11th United Kingdom-Ireland Controlled Release
The 11th Annual UKICRS Symposium took place on January 6th 2005 at the School of Life & Health Sciences at Aston University, Birmingham. The symposium focussed on progress in the area of skin drug delivery. Professor Richard Guy (University of Bath) commenced the symposium with a presentation on iontophoresis and sonophoresis. He initially provided a comprehensive overview of the mechanisms of iontophoretic drug delivery. Electromigration and electroosmosis are both contributory mechanisms to iontophoresis and it has been shown that the follicular pathway is a major route for drug transport in this type of transdermal drug delivery. He explained that the initial expectations for iontophoretic drug delivery were too ambitious. Early hopes of delivering insulin transdermally were never realised into a working delivery system. One exception to this was the glucose monitoring “reverse iontophoresis” system developed by Cygnus. These days, iontophoresis is a technology that is reaching maturity as researchers understand the mechanism of action and select drugs with properties suitable for this route of delivery. This development is reflected in a number of products that may soon reach the market such as Vyteris’ Lidosite® (lidocaine), which has been approved by the FDA, and Alza’s IONSYS® (fentanyl), which uses Alza’s E-TRANS® technology. In contrast, sonophoretic drug delivery technology is still in its infancy. Sonophoresis utilises low frequency ultrasound to increase the permeability of the skin barrier, with the permeability returning to baseline after approximately twelve hours. Sonophoresis has been shown to increase the transport of insulin and albumin across skin. The mechanism of action is not fully understood, but cavitation and heating effects have been suggested. It is known that discreet areas of the skin are permeabilised allowing the movement of molecules through these areas. Professor Guy mentioned that this technology was being developed for continuous glucose monitoring, but its safety and tolerability was still unknown. Dr. Paul Goggin (Vectura, UK) highlighted the need for improvements in topical dosage forms. Until recently, there have been few innovations in topical delivery and the pharmaceutical industry still relies on formulations belonging to a former age. In addition, the excipients currently used in topical formulations, such as surfactants and preservatives, are often highly irritable and can act as sensitizers. This fact appears to make no sense considering that the majority of topical medicines sold are for the treatment of inflammatory disorders, such as eczema, psoriasis and acne. The size of the dermatology market limits the amount of research and development in this area and the introduction of safer, hypoallergenic excipients has been hindered by the cost of toxicity studies. Existing topical dosage forms are also limited when it comes to unit dosing and controlled application to affected areas. Current application and dosing instructions are often confusing and subjective to each patient, which has more serious implications with potent medicines such as steroids and vitamin D3 analogues, where the risks of overdosing and adverse effects to unintentionally treated skin are real. Dr. Goggin concluded his presentation by describing three new topical dosage forms. Skyepharma’s DermaStick® facilitates controlled application to affected skin by formulating the active ingredient in a solid wax stick. Cardinal Health’s DelPouch® and Vectura’s Pandermal® are both unit-dose topical delivery systems. Creams, ointments or lotions can be administered to the skin via a foam pad in the DelPouch® dosage form. In the case of the Pandermal® system, the active ingredient is formulated into unit-dose ‘tabletted’ solid dosage forms, which are applied to the skin using an applicator device. The morning session ended with a presentation by Professor Jonathan Hadgraft (University of London School of Pharmacy). He introduced his presentation by emphasising that the prevalence of dermatological disorders such as eczema has increased dramatically over the last five decades and that these conditions significantly impact on the quality of life of those affected. He suggested that the industry was finally becoming aware of the criteria required to achieve successful dermal delivery, but most products were still based on drugs that have been available for many decades. The requirements for achieving successful dermal delivery include the intrinsic activity of the candidate drug, the ability to formulate the drug into a formulation that will release at the site of action and penetrate across the skin membranes (i.e. the stratum corneum (SC)). The physicochemical characteristics that lend to the ability of a drug to penetrate across membranes have been defined. The compound must have a low molecular weight, possess a log P between 2 and 3 and have a low melting point. Significant advances in various areas have also helped the progress of dermal delivery, in particular in the areas of computational drug design (QSAR), molecular modelling and analytical techniques. Professor Hadgraft explained that both ATR-FTIR and tape-stripping were techniques that have helped to the understanding of the fundamentals of dermal delivery. He described a relatively new technique, the GARField magnet NMR, which allows the study of the distribution of solvents in skin and also the hydration of and water structure within skin, both in vivo and in vitro. He concluded his presentation by describing some exciting dermal delivery systems being developed currently including IDEA’s Transfersomes®, Helix BioPharma’s Biphasix® microvesicles, Disperse Technologies’ Biliquid foams, Alza’s D-TRANS® patches and Acrux’s MDTS® metered-dose spray applicator. The first speaker in the afternoon session was Professor Joke Bouwstra, an expert and opinion leader