Article

Effect of microporation on passive and iontophoretic delivery of diclofenac sodium

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Abstract

Skin pretreatment with a microneedle roller (microporation (MP)) appears a simple and inexpensive technique to increase transdermal delivery of topically applied drug products. This study investigates the effect of MP on the passive and iontophoretic delivery of diclofenac (DCF) by quantifying dermis and plasma levels of DCF in a rabbit model. New Zealand albino female rabbits received either: (i) a topical application of 4 g of Voltaren® 1% gel with or without pretreatment with a microroller (0.5 mm needle length; density 23 microneedles per cm(2) area) or (ii) a DCF solution (40 mg/2.5 mL) via iontophoresis (IOMED transQ(E) medium size patch), with or without microroller pretreatment. A 300 µA/cm(2) cathodic current was applied for 20 min for a total of 80 mA. DCF concentrations were monitored in dermis with microdialysis sampling every 20 min for 5 h. Plasma samples were collected over the same period. In the passive delivery studies, microroller pretreatment increased Cmax by 1.5- and 2.0-fold in skin and plasma, respectively, and AUC by 1.5- and 2.4-fold in skin and plasma, respectively. In the iontophoresis delivery studies, microporation increased Cmax by 2.0-fold both in skin and in plasma, and AUC by 1.1- and 1.8-fold in skin and plasma, respectively. In conclusion, microneedle pretreatment increased significantly the systemic exposure of DCF from either passive or iontophoretic delivery, whereas the effect in skin was less pronounced.

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... Microneedle rollers continue to attract research interest [23,24]. It is a simple and cost-effective technique to increase transdermal delivery of medications applied to the skin [25]. Microneedle rollers contain micron-sized solid needles that are symmetrically aligned on a cylindrical surface, allowing a rolling movement as it is pushed along the skin surface [17,23,25,26]. ...
... It is a simple and cost-effective technique to increase transdermal delivery of medications applied to the skin [25]. Microneedle rollers contain micron-sized solid needles that are symmetrically aligned on a cylindrical surface, allowing a rolling movement as it is pushed along the skin surface [17,23,25,26]. ...
... Indeed, the transdermal drug delivery route has proved efficacious for a number of medications used in the management of neurological disorders. For instance, rotigotine is delivered in therapeutic concentration from the transdermal drug delivery system (Neupro ® ) [25]. In addition, the transdermal delivery route bypasses and avoids the substantial hepatic first pass metabolism observed with the oral medication. ...
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The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm2/h) compared to passive delivery (12.83 ± 6.30 µg/cm2/h). For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm2/h was observed compared to 10.85 ± 0.11 µg/cm2/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm2/h versus 30.74 ± 1.32 µg/cm2/h). Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant.
... Indeed, in the past decade, several studies demonstrated a positive synergism between the two techniques to further enhance delivery of either high-molecular-weight 11 or lowmolecular-weight compound 12,13 in vitro as well as in vivo. 14 Microneedles are micron-size needles that pierce the skin's outer barrier (stratum corneum); however, they are too short to reach the nerves 15,16 and therefore do not cause pain. 17 To understand better the mechanism of transdermal delivery of ETP, we measured the kinetics of ETP and VP in dermis via microdialysis sampling as well as systemic delivery by conventional plasma sampling. ...
... Among all the available sampling techniques to measure dermal concentration, microdialysis permits the continuous, realtime sampling of drug molecules present in the skin extracellular fluid with minimal tissue damage. 18,19 In a previous study, 14 we confirmed the suitability of the rabbit model to use microdialysis sampling with a combination of microneedles pretreatment and iontophoresis. ...
... The microchannel system was preferred over microroller application (Dermaroller) because it requires a single application thereby improving reproducibility. 14 The microporation/iontophoresis combination significantly increased VP plasma concentrations by 50%. However, the length of time spent above the minimum effective plasma concentration did not change significantly. ...
