Transdermal Drug Administration Research Articles

Influence of different surfactants on the physicochemical properties of elastic liposomes

Elastic liposomes are capable to improve drug transport through the skin by acting as penetration enhancers due to the high fluidity and elasticity of the liposome membranes. Therefore, elastic liposomes were prepared and characterized to facilitate the transdermal transport of bioactive molecules. Liposomes consisted of dimyristoylphosphatidylcholine (DMPC) as the structural component, with different surfactants derived from lauric acid as elastic components: C12E5 (polyoxyethylene-5-lauryl ether), PEG4L (polyethyleneglycol-4-lauryl ester), PEG4DL (polyethylene glycol-4-dilauryl ester), PEG8L (polyethylene glycol-8-lauryl ester) and PEG8DL (polyethylene glycol-8-dilauryl ester). The elastic liposomes were characterized in terms of their phospholipid content, mean diameter, size distribution, elasticity and stability during storage, as well as their ability to incorporate surfactant and permeate through 50 nm pore size membranes. The results showed that the phospholipid phase transition temperature, the fluidity of the lipid bilayer resulting from incorporation of the surfactant and the preservation of particle integrity were factors determining the performance of the elastic liposomes in permeating through nanoporous membranes. The best results were obtained using DMPC combined with the surfactants PEG8L or PEG8DL. The findings demonstrate the potential of using elastic liposomes for transdermal administration of drugs.

Pouch drug delivery systems for dermal and transdermal administration.

In this work, we have designed and investigated a new carrier for dermal and transdermal drug delivery. The delivery system is composed of high (>60%) ethanol concentration, phospholipid, polymer, and water. The system forms a structured matrix following non-occluded application on the skin. We call these structured carriers as pouch drug delivery systems (PDDS). The pouch-structured matrix was characterized by electron microscopy, (31)P-NMR and FTIR. The new delivery system exhibits a number of properties adequate for the design of improved dermal and transdermal drug administration for various treatments. Lidocaine PDDS dry faster and has an enhanced dermal drug delivery when compared to a clinical-used product. These proprieties are important for the prevention of premature ejaculation. Results obtained in pharmacodynamics test carried out with brotizolam PDDS in a mice-sleeping model and with ibuprofen PDDS in fevered rats indicated a prolonged hypnotic and antipyretic effect, respectively. The carrier was found nonirritant in tests carried out on EpiDerm(TM) skin model.

Influence of polyethylene glycol-8-lauryl ester in the structural lipid of the elastic liposomes

This study compared the physicochemical characteristics of conventional and elastic liposomes in terms of surfactant incorporation, flow rate, elasticity, mean diameter, phospholipid content and permeation capability. Surfactants were incorporated into conventional liposomes in order to enhance the transdermal transport of drugs through the stratum corneum. The unilamellar liposomes produced composed of egg phosphatidylcholine (PCegg) as the structural component and polyethylene glycol-8-lauryl ester (PEG8L) as the elastic component. Results showed fluidity increased of the lipid bilayer with surfactant incorporation, and particle integrity was preserved. These factors determined the ability of elastic liposomes to permeate nanoporous membranes. The elastic liposomes presented a size of ~100 nm and a polydispersity index of 0.38. The flow rate of the liposomes through membranes obeyed Darcy's law, with characteristics similar to those of water. The findings demonstrate the potential of elastic liposomes for transdermal drug administration. Key words: Liposomes, surfactants, transdermal transport.

Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality.

The interactions between skin and colloidal gold nanoparticles of different physicochemical characteristics are investigated. By systematically varying the charge, shape, and functionality of gold nanoparticles, the nanoparticle penetration through the different skin layers is assessed. The penetration is evaluated both qualitatively and quantitatively using a variety of complementary techniques. Inductively coupled plasma optical emission spectrometry (ICP-OES) is used to quantify the total number of particles which penetrate the skin structure. Transmission electron microscopy (TEM) and two photon photoluminescence microscopy (TPPL) on skin cross sections provide a direct visualization of nanoparticle migration within the different skin substructures. These studies reveal that gold nanoparticles functionalized with cell penetrating peptides (CPPs) TAT and R7 are found in the skin in larger quantities than polyethylene glycol-functionalized nanoparticles, and are able to enter deep into the skin structure. The systematic studies presented in this work may be of strong interest for developments in transdermal administration of drugs and therapy.

