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Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb

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Short review

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Rotigotine: The first new chemical entity for transdermal drug delivery

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Donald A. McAfee a, Jonathan Hadgraft b, Majella E. Lane b,⇑ a b

Dept. of Anaesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada Department of Pharmaceutics, UCL School of Pharmacy, London, United Kingdom

a r t i c l e

i n f o

Article history: Received 14 June 2014 Accepted in revised form 15 August 2014 Available online xxxx Keywords: Rotigotine Parkinson’s disease Restless legs syndrome Transdermal Crystallisation Formulation

a b s t r a c t Rotigotine is the first, and to date, the only new chemical entity to be formulated for transdermal delivery. Although first approved for the management of Parkinson’s disease in Europe in 2007 and Restless Leg Syndrome in 2008, the story of rotigotine began more than twenty years earlier. In this review we outline the historical development of this molecule and its route to licensed medicine status. It has very favourable physicochemical properties for transdermal delivery but it took a significant period to develop from concept to market. The stability problems which led to the temporary withdrawal of the patch are examined and the major clinical studies demonstrating efficacy and safety are outlined. Alternative new therapeutic modalities are also considered. Ó 2014 Published by Elsevier B.V.

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1. Introduction

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Rotigotine is a potent and selective dopamine agonist, first described in the 1980s, and now approved in a transdermal dosage form for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS). All of the other marketed transdermal therapeutics contain drugs previously approved as oral or injectable agents. Marketed as Neupro™, rotigotine is the first transdermal drug to be approved as a new chemical entity (NCE) not previously approved therapy in another dosage form. Parkinson’s disease (PD) is a degenerative condition which is characterised by shaking, rigidity and slowness of movement and was first described by Dr. James Parkinson in 1817 [1]. The death of dopaminergic neurons is believed to be the major cause of PD but the exact cause, whether genetic or environmental remains unknown. The number of individuals with PD over age 50 in the five most populated countries in Europe and the ten most popu-

43 44 45 46 47 48 49 50 51 52 53 54 55 56

Abbreviations: ADME, Absorption Distribution Metabolism Excretion; AUC, area under the plasma concentration time curve; BE, bioequivalence; CGI, Clinical Global Improvement; Cmax, maximum plasma concentration; COMT, catechol-O-methyl transferase; EMA, European Medicines Agency; EDDAs, ergot derived dopamine agonists; GID, gastrointestinal disturbances; i.v., intravenous; MAOIs, monoamine oxidase inhibitors; NCE, new chemical entity; PD, Parkinson’s disease; PBS, phosphate buffered saline; RLS, Restless Leg Syndrome; S.D., standard deviation; TBA, tetra butyl ammonium; TEA, tetra ethyl ammonium. ⇑ Corresponding author. Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom. Tel.: +44 207 7535821; fax: +44 870 1659275. E-mail address: [email protected] (M.E. Lane).

lated countries outside Europe was between 4.1 and 4.6 million in 2005 and is predicted to increase to between 8.7 and 9.3 million by 2030 [2]. The prevalence and incidence of PD are higher in males compared with females with a male to female ratio of 1.6:1 [3,4]. While there are currently no therapeutics that reverse or halt the progress of the disease, substantial advances have been made to control the symptoms. In the 1980s PD was managed with levodopa (L-dopa), ergot alkaloid derived dopamine agonists, dopamine metabolism inhibitors [monoamine oxidase inhibitors (MAOIs) or catechol-O-methyl transferase (COMT) inhibitors] or apomorphine, a non-specific dopamine agonist administered by injection or infusion (Fig. 1). Dopamine does not have the necessary physicochemical properties to cross the blood brain barrier but an amino acid transporter facilitates L-dopa delivery to the brain where it is subsequently converted to dopamine by dopa decarboxylase. L-dopa is the gold standard in the treatment of PD but its use over a long-term period leads to the development of motor complications. A further problem is the eventual manifestation of ‘‘fluctuation syndrome’’, ‘‘end of dose’’, and ‘‘wearing off’’ effects resulting in conditions with alternating on periods of mobility with dyskinesias and off periods with hypokinesia. Though less efficacious, the ergot derived dopamine agonists (EDDAs) can substitute for L-dopa in early stage disease and become adjunct therapy at later stages, thereby delaying or reducing L-dopa induced dyskinesias. However, they are associated with more serious psychiatric side effects than L-dopa as well as pulmonary fibrosis. Because the half-life of L-dopa is relatively short (90 min), plasma levels fluctuate greatly

