Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery.
Medizinische Biophysik, Technische Universität München, Germany.
Agents with MW < or = are being delivered transdermally with the aid of skin permeation enhancers that increase the agent's diffusivity and/or partitioning in the organ. Use of composite, lipidic agent-carriers (liposomes, niosomes) was not successful to date, due to the inability of such vehicles to pass through the narrow (< or = 30 nm) intercellular passages (virtual pores) in the outer skin layers. A solution to this problem are the orders of magnitude more deformable supramolecular aggregates, transfersomes. Such innovative drug-carriers are driven across the skin by the noturally occurring, concentration-insensitive, and probably hydration based, transepidermal gradient(s) and transport very efficient (>> 50%) and reproducibly various agents (200 < or = MW < or = 10(6); lipophilic/hydrophilic) into the body. Transfersomes were successfully used in animals and humans, also for the transcutaneous peptide and protein delivery. The theoretical rational for this is described together with the corresponding experimental models and practical examples.
Influence of the flexible liposomes on the skin deposition of a hydrophilic model drug, carboxyfluorescein: dependency on their composition.
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. email@example.com
This study focuses on the effect of different flexible liposomes containing sodium cholate, Tween 80, or cineol on skin deposition of carboxyfluorescein (CF). Size distribution, morphology, zeta potential, and stability of the prepared vesicles were evaluated. The influence of these systems on the skin deposition of CF utilizing rat skin as membrane model was investigated. Results showed that all of the investigated liposomes had almost spherical shapes with low polydispersity (PDI < 0.3) and particles size range from 83 to 175 nm. All liposomal formulations exhibited negative zeta potential, good drug entrapment efficiency, and stability. In vitro skin deposition data showed that flexible liposomes gave significant deposition of CF on the skin compared to conventional liposomes and drug solutions. This study revealed that flexible liposomes, containing cineole, were able to deliver higher amount of CF suggesting that the hydrophilic drugs delivery to the skin was strictly correlated to the vesicle composition.
The dermal application of drugs is promising due to the ease of application. In this context nano-scale carrier systems were already evaluated in several studies with respect to the skin interaction and the impact on drug penetration. At the same time the upcoming production of engineered nano-scale materials requires a thorough safety evaluation. Drug delivery as well as risk assessment depends crucially on the ability of such carriers to overcome the skin barrier and reach deeper tissue layers. Therefore, the interaction of nanoparticles with skin and especially skin models is an intriguing field. However, the data obtained do not show a clear image on the effect of nano-carriers. Especially the penetration of such particles is an open and controversially discussed topic. The literature reports different results mainly on pig or murine skin showing strong penetration (pig and mouse) or the opposite. Looking only at the sizes of the particles also no conclusive picture can be obtained. Nevertheless, size is regarded to play an important role for skin penetration. Furthermore, the state of the skin influences penetration (hydration) and the mechanical stress is of outmost importance.
Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Transdermal drug delivery is an attractive alternative to conventional techniques for administration of systemic therapeutics. One challenge in designing transdermal drug delivery systems is to overcome the natural transport barrier of the skin. Chemicals offer tremendous potential in overcoming the skin barrier to enhance transport of drug molecules. Individual chemicals are however limited in their efficacy in disrupting the skin barrier at low concentrations and usually cause skin irritation at high concentrations. Multicomponent mixtures of chemicals, however, have been shown to provide high skin permeabilization potency as compared to individual chemicals without necessarily causing irritation. Here we review systems employing synergistic mixtures of chemicals that offer superior skin permeation enhancement. These synergistic systems include solvent mixtures, microemulsions, eutectic mixtures, complex self-assembled vesicles and inclusion complexes. Methods for design and discovery of such synergistic systems are also discussed.
Dipartimento Farmaco Chimico Tecnologico, Università di Cagliari, Via Ospedale, 72, 09124 Cagliari, Italy.
The advent of nanotechnological products in the market, while holding great promise, is raising concerns in consumers. Therefore, this contribution will attempt to compare different particulate formulations and to answer whether their passive penetration into, and potential permeation through the skin may be possible or not. To this end, skin structure, composition, and penetration paths will be concisely reviewed. Parameters generally cited to affect skin absorption will be resumed and commented on from the perspective of potentially penetrating nanosized agents. These sections will provide the basis to understand what is fiction and what is reality.(c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci.
Ethosomes: a novel delivery system for antifungal drugs in the treatment of topical fungal diseases.
Pharmacy Department, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Vadodara 390 001, India.
Aim of this work was to prepare and characterize fluconazole (FLZ) encapsulated ethosomes, incorporate it in suitable dermatological base, and asses its comparative clinical efficacy in the treatment of Candidiasis patients against liposomal gel, marketed product and hydroethanolic solution of the drug. Drug encapsulated ethosomes and liposomes were prepared and optimized by "Hot" method technique and lipid film hydration technique. Vesicular carriers were characterized for % entrapment efficiency, particle size and shape, in vitro drug diffusion study, mean % reduction in dimension of Candidiasis lesion and stability study by using suitable analytical technique. Vesicle size and drug entrapment efficiency of the optimized ethosomes and liposomes were found to be 144 +/- 6.8 nm and 82.68% and 216 +/- 9.2 nm and 68.22% respectively. Microscopic examinations suggest ethosomes to be multilamellar spherical vesicles with a smooth surface. The differential scanning calorimetry results suggest high fluidity of the ethosomes than liposomes. In vitro drug diffusion studies demonstrated that % drug diffused from ethosomes was nearly twice than liposomes and three times higher than the hydroethanolic solution across rat skin. From the clinical evaluation, the developed novel delivery system demonstrated enhanced antifungal activity compared to liposomal formulation, marketed formulation and hydroethanolic solution of the drug.