Extending postoperative opioid analgesia in dogs 2. Transdermal drug administration

Opioid drugs are pivotal to the effective management of acute pain in dogs, and, for this reason, they are the ‘gold standard’ agents for the treatment of postsurgical pain. While...

Electrical, magnetic, photomechanical and cavitational waves to overcome skin barrier for transdermal drug delivery.

Transdermal drug delivery is hindered by the barrier property of the stratum corneum. It limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500Da and melting point of less than 200°C. Active methods such as iontophoresis, electroporation, sonophoresis, magnetophoresis and laser techniques have been investigated for the past decades on their ability, mechanisms and limitations in modifying the skin microenvironment to promote drug diffusion and partition. Microwave, an electromagnetic wave characterized by frequencies range between 300MHz and 300GHz, has recently been reported as the potential skin permeation enhancer. Microwave has received a widespread application in food, engineering and medical sectors. Its potential use to facilitate transdermal drug transport is still in its infancy stage of evaluation. This review provides an overview and update on active methods utilizing electrical, magnetic, photomechanical and cavitational waves to overcome the skin barrier for transdermal drug administration with insights into mechanisms and future perspectives of the latest microwave technique described.

Development of Piroxicam loaded SLN-based Hydrogel for Transdermal Delivery

The aim of present study was to construct and investigate the efficacy of solid lipid nanoparticles (SLNs) based hydrogel for transdermal delivery of non-steroidal anti-inflammatory drug (NSAID) piroxicam. Solid lipid nanoparticles (SLNs) of piroxicam were produced by solvent emulsification diffusion method in a solvent saturated system. The SLNs were composed of tripalmitin lipid, polyvinyl alcohol (PVA) as stabilizer, and solvent ethyl acetate. All the formulations were subjected to particle size analysis, zeta potential, drug entrapment efficiency, percent drug loading determination and in-vitro release studies. The SLNs formed were in nano-size range with maximum entrapment efficiency of 88.50±0.92. Further, Carbopol-934 was used as a gel matrix for preparation of hydrogel for improving the penetration rate across the skin and viscosity of piroxicam loaded SLNs for transdermal drug administration. The drug release behaviors from piroxicam loaded SLNs based hydrogel exhibited long duration and constant rate of drug release over 24 hr. Skin penetration of piroxicam loaded SLNs based hydrogel was assessed by confocal laser scanning microscopy (CLSM).

Multiple Risks for Patients Using the Transdermal Fentanyl Patch

Multiple Risks for Patients Using the Transdermal Fentanyl Patch

Transdermal Application of Drugs and Techniques Affecting Skin Barrier

The development in the field of pharmaceutical dosage forms results in discovery of additional highly sophisticated drug delivery systems that allow maintaining constant level of active substance in organism. Transdermal administration of drugs represents an excellent alternative to conventional pharmaceutical dosage forms. However, transdermal drug delivery often faces the problem of insufficient or no penetration of active pharmaceutical substances through the skin.

Pluronic® F-127 and Pluronic Lecithin Organogel (PLO): Main Features and their Applications in Topical and Transdermal Administration of Drugs

Topical drug treatment aims at providing high concentrations of drugs at the site of application so as to avoid adverse systemic effects associated with oral administration. Smart polymers, or stimuli-responsive polymers, are able to respond to a stimulus by showing physical or chemical changes in their behaviour as, for example, the delivery of the drug carried by them. The thermo-responsive nature of Pluronic® F-127 (Basf, Ludwigshafen, Germany) makes it an excellent candidate for the delivery of drugs at various application sites. In recent years, PF-127, and later, Pluronic lecithin organogels (PLO), have attracted particular interest in the design of dermal and transdermal delivery systems with a view to promoting, improving or retarding drug permeation through the skin, bearing in mind that for topical delivery systems, accumulation in the skin with minimal permeation is desired, while for systemic delivery, the opposite behaviour is preferred. In this review, we discuss the properties and characteristics of PF-127 and Pluronic lecithin organogels (PLO), and present many examples and advantages of the application of these polymeric systems in topical and transdermal administration of drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Comparison of transdermal electromotive administration of verapamil and dexamethasone versus intra‐lesional injection for Peyronie's disease