http://dx.doi.org/10.1016/j.ejpb.2014.08.007 0939-6411/Ó 2014 Published by Elsevier B.V.

Please cite this article in press as: D.A. McAfee et al., Rotigotine: The first new chemical entity for transdermal drug delivery, Eur. J. Pharm. Biopharm. (2014), http://dx.doi.org/10.1016/j.ejpb.2014.08.007

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Rotigotine

Fig. 1. Dopamine agonist anti-parkinson agents. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

114

between doses. It was hypothesised at the time that pulsatile delivery might be responsible for the fluctuation syndrome problem [5]. Continuous subcutaneous infusion of apomorphine was also known to reduce fluctuation suggesting that a constant level of dopamine receptor activation might provide better therapeutic control of PD [6]. Continuous parental infusion is expensive, inconvenient, and is associated with increased risk of infection and tissue degeneration. Slow release forms of L-dopa were developed but provided only minor improvement. To address the unmet clinical need for continuous drug delivery of a dopamine agonist transdermal dosage forms were tested. The ergot agonists, such as lisuride and pergolide apparently were not sufficiently transdermally bioavailable. PHNO, a novel selective D2 agonist was transdermally bioavailable, but development was discontinued because of unacceptable side effects. However, rotigotine, the most potent D2 agonist known at the time was shown to be transdermally bioavailable and entered into development in 1987. Structurally rotigotine is (—)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol. The racemate (N-0437) was originally synthesised by Horn and colleagues [7] and licensed to Nelson Research in Irvine CA. In 1987 the Ethyl Corporation (Richmond VA) acquired Nelson Research, renaming it Whitby Pharmaceuticals, and initiated development of N-0437 for the treatment of PD. This article reviews with an insider’s perspective the historical development of rotigotine for transdermal delivery as well as its pharmacokinetics and metabolism. Patch technology currently used to deliver the drug is examined as well as recent stability issues. Finally novel formulation approaches for transdermal rotigotine delivery are considered.

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2. Transdermal patch development and clinical evaluation

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A comprehensive in vitro and in vivo programme established that the S-enantiomer of N-0437 was a potent and specific dopamine receptor agonist in vitro and that subcutaneous injections were effective in rat and monkey models of PD [8]. The S-enantio-

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113

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mer (N-0923, SPM 962 or rotigotine) resembles dopamine structurally but is highly selective for D3 and D2 receptors and has a higher receptor affinity. Table 1 summarises the physicochemical properties of rotigotine. Subsequent, but unpublished studies established that tinctures of rotigotine when applied topically in rat and monkey models also demonstrated efficacy, establishing that this molecule was transdermally bioavailable in these species. The initial clinical studies carried out with rotigotine were intravenous infusions in patients with PD to determine if this molecule had true anti-parkinson efficacy and to uncover any toxicity or unexpected side effects. Such studies confirmed the potential for anti-parkinson efficacy. In one study [9] the average Modified Columbia Rate Scale (MCRS), a score to assess severity and progression of PD, was reduced by 50% with an infusion of 10 lg/kg/h, generating plasma levels of 0.75 ng/ml. Only at higher infusion rates did the patients experience the typical nausea and vomiting associated with dopaminergic agonists. In 1993, Ethyl Corp divested all non-petroleum businesses and Whitby Research was closed. However, the Whitby executive management, after raising venture capital (Sanderling Ventures, Menlo Park, CA), bought the Whitby technology and established Discovery Therapeutics Inc. (Richmond VA). A clear path to a transdermal product was evident as N-0923 had demonstrated efficacy and potency when intravenously injected. The major challenge for Table 1 Properties of rotigotine. Empirical formula Molecular weight Log P* pKa* Melting point Solubility in ethanola

* a

120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144

Q2 C19H25NOS 315.5 4.03 7.9, 10.3 Form I 77 ± 2 °C Form II 97 ± 2 °C Form I 500 mg/ml Form II 60–100 mg/ml

Calculated and reported by Honewyell-Nguyen et al. [35]. From WO 2009/068520 [18].

