Effect of electroporation on the electroosmosis across hairless mouse skin in vitro.

The effect of electroporation on the iontophoresis-produced electroosmosis across the skin was evaluated by measuring the permeability of hairless mouse skin, to mannitol, a non-electrolyte, in vitro. Immediately after electroporation by squared pulses (10 times/s) at 100, 150 or 200 V for 1 ms, anodal iontophoretic permeations were determined at 0.4 mA/cm2 for 4 h. The observed iontophoretic permeability of mannitol was higher with electroporation pretreatment than without pretreatment. The enhanced flux of mannitol induced by electroporation, however, was due to increased passive diffusion. The contribution of convective or osmotic flow caused by anodal iontophoresis on skin permeation of mannitol was decreased by the pretreatment. In addition, osmotic flow was decreased with an increase in the applied voltage for electroporation. In contrast, mannitol flux during cathodal iontophoresis at 0.4 mA/cm2 after 150 or 200 V electroporation was higher than without electroporation as well as anodal iontophoresis, but cathodal iontophoretic flux after electroporation was lower than without iontophoresis. The neutral high-molecular compound dextran rhodamine B was also used as a second model. Anodal iontophoresis alone did not increase skin permeability of the compound. However, electroporation pretreatment before anodal iontophoresis enhanced the skin permeation of dextran rhodamine B, which was due to increased osmotic flow induced by this combination. These results suggest that electroporation decreases the electroosmosis produced by iontophoresis, and that electroporation increases skin permeability to neutral low and high model compounds (mannitol and dextran rhodamine B) probably due to an enlarged permeation pathway. Thus, electroporation affects osmotic flow from the anode to cathode during iontophoresis. Therefore, one has to pay attention to the change in electroosmosis produced by iontophoresis for the combined use of electroporation and iontophoresis to attain a high skin-penetration enhancing effect.     

Drug delivery across the skin

For more than two decades, researchers have attempted to find a way to use the skin as a portal of entry for drugs in order to overcome problems associated with traditional modes of drug administration. This has been a complicated task due to the highly effective barrier properties of the skin. In order to deliver drugs through the skin, most compounds require various degrees of permeation enhancement. Classic enhancement methods focused primarily on chemical enhancement or modulation of interactions between the drug and the vehicle. More recent research makes use of innovative vesicular carriers, electrically assisted delivery and various microinvasive methods, some incorporating technologies from other fields. These new and exciting methods for drug delivery are already increasing the number and quality of dermal and transdermal therapies. This review discusses the different types of permeation enhancement, both classic and innovative, and summarises the current strengths and shortcomings in the field with an emphasis on those that have led to products on the market or in the pipeline.     

Drug delivery across the skin

For more than two decades, researchers have attempted to find a way to use the skin as a portal of entry for drugs in order to overcome problems associated with traditional modes of drug administration. This has been a complicated task due to the highly effective barrier properties of the skin. In order to deliver drugs through the skin, most compounds require various degrees of permeation enhancement. Classic enhancement methods focused primarily on chemical enhancement or modulation of interactions between the drug and the vehicle. More recent research makes use of innovative vesicular carriers, electrically assisted delivery and various microinvasive methods, some incorporating technologies from other fields. These new and exciting methods for drug delivery are already increasing the number and quality of dermal and transdermal therapies. This review discusses the different types of permeation enhancement, both classic and innovative, and summarises the current strengths and shortcomings in the field with an emphasis on those that have led to products on the market or in the pipeline.     

Microsecond thermal ablation of skin for transdermal drug delivery

Thermal ablation is a promising mechanism to increase permeability of the skin's outer barrier layer of stratum corneum while sparing deeper living tissues. In this study, finite element modeling predicted that the skin surface should only be heated on the microsecond timescale in order to avoid significant temperature rises in living cells and nerve endings in deeper tissue. To achieve such short thermal pulses, we developed a microdevice that rapidly heats a few microliters of water by an electrical discharge and ejects the resulting superheated steam at the skin surface on a timescale on the order of 100 μs. According to its design, we showed that this microdevice selectively removed stratum corneum of cadaver skin without significantly removing deeper tissue. This one-dimensional depth control was supplemented through the use of a masking film containing 100 μm-diameter holes placed on the skin surface during ablation to define the ablated skin area and thereby provide three-dimensional control over tissue removal. Using this approach, thermal ablation increased skin permeability to sulforhodamine B and bovine serum albumin by at least 1000-fold in vitro. We conclude that microsecond thermal ablation of skin can selectively remove stratum corneum and thereby dramatically increase skin permeability for transdermal drug delivery.     

Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin.

Melatonin (MT) is a hormone secreted by the pineal gland that plays an important role in the regulation of the circadian sleep-wake cycle. It would be advantageous to administer MT using a transdermal delivery system for the treatment of sleep disorders such as delayed sleep syndrome, jet lag in travelers, cosmonauts and shift workers. The porcine skin has been found to have similar morphological and functional characteristics as human skin. The elastic fibres in the dermis, enzyme pattern of the epidermis, epidermal tissue turnover time, keratinous proteins and thickness of epidermis of porcine skin are similar to human skin. However, the fat deposition and vascularisation of the cutaneous glands of porcine skin are different from human skin. In addition, porcine skin has been found to have a close permeability character to human skin. However, the comparative effect of chemical penetration enhancers on the permeation of drugs between porcine and human skin has not been reported. The purpose of this study was to compare the effect of fatty alcohols on the permeability of porcine and human skin using MT as a model compound. The effect of saturated fatty alcohols (octanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol) and unsaturated fatty alcohols (oleyl alcohol, linoleyl alcohol, linolenyl alcohol) at 5% concentration was tested across dermatomed porcine and human skin. Our studies showed a parabolic relationship between the carbon chain length of saturated fatty alcohols and permeation enhancement of MT with both porcine and human skin. Maximum permeation of MT was observed when fatty alcohol carbon chain length was 10. In general, as the level of unsaturation increased from one to two double bonds, there was an increase in the permeation of MT both in porcine and human skin. However, a decrease in the permeation was observed with three double bonds. Regression analysis using the steady state flux data showed a significant positive correlation between porcine and human skin for saturated fatty alcohols (r(2)=0.8868, P=0.0005). However, though a positive correlation was observed between the porcine and human skin (r(2)=0.8638), the correlation was statistically insignificant (P=0.0706). The static diffusion cell system employed in this study has major artifact compared to a flow through system. In conclusion, the permeability of porcine skin to MT in the presence of saturated and unsaturated fatty alcohols was qualitatively similar to human skin but quantitatively different with some fatty alcohols.     

Bioadhesive film for the transdermal delivery of lidocaine: in vitro and in vivo behavior.

The aim of this work was to study, in vitro and in vivo, the behavior of a skin bioadhesive film containing lidocaine. The film characterization included drug transport studies through skin in vitro and in vivo tape stripping with and without iontophoresis. We studied the effect of drug loading in order to identify the release mechanism. Finally, the release rate was compared with a lidocaine commercial gel, to assess the therapeutic value. From the data obtained it can be concluded that the monolayer film acts as a water-permeable transdermal/dermal patch on application to the skin. The permeation kinetics across the skin was not linear, but the patch acted as a matrix controlling drug delivery. Additionally, the permeation rate increased with drug loading. The in vivo experiments with tape stripping indicated that the presence of water during film application is essential to achieve not only the proper adhesion but also an effective accumulation. The application of electric current to the patch can further increase the amount of drug accumulated in the stratum corneum.     

The electrostability and electrically assisted delivery of an organophosphate pretreatment (physostigmine) across human skin in vitro.

