Elka Touitou

Enhanced delivery of drugs into and across the skin by ethosomal carriers

In dermal and transdermal delivery, the skin is used as a portal of entry for drugs, for localized and systemic treatment. Because of the barrier properties of the outer layer of the skin, in many cases, permeation‐enhancing agents are needed to achieve therapeutic levels of drug. Classic liposomal systems were found to be effective at forming drug reservoir in the upper layers of the skin, for local skin therapy. Recently, it was found that ethosomal carriers, phospholipid vesicular systems containing relatively high concentrations of alcohol, were very effective at enhancing dermal and transdermal delivery of both lipophilic and hydrophilic molecules. Fluorescent probes delivered from ethosomal systems reached the deep strata of the skin. Delivery of minoxidil to the pilosebaceous units from ethosomes was much greater compared to delivery from classic liposomes. In addition, clinical studies with aciclovir showed that ethosomal formulations were superior to the currently available topical therapy at treating recurrent herpes labialis. Ethosomal systems were also highly effective at transdermal delivery of drugs. In vivo skin permeation of testosterone from patches containing ethosomal drug were more effective at delivering testosterone through rabbit pinna skin than commercially available Testoderm patches. Results using trihexyphenidyl hydrochloride ethosomes indicated that this system has the potential to be further developed into an antiparkinsonian patch. Lastly, the transdermal delivery of insulin from an ethosomal carrier resulted in lower blood glucose levels in normal and diabetic rats in vivo, with a plateau effect lasting for at least 8 h. Drug Dev. Res. 50:406–415, 2000.

Methods for quantitative determination of drug localized in the skin

The quantification of drugs within the skin is essential for topical and transdermal delivery research. Over the last two decades, horizontal sectioning, consisting of both tape stripping and parallel slicing through the deeper tissues has constituted the traditional investigative technique. In recent years, this methodology has been augmented by such procedures as heat separation, qualitative autoradiography, isolation of the pilosebaceous units and the use of induced follicle-free skin. The development of skin quantitative autoradiography represents an entirely novel approach which permits quantification and visualization of the penetrant throughout a vertical cross-section of skin. Noninvasive strategies involve the application of optical measuring systems such as attenuated total reflectance Fourier transform infrared, fluorescence, remittance or photothermal spectroscopies.

Targeted enteral delivery of insulin to rats

The aim of the present work was to investigate the effectiveness of a dosage form approach for monitoring both the inactivation and the absorption processes by targeting insulin delivery to the colon. The dosage form design is based on incorporating insulin into small, soft gelatin capsules coated with polyacrylic polymer (Eudragit) having pH-dependent properties. The capsules were filled with 100 mg of the following formulation: 8 units (u) porcine insulin and 20 mg of surfactant mixture (sodium laurate: cetyl alcohol 2 : 8) in arachis oil, and were coated with mixtures of various ratios of Eudragit RS, L and S. The in vitro pH-dependent release rates of coated capsules were tested by scintillation counting using [125I]insulin and two formulations which released the drug the most between pHs 7.5 and 8.0 (RS1 and RS2) were chosen for further studies in rats. Insulin absorption was measured by its hypoglycemic effect. Blood glucose concentrations were determined at 610 nm using the GOD-Perid method. The oral administration of the two chosen insulin-containing formulations gave significant (P<0.01) hypoglycemia when compared with controls. However, the duration, course and the intensity of effect were different for each formulation: the longest effect was obtained with formulation RS1 while the maximum glucose level reduction (up to 45% of initial value) occurred with formulation RS2. It was interesting to observe that the preadministration of a surfactant capsule did not change the glycemic profile; however, its post-administration prolonged the effect of RS2 by one hour.