University of Cagliari, Dipartimento Farmaco Chimico Tecnologico, 09124 Cagliari -Italy.
The skin can offer several advantages as a route of drug administration although its barrier nature makes it difficult for most drugs to penetrate into and permeate through it. During the past decades there has been a lot of interest in lipid vesicles as a tool to improve drug topical delivery. Vesicular systems such as liposomes, niosomes, ethosomes and elastic, deformable vesicles provide an alternative for improved skin drug delivery. The function of vesicles as topical delivery systems is controversial with variable effects being reported in relation to the type of vesicles and their composition. In fact, vesicles can act as drug carriers controlling active release; they can provide a localized depot in the skin for dermally active compounds and enhance transdermal drug delivery. A wide variety of lipids and surfactants can be used to prepare vesicles, which are commonly composed of phospholipids (liposomes) or non-ionic surfactants (niosomes). Vesicle composition and preparation method influence their physicochemical properties (size, charge, lamellarity, thermodynamic state, deformability) and therefore their efficacy as drug delivery systems. A review of vesicle value in localizing drugs within the skin at the site of action will be provided with emphasis on their potential mechanism of action.
The influence of porosity changes in human epidermal membrane during iontophoresis on the permeability enhancement of a model peptide.
Division of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA. firstname.lastname@example.org
PURPOSE We tested the hypothesis that the increases in the porosity of the skin during iontophoresis would not significantly increase the transport of peptides due to the small size of electrically induced pores. To investigate this mechanistically, we used human epidermal membrane under constant voltage conditions, applying the Nernst-Planck equation to the transport of a small ionic solute, tetraethylammonium bromide (TEAB), and a model peptide, luteinizing hormone releasing hormone. METHODS Steady-state flux of the drugs was determined under passive conditions and also during iontophoresis using constant DC voltages applied across side-by-side diffusion cells. Electrical conductance measurements were used to monitor the porosity changes that occur during electrical field application. RESULTS Porosity increases observed in the membrane substantially increased the permeability enhancement of the small ionic solute TEAB. The permeability enhancement was well described by Nernst-Planck model predictions after porosity changes in the membrane were taken into account. Enhancement of luteinizing hormone releasing hormone under identical conditions was much less than TEAB. The porosity increases induced by iontophoresis had little or no effect on the permeability enhancement of the larger molecule. CONCLUSIONS These findings closely parallel those reports that have found electrically induced pores to be significantly smaller than preexisting pores in the human epidermal membrane. The data obtained also support the view that iontophoresis-induced pores, alone, may provide limited benefit for macromolecule transport across the skin.
Effect of topically applied sphingomyelin-based liposomes on the ceramide level in a three-dimensional cultured human skin model.
Yoshihiro Tokudome, Raina Uchida, Takeshi Yokote, Hiroaki Todo, Nobuko Hada, Tatsuhiko Kon, Junko Yasuda, Hidenori Hayashi, Fumie Hashimoto, Kenji Sugibayashi
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
Sphingomyelin-based liposomes were prepared and applied to the stratum corneum side or basal layer side of a three-dimensional (3D) cultured human skin model, and the increase in the type II ceramide (ceramide II) content of the cultured skin model was evaluated. The sphingomyelin-based liposomes were prepared by a high-pressure emulsification method, and the obtained liposomes were characterized; the particle diameter and zeta potential of the liposomes were 155.3 nm and -11.4 mV, respectively. Their spherical shape and lamella structure were observed by transmission electron microscopy. The sphingomyelin-based liposomes or saline were applied to the cultured skin model, and ceramide II was extracted from the skin model. The extracted ceramide II was separated by high-performance thin-layer chromatography and quantified by a densitometer. The amount of ceramide II in the cultured skin model was significantly increased by the application of the sphingomyelin-based liposomes, compared with the nonapplication group. Thus, sphingomyelin-based liposomes are useful for enriching the ceramide level in 3D cultured skin models.
AFM phase imaging of soft-hydrated samples: a versatile tool to complete the chemical-physical study of liposomes.
Barbara Ruozi, Giovanni Tosi, Massimo Tonelli, Lucia Bondioli, Adele Mucci, Flavio Forni, Maria Angela Vandelli
Department of Pharmaceutical Science, University of Modena and Reggio Emilia, Modena, Italy.
Despite of the several approaches applied to the physicochemical characterization of liposomes, few techniques are really useful to obtain information about the surface properties of these colloidal drug-delivery systems. In this paper, we demonstrate a possible new application of tapping mode atomic force microscopy (AFM) to discriminate between conventional and pegylated liposomes. We showed that the differences on liposomal surface properties revealed by the phase images AFM approach well correlate with the data obtained using classical methods, such as light scattering, hydrodynamic, and nuclear magnetic resonance analysis.