Physostigmine is a tertiary carbamate that is utilised as a pretreatment against organophosphate intoxication. Oral delivery of physostigmine is not practical due to high first pass metabolism and short elimination half life. Transdermal administration of physostigmine may circumvent such problems. The aim of this study was to assess the electrostability of physostigmine and the feasibility of electrically assisted transdermal drug delivery of physostigmine through isolated human skin in vitro. Buffered solutions of physostigmine (free base, salicylate and sulphate) were electrostable under conditions of iontophoresis and electroporation as measured by HPLC, although instability of the chloridised silver electrodes was observed. Physostigmine sulphate was chosen for further study as it appeared to prevent degradation of the electrodes. Under conditions of iontophoresis (0.8 mA cm(-2), applied for 5- or 2.5-min durations for a maximum period of 45 min over 8 h), the total quantity of physostigmine sulphate that penetrated was 6.5+/-2.3% and 3.9+/-1.7% (pH 5.0 and pH 5.5) of the total applied dose (2 mg). Physostigmine did not penetrate the skin when electroporated at a frequency of 0.1 Hz or 10 Hz (100 V, 1 ms pulse width, duration 1 s, repetition 5-10 s), but significant amounts were delivered at a frequency of 100 Hz, being 11.3+/-2.9% and 5.8+/-2.5% of the applied dose (pH 5.0 and pH 5.5, respectively). These data indicate that iontophoretic and electroporative drug delivery of physostigmine sulphate was buffer-dependent, an effect tentatively attributed to a combination of co-ion competition, mono/di-cation ratio and applied charge effects.     

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.     

超声波对盐酸青藤碱凝胶经皮渗透的促进作用

目的研究超声波对盐酸青藤碱经皮渗透的影响。 方法取离体Sprague-Dawley大鼠皮肤,置于改良Franz扩散池,皮肤角质层朝上,并均匀涂抹盐酸青藤碱凝胶,保持扩散体系温度为（32±0.5）℃,接受介质采用20%聚乙二醇400生理盐水溶液。实验分为药物被动经皮渗透组（对照组）和药物超声波透入组（超声波组）。对照组不加超声波作用,超声波组按超声波作用参数不同分为Ta组（频率800 kHz,强度0.75 W/cm2,作用时间10 min）、Tb组（频率1 MHz,强度0.70 W/cm2,作用时间10 min）、Tc组（频率1 MHz,强度0.35 W/cm2,作用时间10 min）、Td组（频率800 kHz,强度1.50 W/cm2,作用时间10 min）和Te组（频率800 kHz,强度1.50 W/cm2,作用时间5 min）。每组均同时进行6个平行实验,每个平行实验持续时间为8 h,每隔1 h分别吸取接受室溶液,并加入空白接受介质,测定接受液药物浓度,计算平均累积单位面积渗透量Q（μg/cm2）和平均稳态透皮速率Js（μg/cm2/h）,并进行比较。 结果对照组Q8h值为（20.65±10.23）μg/cm2,Js值为（3.02±0.11）μg/cm2/h;Ta、Tb组的Q8h和Js值均明显高于对照组（P<0.05）;Tb组Q8h和Js值明显高于Tc组（P<0.05）;Td组Q8h和Js值明显高于Ta组和Te组（P<0.05）。超声波透入后,皮肤组织切片经光学显微镜观察没有明显改变,扫描电子显微镜下可见角质层表面呈现粗糙、多孔状。 结论超声波透入对盐酸青藤碱的经皮吸收有明显促进作用,渗透效果与超声波强度、作用时间有关,超声波作用的强度在0~1.5 W/cm2范围内,对皮肤组织比较安全     

Electrically-assisted transdermal delivery of buprenorphine.

The objective of this study was to explore the electrically assisted transdermal delivery of buprenorphine. Oral delivery of buprenorphine, a synthetic opiate analgesic, is less efficient due to low absorption and large first-pass metabolism. While transdermal delivery of buprenorphine is expected to avoid the first-pass effect and thereby be more bioavailable, use of electrical enhancement techniques (iontophoresis and/or electroporation) could provide better programmability. Another use of buprenorphine is for opiate addiction therapy. However, a patch type device is subject to potential abuse as it could be removed by the addict. This abuse can be prevented if drug particles are embedded in the skin. The feasibility of doing so was investigated by electro-incorporation. Buprenorphine HCl (1 mg/ml) in citrate buffer (pH 4.0) was delivered in vitro across human epidermis via iontophoresis using a current density of 0.5 mA/cm(2) and silver-silver chloride electrodes. Electroporation pulses were also applied in some experiments. For electro-incorporation, drug microspheres or particles were driven into full thickness human skin by electroporation. It was observed that the passive transdermal flux of buprenorphine HCl was significantly enhanced by iontophoresis under anodic polarity. The effectiveness of electro-incorporation seemed inconclusive, with pressure also playing a potential role. Delivery was observed with electro-incorporation, but the results were statistically not different from the corresponding controls.     