To compare the efficacy of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone for the treatment of Peyronie's disease. Patients with Peyronie's disease of less than 2-year duration were randomized into two groups of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone. During the 6-week therapy period, a single weekly dose of 10mg verapamil and 4mg dexamethasone solution was administered to 30 patients in each group either by transdermal electromotive method or via the conventional injection method by a syringe connected to a 25 G needle. Evaluations of plaque length, width, and volume, penile curvature, erectile dysfunction and penile deviations were carried out before and after 1 and 3months of the interventions. Erectile pain was reduced in the electromotive group from a mean of 5.1-1.0 in scale of 10 and from 5.4 to 3.6 in the injection group (p=0.006). Regarding plaque length, plaque width, penile curvature plaque volume and erectile dysfunction, the electromotive administration group showed better results which, however, were not statistically significant. (p>0.05). Transdermal electromotive drug administration yielded comparable results as against current conventional intra-lesional injection technique and fared better in controlling erectile pain.

Efficient Intradermal Delivery of Superoxide Dismutase Using a Combination of Liposomes and Iontophoresis for Protection against UV-Induced Skin Damage

Superoxide dismutase (SOD) is a potent antioxidant agent that protects against UV-induced skin damage. However, its high molecular weight is a significant obstacle for efficient delivery into the skin through the stratum corneum and development of antioxidant activity. Recently, we developed a non-invasive transfollicular delivery system for macromolecules using a combination of liposomes and iontophoresis, that represents promising technology for enhancing transdermal administration of charged drugs (IJP, 403, 2011, Kajimoto et al.). In this study, in rats we attempted to apply this system to intradermal delivery of SOD for preventing UV-induced skin injury. SOD encapsulating in cationic liposomes was subjected to anodal iontophoresis. After iontophoretic treatment, the liposomes were diffused widely in the viable skin layer around hair follicles. In contrast, passive diffusion failed to transport liposomes efficiently into the skin. Iontophoretic delivery of liposomes encapsulating SOD caused a marked decrease in the production of oxidative products, such as malondialdehyde, hexanoyl lysine, and 8-hydroxi-2-deoxyguanosine, in UV-irradiated skin. These findings suggested that functional SOD can be delivered into the skin using a combination of iontophoresis and a liposomal system. In conclusion, we succeeded in developing an efficient intradermal SOD delivery system, that would be useful for delivery of other macromolecules.

Efficient skin permeation of soluble proteins via flexible and functional nano-carrier

In spite of several intrinsic and distinct advantages, a topical and transdermal administration of drugs has been limited mainly due to very low permeability of drugs across skin. Especially, it is generally regarded that hydrophilic macromolecules such as proteins, peptides, and vaccines cannot penetrate across skin. In this study, we demonstrated that chitosan-conjugated, Pluronic-based nano-carrier (nanogel) can act as an efficient delivery vehicle of hydrophilic proteins across human skin. The functional nano-carrier (<100nm in size), chemically-crosslinking Pluronic F 127 with chitosan conjugation, is flexible and soft with reservoir characteristics for biomacromolecules. The in-vitro permeation experiments through human cadaver skin revealed remarkable permeability of hydrophilic proteins of various sizes including FITC-BSA (67kDa) and FITC-Insulin (6kDa) by direct penetration of the nano-carrier across skin. The bioactivity post-permeation of proteins via the functional nano-carrier was also confirmed by delivering ß-galactosidase. Results presented in this paper suggest the use of chitosan-conjugated flexible nano-carrier as a novel platform for transcutaneous delivery of hydrophilic macromolecules and other drug-delivery applications.

