Ultrasound-mediated transdermal transport of insulin in vitro through human skin using novel transducer designs

Recent studies have shown that ultrasound (US)-mediated transdermal drug delivery offers a promising potential for noninvasive drug administration. The purpose of this study was to improve low-frequency (20 kHz) US methods for enhancing the transport of insulin in vitro across human skin. The feasibility of using US produced by small, lightweight novel transducers was explored for enhancing the transport of insulin across skin. Previous investigators have used US devices such as large, heavy sonicators or commercially obtained transducers for this type of research. The experiments carried out in this study used two low-profile novel US transducer arrays, the stack and standard array, for improved transport of insulin. The stack array generated a spatial peak temporal peak intensity (I(SPTP)) of 15.4 +/- 0.6 mW/cm(2) and the standard array had an I(SPTP) of 173.7 +/- 1.2 mW/cm(2). Spectrophotometeric absorption techniques were used for determining insulin transport in vitro across human skin. Compared with passive transmission (4.1 +/- 0.5 U) over an exposure period of 1 h, the standard array facilitated over a sevenfold increase in the noninvasive transdermal transport of Humulin R insulin (45.9 +/- 12.9 U). Using Humalog insulin with the standard array, there was a fourfold increase in the US-facilitated transmission over that in the control. These promising results indicate that low-frequency US can be used in a practical device for enhanced transport across the stratum corneum.     

Painless electroporation with a new needle-free microelectrode array to enhance transdermal drug delivery

A microelectrode array was designed to minimize the pain sensation of electroporation for enhancing transdermal drug delivery. The influence of the size of the electrode–skin contact area and of the distance between electrodes on the pain sensation was tested on human volunteers. The pain level decreased with the dimension of electrode–skin contact area and with inter-electrode distance. When both reached about 0.5 mm, the pain level was not perceptible even at the threshold of transdermal electroporation level of sixty electric pulses at 150 V, 1 ms at 1–10 Hz. An array of 11 × 11 alternately connected electrodes with 0.6 × 0.6 mm dimension was fabricated. The electric thresholds for effective drug delivery, using toluidine blue O as a marker on mouse skin, was found to be the same for microelectrode arrays as for larger electrodes and wider inter-electrode distances. In vivo transdermal electroporation using microelectrode array with 180 pulses of 150 V, 0.2 ms at 1 Hz, followed by 30 min methotrexate (MTX) occlusion increased more than 4 fold the systemic MTX level in mice. The results demonstrated the potential of painless delivery of significant amounts of chemotherapeutic agents through skin with the new electrode arrays in a clinical setting.     

Effect of sonication parameters on transdermal delivery of insulin to hairless rats.

Application of low-frequency ultrasound has been shown to enhance transdermal drug transport of large molecules such as insulin. In this study, we investigated the dependence of ultrasound-induced transdermal delivery of insulin on ultrasound parameters. Insulin was delivered in vivo to hairless rats using 20 kHz ultrasound applied over a range of ultrasound intensity, application time and pulse length. Change in blood glucose levels of the animals was monitored to assess insulin transport. The results showed a threshold below which no detectable changes in blood glucose level was observed for each ultrasound parameter. Moreover, our findings indicated that sonophoretic enhancement is dependent on energy dose and length of ultrasound pulse that is consistent with a cavitation-based mechanism. The more significant effect of lowering glycemia was obtained with application of less than 15 min ultrasound and was similar to subcutaneous injection of 0.5 U of insulin. Pretreatment of hairless rat skin with ultrasound followed by application of insulin resulted in no significant modification in blood glucose level, indicating that transdermal transport of insulin mainly occurred during sonication. Sonophoresis may therefore potentially be applied for non-invasive and painless delivery of insulin in the treatment of insulin-dependent diabetes.     