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Cancer chemotherapy frequently requires long periods of multiple intravenous infusions that often results in patients opting out of treatment. The main purpose of this study was to investigate the feasibility of delivering one of these anticancer agents: etoposide phosphate (ETP) transdermally using iontophoresis and a combination of iontophoresis/microporation. The iontophoresis conditions for ETP were first optimized in vitro then tested in vivo in a rabbit model. Both ETP and its active form etoposide (VP) were quantified in dermis (via microdialysis sampling) and in plasma, with a specially developed high-performance liquid chromatography method. In vitro, the amount of total etoposide permeated and the steady state flux increased (p < 0.05) with increase in iontophoretic current densities (100-400 μA/cm2). At 300 μA/cm2, microporation/iontophoresis further improved both parameters by 2- and 2.8-fold, respectively. In vivo, exposure increased proportionally to current density in plasma, whereas dermal concentration dropped significantly at the highest current density. Microporation led to a 50% increase in Cmax and AUClast values in both skin and plasma. In conclusion, a mild current density (300 μA/cm2) and a small surface area (10.1 cm2) achieved and maintained the minimum effective concentration for the entire duration of electrical current delivery; microporation further increased the plasma concentrations at the same current density.
... Cutaneous microdialysis is a semi-invasive sampling technique used to study the time course of endogenous or exogenous substances in the skin in-vivo (Schnetz & Fartasch, 2001). Examples of cutaneous microdialysis applications include investigation of physiological processes in skin (Johnson & Kellogg, 2010;Borge, Iversen, & Reed, 2006), optimization of delivery systems (Shukla, Friden, Juluru, & Stagni, 2009;Joshi et al., 2014), insight on drug transport mechanism through skin (Patel, Joshi, & Stagni, 2015;Patel, Joshi, Joshi, & Stagni, 2016), or the study of topical bioavailability and bioequivalence (Holmgaard, Nielsen, & Benfeldt, 2010). Additionally, the use of microdialysis (MD) can also be extended to study the pharmacokinetics in skin for the drugs that are administered systemically with the purpose to elicit their pharmacological effect in skin (Shukla, Patel, Juluru, & Stagni, 2009), or as an indirect measurement of systemic exposures in a situation where traditional blood sampling is difficult or unethical (Juluru, Shukla, Yin, & Stagni, 2011). ...
Article
Introduction: Microdialysis is a technique that allows interstitial-fluid sampling with minimal tissue-damage. In a microdialysis study, samples are collected serially (continuous microdialysis, CMD) and participant's movements are reduced for the entire study. Intermittent Cutaneous Microdialysis (IMD) is a modified version of CMD, which allows for unrestrained periods in between samples. However, in separate experiments, pharmacokinetic parameters estimated with IMD showed higher variability than with CMD. The purpose of this study is to simultaneously assess and compare the skin pharmacokinetic profiles obtained with a combination of CMD and IMD with those obtained with traditional CMD sampling only, in the same experiment. Methods: Two linear microdialysis (MD) probes were inserted into the shaved dorsal skin of three rabbits. Following the oral administration of three different doses (20, 40 and 80mg/kg) of ciprofloxacin (CPLX), for the first two hours, samples were collected from both probes according to traditional CMD in order to assess intrinsic differences between the two sites. After two hours, one of the probes was switched to IMD schedule. Skin-exposure parameters were estimated with non-compartmental analysis. Results: Two of the nine experiments showed a difference larger than 30% between the concentrations measured from the two probes when both were on the CMD schedule. Otherwise, the skin concentration profiles were almost superimposable. Pharmacokinetic parameters were not statistically different. Conclusion: The results of this study show that skin pharmacokinetic parameters measured via a combination of CMD and IMD were not statistically different from those estimated via traditional CMD sampling alone.
... For assessment of transdermal delivery of the drugs prepared in different drug formulations Table 1Recent publications for application of iontophoresis to improve dermal drug delivery monitored by skin microdialysis. Substance Species Formulation Reference Diclofenac Human 1% in gel [44] Diclofenac Rabbit 1% Voltaren gel [45] Diclofenac Rat Hydroxymethylcellulose, polyvinylpyrrolidone hydrogels [46] Diclofenac Hairless rat Patches [47] Diclofenac sodium, prednisolone sodium phosphate Rat [48] Ddexamethasone sodium phosphate (DSP) Human 4.4 mg/mL DSP solution [49] Dexamethasone Human Patches [50] Lidocaine/prilocaine Human Cream 1 g [51] Lidocaine Human 2% lidocaine solution ± epinephrine [52] Lidocaine, mepivacaine Hairless rat Patches 2% lidocaine, 3% mepivacaine [53] 5-OH-DPAT Rat Patches [54] 5-OH-DPAT Rat Patches [55] Acyclovir Hairless rat skin In vitro [56] Acyclovir Rabbit Ointment, patches [57] Enoxacin Rat Methylcellulose, polyvinypirrolydon hydrogels [58] Flurbiprophen Hairless rat Patches [59] Methotrexate Hairless rat 200 mg MTX gel in 1% hydroxyethyl cellulose in cartridge [60] Amoxicillin Rabbit 10 μg/mL solution [61] Cefuroxim Rabbit 10 μg/mL solution [61] Daniplestim (DP) Hairless rat Patches 5 mg/mL DP [62] Sodium fluorescein Human Retrodialysis [63] 5-OH-DPAT: 5-hydroxy-2-(N,N,-di-npropylamino) tetralin; MTX: methotrexate. [76] Metronidazole Human with or w/o irritant dermatitis Flagyl 1% cream [77] Metronidazole Human with or w/o atopic dermatitis ...