Dissolving microneedles for transdermal drug administration prepared by stepwise controlled drawing of maltose

Dissolving microneedles, three-dimensional polymer structures with microscale cross-sectional dimensions, have been introduced as a means of safe transdermal drug delivery. Most dissolving microneedles have been fabricated using a traditional micro-casting method that cures biopolymers within three-dimensional mold, nevertheless, repeated molding process may cause damage to encapsulated drugs, a critical hurdle for clinical application. Here, we describe the stepwise controlled drawing technique that can directly fabricate dissolving microneedle from maltose by precise controlling the drawing time and the viscosity of the maltose. Controlled drawing shaped the particular sharp-conical microneedles of 1200 μm length with tip diameter of 60 μm, and dissolved within 20 min in-vivo after inserting to the skin. This technique surpasses the limitations of micro-casting for dissolving microneedle. Furthermore, transdermal delivery of impermeable hydrophilic molecules such as ascorbic acid-2-glucoside and niacinamide was confirmed as inhibition of cutaneous hypermelanosis. We anticipate that controlled drawing technique will be suitable to design dissolving microneedles for use in minimally invasive transcutaneous drug delivery to patients.

Transferosomes - A vesicular transdermal delivery system for enhanced drug permeation

Transdermal administration of drugs is generally limited by the barrier function of the skin. Vesicular systems are one of the most controversial methods for transdermal delivery of active substances. The interest in designing transdermal delivery systems was relaunched after the discovery of elastic vesicles like transferosomes, ethosomes, cubosomes, phytosomes, etc. This paper presents the composition, mechanisms of penetration, manufacturing and characterization methods of transferosomes as transdermal delivery systems of active substances. For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/barriers at various locations. Such a movement of drug across the membrane is called as drug transport. For the drugs to be delivered to the body, they should cross the membranous barrier. The concept of these delivery systems was designed in an attempt to concentrate the drug in the tissues of interest, while reducing the amount of drug in the remaining tissues. Hence, surrounding tissues are not affected by the drug. In addition, loss of drug does not happen due to localization of drug, leading to get maximum efficacy of the medication. Therefore, the phospholipid based carrier systems are of considerable interest in this era.

Formation of polymer microneedle arrays using soft lithography

We demonstrate the fabrication of polymer microneedle arrays using soft lithography. A photomask was designed to use Fresnel diffraction of UV light to create sharp, tapered hollows in SU-8, a negative photoresist, after development. Polymer microneedles were formed using these SU-8 structures as a mold. These polymer needles may be applicable as flexible electrodes in brain-machine interfaces because they are more likely to survive movement of the skin than conventional brittle silicon needles. Similar needles, made from medicinal substances, could be used for transdermal drug administration. For these applications, the needles must be long, sharp, and stiff enough to penetrate the stratum corneum (∼20 μm in thickness) and reach the viable epidermis (200-300 μm in thickness), but must not reach the dermis, which contains sensitive nerve endings. We successfully manufactured 20×20 microneedle arrays of polydimethylsiloxane with a needle length of 200 μm. We experimentally verified that these manufactured electrodes successfully penetrated the stratum corneum of a cultured skin.

Noninvasive and persistent transfollicular drug delivery system using a combination of liposomes and iontophoresis

Iontophoresis is a promising technique for enhancing transdermal administration of charged drugs. However, conventional iontophoresis is not sufficient for effective delivery of large, hydrophilic, or electrically neutral molecules. In this study, we utilized charged liposomes as carriers, focused on a transfollicular route for delivery of the liposomes, and optimized iontophoretic conditions and lipid composition for this method in both in vitro and in vivo conditions. As a result, we identified the optimum condition (lipid composition: DOTAP/EPC/Chol=2:2:1, current supply: 0.45mA/cm2, duration: 1h) for effective iontophoretic delivery of aqueous solution, which cannot be transferred into the skin without charged liposomes. We also examined the pharmacological effects of iontophoresis of liposomes encapsulating insulin (INS-lipo) using a rat model of type I diabetes. Interestingly, iontophoresis of INS-lipo onto a diabetes rat skin resulted in a gradual decrease in blood glucose levels, with levels reaching 20% of initial values at 18h after administration. These lower blood glucose levels were maintained for up to 24h. Significant amount of insulin were also detected in plasma 18h after iontophoresis of INS-lipo. We succeeded in developing a non-invasive and persistent transfollicular drug delivery system that used a combination of liposomes and iontophoresis.