Effect of ultrasound on transdermal drug delivery to rats and guinea pigs.

The effect of therapeutic range ultrasound (1 MHz) on skin permeation of D-mannitol, a highly polar sugar alcohol, inulin, a high molecular weight polysaccharide and physostigmine, a lipophilic anticholinesterase drug was studied in rats and guinea pigs. D-Mannitol and inulin are totally and rapidly excreted, once they have penetrated through the skin into the blood stream, permitting direct in vivo monitoring. For evaluating skin penetration of physostigmine the decrease of whole blood cholinesterase was measured. Ultrasound nearly completely eliminated the lag time usually associated with transdermal delivery of drugs. 3-5 min of ultrasound irradiation (1.5 W/cm2 continuous wave or 3 W/cm2 pulsed wave) increased the transdermal permeation of inulin and mannitol in rats by 5-20-fold within 1-2 h following ultrasound application. Ultrasound treatment also significantly increased (P less than 0.05) the inhibition of cholinesterase during the first hour after application in both physostigmine treated rats and guinea pigs: while in control guinea pigs no significant inhibition of cholinesterase could be detected during the first 2 h after application of physostigmine, the ultrasound treated group showed a 15 +/- 5% (mean +/- SEM) decrease in blood cholinesterase 1 h after ultrasound application. For physostigmine-treated rats the level of cholinesterase inhibition 1 h after ultrasound application was 53 +/- 5% in the ultrasound-treated group and 35 +/- 5% in the controls.     

Peptide-mediated transdermal delivery of botulinum neurotoxin type A reduces neurogenic inflammation in the skin

Release of inflammatory pain mediators from peripheral sensory afferent endings contributes to the development of a positive feedback cycle resulting in chronic inflammation and pain. Botulinum neurotoxin type A (BoNT-A) blocks exocytosis of neurotransmitters and may therefore block the release of pain modulators in the periphery. Subcutaneous administration of BoNT-A (2.5, 5 and 10 U) reduced plasma extravasation (PE) caused by electrical stimulation of the saphenous nerve or capsaicin in the rat hindpaw skin (ANOVA, Post hoc Tukey, p < 0.05, n = 6). Subcutaneous BoNT-A also reduced blood flow changes evoked by saphenous nerve stimulation (ANOVA, Post hoc Tukey, p < 0.05, n = 6). Subcutaneous BoNT-A had no effect on PE induced by local injection of substance P (SP) or vasodilation induced by local CGRP injection. Although BoNT-A is an effective treatment for a wide range of painful conditions, the toxin’s large size necessitates that it be injected at numerous sites. We found that a short synthetic peptide (TD-1) can facilitate effective transdermal delivery of BoNT-A through intact skin. Coadministration of TD-1 and BoNT-A to the hindpaw skin resulted in a significant reduction in PE evoked by electrical stimulation. The findings show that BoNT-A can be administered subcutaneously or topically with a novel transdermal delivery peptide to reduce inflammation produced by activating nociceptors in the skin. Peptide-mediated delivery of BoNT-A is an easy and non-invasive way of administering the toxin that may prove to be useful in clinical practice.     

Successful treatment of photo-damaged skin of nano-scale atRA particles using a novel transdermal delivery.

We show a novel drug delivery system (DDS) for improved all-trans retinoic acid (atRA) therapy for external treatments of photo-damaged skin. We prepared inorganic-coated atRA nanoparticles, in turn an egg-like structure in nano-scale (Nano-atRA), using boundary-organized reaction droplets. The interfacial properties of organic architectures, in atRA micelles, were used to template the nucleation of inorganic minerals. As a result, irritation and inflammation associated with atRA therapy were substantially reduced due to the complete encapsulation of the carboxylic function. Both irritative symptoms and physicochemical instability of the atRA micelle were improved. Since Nano-atRA which is prepared following to this new DDS system developmentally improved the permeability to the stratum corneum, the remarkable pharmacological effects were resulted in comparison with atRA as such as follows: (1) thicker epidermis than classical atRA treatment and (2) the overexpression of mRNA for heparin-binding epidermal growth factor (HB-EGF) as the provocation epidermal hyperplasia. Furthermore, we found a surprising boost in production of hyaluronan (HA) among the intercellular spaces of the basal and spinous cell layers in epidermis. Nano-atRA technology for atRA therapy could not only efficiently regulate keratinocyte cell proliferation and differentiation, but also markedly produce the additional benefit. Severely injured human skin by chronic ultraviolet irradiation will completely repair due to the accelerated turnover of skin tissue, which is induced by Nano-atRA.     