Preparation and characterization of ceramide-based liposomes with high fusion activity and high membrane fluidity.
Cutaneous Drug Research Laboratories, POLA Chemical Industries, INC., 244-0812 Yokohama, Japan. email@example.com
Liposomes are useful vesicles that deliver drugs effectively to various organs. For transdermal applications, liposomes with high membrane fluidity, high fusion activity, and comprising stratum corneum lipid have been used for drug delivery. With the aim to increase drug distribution to the skin, we developed new liposomes with three characteristics: high membrane fluidity, high fusion activity to the stratum corneum lipid liposomes (SCLL), and lipid compositions based on stratum corneum lipids. New liposomes were prepared based on SCLL. First, lipid compositions of SCLL were optimized. Second, the alkyl chain length of ceramides and fatty acids, and the saturation degree of fatty acids were altered. As a result, liposomes with the highest membrane fluidity and fusion activity to SCLL were composed of C-8 ceramide/cholesterol/linolenic acid/cholesterol sulfate = 45/5/5/45 (w/w%), and named C8L. C8L had 1.54-times greater membrane fluidity and 6.57-times greater fusion activity to SCLL than SCLL. Transmission electron microscopy revealed that C8L had a spherical structure. The surface charge and the particle size were approximately -47.7 mV and 184 nm, respectively. Thus, in the future, C8L will be used to facilitate drug delivery to the skin.
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IDEA AG, Frankfurter Ring 193a, D-80807 Munich, Germany. firstname.lastname@example.org
We compared a new formulation of ketoprofen (Diractin) based on ultradeformable vesicle (Transfersome) carriers with conventional topical gels with the drug (Gabrilen; Togal Mobil Gel; Fastum). Depending on water concentration, between a few percent and >95% of ketoprofen in Diractin is associated with the vesicles. The low free drug concentration on open skin (1-3%) minimises ketoprofen diffusion from Diractin through the organ, keeping effective permeability coefficient for the product (even after increase to approximately 3.5 x 10(-3) cm h(-1) at 24h) below that of conventional gels ( approximately 0.3-2.1 x 10(-1) cm h(-1)). The carrier's stress-responsiveness enables constriction crossing without vesicle breakdown. The carrier stiffening upon dilution, e.g. in tissues below the skin's diffusive barrier, helps avoiding the drug uptake in cutaneous blood capillaries. Diractin therefore can deposit ketoprofen in deep subcutaneous tissues, which the drug from conventional gels reaches mainly via systemic circulation. In vitro efficacy of daily drug delivery through skin is < or =1.6% for conventional topical NSAID gels and merely approximately 0.05% for Diractin. In contrast, in vivo ketoprofen transport by ultradeformable carriers through non-occluded skin into living pigs' subcutaneous muscles is 5-14x better than for conventional gels. Locally targeted drug transport by the self-regulating, ultradeformable vesicles is thus clearly non-diffusive and quite efficient.
Surface-induced x-ray reflection visualization of membrane orientation and fusion into multibilayers.
The fusion of lipid membranes at the air-water interface has been detected with the use of x-ray reflection as a high-resolution, surface-sensitive technique. The rate of this fusion for dimyristoylphosphatidylcholine (DMPC) bilayers is the highest at 29 degrees C, which coincides with the chain-melting phase-transition temperature for the top membrane layers. After 6 hours of incubation a stack of at least ten surface-ordered membrane bilayers in equilibrium with the bulk vesicle suspension is formed. Such fusion is thus surface-catalyzed but not restricted to the first surface layer. The process involves partial membrane dehydration near the solution surface which decreases toward the bulk.
The use of solvent relaxation technique to investigate headgroup hydration and protein binding of simple and mixed phosphatidylcholine/surfactant bilayer membranes.
IDEA AG, Frankfurter Ring 193 a, 80807 Munich, Germany.
The subject of this report was to investigate headgroup hydration and mobility of two types of mixed lipid vesicles, containing nonionic surfactants; straight chain Brij 98, and polysorbat Tween 80, with the same number of oxyethylene units as Brij, but attached via a sorbitan ring to oleic acid. We used the fluorescence solvent relaxation (SR) approach for the purpose and revealed differences between the two systems. Fluorescent solvent relaxation probes (Prodan, Laurdan, Patman) were found to be localized in mixed lipid vesicles similarly as in pure phospholipid bilayers. The SR parameters (i.e. dynamic Stokes shift, Deltanu, and the time course of the correlation function, C(t)) of such labels are in the same range in both kinds of systems. Each type of the tested surfactants has its own impact on water organization in the bilayer headgroup region probed by Patman. Brij 98 does not modify the solvation characteristics of the dye. In contrast, Tween 80 apparently dehydrates the headgroup and decreases its mobility. The SR data measured in lipid bilayers in presence of Interferon alfa-2b reveal that this protein, a candidate for non-invasive delivery, affects the bilayer in a different way than the peptide melittin. Interferon alfa-2b binds to mixed lipid bilayers peripherally, whereas melittin is deeply inserted into lipid membranes and affects their headgroup hydration and mobility measurably.