Transdermal delivery of fentanyl: rapid onset of analgesia using skin electroporation

Skin electroporation has recently been shown to increase transdermal transport of small-size drugs as well as considerably larger molecules by up to 4 orders of magnitude in vitro. Nevertheless, no in vivo studies have proven that high-voltage pulses can induce therapeutic plasma levels of drug. The aim of the present report was precisely to study the potential of skin electroporation in transdermal delivery of fentanyl in vivo. Fentanyl was transdermally delivered to hairless rats using high-voltage pulsing. Following the administration, the pharmacokinetics and pharmacodynamics were assessed. Significant fentanyl plasma concentrations were rapidly achieved using skin electroporation. Immediately after the 5 min pulsing, fentanyl plasma levels reached one third of the maximal plasma concentration of 30 ng/ml, the peak occurring 30 min after the electroporation. Deep analgesia and supraspinal effects were achieved, antinociception lasting for an hour. The magnitude of the effects was, however, dependent on the electrical parameters of the pulses.     

Transdermal delivery of timolol by electroporation through human skin.

The purpose was to achieve therapeutic fluxes of timolol by transdermal delivery using skin electroporation. The transdermal transport of timolol through human stratum corneum was studied in three compartment diffusion cells. The electrodes, buffer composition and pulse conditions were optimized. Timolol maleate concentration in the donor compartment was 40 mg/ml. Square wave pulses were applied. Electroporation enhanced the transdermal transport of timolol by 1-2 orders of magnitude as compared to passive diffusion. Even though the current application lasted for only 10 s, the transdermal transport remained high after pulsing for at least 6 h. Higher fluxes were obtained with Pt electrodes close to the skin and a phosphate buffer. 10 pulses of 400 V-10 ms were more efficient than 10 low voltage-long duration pulses. Therapeutic fluxes of timolol (>50 microg/cm(2) per h) through human stratum corneum were achieved by electroporation.     

Comparison of the effects of short, high-voltage and long, medium-voltage pulses on skin electrical and transport properties.

High-voltage pulses have been shown to increase rates of transport across skin by several orders of magnitude on a time scale of minutes to seconds. Two main pulse protocols have been employed to promote transport: the intermittent application of short ( approximately 1 ms) high-voltage (approximately 100 V across skin) pulses and a few applications of long (=100 ms) medium-voltage (>30 V across skin) pulses. In order to better evaluate the benefits of each protocol for transdermal drug delivery, we compared these two protocols in vitro in terms of changes in skin electrical properties and transport of sulforhodamine, a fluorescent polar molecule of 607 g/mol and a charge of -1. Whereas both protocols induced similar alterations and recovery processes of skin electrical resistance, long pulses of medium-voltage appeared to be more efficient in transporting molecules across skin. Skin resistance decreased by three (short pulses) and two (long pulses) orders of magnitude, followed by incomplete recovery in both cases. For the same total transported charge, long pulses induced faster and greater molecular transport across skin than short pulses. In addition, a greater fraction of the aqueous pathways created by the electric field was involved in molecular transport when using long pulse protocols. Transport was concentrated in localized transport regions (LTRs) for both protocols but LTRs created by long pulses were an order of magnitude larger than those formed by short pulses and the short pulses created an order of magnitude more LTRs. Overall, this study is consistent with the creation of fewer, but larger aqueous pathways by long, medium-voltage pulses in comparison to short, high-voltage pulses.     

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent.     

Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro.

The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and 5 h of passive diffusion. The influences of the following parameters on the flux were studied: donor solution pH, NaCl concentration, drug donor concentration, current density and skin type. A current density of 0.5 mA cm(-2) was used, except for one series of experiments to study the current density effect. Probably due to the influence of the skin perm-selectivity and the competition with H(+), increase in pH from 3 to 5 resulted in a significant increase in flux. Further increase in pH to 6 did not further increase the flux. The iontophoretic transport was found to increase linearly with concentration and current density, providing a convenient way to manage dose titration for Parkinson's disease therapy. Increase in concentration of NaCl dramatically reduced the flux of 5-OH-DPAT as a result of ion competition to the transport. When DHS was used, the iontophoretic transport was less. Also, with DHS the response in flux profile, by switching the current on and off, was shallower than that with HSC. With the optimum condition, a delivery of 104 microg of 5-OH-DPAT per cm(2) patch per hour is feasible, indicating that the therapeutic level could be achieved with a smaller patch size than required in case of rotigotine. Thus, based on this in vitro study, transdermal iontophoretic delivery of 5-OH-DPAT is very promising.     