Modulation of caffeine skin delivery by carrier design: liposomes versus permeation enhancers

Abstract Delivery systems for caffeine have been designed for two different purposes: (1) enhancing drug permeation through the skin for systemic delivery and (2) accumulating drug reservoir in the skin for local delivery. Caffeine exhibited concentration-dependent growth inhibition of normal and psoriatic human fibroblasts, as well as 3T3 mouse fibroblasts. High flux of caffeine through the skin was obtained from an aqueous solution containing an enhancing mixture of 20% Transcutol and 10% oleic acid. The presence of the enhancers resulted in caffeine flux 40 times greater than in their absence. The high flux of caffeine through the skin in vitro which was obtained using the enhancing composition was shown to be parallel to increased serum concentrations of drug in rats in vivo. Application of caffeine in aqueous solution containing enhancing mixture resulted in high serum concentrations of 50–60 μ ml after 1 h, which remained high for at least 12 h following. The greatest caffeine accumulation in the skin was measured from small liposomal vesicles, 2260 solμg cm 2 , this being 3 times greater than from aqueous solution containing enhancers, the system which exhibited the second largest accumulation of drug in the skin. Using quantitative skin autoradiography, it was found that after 24 h, the greatest concentration of caffeine (280 μg g tissue) was localized in the epidermis and the lowest amount (50 μg g tissue) in the dermis. In addition, a relatively high concentration of caffeine was found in the appendages.

Enhancement in drug delivery

Promoted Gastrointestinal Drug Absorption Gastrointestinal Anatomy, Physiology and Permeation Pathways Abraham Rubinstein Enhancers for Enteral Delivery of Macromolecules with Emphasis on Surfactants Biana Godin and Elka Touitou Improvement of Oral Drug Absorption by Chitosan and its Derivatives Hiraku Onishi and Yoshiharu Machida Targeted GI Delivery David R. Friend Inhibition of Enzymes and Secretory Transport Martin Werle and Andreas Bernkop-Schnurch Enhanced Gastrointestinal Absorption of Lipophilic Drugs Arik Dahan and Amnon Hoffman Promoted Rectal Absorption Permeation Pathway in Rectal Absorption Yoshiteru Watanabe Cyclodextrins and Other Enhancers in Rectal Delivery Hidetoshi Arima and Kaneto Uekama Enhancement of Buccal and Sublingual Absorption Basic Biopharmaceutics of Buccal and Sublingual Absorptions Priya Batheja, Rashmi Thakur, and Bozena Michniak Chemical Enhancers in Buccal and Sublingual Absorptions John D. Smart Transdermal Enhanced Delivery The Lipid Organization in Stratum Corneum and Model Systems Based on Ceramides Miranda W. de Jager, Maja Ponec, and Joke A. Bouwstra Chemical Permeation Enhancement Adrian C. Williams and Brian W. Barry Vesicular Carriers for Enhanced Delivery through the Skin Elka Touitou and Biana Godin Iontophoresis in Transdermal Delivery B. Mudry, Richard H. Guy, and M. Begona Delgado-Charro Electroporation as a Mode of Skin Penetration Enhancement Michael C. Bonner and Brian W. Barry Ultrasound in Percutaneous Absorption Joseph Kost Combined Chemical and Electroporation Methods of Skin Penetration Enhancement Michael C. Bonner and Brian W. Barry Stratum Corneum Bypassed or Removed James C. Birchall Nasal Absorption Optimization Physiological Factors Affecting Nasal Drug Delivery Sian Tiong Lim, Ben Forbes, Marc B. Brown, and Gary P. Martin Nasal Delivery of Peptide Drugs Dennis J. Pillion, John J. Arnold, and Elias Meezan Drug Absorption from Vagina and Uterus Vagina and Uterus as Drug-Absorbing Organs R. Karl Malcolm, Stephen D. McCullagh, Ryan J. Morrow, and A. David Woolfson Strategies to Improve Systemic and Local Availability of Drugs Administered via Vaginal Route Giuseppina Sandri, Silvia Rossi, Franca Ferrari, Maria Cristina Bonferoni, and Carla Caramella Systemic Absorption through the Ocular Route Eye Structure and Physiological Functions Clive G. Wilson, Ekaterina M. Semenova, Patrick M. Hughes, and Orest Olejnik Drug Delivery Systems for Enhanced Ocular Absorption Muhammad Abdulrazik, Francine Behar-Cohen, and Simon Benita Ocular Penetration Enhancers Indu Pal Kaur and Anupam Batra Iontophoresis for Ocular Drug Delivery Esther Eljarrat-Binstock, Joseph Frucht-Pery, and Abraham J. Domb Drug Delivery to the Central Nervous System Structure and Function of the Blood-Brain Barrier David J. Begley Strategies to Overcome the Blood-Brain Barrier Elena V. Batrakova and Alexander V. Kabanov