Medizinische Biophysik, Technische Universität München, Klinikum r.d.l., Ismaningerstr. 22, D-81675 München, E.U., Germany.
Molecular recognition plays a key role in life. Macromolecular interactions at and with interfaces are of paramount importance in this respect. It is therefore crucial to understand and quantify the forces near the surfaces of biological interest in sufficient detail. Specific binding of large molecules, such as antibodies, is affected by the proximity of polar surfaces, for example. On the one hand, the presence of the net surface charges may raise or lower the local macromolecular concentration depending on the relative sign of the charges involved. On the other hand, the ligands attached to strongly polar surfaces always attract and bind their corresponding antibodies less efficiently than the corresponding dissolved molecules. The reason for this is the non-Coulombic repulsion between the ligand-presenting polar surface and the approaching macromolecule. This force is promoted by the surface hydrophilicity and the width of the interfacial region. A simple, direct hydration force is seldom, if ever, seen in such systems.(This is owing to the very short range (Lambda (h ) reverse similar 0.1 nm ) of pure hydration force.) The non-specific adsorption of proteins to the lipid bilayer is also little affected by the overall repulsion between the macromolecule and the bilayer surface; such an adsorption is governed more by the number of defects and/or by the availability of the hydrophobic binding sites in the interfacial region. Artificial lipid membranes typically offer numerous such binding sites to the surrounding macromolecules. Multiple non-specific protein adsorption, which results in partial macromolecular denaturation or complement activation, is therefore one of the main reasons for the rapid elimination of lipid vesicles from the blood stream in vivo. To promote the circulation time of an intravenously injected lipid suspension it is therefore necessary to modify the surfaces of their constituent lipid bilayers. Increasing the surface net charge density and/or increasing the bilayer surface hydrophilicity is of little use in this respect. In order to affect the non-specific bilayer-protein interactions significantly, an optimal number of water-soluble, short and sufficiently mobile polymers must be attached to the lipid head-groups. These polymers then increase the repulsive barrier of the membrane surface dramatically, due to the generation of a thick and mobile as well as strongly hydrated interface. Owing to this, the affinity for proteins of the resulting surface is lowered and the surface-induced protein denaturation or complement insertion is hampered. Polymer-coated liposomes, consequently, are not attractive for the phagocytic cells. Such liposomes, consequently, remain in the blood circulation much longer than simple lipid vesicles; the former, consequently, may spontaneously accumulate in tumors.
Permeabilisation and solubilisation of soybean phosphatidylcholine bilayer vesicles, as membrane models, by polysorbate, Tween 80.
INETI, Departamento de Biotecnologia, UNFAB, Estada do Paço do Lumiar, 22, Edifício F, 1649-038 Lisboa, Portugal.
To understand better the wide-spread pharmaceutical use of non-ionic surfactant Tween 80 (TW), the colloidal properties of the surfactant alone and in combinations with the common phospholipid, phosphatidylcholine (PC), were studied. Static and dynamic light scattering revealed that TW solubilises PC at TW/PC approximately 2.75/1 mol/mol and that TW micelle disintegration occurs on time-scale of 2.5 min, independent of amphipath concentration. This is up to nearly 300-times faster than the TW caused dissolution of PC containing unilamellar vesicles. The apparent dissolution time of TW/PC mixed aggregates, in contrast, decelerates from >700 min to <5 min upon increasing starting total amphipath concentration, with thermal activation energy > or =24 (< or =80) kJ mol(-1). The aggregate dissolution rate in highly concentrated TW/PC suspensions reflects the dissolved polysorbate-aggregate exchange rate (approximately 6.7 x 10(-3)s(-1)) rather than TW flip-flop rate across a bilayer (>0.2 min(-1)). PC solubilisation proceeds linearly with the square-root of time, and is kinetically governed by the speed of surfactant diffusion through the bulk (D approximately 2.8 x 10(-11)m2 s(-1)). Creation of small Tween-phosphatidylcholine mixed micelles is typically preceded by pre-solubilisation structures, first in the form of deformable, strongly fluctuating, bilayer vesicles and then of elongated, presumably thread-like, mixed micelles. TW/PC mixed micelles become smaller with growing surfactant/lipid molar ratio, whereas TW/PC mixed vesicles become more and more leaky with increasing surfactant concentration. Our results highlight the molecular and kinetic aspects of polysorbate-membrane interactions and provide a rationale for the popularity of Tween surfactants in pharmaceutical products: such surfactants can solubilise fatty molecules and bilayer membranes but need quite a long time for this, which is available in pharmaceutical preparations but normally not in vivo; this makes Tweens relatively efficient and safe. Furthermore, our data could help design better ultra-deformable mixed lipid-surfactant vesicles for the non-invasive transdermal drug delivery across the skin.