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This study focused on the in vitro evaluation of skin perforation using a new microneedle device (Dermaroller®) with different needle lengths (150, 500 and 1500 μm). The influence of the microneedle treatment on the morphology of the skin surface (studied by light and scanning electron microscopy), on the transepidermal water loss (TEWL) and on the penetration and permeation of hydrophilic model drugs was investigated using excised human full-thickness skin. Furthermore, invasomes – highly flexible phospholipid vesicles containing terpenes and ethanol as penetration enhancer – were compared with an aqueous solution.Elevated TEWL values were measured after Dermaroller® treatment compared to untreated human skin with a gradual increase of the TEWL over the first hour whereas afterwards the TEWL values decreased probably caused by a reduction of the pore size with time. Skin perforation with the Dermarollers® enhanced drug penetration and permeation for both formulations tested. Invasomes were more effective to deliver hydrophilic compounds into and through the skin compared to the aqueous drug solutions and the combination with skin perforation further enhanced drug penetration and permeation.In conclusion, Dermarollers® being already commercially available for cosmetic purposes appear also promising for drug delivery purposes particularly those with medium (500 μm) and shorter (150 μm) needle lengths.
Article
This paper investigates the microneedle (MN) mediated in vitro transdermal iontophoretic delivery of prochlorperazine edisylate (PE) across dermatomed human skin. The Dermaroller™ induced microchannels were visualized using methylene blue staining and scanning electron microscopy. In vitro skin permeation studies were performed using vertical static Franz diffusion cells. Iontophoretic protocols involved application of direct current at a density of 0.4 mA/cm(2) using Ag as an anode and Ag/AgCl as a cathode. The effect of PE concentration (20, 50 and 100 mg/mL), number of passes of microneedles (0, 5, 10 and 20) on both iontophoretic and passive delivery of PE was studied. The Dermarollertm was found to successfully breach the skin barrier and a linear relationship (r(2) = 0.99) was observed between the number of passes of the Dermaroller™ and the number of microchannels created. Passive transdermal flux of PE (0.060 ± 0.003 µg/cm(2)/h) at 50 mg/mL donor PE concentration) was low and increased (4.15 ± 0.57 µg/cm(2)/h) with the application of direct current. Application of iontophoresis in conjunction with microneedle pre-treatment resulted in enhanced flux (4.90 ± 0.39 µg/cm(2)/h at 50 mg/mL donor PE concentration) of PE. The projected transdermal PE flux indicates that a 9 cm(2) patch could deliver PE in a sufficient amount to maintain therapeutic levels of the drug. In conclusion, microneedles when used in conjunction with iontophoresis significantly enhanced the transdermal delivery of PE and it may be feasible to develop an iontophoretic transdermal patch that could be integrated with MN.
Article
Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied.
Article
Transdermal delivery of therapeutic agents for cosmetic therapy is limited to small and lipophilic molecules by the stratum corneum barrier. Microneedle technology overcomes this barrier and offers a minimally invasive and painless route of administration. DermaRoller(®), a commercially available handheld device, has metal microneedles embedded on its surface which offers a means of microporation. We have characterized the microneedles and the microchannels created by these microneedles in a hairless rat model, using models with 370 and 770 μm long microneedles. Scanning electron microscopy was employed to study the geometry and dimensions of the metal microneedles. Dye binding studies, histological sectioning, and confocal microscopy were performed to characterize the created microchannels. Recovery of skin barrier function after poration was studied via transepidermal water loss (TEWL) measurements, and direct observation of the pore closure process was investigated via calcein imaging. Characterization studies indicate that 770 μm long metal microneedles with an average base width of 140 μm and a sharp tip with a radius of 4 μm effectively created microchannels in the skin with an average depth of 152.5 ± 9.6 μm and a surface diameter of 70.7 ± 9.9 μm. TEWL measurements indicated that skin regains it barrier function around 4 to 5 h after poration, for both 370 and 770 μm microneedles. However, direct observation of pore closure, by calcein imaging, indicated that pores closed by 12 h for 370 μm microneedles and by 18 h for 770 μm microneedles. Pore closure can be further delayed significantly under occluded conditions.
