Dopamine agonists. Due to the difficult permeability properties of the skin, the choice of potential candidates of dopamine agonists for passive transdermal delivery is limited. In order to penetrate the skin, the permeant should be potent, since the relative bioavailability is low and should have specific physicochemical properties: moderate hydrophilicity and low molecular weight (<500 Mw). Despite these restrictions several molecules have been investigated for the symptomatic treatment of ▇▇▇▇▇▇▇▇▇’▇ disease with transdermal passive delivery. All the DA of which the feasibility of (passive and/or iontophoretic) transdermal delivery has been investigated together with the structure of levodopa are depicted in Figure 3. In the 1980’s naxagolide was identified as a very potent dopamine agonist and a potential candidate for transdermal delivery due to its moderate lipophilic nature. Despite the very promising results that were obtained in vitro and later in vivo in primates and humans [69-70], the further development was discontinued because of the lack of efficacy as monotherapy and concerns about the toxicity [71]. These results encouraged further investigations with other potential candidates. A number of gel formulations for bromocriptine, an ergot derived dopamine agonist, were developed and transdermal delivery was compared with oral delivery in rabbits. It was observed that a gel, formulated with chitosan showed similar plasma concentration profile as with a commercially available tablet [72]. An enhancement in transdermal transport in vitro of pergolide, another ergot derived dopamine agonist, was obtained using elastic vesicles, but further investigation in vivo is necessary [73]. Transdermal delivery of a third ergot derivative dopamine agonist, lisuride showed promising efficacy as add-on therapy for Pd. Axxonis Pharma, a pharmaceutical company in Germany, recently submitted a European marketing authorization application for the transdermal patch and subcutaneous infusion of lisuride [50, 74]. The non-ergot derivatives, such as piribedil, apomorphine and rotigotine do not cause serious fibrotic reactions, associated with the use of the older ergot-derived compounds, described above. For this reason the non-ergot derivatives are the preferred dopamine agonists to commence therapy, especially in younger patients [1]. A randomized double blind clinical study, including 72 patients with Pd, failed however to show clinical efficacy of transdermal delivery of piribedil, explained by low plasma concentrations [75]. However one year later a study was published on transdermal peribidil that demonstrated, a long-lasting effect (reversal of motor deficits) in MPTP-treated common marmosets [76]. Apomorphine is regarded as a potent dopamine agonist, since its introduction for the treatment for Pd in 1951. Different administration routes have been explored for this D1/D2 dopamine agonist, including transdermal delivery [1]. The transdermal delivery of apomorphine, formulated as a hydroxyl-propyl-methyl-cellulose gel and formulated in microemulsions was investigated in rabbits and mice, respectively. Both studies reported sufficient bioavailability and suggested potential use in humans [77-78]. One of the two microemulsions, used for the in vivo study in mice, was applied transdermally in 21 patients with Pd. The transdermal delivery of this micro- emulsion, containing apomorphine, provided a sustained release of apomorphine, resulting in stable therapeutic plasma levels and reduction of off periods [79]. However the clinical efficacy and tolerability has not been investigated in a placebo controlled double blind study. Another potent dopamine agonist rotigotine, the (-)-enantiomer of the aminotetralin derivative, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin, is the first transdermal delivery system (Neupro®) approved by the regulatory authorities for the symptomatic treatment of all stages of Pd in Europe and of early-stage Pd in USA [80]. Due to drug stability (crystallization inside the patch), compromising the bioavailability, the EMEA limited the supply of rotigotine and the FDA asked professionals and patients for a recall of Neupro® [80]. After adjustments concerning storage conditions, Neupro® is since June 2009 available in Europe for symptomatic ▇▇ ▇▇ OH NH2 Levodopa (Mw:197.2 g.mol-1) OH3C HO