Since the introduction of the first through the skin (TTS) therapeutic in 1980, a total of 34 TTS products have been marketed and numerous drugs have been tested by more than 50 commercial organisations for their suitability for TTS delivery. Most of the agents which have been tested have had low molecular weights, due to the impermeability of the skin barrier. This barrier resides in the outermost skin layer, the stratum corneum. It is mechanical, anatomical, as well as chemical in nature; laterally overlapping cell multi-layers are sealed by tightly packed, intercellular, lipid multi-lamellae. Chemical skin permeation enhancers increase the transport across the barrier by partly solubilising or extracting the skin lipids and by creating hydrophobic pores. This is often irritating and not always well-tolerated. The TTS approach allows drugs (< 400 kDa in size) to permeate through the resulting pores in the skin, with a short lag-time and subsequent steady-state period. Drug bioavailability for TTS delivery is typically below 50%, avoiding the first pass effect. Wider, hydrophilic channels can be generated by skin poration, with the aid of a small electrical current (> 0.4 mA/cm2) across the skin (iontophoresis) or therapeutic ultrasound (few W/cm2; sonoporation). High-voltage (> 150 V, electroporation) widens the pores even more and often irreversibly. These standard poration methods require experience and equipment and are therefore, not practical; at best, charged/small molecules (< or = 4000 kDa in size) can be delivered efficiently across the skin. In spite of the potential harm of gadget-driven skin poration, this method is used to deliver molecules which conventional TTS patches are unable to deliver, especially polypeptides. Lipid-based drug carriers (liposomes, niosomes, nanoparticle microemulsions, etc.) were proposed as alternative, low-risk delivery vehicles. Such suspensions provide an improved drug reservoir on the skin, but the aggregates remain confined to the surface. Conventional carrier suspensions increase skin hydration and/or behave as skin permeation enhancers. The recently developed carriers; Transferomes, comprise pharmaceutically-acceptable, established compounds and are thought to penetrate the skin barrier along the naturally occurring transcutaneous moisture gradient. Transfersomes are believed to penetrate the hydrophilic (virtual) channels in the skin and widen the former after non-occlusive administration. Both small and large hydrophobic and hydrophilic molecules are deliverable across the stratum after conjugation with Transfersomes. Drug distribution after transdermal delivery probably proceeds via the lymph. This results in quasi-zero order kinetics with significant systemic drug levels reached after a lag-time of up to a few hours. The relative efficiency of TTS drug delivery with Transfersomes is typically above 50 %; with the added possibility of regional drug targeting.
The effect of cholate on solubilisation and permeability of simple and protein-loaded phosphatidylcholine/sodium cholate mixed aggregates designed to mediate transdermal delivery of macromolecules.
UNFAB, Departamento de Biotecnologia, INETI, Lisboa, Portugal, EU.
Carriers for non-invasive administration of biologically important antioxidant enzymes Cu,Zn-superoxide dismutase (SOD) and catalase (CAT) were developed. Solubilisation and permeabilities of various soybean phosphatidylcholine/sodium cholate (SPC/NaChol) mixtures, mainly in the form of lipid bilayers, focussing on system properties relevant for non-invasive enzyme delivery were investigated in this work. Static and dynamic light scattering measurements gave information on the behaviour of the systems containing up to 40 mM NaChol and 30.6-1.2 mM SPC in the final suspension. The average size of such mixed aggregates was in the 100-200 nm range. Suspension turbidity decreased by 50% upon increasing nominal molar detergent/lipid ratio to NaChol/SPC = 7 and 1.25, in case of SPC = 1.2 and 19.6 mM, respectively. The effective NaChol/SPC molar ratio in bilayers saturated with the detergent was found to be: R(e)(sat)= 0.70 +/- 0.01; bilayer solubilisation point corresponded to R(e)(sol)= 0.97 +/- 0.02, independently of enzyme loading. Vesicles became very permeable to SOD when membrane bound NaChol concentration exceeded 13.7 mM, in case of total starting lipid concentration of 138 mM diluted to SPC = 19.6 mM. Specifically, we measured a 50% loss of SOD from the vesicles with an aggregate-associated molar detergent ratio NaChol/SPC approximately 0.7, which is near the saturation but well below the solubilisation limit. Calcein efflux from such vesicles was compared with SPC/NaChol/SOD mixed aggregates. Our results should contribute to the future design of vesicle mediated transdermal delivery of antioxidant enzymes.
Improved risk-benefit ratio for topical triamcinolone acetonide in Transfersome in comparison with equipotent cream and ointment: a randomized controlled trial.
Department of Dermatology and Allergy, Technical University Munich, Biedersteinerstr. 29, 80802 Munich, Germany. email@example.com
BACKGROUND Transfersome is a drug delivery technology based on highly deformable, ultraflexible lipid vesicles which penetrate the skin when applied non-occlusively. OBJECTIVES To assess the advantages of this carrier-based formulation in humans, the efficacy and the atrophogenic potential of triamcinolone acetonide (TAC) in Transfersome was compared with commercially available TAC-containing cream and ointment. METHODS Healthy volunteers were enrolled in double-blind, placebo-controlled clinical trials with random study medication assignment to the test areas. RESULTS A 10-fold lower dose of TAC in Transfersome(R)(2.5 micro g cm-2) was bioequivalent to 25 micro g cm-2 TAC in conventional formulations as measured by erythema suppression (cream: P = 0.01, ointment: P < 0.001). A skin blanching assay revealed different kinetics of the formulations, with a delayed onset of action of the Transfersome and ointment preparations. Ultrasonic measurements revealed a significantly reduced atrophogenic potential. There was a 12.1% reduction in skin thickness given by TAC in Transfersome compared with a 21.1% reduction given by a bioequivalent dose in TAC cream after a 6-week treatment period (P = 0.007). CONCLUSIONS Transfersome may significantly improve the risk-benefit ratio of topically applied glucocorticosteroids.