Article
Microneedle arrays are promising devices for the delivery of drugs and vaccines into or the skin. However, little is known about the safety of the microneedles. In this study we obtained insight in the ability of microneedles to disrupt the skin barrier, which was evaluated by transepidermal water loss (TEWL). We also determined the safety in terms of skin irritation (skin redness and blood flow) and pain sensation. We applied microneedle arrays varying in length and shape on the ventral forearms of 18 human volunteers. An effect of needle length was observed, as TEWL and redness values after treatment with solid microneedle arrays of 400 microm were significantly increased compared to 200 microm. The blood flow showed a similar trend. Needle design also had an effect. Assembled microneedle arrays induced higher TEWL values than the solid microneedle arrays, while resulting in less skin irritation. However, for all microneedles the irritation was minimal and lasted less than 2h. In conclusion, the microneedle arrays used in this study are able to overcome the barrier function of the skin in human volunteers, are painless and cause only minimal irritation. This opens the opportunity for dermal and transdermal delivery of drugs and vaccines.
Article
A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0 × 1.0 cm, contains 100 microneedle arrays in a 10 × 10 matrix. The mean lengths of DMs were 496.6 ± 2.9 μm for h-DM and 494.5 ± 1.3 μm for d-DM. The diameters of the array basement were 295.9 ± 3.9 μm (d-DM) and 291.7 ± 3.0 μm (h-DM), where ST contents were 31.6 ± 4.5 μg and 24.1 ± 0.9 μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6 ± 4.9 ng/ml and 24.6 ± 3.9 ng · h/ml for h-DM and 38.4 ± 2.7 ng/ml and 14.1 ± 1.5 ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7 ± 18.8% for h-DM and 93.6 ± 10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, −80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0 ± 0.3%, 97.8 ± 0.2%, 98.8 ± 0.2%, and 100.7 ± 0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.
Article
Microneedle rollers have been used to treat large areas of skin for cosmetic purposes and to increase skin permeability for drug delivery. In this study, we introduce a polymer microneedle roller fabricated by inclined rotational UV lithography, replicated by micromolding hydrophobic polylactic acid and hydrophilic carboxy-methyl-cellulose. These microneedles created micron-scale holes in human and porcine cadaver skin that permitted entry of acetylsalicylic acid, Trypan blue and nanoparticles measuring 50nm and 200nm in diameter. The amount of acetylsalicylic acid delivered increased with the number of holes made in the skin and was 1-2 orders of magnitude greater than in untreated skin. Lateral diffusion in the skin between holes made by microneedles followed expected diffusional kinetics, with effective diffusivity values that were 23-160 times smaller than in water. Compared to inserting microneedles on a flat patch, the sequential insertion of microneedles row by row on a roller required less insertion force in full-thickness porcine skin. Overall, polymer microneedle rollers, prepared from replicated polymer films, offer a simple way to increase skin permeability for drug delivery.
Article
Diclofenac is a proven, commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been shown to be effective in treating a variety of acute and chronic pain and inflammatory conditions. As with all NSAIDs, diclofenac exerts its action via inhibition of prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency. However, extensive research shows the pharmacologic activity of diclofenac goes beyond COX inhibition, and includes multimodal and, in some instances, novel mechanisms of action (MOA). Literature retrieval was performed through PubMed/MEDLINE (through May 2009) using combinations of the terms diclofenac, NSAID, mechanism of action, COX-1, COX-2, and pharmacology. Reference citations resulting from publications identified in the literature search were reviewed when appropriate. This article reviews the established, putative, and emerging MOAs of diclofenac; compares the drug's pharmacologic and pharmacodynamic properties with other NSAIDs to delineate its potentially unique qualities; hypothesizes why it has been chosen for further recent formulation enhancement; and evaluates the potential effect of its MOA characteristics on safety. Research suggests diclofenac can inhibit the thromboxane-prostanoid receptor, affect arachidonic acid release and uptake, inhibit lipoxygenase enzymes, and activate the nitric oxide-cGMP antinociceptive pathway. Other novel MOAs may include the inhibition of substrate P, inhibition of peroxisome proliferator activated receptor gamma (PPARgamma), blockage of acid-sensing ion channels, alteration of interleukin-6 production, and inhibition of N-methyl-D-aspartate (NMDA) receptor hyperalgesia. The review was not designed to compare MOAs of diclofenac with other NSAIDs. Additionally, as the highlighted putative and emerging MOAs do not have clinical data to demonstrate that these models are correct, further research is necessary to ascertain if the proposed pathways will translate into clinical benefits. The diversity in diclofenac's MOA may suggest the potential for a relatively more favorable profile compared with other NSAIDs.