Spatially constrained skin electroporation with sodium thiosulfate and urea creates transdermal microconduits.

Controlled transport of molecules through the skin's main barrier, the stratum corneum (SC), is a long standing goal of transdermal drug delivery. Traditional, needle-based injection provides delivery of almost any water soluble compound, by creating a single large aqueous pathway in the form of the hollow core of a needle, through which drug is delivered by pressure-driven flow. We extend previous work to show that SC-spanning microconduits (here with diameters of about 200 microm) can be created in vivo by skin electroporation and low-toxicity, keratolytic molecules (here sodium thiosulfate and urea). A single microconduit in isolated SC can support volumetric flow of the order of 0.01 ml s(-1) by a pressure difference of only 0.01 atm (about 10(2) Pa), demonstrating that the SC barrier has been essentially eliminated within this microscopic area.     

Iontophoretic delivery of drugs: Fundamentals,developments and biomedical applications

Iontophoretic drug delivery implies the delivery of ionic (charged) drugs into the body by the use of electric current. The technique is not new and has been used clinically in delivering medication to surface tissues for several decades. However, its potential is recently being rediscovered for transdermal systemic delivery of ionic drugs including peptide/protein drugs which are normally difficult to administer except by parenteral route. The technique has been observed to enhance the transdermal permeation of ionic drugs severalfold, and this can expand the horizon of transdermal controlled drug delivery for systemic medication. However, miniaturization of iontophoretic devices and electrodes and prevention of any possibility of skin burns are required to make this technique useful for biomedical applications. While the literature on iontophoretic systemic drug delivery is relatively recent and not extensive, the published results on clinical usage and other related aspects can be quite informative and could stimulate and assist the readers to explore other biomedical applications. This article is intended to review old as well as very recent literature on the technique, methodology, clinical findings, influencing factors, relevant electronics and other related aspects of iontophoretic drug delivery, and to provide the readers a comprehensive overview of the state-of-art of this potential new area of biomedical research.     

In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species.

Transdermal iontophoresis would be a promising method for the systemic delivery of water soluble and ionic drugs of relatively high molecular size, including peptides. In the present study, the effect of biological parameters such as age of the animal and species variation (rat, rabbit, mouse, guinea pig and human) on the transdermal iontophoretic transport was studied using timolol maleate (TM) as a model drug. The iontophoretic transport of TM across the skins obtained from the rats of different age groups was found to be similar. The results of the present study suggest that the age of the animal (Wistar rats: 1-8 months) did not appear to influence the transdermal iontophoretic transport of TM significantly. The amount of TM transported during iontophoresis (2 h) was significantly different among the different skin species. But the total amount of TM transported up to 24 h (2 h iontophoresis+22 h post-iontophoretic passive diffusion) was not significantly different among the different species studied. The present study provides further evidence that iontophoresis technique reduces the interspecies differences in the transdermal permeation of drugs, which is normally observed in passive diffusion of drugs. However, it must be noted that excised skins have been used in the present study to investigate the role of age and species variation on the iontophoretic transport of TM. The influence of these parameters under in vivo conditions might be different considering the physiological differences in different species and in the animals of different age groups.     

基于STC12C5S60S2单片机经皮给药系统的设计

背景:经皮给药技术为蛋白质多肽类药物的导入提供了一种方便有效的方式。目的:研制一种基于微控制器的经皮给药系统,实现药物经皮无创导入的同时维持药物的活性,提高药物的生物利用度。方法:经皮给药系统以微控制器为核心,采用电致孔导入技术,电离导入技术和超声波导入技术从不同角度克服皮肤屏障,促进药物经皮吸收,在软硬件上合理的设计实现3种机制的协同作用,提高药物导入的效率。结果与结论:试制出经皮给药系统样机,该系统操作简便,以无创的方式经皮给药可以提高患者的依从性,通过各治疗参数的调节,可用于多种药物的经皮导入,为实现个体化治疗提供可能。     