New, highly efficient formulation of diclofenac for the topical, transdermal administration in ultradeformable drug carriers, Transfersomes.
Medizinische Biophsik, Technische Universität Müchen, Munich, Germany. firstname.lastname@example.org
Transfenac, a lotion-like formulation of diclofenac, is described. It consists of pharmaceutically acceptable ingredients and mediates the agent transport through intact skin and into the target tissues. Therapeutically meaningful drug concentrations in the target tissue are reached even when the administered drug dose in Transfenac is below 0.5 mg/kg body weight. Ultradeformable agent carriers, called Transfersomes, form the basis of Transfenac. These Transfersomes are proposed to cross the skin spontaneously under the influence of transepidermal water activity gradient (see [Biochim. Biophys. Acta 1104 (1992) 226]). Diclofenac association with ultradeformable carriers permits it to have a longer effect and to reach 10-times higher concentrations in the tissues under the skin in comparison with the drug from a commercial hydrogel. For example, Transfenac achieves intramuscular agent concentrations between 0.5 and 2 microg/g and 2 and 20 microg/g at t=12 h, depending on the tissue depth, when it is administered in the dose range 0.25-2 mg/kg of rat body weight. A much higher drug concentration in a hydrogel (1.25-10 mg/kg body weight) creates the drug level of only <0.5 microg/g in the muscle. The drug concentration in the rat patella for these two types of formulation is between 1 microg/g and 5 microg/g or 0.4 microg/g, respectively. The relative advantage of diclofenac delivery by means of ultradeformable carriers increases with the treated muscle thickness and with decreasing drug dose, as seen in mice, rats and pigs; this can be explained by assuming that the drug associated with carriers is cleared less efficiently by the dermal capillary plexus. In pigs it suffices to use 0.3 mg of diclofenac in highly deformable vesicles per kg body weight, spread over an area of 25 cm(2), to ensure therapeutic drug concentration in a 5-cm thick muscle specimen, collected under the agent application site. When the drug is used in a hydrogel at 8 times higher dose, the average intramuscular concentration is at least three times lower and subtherapeutic. This suggests that diclofenac in Transfersomes has the potential to replace combined oral/topical diclofenac administration in humans.
Medizinische Biophysik, Technische Universität München, Klinikum r.d.I., Ismaningerstrasse 22, D-81675, Munich, Germany
Membrane fusion is essential for cell survival and has attracted a great deal of both theoretical and experimental interest. Fluorescence (de)quenching measurements were designed to distinguish between bilayermerging and vesicle-mixing. Theoretical studies and various microscopic and diffraction methods have elucidated the mechanism of membrane fusion. These have revealed that membrane proximity and high defect density in the adjacent bilayers are the only prerequisites for fusion. Intermediates, such as stalk or inverse micellar structures can, but need not, be involved in vesicle fusion. Nonlamellar phase creation is accompanied by massive membrane fusion although it is not a requirement for bilayer merging. Propensity for membrane fusion is increased by increasing the local membrane disorder as well by performing manipulations that bring bilayers closer together. Membrane rigidification and enlarged bilayer separation opposes this trend. Membrane fusion is promoted by defects created in the bilayer due to the vicinity of lipid phase transition, lateral phase separation or domain generation, high local membrane curvature, osmotic or electric stress in or on the membrane; the addition of amphiphats or macromolecules which insert themselves into the membrane, freezing or other mechanical membrane perturbation have similar effects. Lowering the water activity by the addition of water soluble polymers or by partial system dehydration invokes membrane aggregation and hence facilitates fusion; as does the membrane charge neutralization after proton or other ion binding to the lipids and intermembrane scaffolding by proteins or other macromolecules. The alignment of defect rich domains and polypeptides or protein binding is pluripotent: not only does it increase the number of proximal defects in the bilayers, it triggers the vesicle aggregation and is fusogenic. Exceptions are the bound molecules that create steric or electrical barriers between the membranes which prevent fusion. Membrane fusion can be non-leaky but it is very common to lose material from the vesicle interior during the later stages of membrane unification, that is, after a few hundred microseconds following the induction of fusion.
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Pharm Res. 2012 Nov 10;: 23138262
Skin Permeation of Small-Molecule Drugs, Macromolecules, and Nanoparticles Mediated by a Fractional Carbon Dioxide Laser: The Role of Hair Follicles.
Graduate Institute of Medical Sciences,, Taipei Medical University, Taipei, 110, Taiwan.