Article
This study characterizes skin perforation by commercially available microneedle rollers and evaluates the efficacy of transdermal delivery of insulin to diabetic rats. Three different needle lengths, 250, 500 and 1000 microm, were used in this work. Creation and resealing of the skin holes that were produced by the needles were observed by Evan's blue (EB) staining and transepidermal water loss (TEWL) measurements. EB clearly showed that microchannels were formed in the skin and that the pores created by the longest microneedle (1000 microm) persisted no longer than 8h, while the hypodermic injury was still observed 24h later. TEWL significantly increased after the application of the needles and then decreased with time, which explains the recovery of skin barrier function and agrees well with EB results. The extent of permeation was demonstrated by insulin delivery in vivo. The rapid reduction of blood glucose levels in 1h was caused by the increased permeability of the skin to insulin after applying microneedle rollers. The reduced decrease after 1h is closely associated with hole recovery. In conclusion, microneedle rollers with 500-microm or shorter lengths are safe and useful in transdermal delivery of insulin in vivo.
Article
Solid silicon microneedle arrays with different needle lengths (ranging from 100 to 1100 microm) and needle densities (ranging from 400 to 11,900 needles/cm(2)) were used to penetrate epidermal membrane of human cadaver skin. After this pretreatment, the electrical resistance of the skin and the flux of acyclovir across the skin were monitored. A linear correlation between the acyclovir flux and the inverse of the skin electric resistance was observed. Microneedle arrays with longer needles (>600 microm) were more effective in creating pathways across skin and enhancing drug flux, and microneedle arrays with lower needle densities (<2000 needles/cm(2)) were more effective in enhancing drug flux if the microneedles with long enough needle length (>600 microm). In addition, the microneedle arrays were used to penetrate hairless rat skin in vivo, and the trans-epidermal water loss (TEWL) of the rat skin was measured before and after the pretreatment. Treating rat skin with microneedle arrays of lower needle density and longer needle length was more effective in increasing TEWL. Integrity of the stratum corneum barrier of the penetrated rat skin as measured by TEWL recovered back to its base line level within 24h after the microneedle pretreatment.
Article
The effects of diclofenac sodium and naproxen on the gastric mucosa were studied in a double-blind trial by gastroscopy, gastrophotography and histological examination of the mucosa in six healthy volunteers. Detectable lesions were evident in the mucosa of four subjects after administration of both drugs, and the lesions were more extensive after the ingestion of naproxen than after diclofenac sodium in all of these cases. The most serious lesions verified by both gastroscopy and histology always occurred after exposure to naproxen. The histology of the gastric mucosa of two subjects with severe lesions showed spotty to moderate chronic superficial gastritis, whereas the overall histological appearance of the mucosa was normal in subjects with slight or moderate lesions after drug administration. The maximal acid output was positively correlated with the severity of the lesions. Subjective symptoms occurred in one person during diclofenac sodium and in three during naproxen administration.
When microdialysis (MD) is used to study dermal delivery by iontophoresis, the effects of current may alter MD recovery through an increase in temperature, a change of pH, hyperemia, and dermal hydration. The objective of this work is to assess whether these effects of current may cause a measurable change in the retrodialysis of a model compound (sodium fluorescein, Fl). Two linear MD-probes were inserted in the forearm dermis of healthy human volunteers and perfused with Ringer's solution containing Fl. Two identical iontophoresis chambers (IC, filled with NaCl in propylene glycol) were placed over the MD-probes. Each IC included a laser Doppler flowmetry probe to monitor skin blood flow. At one IC, current was applied for two periods of 30 min each, separated by 30 min of no current. No current was applied to the control site. Dialysate samples were collected every 5 min and analyzed for Fl by HPLC. Skin blood flow increased in response to iontophoresis, on average, 570% compared to the control site. However, there was no difference in the recovery of Fl between the current-active site versus the control site, and between the period with applied current versus the period with no current. In conclusion, iontophoretic current did not affect intradermal MD recovery.