N CH3 CH3 H3C H3C N O H3C NH CH3 CH3 O CH3 HN N CH3 H -1 -1 Lisuride (Mw:338.4 g.mol-1) HO CH3 ▇▇ HO O -1 CH3 -1 -1 H3C CH3 CH3 H3C CH3 H ▇▇ ▇▇ Ropinirole (Mw:260.4 g.mol-1) Rotigotine (Mw:315.5 g.mol-1) 4 g. mol-1) treatment of Pd. In the USA up to the present time Neupro is not yet available on the market. In addition to approval for the symptomatic treatment of Pd, Neupro® has been approved for the treatment of moderate to severe restless leg syndrome in adult patients [81]. Patches releasing 1, 2, 4, 6, 8 mg of rotigotine during 24 h are available [82]. In 63 patients with early Pd after repeated daily administration of 8 mg/24h stable steady-state plasma concentrations were observed [83] and animal studies demonstrated that continuous plasma concentrations translate into continuous dopamine stimulation [47, 84]. Three large-scale placebo-controlled phase III trials investigated the efficacy of transdermal delivery of rotigotine as mono-therapy for early stage Pd. All three trials showed an improvement in UPDRS (unified ▇▇▇▇▇▇▇▇▇’▇ disease rating scale)-ADL (activities daily living)-Motor subscores in baseline vs placebo [80, 85-87]. In addition the first phase III clinical trial reported that response reached a plateau when delivering between 6 and 8 mg/24h. This was the base to set the maximum approved dose as monotherapy in the USA and Europe to 6 and 8 mg rotigotine per 24h, respectively [80]. Furthermore a subgroup analysis in the second trial showed that the efficacy is independent of gender, age, disease severity and disease duration [80]. Finally the third trial, which compared transdermal rotigotine vs ropinirole over a 37-week period, reported that ropinirole resulted in a better symptomatic effect than rotigotine, which could be explained by possible under-dosing of the patients receiving rotigotine, compared to ropinirole [87]. Two large phase III trials (▇▇▇▇▇▇ and ▇▇▇▇▇▇▇▇▇ PD-study) investigated the efficacy of transdermal rotigotine as adjunct therapy to L-dopa in advanced Pd [80, 88-89]. The phase III trials showed a significant improvement in the UPDRS- Motor score and one phase III trial did not show any reduction in the required L- dopa dose. However both phase III trials showed a significant reduction in daily off time and an increase in on time without dyskinesia after waking for rotigotine vs placebo [88-89]. Thus as monotherapy for early stage Pd and as adjunct therapy for advanced stage Pd, transdermal rotigotine has been proven to be efficacious and useful. In addition, continuous dopamine stimulation has been suggested to contribute to the prevention of motor complications later in the disease course. Moreover dopamine agonists have been less associated with motor complication than levodopa, emphasizing the potential of transdermal rotigotine to play an important role in the symptomatic treatment of Pd. Although the passive delivery of dopamine agonist has great potential, investigations to improve the transdermal delivery are required to increase the delivery rate and to expand the number of potential candidates for continuous delivery via the skin. The first major approach to overcome the skin barrier and to improve transdermal delivery is the use of chemical enhancers, such as azones, glycols, terpenes etc. They facilitate stratum corneum transport by interaction with the lipids in the skin and/or increase partitioning [90]. A second approach is the use of particulate systems (e.g. nano-particles, vesicles, liposomes). These systems can increase the skin transport by improving drug solubilization in the formulation, drug partitioning into the skin and skin permeability [91]. The use of chemical enhancers and particulate systems can cause skin irritation and therefore limit the number and concentration (in formulation) of enhancers used [90]. Finally a third approach for permeation increase is the use of physical enhancement methods, such as sonophoresis (ultrasound), electroporation, microneedles thermal ablation, microdermabrasion and iontophoresis [91]. Whereas ultrasound, microneedles and thermal ablation show potential for delivery of macromolecules, such as vaccines and therapeutic proteins [91], iontophoresis is promising method for the delivery of small and moderate hydrophilic molecules, such as dopamine agonists.
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