Altered skin permeation of a highly lipophilic molecule: tetrahydrocannabinol

The effect of decylmethylsulfoxide (decylMSO) and oleic acid on the skin permeation of the highly lipophilic compound, tetrahydrocannabinol (THC), was investigated. The solvents were propylene glycol (PG)-ethanol (EtOH) and PG-EtOH-H2O mixtures. For comparison, similar compositions containing the hydrophilic drug 5-fluorouracyl (5FU) were also tested. Twenty-four-hour experiments were performed with diluted solutions of the drugs in Valia-Chien diffusion cells through hairless mouse skin. The results were treated using the Transderm computer program. The results show that the permeability coefficient of THC was: (1) increased by an order of magnitude by water; (2) increased 6 times by 3% oleic acid in PG-EtOH solutions; (3) increased fourteen times by 3% oleic acid in PG-EtOH-H2O solutions; (4) not affected by decylMSO in PG-EtOH solutions; and (5) decreased 25% by decylMSO in PG-ETOH-H2O solutions. A different behavior was observed when similar systems containing the hydrophilic 5FU were tested. The permeability coefficient of 5FU was: (1) not affected by presence of water; (2) not affected by oleic acid; (3) not affected by decylMSO in PG-EtOH; and (4) increased 14 times by decylMSO in PG-EtOH-H2O. These results emphasize that the selective effect of an enhancer is the result of a tridimensional interaction between the drug, the skin, and the enhancer, in a specific environment.

Testosterone Ethosomes for Enhanced Transdermal Delivery

Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel®). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm2. This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.

Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes.

Permeation enhancers (PE) are frequently used in the field of dermal research and for the development of transdermal delivery products. However, their influence on skin epidermal Langerhans cells (LC) has not yet been investigated. In this work we studied the effect of four PE, oleic acid (OA), propylene glycol (PG), ethanol, and diethylene glycol monoethyl ether (DGME), and an iontophoretic treatment on the morphometric parameters of epidermal Langerhans cells (LC). Retinoic acid (RA) was used as a positive control. Test solutions were applied to the footpad of Sabra mice. The area, perimeter, density and shape factor (SF) were the morphometric parameters evaluated following ATPase staining of LC. Application of RA led to a large decrease in cell density (-50.2%, P<0.01) and dendritic shape (19.8%, P<0.01). Treatment with 10% OA in ethanolic solution caused a severe decrease in LC density (-69.0%, P<0.01), accompanied by a decrease in dendricity as measured by the changes in SF. Ethanol had no statistically significant effect on the LC morphologic parameters tested. All other PE had a mild, if any, effect on LC morphology. SEM micrographs of the skin of IOPS hairless rats demonstrated that 24 h in vivo treatment with 10% OA in ethanolic solution resulted in the generation of pores on the surface of epidermal corneocytes.

Transdermal delivery of tetrahydrocannabinol

The skin permeation behavior of a tetrahydrocannabinol (THC) is described for the first time. In the design of transdermal delivery systems, Δ8-THC was chosen over Δ9-THC due to the formers better stability and its lower psychotropic potency. Sk permeation kinetic parameters were established through rat and human skin in vitro. The rat skin was found to be about 13-fold more permeable to Δ8-THC than the human skin. Autoradiographs showed that 24 h after application the drug was concentrated in the stratum corneum, in the upper epidermis, and around the hair follicles, indicating that THC penetrates the skin through the lipophilic pathways. A transdermal formulation containing oleic acid as a permeation enhancer was tested in rats. A serum level of about 50 ng/ml cross-reacting cannabinoids (THC + metabolites) was maintained for about 24 h, indicating a sustained delivery of THC to the bloodstream. The transdermal preparation presented in this study is designed for future clinical studies.

Drug delivery across the skin

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