Article
Diclofenac sodium is a nonsteroidal anti-inflammatory drug with analgesic, antipyretic, and anti-inflammatory activity. When used in a topical application, diclofenac can diffuse through the skin and into the subcutaneous tissue to effect the anti-inflammatory action. In this study, in vitro evaluations of the percutaneous transport of diclofenac sodium in various bases containing fatty alcohols/propylene glycol or fatty acid/propylene glycol mixtures through the abdominal skin of the rabbit were investigated. Results show that the transdermal flux of diclofenac sodium in the fatty alcohol/propylene glycol bases of the same ratio is affected by the chain length of the fatty alcohol, and its effect is in the order of C10 > C12 > C14 > C18. However, the transdermal flux of diclofenac sodium in the fatty acid/propylene glycol bases of the same ratio is also affected by the chain length of the fatty acid, but no absolute relationship was found. For the same chain length of fatty acid and fatty alcohol used in the formulation base that was otherwise the same, the transdermal flux of diclofenac sodium is higher in the formula containing fatty alcohol than that containing fatty acid.
Article
To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1-1.0 mA/cm(2) applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm(2) for up to 4 h, no significant irritation was observed. 2 mA/cm(2) applied through an area of 1 cm(2) for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm(2) under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm(2) current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm(2) applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm(2). When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3-5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.
Article
The pharmacokinetics of methotrexate (MTX) in rabbit's skin and plasma after iv-bolus and iontophoretic delivery at different current densities was studied. Linear microdialysis probes were introduced into the upper dorsal shaved skin of tranquilized rabbits. Commercially available patches were used to deliver MTX for 1 h at different current densities (100, 200, and 300 microA/cm2) on different occasions. Iv-boluses (10 mg/kg) of MTX were also administered. Retrodialysis was performed at the end of the experiments to estimate probe recovery. Plasma and microdialysis samples were analyzed using a validated HPLC assay. Following iv-bolus, MTX showed a bi-exponential decay both in plasma and in skin. Cmax in skin occurred with a delay of 22 min compared with plasma. No quantifiable concentration of MTX was detected in the skin on passive drug delivery. Systemic exposure to MTX (AUC) and Cmax increased linearly with current density. Nevertheless, exposure to MTX in the skin did not increase linearly with current density, whereas Cmax did. In conclusion, iontophoresis remarkably improved the dermal delivery of MTX over passive diffusion. However, total exposure did not increase with current density in the skin, suggesting that for local applications lower current densities may achieve the same effects with minimal systemic exposure.
Article
Independently, both transepidermal water loss (TEWL) and percutaneous absorption measurements accurately gauge stratum corneum skin water barrier integrity. Both TEWL and percutaneous absorption rates increase when the integrity of the SC barrier is compromised. Experiments to discern a quantitative and/or qualitative correlation between the two indicators have resulted in controversy. This paper reviews some major studies investigating this correlation. (c) 2005 Elsevier B.V. All rights reserved.
Article
The direct effects of ultrasound (US) and phonophoresis of a nonsteroidal anti-inflammatory drug (NSAID) on injured peripheral tissue have been widely investigated, but evidence concerning the effects of central spinal nociceptive modulation seems to be lacking. The purpose of this study was to investigate the peripheral influences of US and phonophoresis on the modulation of spinal inducible nitric oxide synthase (iNOS) expression elicited by hind paw stimulation with an ankle injection of complete Freund adjuvant (CFA). Inflammatory arthritis was induced in 18 male Wistar rats with intra-articular tibiotarsal injections of CFA. Serial changes in inflammatory pain reactions, including hind-limb edema, and the locomotor activity of the arthritic animals were measured. Arthritic rats underwent US (n=6), diclofenac phonophoresis (n=6), or sham treatment (n=6) on the CFA-injected leg at 18 hours after injection. At 20 hours after injection, spinal inducible nitric oxide synthase-like immunoreactive (iNOS-LI) cells were examined. Following the CFA injection, all animals' paw diameters and ankle circumferences ipsilateral to the injected leg were significantly increased compared with the values prior to injection. The rearing behavior of arthritic animals had improved significantly after US and diclofenac phonophoresis treatments. The mean total number (+/-SD) of iNOS-LI cells per section of segments L1 and L2 of the bilateral spinal cord of the sham treatment, US, and phonophoresis groups were 531.20+/-6.11, 124.20+/-4.09, and 114.80+/-3.23, respectively. The total numbers of iNOS-LI cells in rats treated with US and diclofenac phonophoresis were significantly smaller than in those receiving sham treatment. There were no significant differences in the total number of iNOS-LI cells ipsilateral to the injected leg between the US and diclofenac phonophoresis groups. Ultrasound and phonophoresis treatments probably modulate and prevent the CFA-insult-induced increase in total and regional iNOS-LI neurons. Peripheral use of diclofenac phonophoresis offers little advantage over US alone in affecting the central mechanisms of nociception. The peripheral influences of US and phonophoresis on the central modulation of the spinal nociceptive processing system are important and may reflect the work being done through the neuroplasticity of spinal cord in response to peripheral input of US and phonophoresis.