in the field of SC biology and biophysics from the Leiden-Amsterdam Centre for Drug Research in the Netherlands. She described the delivery of a model drug, rotigotine, using elastic (liquid-state) vesicles and rigid (gel-state) vesicles. The elastic vesicles consisted of a surfactant known as L-595 and a micelle-forming surfactant, whereas the rigid vesicles contained L-595 only. Both types of vesicles contained small amounts of sulfosuccinate for stabilisation. Using the tape-stripping technique, it has been demonstrated that elastic vesicles can be transported more effectively across the SC than rigid vesicles or micelles. It has also been demonstrated that drug transport could be improved by increasing the association of the drug with the vesicles. Through the use of tape-stripping and ATR-FTIR techniques, Professor Bouwstra’s group has demonstrated that the rigid vesicles did not penetrate the SC, but the elastic vesicles rapidly penetrate the SC. An in vivo study using tape-stripping and freeze-fracture electron microscopy (FFEM) demonstrated the presence of intact elastic vesicles in channel-like regions located within the intercellular lipid lamellae. In addition, no lamellae abnormalities were detected in the skin structure. With the rigid vesicles, extensive vesicle fusion was observed, resulting in the formation of lipid bilayers on the surface of the SC. It is likely that elastic vesicles partition into the SC and move into the viable epidermis via channel-like regions. The vesicles destabilise near the viable epidermis and drug is released. The final two presentations provided information on two non-viral, pain-free and minimally invasive cutaneous gene delivery techniques. Dr. Mark Kendall (Associate Director at the PowderJect Centre, University of Oxford) outlined that genetic material can be delivered directly into cells using a technique in which 2 µm diameter gold particles, coated with the genetic material and ‘fired’ into the cell. This genetic engineering technique is called Biolistics and gets this name because the technology involved combines ballistics with aspects of biology. Dr. Kendall explained that high-speed gas flow is used to propel the gold particles to speeds of 1500 miles per hour. To achieve the uniform velocity and high impact required for delivery the particles to the target depth within the skin, a contoured shock tube is used. A commercial disposable hand-held shock tube-based device has been developed by PowderJect. The device consists of a high-pressure helium reservoir connected to a driver, a cassette containing the gold particles surrounded by two diaphragms, a contoured shock tube and a nozzle encased within a silencer housing. Operation commences with the opening of the reservoir valve, allowing the filling of the driver volume until the rupture pressure of the diaphragms is reached. Once the diaphragms are ruptured, the particles are accelerated through the shock tube and nozzle to the skin target. Dr. Kendall went on to explain the use of this technology to delivery genetic materials to the Langerhans cells residing within the viable epidermis. He also cited the preclinical hepatitis B vaccine studies in mice which results in positive immune outcomes and the potential for DNA vaccination. Dr. James Birchall (Gene Delivery Research Group at the Welsh School of Pharmacy, Cardiff) has research interests in the development of gene delivery vectors and formulations for use with microneedles for cutaneous gene delivery. The use of microneedles for drug delivery was first described by Dr. Mark Prausnitz at the Georgia Institute of Technology. In recent years many different designs of microneedles have been evaluated. Many prominent drug delivery companies have also developed their own versions, including Alza’s Macroflux® and Becton Dickinson’s Microinfuser®. Microneedles can be used to deliver drugs or genes in several different ways. A drug solution can be delivered to the viable epidermis via hollow microneedles or microneedles can be coated with the drug of interest. The method employed by Dr. Birchall’s group involves the application of a drug formulation onto the skin surface followed by the application of the silicon microneedle array over the drug formulation. He explained that the manufacture of silicon microneedles is very expensive due to the materials used and design requirements. Needle fragility posed a major problem with early microneedle research. The microneedles used in the research undertaken at Cardiff are cylindrical in shape and are manufactured specially by the National Microelectronics Research Centre (NMRC) in Cork, Ireland. Dr. Birchall described the successful use of his microneedle arrays with an LPD (lipid (DOTAP)-polycation-DNA) vector to effect significant levels of gene expression in keratinocytes. He also described the use of microneedles and thermosensitive gel formulations as a method of controlled gene release. This early stage work is set to move to preclinical assessment in mouse models. The symposium ended with three short graduate and postgraduate presentations. Dr. Tahir Nazir from MedPharm (Kings College, London) spoke about the use of nail softeners and chemical penetration enhancers to improve perungual drug delivery for treatment of fungal infections. Ismaiel Tekko from the University of Bradford presented on the evaluation of glucosamine as a candidate for transdermal delivery. Finally, Dr Ashish Kumar Kholi from the London School of Pharmacy described the use of poly(L-lactide) (PLA) biodegradable nanoparticles for transcutaneous immunisation using albumin as cargo. He concluded that gelatin-A surface-modified nanoparticles could elicit a specific immune response in mice and suggested that the use of these nanoparticles may be used in combination with mucosal adjuvants to boost the overall immune response. Prepared by Dr Tom Li &
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