榄香烯透皮凝胶的制备及体外透皮性能

背景:选择合适的载体材料对药物透皮性能的影响是制备榄香烯透皮制剂首先要解决的问题。目的:建立一种榄香烯透皮凝胶并观察其体外透皮性能。方法:采用具有良好生物相容性的亲水性高分子材料聚乙烯醇和羧甲基纤维素钠制备榄香烯透皮制剂。在体外透皮实验装置上,用鼠背皮肤为屏障进行经皮渗透实验,高效气相色谱检测榄香烯的经皮渗透量。结果与结论:聚乙烯醇和羧甲基纤维素钠的使用比例对榄香烯的透皮能力没有显著影响;两种高分子骨架材料在凝胶基质中的浓度对榄香烯透皮能力有一定的影响,以30%含量(聚乙烯醇与羧甲基纤维素钠总量)为最佳。提示此种透皮凝胶可用作榄香烯的良好载体。     

Optimization of a vehicle mixture for the transdermal delivery of melatonin using artificial neural networks and response surface method.

The objective of this study was to optimize a suitable vehicle composition, using response surface method (RSM) and artificial neural networks (ANN), for the transdermal delivery of melatonin (MT). MT is a hormone produced by the pineal gland that influences mammalian sleep and reproductive patterns. A successful treatment for sleep disorders can be developed if MT is delivered with a rate at which it is produced in the body (endogenous rhythm). Prominent hepato-gastrointestinal first-pass metabolism and short half-life of MT in the body, limits the ability of oral route to mimic the endogenous rhythm. Transdermal route is supposed to avoid first-pass metabolism, and maintain steady-state plasma MT concentrations for a required period of time. However, MT by itself can not pass through the dense lipophilic matrix of stratum corneum. Hence solvents like water (W), ethanol (E), propylene glycol (P), their binary and ternary mixtures were employed to increase MT flux and reduce lag time. Special quartic model (RSM) and deltaW:P (50:50) were predicted as the effective vehicles. W:E:P was considered as the best vehicle, both in terms of flux (12.75 microg/cm(2) per h) and lag time (5 h). RSM and ANN prediction of the best mixtures coincided very well. The ability of these tools to summarize various responses (solubility, flux, and lag time) with respect to vehicle composition enabled us to study the inter-relativity between the responses.     

Synergistic enhancement of testosterone transdermal delivery.

In this study, the effects of occlusion, octisalate (OS), and propylene glycol (PG) on the in vitro skin permeability of testosterone (TES) have been investigated. TES (either alone or with OS 5% w/v) was applied as a finite dose to full-thickness neonatal porcine skin mounted in flow-through diffusion cells and the amount of TES appearing in the receptor solution (20% v/v ethanol) was determined over 24 h. The skin was occluded with a microscope glass cover slip and to determine the effect of PG, 400 microl of PG/water mixtures (of varying PG concentration) was applied. In addition, the effect of Solugel (a proprietary hydrogel containing PG 25% w/w) and Tegaderm (a semipermeable film dressing) on the permeation of TES was assessed. Occlusion had no effect on the permeation of TES, however, OS increased the flux of TES 2.9-fold. The concentration of PG which produced optimal TES flux was 20% v/v, and this concentration resulted in a 1.9-fold increase in TES permeation. By combining OS, PG, and occlusion, TES permeation was increased 8.7-fold, which was a synergistic enhancement. In addition, Solugel and Tegaderm, when applied to the skin, produced a similar enhancement in TES permeation to that produced by PG 25% w/w and occlusion.     