Article
The objective of this study was to evaluate the transdermal delivery potential of diclofenac-containing microemulsion system in vivo and in vitro. It was found that the transdermal administration of the microemulsion to rats resulted in 8-fold higher drug plasma levels than those obtained after application of Voltaren Emulgel. After s.c. administration (3.5 mg/kg), the plasma levels of diclofenac reached a peak of 0.94 microg/ml at t=1 h and decreased rapidly to 0.19 microg/ml at t=6 h, while transdermal administration of the drug in microemulsion maintained constant levels of 0.7-0.9 microg/ml for at least 8 h. The transdermal fluxes of diclofenac were measured in vitro using skin excised from different animal species. In three rodent species, penetration fluxes of 53.35+/-8.19 (furry mouse), 31.70+/-3.83 (hairless mouse), 31.66+/-4.45 (rat), and 22.89+/-6.23 microg/cm(2)/h (hairless guinea pig) were obtained following the application of the microemulsion. These fluxes were significantly higher than those obtained by application of the drug in aqueous solution. In contrast to these results, a 'flip-flop' phenomenon was observed when frozen porcine skin (but not fresh skin) was significantly more permeable to diclofenac-in-water than to the drug-in-microemulsion. In fact, the drug penetration from the microemulsion was not affected by the skin storage conditions, but it was increased when an aqueous solution was applied. However, this unusual phenomenon observed in non-freshly used porcine skin places a question mark on its relevancy for in vitro penetration studies involving aqueous vehicle systems.
Article
This article reports an in vitro study of microneedle-array-enhanced transdermal transport of model drug compounds dispersed in chitosan films. Each microneedle array has 400 out-of-plane, needle-shaped microstructures fabricated using micro-electro-mechanical systems (MEMS) technology to ensure adequate mechanical strength and high precision, and consistency. A nanometer coating on the microneedles ensured the biocompatibility that is important in the application of transdermal drug delivery. Model drugs selected to investigate skin permeation in vitro were calcein, a small molecule (molecular weight, 623 d) that has little skin penetration, and bovine serum albumin (BSA) (molecular weight, 66,000 d), a hydrophilic biological macromolecule. A Franz permeation cell was used to characterize the permeation rate of calcein and BSA through the rat skin. The transdermal transport behavior of BSA was investigated from solid films coated on the surface of microneedle arrays with various chitosan concentrations, film thicknesses, and BSA contents. The BSA permeation rate decreased with the increase of the chitosan concentration; the thicker the film, the slower the permeation rate. In addition, the permeation rate increased with the increase of BSA loading dose. A linear relationship existed between the permeation rate and the square root of the BSA loading dose. Results showed that the chitosan hydrophilic polymer film acts as a matrix that can regulate the BSA release rate. The controlled delivery of BSA can be achieved using the BSA-containing chitosan matrix film incorporated with the microneedle arrays. This will provide a possible way for the transdermal delivery of macromolecular therapeutic agents such as proteins and vaccines.
Dermatokinetics of theraputic agents
  • G Stagni
Stagni G. Cutaneous microdialysis. In: Murthy NS, ed. Dermatokinetics of theraputic agents. Boca Raton, London, New York: CRC Press, Taylor & Francis Group; 2011:131-47.
Pharmacokinetics of diclofenac sodium in plasma and skin following IV-infusion in a rabbit model
  • S Velisetty
Velisetty S. Pharmacokinetics of diclofenac sodium in plasma and skin following IV-infusion in a rabbit model [master thesis].