Adhesion-to-skin performance of a new transdermal nitroglycerin adhesive patch

Six men and six women participated in a study designed to compare adhesion-to-skin measurements of three transdermal nitroglycerin patch formulations (Minitran, Transderm-Nitro 5, and Nitro-Dur II) with an occlusive surgical tape control. After 24 hours of wear, Minitran was found to be superior to the other three products in skin adhesion. The force required to remove Minitran was significantly higher than that required to remove the other products. Maintaining good skin contact over the entire application period is essential for consistent drug delivery. Improved skin contact can increase transdermal drug delivery. This increase in delivery of nitroglycerin may result in the development of smaller patches rated to deliver the same quantity of nitroglycerin over a 24-hour period.     

Kinetics of skin resealing after insertion of microneedles in human subjects

Over the past decade, microneedles have been shown to dramatically increase skin permeability to a broad range of compounds by creating reversible microchannels in the skin. However, in order to achieve sustained transdermal drug delivery, the extent and duration of skin's increased permeability needs to be determined. In this study, we used electrical impedance spectroscopy to perform the first experiments in human subjects to analyze the resealing of skin's barrier properties after insertion of microneedles. Microneedles having a range of geometries were studied in conjunction with the effect of occlusion to test the hypothesis that increasing microneedle length, number, and cross-sectional area together with occlusion leads to an increase in skin resealing time that can exceed one day. Results indicated that in the absence of occlusion, all microneedle treated sites recovered barrier properties within 2 h, while occluded sites resealed more slowly, with resealing windows ranging from 3 to 40 h depending on microneedle geometry. Upon subsequent removal of occlusion, the skin barrier resealed rapidly. Longer microneedles, increased number of needles, and larger cross-sectional area demonstrated slower resealing kinetics indicating that microneedle geometry played a significant role in the barrier resealing process. Overall, this study showed that pre-treatment of skin with microneedles before applying an occlusive transdermal patch can increase skin permeability for more than one day, but nonetheless allow skin to reseal rapidly after patch removal.     

The pharmacokinetics of the removal and re-application of transdermal patches

The problems of removal of a transdermal patch, (1) without applying a new patch, and (2) with applying a new patch to a different skin location, are studied. The critical parameter for understanding these problems is R, the product of the pharmacokinetic elimination constant and the diffusional time lag. From the solution to the patch removal problem, it is evident that transdermal delivery can often be terminated rapidly compared to other forms of drug delivery. When R 0.4 and the diffusional time lag is long, however, the rate of termination of transdermal delivery is relatively slow. The patch re-application problem is used to study deviations from zero-order transdermal delivery in a multiple dosing regimen. For all R, transdermal delivery is remarkably close to zero order even during the period when the patch is replaced. In the worst case of R 1.6, the concentration of drug in the blood does not exceed 1.5 times the steady-state blood level.     

The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones.

Electrically-assisted delivery by iontophoresis and/or electroporation was used in vitro to deliver the calcium regulating hormones, salmon calcitonin (sCT) and parathyroid hormone (1-34) (PTH) through human epidermis. Such delivery could be useful for chronic treatment of post-menopausal osteoporosis and other clinical indications as a superior alternative to parenteral delivery. sCT (50 microg/ml) or PTH (1-34) (100 microg/ml) formulation was prepared in citrate buffer (pH 4.0 or 5.0, respectively). Epidermis separated from human cadaver skin was used. Iontophoresis was applied using a constant current power source and electroporation with an exponential pulse generator. Silver/silver chloride electrodes were used. A combination of electroporation and iontophoresis resulted in higher transdermal permeation than either one technique alone. Electroporation also shortened the lag time of iontophoretic transdermal delivery of salmon calcitonin. Pulsing at lower voltages followed by iontophoresis did not result in increased transport (over iontophoresis alone), perhaps because the transdermal voltage was very low. The transdermal transport of salmon calcitonin by pulsing with 15 pulses (1 ppm) of 500 V (200 ms) followed by iontophoresis led to a quick input and high flux. The average transdermal voltage was only about 50 V for a 500 V study.