PURPOSE: To evaluate skin permeation enhancement mediated by fractional laser for different permeants, including hydroquinone, imiquimod, fluorescein isothiocyanate-labeled dextran (FD), and quantum dots. METHODS: Skin received a single irradiation of a fractional CO(2) laser, using fluence of 2 or 4 mJ with densities of 100 ∼ 400 spots/cm(2). In vitro and in vivo skin penetration experiments were performed. Fluorescence and confocal microscopies for imaging delivery pathways were used. RESULTS: The laser enhanced flux of small-molecule drugs 2 ∼ 5-fold compared to intact skin. A laser fluence of 4 mJ with a 400-spot/cm(2) density promoted FD flux at 20 and 40 kDa from 0 (passive transport) to 0.72 and 0.43 nmol/cm(2)/h, respectively. Microscopic images demonstrated a significant increase in fluorescence accumulation and penetration depth of macromolecules and nanoparticles after laser exposure. Predominant routes for laser-assisted delivery may be intercellular and follicular transport. CO(2) laser irradiation produced 13-fold enhancement in follicular deposition of imiquimod. Laser-mediated follicular transport could deliver permeants to deeper strata. Skin barrier function as determined by transepidermal water loss completely recovered by 12 h after irradiation, much faster than conventional laser treatment (4 days). CONCLUSIONS: Fractional laser could selectively enhance permeant targeting to follicles such as imiquimod and FD but not hydroquinone, indicating the importance of selecting feasible drugs for laser-assisted follicle delivery.
AAPS PharmSciTech. 2012 Oct 27;: 23104306
Formulation of Niosomal Gel for Enhanced Transdermal Lopinavir Delivery and Its Comparative Evaluation with Ethosomal Gel.
Centre for Research in Pharmaceutical Sciences, The M.S. University of Baroda, Shri G.H. Patel Pharmacy Building, Vadodara, 390002, India.
The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0→∞), 72.87 h × μg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.
Int J Dermatol. 2012 Aug 23;: 22913389
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei Department of Director Office, Animal Technology Institute Taiwan, Miaoli Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei Department of R & D, PRIT Biotech Company, Miaoli Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
Objectives The primary objective of this study was to investigate the feasibility of using niosomes as a delivery vehicle for the dermal administration in vitro of black tea extract (BTE) as a sunscreen. Methods Multi-lamellar niosomes were obtained by means of a previously reported method of lipid hydration films. In vitro penetration experiments through nude mouse skin were carried out to evaluate the potential of niosomes as a dermal formulation. The nude mouse skin membrane allowed the effects of penetration with a niosome formulation to be evaluated. Penetration rates of caffeine- and gallic acid-loaded niosomes in a steady state were higher than dispersion in aqueous solutions. Results For skin permeation, higher transdermal absorption rates were seen with solutions of caffeine and gallic acid. Conclusions In the near future, BTE as a sunscreen agent will be dermally delivered by niosomes.
The impact of AT1002 on the delivery of ritonavir in the presence of bioadhesive polymer, carrageenan.
Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, Baltimore, 21201, USA. email@example.com
New insights into the modification of the tight junctions theoretically offer the opportunity to regulate the diffusion barrier and then make it possible to investigate a permeation enhancer of low-bioavailability therapeutic agents. AT1002, a minimum biologically active fragment of zonula occludens toxin which reversibly opens intercellular tight junctions after binding to the Zonulin receptor, increased the transport of various molecular weight markers or low-bioavailability agents. The objective of this study was continuously to evaluate the permeation-enhancing ability of AT1002 in the presence of the bioadhesive agent, carrageenan after intranasal administration of the antiretroviral drug, ritonavir, and the permeation enhancement ratio compared with the previous results. The permeation-enhancing effect of AT1002 was significantly promoted by the bioadhesive agent, carrageenan. The administration of ritonavir with AT1002 and carrageenan resulted in a 2.55-fold increase in AUC(0-240min) and a 2.48-fold increase in C(max) compared with the control group. However, AT1002 in the absence of carrageenan did not produce a statistic enhancement in the absorption of ritonavir. Hence, AT1002 together with the addition of carrageenan may open a new approach of research in the tight junction modulated permeation enhancer, and allow the development of the mucosal drug delivery of therapeutic agents.
Department of Pharmaceutics, School of Pharmacy, University of Mississippi, University, MS, USA.
PURPOSE The objective of the present work was to investigate the effect of combination of a novel physical permeation enhancement technique, magnetophoresis with chemical permeation enhancers on the transdermal delivery of drugs. METHODS The in vitro drug transport studies were carried out across the freshly excised abdominal skin of Sprague-Dawley rats using transdermal patch systems (magnetophoretic and non-magnetophoretic) of lidocaine hydrochloride (LH). LH gel prepared using hydroxypropyl methylcellulose (HPMC) was spread over the magnets as a thin layer. To investigate the effect of chemical permeation enhancers, menthol, dimethyl sulfoxide, sodium lauryl sulfate and urea (5% w/v) were incorporated in the gels prior to loading on the patch system. RESULTS The flux of lidocaine from magnetophoretic patch was ~3-fold higher (3.07 ± 0.43 µg/cm(2)/h) than that of the control (non-magnetophoretic patch)(0.94 ± 0.13 µg/cm(2)/h). Incorporation of chemical permeation enhancers in the gel enhanced the magnetophoretic delivery flux by ~4 to 7-fold. CONCLUSIONS The enhancement factor due to combination of chemical permeation enhancer was additive and not synergistic. Mechanistic studies indicated that magnetophoresis mediated drug delivery enhancement was via appendageal pathway.