In vitro acyclovir distribution in human skin layers after transdermal iontophoresis

The purpose of the present work was to study the in vitro distribution of acyclovir in human skin layers after iontophoresis, applied in order to increase the amount of drug in the basal epidermis, site of Herpes simplex infections. Experiments were done with Franz diffusion cells applying, as donor, acyclovir solutions (pH values: 3.0 and 7.4) or a commercial cream. Quantification of drug at different skin depths was performed by horizontal slicing of frozen skin, and drug extraction and analysis by high-performance liquid chromatography. Seven h of transdermal iontophoresis (0.5 mA cm⁻²) induced an accumulation of acyclovir in epidermis and dermis ranging from 80 to 150 μg cm⁻³, characterized by homogeneous distribution of the drug in skin layers. After short current application time (30 min) however, the concentration profile of drug in skin was not significantly different from that obtained after seven h of passive diffusion, employing pH 3.0 donor solution. After 30 min of iontophoresis, the acyclovir reservoir on the skin was maintained for up to five h producing a dramatic increase of drug concentration in skin, evening out over 80 μg cm⁻³ until a depth of 300 μm. Acyclovir can be accumulated at target site more quickly and maintained at higher level through application of a iontophoretic pulse and by keeping the drug reservoir on skin.     

Improved skin adherence and patient acceptance in a new transdermal nitroglycerin delivery system

Sixty-five patients with angina pectoris participated in a two-week, randomized, crossover, open-label, multicenter trial to compare patient preferences between two transdermal nitroglycerin delivery systems: Minitran and Nitro-Dur II (ND II). Patients were enrolled if they had stable angina pectoris and had been on a stabilized dose (5, 10, or 15 mg/24 hr) of Transderm-Nitro (TDN) for at least one month before entering the study. Patients with a bias against ND II or with any of the contraindications for transdermal nitroglycerin therapy were excluded. During the first one-week treatment period, the patients received their prestudy dose regimen of either Minitran or ND II. During the second week, the patients were crossed over to the transdermal delivery system that they had not received in the first week. Patients completed daily diaries, weekly questionnaires, and poststudy patient preference evaluation forms. Two patients, one in each treatment group, withdrew from the study because of increased angina, which was probably not related to the use of transdermal nitroglycerin. Fifty-seven percent of the patients preferred Minitran overall (P less than or equal to 0.05), 27% preferred ND II, and 16% had no overall preference.     

Engineering hydrogel nanoparticles to enhance transdermal local anaesthetic delivery in human eyelid skin

Herein, we focused on developing the feasibility of nano-enabled local anaesthetic (LA) delivery to anaesthetise the full thickness of eyelid skin. For this purpose a temperature-responsive hydrogel poly(N-vinylcaprolactam-co-hyaluronic acid) (p(VCL-co-HA)) was prepared through aqueous emulsion polymerization with a Food and Drug Administration (FDA) approved p(VCL) and hyaluronic acid (HA) showing remarkably high LA drug loading capacity.

Nano-enabled local anaesthetic delivery was achieved using FDA-approved materials with remarkably high loading capacity.

