ABSTRACT
The nonergoline dopamine agonist rotigotine, is delivered transdermally using a silicone-based patch (Neupro(R); UCB Pharma GmbH), which promotes unidirectional drug flow from the transdermal system to the skin. Pharmacokinetic data show stable steady-state plasma concentrations over 24 h, maintained with once-daily patch administration. Stable plasma concentrations are reflected by stable concentrations in the brain, as has been shown in animal studies. This suggests a continuous stimulation of dopaminergic receptors, which may result in a reduction in or prevention of abnormal involuntary movements in Parkinson's disease (PD) after prolonged treatment. Clinical trials have demonstrated that rotigotine is efficacious as monotherapy for PD and restless legs syndrome (RLS), and open-label extension studies have shown its long-term efficacy. Furthermore, rotigotine can be used effectively in coadministration with levodopa, enabling a reduction of the levodopa treatment doses in PD. Transdermal application also yields favorable pharmacokinetics for rotigotine: rapid metabolism and lack of skin accumulation allow for good control of chronic administration or withdrawal by patch removal, and the transdermal application approach circumvents problems of gastrointestinal absorption and enables administration prior to, during or following surgery. In addition, no dose adaptation is required regarding gender or ethnicity, or for patients with impaired liver or kidney function or on hemodialysis. The safety profile of rotigotine transdermal patch is favorable; common side effects attributed to transdermal delivery or dopaminergic stimulation are generally mild to moderate in intensity. Importantly, augmentation of RLS is uncommon under long-term rotigotine treatment and dyskinesia in PD patients mostly developed only after levodopa initiation. Overall, rotigotine transdermal patch has demonstrated favorable clinical efficacy and tolerability in the treatment of PD and RLS.
Subject(s)
Dopamine Agonists/administration & dosage , Parkinson Disease/drug therapy , Restless Legs Syndrome/drug therapy , Tetrahydronaphthalenes/administration & dosage , Thiophenes/administration & dosage , Administration, Cutaneous , Dopamine Agonists/adverse effects , Dopamine Agonists/pharmacokinetics , Dosage Forms , Evidence-Based Medicine , Humans , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/adverse effects , Thiophenes/pharmacokinetics , Treatment OutcomeABSTRACT
The transdermal delivery of a new salt form of the dopamine agonist rotigotine, rotigotine.H(3)PO(4) is presented and compared to rotigotine.HCl. A comparison was made on the level of solubility, passive and iontophoretic delivery. Different aspects of the delivery were investigated: delivery efficiency, maximum flux, donor pH, electro-osmotic contribution and transport number. Changing the salt form from rotigotine.HCl to rotigotine.H(3)PO(4) increases significantly the solubility and rules out the influence of NaCl on the solubility by the absence of the common-ion effect. At low donor concentration, no difference in transdermal delivery was observed between the salt forms. Due to an increase in the maximum solubility of rotigotine.H(3)PO(4), a 170% increase in maximum flux, compared to rotigotine.HCl, was achieved. A balance between solubility and delivery efficiency can be obtained by choosing the correct donor pH between 5 and 6. A slight increase in electro-osmotic contribution and transport number was observed. Using the parameters, determined by modeling the in vitro transport, in vivo simulations revealed that with iontophoresis therapeutic levels can be achieved with a rapid onset time and be maintained in a controlled manner by adjusting the current density.
Subject(s)
Chemistry, Pharmaceutical/methods , Dopamine Agonists/administration & dosage , Iontophoresis/methods , Salts/administration & dosage , Tetrahydronaphthalenes/administration & dosage , Thiophenes/administration & dosage , Administration, Cutaneous , Computer Simulation , Dopamine Agonists/chemistry , Epidermis/metabolism , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Nonlinear Dynamics , Salts/chemistry , Solubility , Tetrahydronaphthalenes/chemistry , Thiophenes/chemistryABSTRACT
The currently marketed delivery systems for transdermal nitroglycerin (GTN) develop fairly constant GTN plasma concentrations throughout the 24-h application period. This may be associated with tolerance, particularly when higher doses are employed. Because of this problem, a new GTN transdermal delivery system (TDS) has been developed which provides a time-dependent, non-constant drug delivery rate. This system was engineered to provide high GTN plasma concentrations during the first 12h of application which should prevent exercise-induced angina and low nitroglycerin levels during the second 12-h period to prevent tolerance. This GTN TDS with a phasic release profile is described and the in vitro and in vivo release rates and resulting plasma concentrations are contrasted with those of conventional GTN transdermal patches.