Eur J Pharm Biopharm. 2011 Feb 12;: 21303691
Department of Pharmaceutical Sciences, Calabria University, Rende, Italy.
The central motivation for this study was to evaluate if the increased hydrophilic drug permeation across the skin, which is always observed in presence of vesicular systems, is dependent on the structural organization of niosomes, that are used to transport the active molecules, or if it is only dependent on the surfactant dual nature. To answer this question, non-ionic surfactants belonging to the class of Pluronic and sucrose esters were used both as components of niosomal systems or in the form of sub-micellar solutions. The obtained niosomes were characterized by their entrapment efficiency, size and morphology. The enhancing effect of niosomes on the ex vivo percutaneous penetration of a model drug was investigated using a Franz-type diffusion chamber and compared to that obtained by using sub-micellar solution of surfactant or achieving pretreatment of the skin with surfactants' sub-micellar solution or empty niosomes. The results suggest that the surfactants used in this study could be considered as percutaneous permeation enhancers only when they are in the form of drug-loaded vesicular systems: no percutaneous promotion was achieved by using sub-micellar solution containing free Sulfadiazine sodium salt or performing pretreatment with empty niosomes or sub-micellar solutions of the surfactant. In our experiments, only niosomes act as effective transdermal drug delivery systems.
Ther Deliv. 2010 Jul ;1 (1):109-131 21132122
Kalpana S Paudel, Mikolaj Milewski, Courtney L Swadley, Nicole K Brogden, Priyanka Ghosh, Audra L Stinchcomb
College of Pharmacy, University of Kentucky, Lexington, KY 40536-0200, USA.
Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs.
J Liposome Res. 2010 Jun 18;: 20557280
Efficacy study of vesicular gel containing methotrexate and menthol combination on parakeratotic rat skin model.
Drug Delivery Laboratory, TIFAC Center of Relevance and Excellence in NDDS, Department of Pharmacy, The M.S. University of Baroda, Vadodara, India.
Methotrexate (MTX) is indicated in the symptomatic control of severe, recalcitrant, and disabling psoriasis. The oral or parenteral route of administration causes systemic toxicity. The topical route of delivery, though, reduces systemic toxicity and has limited applicability due to restricted permeability. Liposomal and niosomal MTX topical formulations have also been investigated with limited success to achieve drug localization in the skin. Menthol has been suggested in conditions of psoriasis, in addition to its skin-penetration-enhancing effect on drugs. The present work aimed at investigating the potential benefits of combining menthol with MTX in a vesicular gel base for not only improving the penetration and dermal availability of MTX, but also to render such a formulation more effective with greater patient acceptability. MTX liposomes were prepared by thin-film hydration, and the vesicles were characterized for drug-entrapment efficiency, size, and morphology. These liposomal vesicles were incorporated in a gel base, and this vesicular gel was evaluated for transdermal drug permeation and extent of drug accumulation in the skin, using a rat skin ex vivo model. Skin histology studies were carried out to investigate any structural changes caused by the permeation enhancers. Antipsoriatic efficacy of the formulations was tested in vivo, using the rat tail model. The results indicated that the vesicular gel containing menthol could cause maximum drug retention in the skin. The skin treated with menthol had a disrupted epidermis and microcavities. The in vivo studies also ascertained the effectiveness of the formulation in inducing a normal pattern of differentiation in the rat tail skin that initially showed parakeratosis, which is also characteristic of psoriatic epidermis. These results show the potential of vesicular gel containing MTX and menthol to improve penetration into the skin and cause drug retention in skin appendages.
Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride.
In Hee Han, Sung-Up Choi, Dae Young Nam, Young Mi Park, Myung Joo Kang, Kyoung Hoon Kang, Yong Min Kim, Gunho Bae, Il Young Oh, Jong Hyeok Park, Jin Soo Ye, Yoon Bae Choi, Duk Ki Kim, Jaehwi Lee, Young Wook Choi
Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Korea.
As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.
José Juan Escobar-Chávez Dr, Dalia Bonilla-Martí Nez, Martha Angélica Villegas-González, Alma Luisa Revilla-Vázquez
Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México.
Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of high-voltage pulses to the skin increases its permeability (electroporation) and enables the delivery of various substances into and through the skin. The application of electroporation to the skin has been shown to increase transdermal drug delivery. Moreover, electroporation, used alone or in combination with other enhancement methods, expands the range of drugs (small to macromolecules, lipophilic or hydrophilic, charged or neutral molecules) that can be delivered transdermally. The efficacy of transport depends on the electrical parameters and the physicochemical properties of drugs. The in vivo application of high-voltage pulses is well tolerated, but muscle contractions are usually induced. The electrode and patch design is an important issue to reduce the discomfort of the electrical treatment in humans. This review presents the main findings in the field of electroporation-namely, transdermal drug delivery. Particular attention is paid to proposed enhancement mechanisms and trends in the field of topical and transdermal delivery.