Single Layer Transdermal Film Containing Lidocaine: Water and Lidocaine Mobility Determined using Neutron Scattering

The diffusivity of lidocaine through a polymer film developed for transdermal drug administration has been characterized by macroscopic permeation experiments and by neutron quasielastic spectroscopy that provides information on microscopic diffusivity parameters. It turns out that film hydration plays a key role on the performance and efficiency of the investigated system. Diffusion of lidocaine, at the microscopic level, is triggered by the presence of "mobile water." At hydration levels below 15% (weight water/weight hydrated film) neither lidocaine nor water show any appreciable long-range diffusion. At higher hydration levels, the onset of water long-range diffusion triggers diffusion of lidocaine through the film. The use of neutron quasielastic scattering makes it possible to measure lidocaine mobility within the film without the need of any additional physical barrier.

Validation of a Static Franz Diffusion Cell System for In Vitro Permeation Studies

Over the years, in vitro Franz diffusion experiments have evolved into one of the most important methods for researching transdermal drug administration. Unfortunately, this type of testing often yields permeation data that suffer from poor reproducibility. Moreover, this feature frequently occurs when synthetic membranes are used as barriers, in which case biological tissue-associated variability has been removed as an artefact of total variation. The objective of the current study was to evaluate the influence of a full-validation protocol on the performance of a tailor-made array of Franz diffusion cells (GlaxoSmithKline, Harlow, UK) available in our laboratory. To this end, ibuprofen was used as a model hydrophobic drug while synthetic membranes were used as barriers. The parameters investigated included Franz cell dimensions, stirring conditions, membrane type, membrane treatment, temperature regulation and sampling frequency. It was determined that validation dramatically reduced derived data variability as the coefficient of variation for steady-state ibuprofen permeation from a gel formulation was reduced from 25.7% to 5.3% (n = 6). Thus, validation and refinement of the protocol combined with improved operator training can greatly enhance reproducibility in Franz cell experimentation.

Ionic liquid-in-oil microemulsion as a potential carrier of sparingly soluble drug: Characterization and cytotoxicity evaluation

Pharmaceutical industries have posed challenges in the topical and transdermal administration of drugs which are poorly soluble or insoluble in water and most of organic solvents. In an approach to overcome this limitation, ionic liquid-in-oil (IL/o) microemulsions (MEs) were employed to increase the solubility of a sparingly soluble drug to enhance its topical and transdermal delivery. The formulation of MEs was composed of a blend of nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20), isopropyl myristate (IPM) as an oil phase, and IL [C 1mim] [(CH 3O) 2PO 2] (dimethylimidazolium dimethylphosphate) as a pseudophase. Among various weight ratios of Tween-80 to Span-20 investigated in the ME systems, the ratio 3:2 showed excellent solubility and skin permeation enhancing effect for acyclovir (ACV) used as a model sparingly soluble drug. The size and size distribution of the ME droplets with and without drug were determined by dynamic light scattering. The permeability study of ACV incorporated in IL droplets as well as other formulations was performed into and across the Yucatan micropig (YMP) porcine skin, and the use of IL/o MEs has been shown to dramatically increase ACV administration. Finally, the cytotoxicity of the new carrier was evaluated in vitro using the reconstructed human epidermal model LabCyte™ EPI-MODEL12. It was found that the cell viability of IL/o MEs containing 4 wt% IL was over 80% compared to Dulbecco's Phosphate-Buffered Salines, indicating low cytotoxicity of the carrier. Taken together these results, it can be assumed that IL-assisted nonaqueous ME could serve as a versatile and efficient nanodelivery system for insoluble or sparingly soluble drug molecules that require solubilizing agents for delivery.