Eyelid surgery is most commonly performed under local anesthesia all over the world. Unfortunately not all patients experience local anesthetic injections in the same way. Many people have needle phobias and feel highly anxious at the prospect of an injection along with the pain associated with it, which adds to the overall trauma. Furthermore during prolonged procedures as the anesthetic effect wears off the pain returns, which adds to the traumatic experience. The aforementioned discomfort not only discourages the needle phobic patients but also other patients who have a low threshold for pain or are undergoing their first surgical procedure in the ophthalmic department. This fear may cause delays in seeking ophthalmic care early for serious conditions such as eyelid cancer and may also increase the amount of local anesthesia required for minor procedures which can have risks of systemic side effects from the anesthetic drugs. Both examples have significant impacts on the economy of national health care.The current method of achieving sufficient dermal anesthesia in the eyelid for surgical procedures is subcutaneous injection of the LA drug lidocaine. An interest in non-invasive (needleless) LA drug delivery is well sought to minimize patient discomfort as well as surgical challenges such as intra-operative tissue distortion associated with the infiltration of anesthesia.^1,2The use of topical anesthetic products as an alternative for dermatological procedures on skin elsewhere in the body is well established.³ The most commonly used LA drug in the commercially available topical preparations is lidocaine which can be found for example in the form of a liposomal preparation of 4% lidocaine (LMX4 cream, Ferndale Laboratories Inc., Ferndale, MI, USA) or as an eutectic mixture of 2.5% lidocaine combined with 2.5% prilocaine (EMLA®, AstraZeneca AB, Södertälje, Sweden).³ Other products may contain tetracaine such as the 4% gel preparation Ametop or betacaine (Betacaine Enhanced Gel 4, Tiberius Inc, Tampa, FL).⁴Though most of these preparations require a long application time and the need for occlusion to enhance deep penetration of the LA drug, the achieved anaesthesia is still insufficient to carry out procedures involving full thickness of eyelid skin.³ Furthermore eyelid dynamics prohibit the use of the aforementioned formulations that may cause ocular surface irritation or chemical injury in severe cases.⁵In recent years, much interest has been given to nanocarriers that show potential for enhanced transdermal anaesthetic delivery via a range of routes (including the intracellular, intercellular and transappendageal) which is due to their small size. The carriers offer several advantages such as increased drug-loading capacity, entrapment efficiency and cumulative drug release.⁶Hydrophilic polymeric networks that are capable of imbibing huge volumes of water and undergoing swelling and shrinkage to suitably facilitate controlled drug-release are called hydrogels. Nanogels are synthesized by the cross-linking of N,N′-methylenebisacrylamide and ammonium persulfate (APS) as an initiator using a radical polymerization technique. Their porosity and compatibility with aqueous environments make them highly attractive bio-compatible drug delivery vehicles. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. New synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range of drugs, peptides, and protein delivery applications. HA is an FDA approved co-polymer and is an important component of the cellular matrix and various tissues that make up the organisms which have high moisture retention and high viscoelasticity. HA is widely used in anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic, and non-immunogenic, it can be chemically modified to become a good drug carrier.^7,8For biomedical applications, poly(N-vinylcaprolactam)-based (p(VCL)) hydrogel nanoparticles are ideal as they have similar water content to natural tissue. In addition they are one of the most popular thermoresponsive polymers used in the cosmetic industry as their phase transition in response to temperature can be utilized to optimise skin application. The polymers are often synthetized as co-polymers with other chemicals to achieve additional benefits such as biotechnological applications due to their tunable size from nanometres to micrometres, a large surface area for multivalent bioconjugation and an internal network useful for incorporation of biomolecules or drugs.^9,10In this work we aim to explore the feasibility of nano-enabled LA delivery to anaesthetise the full thickness of the eyelid skin. For this purpose a temperature-responsive hydrogel poly(N-vinylcaprolactam-co-hyaluronic acid) (p(VCL-co-HA)) was prepared through aqueous emulsion polymerization with p(VCL) and HA for high LA drug loading capacity.     

Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs.

The aim of this study was to increase the skin penetration of two drugs, granisetron hydrochloride and diclofenac sodium, using a microelectronic device based on an ablation of outer layers of skin using radiofrequency high-voltage currents. These radiofrequency currents created an array of microchannels across the stratum corneum deep into the epidermis. The percutaneous penetration studies were first performed in vitro using excised full thickness porcine ear skin. An array of 100 microelectrodes/cm(2) was used in these studies. The skin permeability of both molecules was significantly enhanced after pretreatment with the radiofrequency microelectrodes, as compared to the delivery through the untreated control skin. Steady state fluxes of 41.6 micro g/cm(2)/h (r=0.997) and 23.0 micro g/cm(2)/h (r=0.989) were obtained for granisetron and diclofenac, respectively. The enhanced transdermal delivery was also demonstrated in vivo in rats. It was shown that diclofenac plasma levels in the pretreated rats reached plateau levels of 1.22+/-0.32 micro g/ml after 3 h to 1.47+/-0.33 micro g/ml after 6 h, as compared to 0.16+/-0.04 micro g/ml levels obtained after 6 h in untreated rats. Similarly, application of granisetron patches (3% in crosslinked hydrogel) onto rats' abdominal skin pretreated with radiofrequency electrodes resulted in an averaged peak plasma level of 239.3+/-43.7 ng/ml after 12 h, which was about 30 times higher than the plasma levels obtained by 24-h passive diffusion of the applied drug. The results emphasize, therefore, that the new transdermal technology is suitable for therapeutic delivery of poorly penetrating molecules.