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Discovery Therapeutics was the fact that development of a transdermal product for a new chemical entity had not been conducted previously. The initial proof of concept transdermal clinical trial (unpublished) was conducted with a two-phase pilot patch (20 cm2) formulated with rotigotine hydrochloride (10 mg). The patch was manufactured by Cygnus Therapeutic Systems (Menlo Park, CA). In a dose-ascending study in twelve healthy volunteers, a 30 h application of up to 3 patches was sufficient to produce plasma levels of 0.77 ng/ml. In nine patients with Parkinson’s disease, 1–3 patches produced 18–78% reductions in MCRS scores within 30 h (unpublished). Clearly, the proof of concept was demonstrated and Discovery Therapeutics set out to initiate a programme that would secure a development partner with sufficient resources to finish development and commercialisation. After considerable business development negotiations with several companies, Discovery Therapeutics entered into an agreement with Lohmann Therapie Systems (Andernach, Germany) to develop a matrix adhesive patch with a formulation that would provide adequate transdermal flux. Using these patches, which contained the free base, Discovery mounted a major randomised placebocontrolled 21 day, phase II study of 85 patients with moderate to severe Parkinson’s disease who were currently taking L-dopa [10]. Patients were removed from their L-dopa on Day 1 and 1–3 patches were applied and replaced once each day for the next 21 days. Within 8 h L-dopa dosing was restarted at low levels and increased as necessary until optimum. The primary measure of efficacy was the reduction in L-dopa dose and the Clinical Global Improvement scale (CGI). Patients not currently using dopamine agonists were able to significantly reduce their dose of L-dopa in a dose dependent manner without any reduction in anti-parkinson efficacy (see Table 2). On the strength of this study Discovery Therapeutics was able, in 1998, to license rotigotine and the patch formulation to Schwarz Pharma (Monheim, Germany) who invested in an intensive development campaign. Schwarz in collaboration with Lohmann modified the formulation, conducted a pharmacokinetic study to characterise the flux potential of the patch and initiated a strategy to develop the patch first for early stage PD and then for late stage disease. In early stage disease, dopamine agonists can be used in monotherapy, but typically as the disease progresses L-dopa must be introduced. In this case, dopamine agonists become adjunct therapy to L-dopa, but by limiting the dose of L-dopa they reduce the incidence of L-dopa induced motor complications. With their new formulation, Schwarz conducted a potentially pivotal Phase II trial with the Parkinson’s study group and reported the results of a study in 242 patients with early stage PD dosed only with rotigotine (monotherapy) for 11 weeks [11]. A significant improvement in patient symptoms which was dose-related was observed. The side effects were comparable with other dopamine agonists (nausea, application site reactions, dizziness, insomnia, somnolence, vomiting and fatigue) except for skin irritation, to

Table 2 Initial Phase II trial for N-0923 in Parkinson’s disease.

* **

N-0923 (mg)

Patch area (cm2)

Baseline L-dopa dose (mg)

Day 21 L-dopa dose (mg)

Decrease in Ldopa dose (%)

Placebo 8.4 16.8 33.5 67.0

Placebo 5 10 20 40

767 662 635 941 483

693 629 521 647 181

10 5 18* 31** 63**

p < 0.04. p < 0.001.

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those for other dopamine agonists. Of the nine serious adverse events, only two (sudden onset of sleep and loss of consciousness) were considered to be linked to the drug treatment. It was clear that dose could be controlled by surface area of the applied patches and this dictated the manufacture of patches of various surface areas for subsequent therapeutic dosing. With this strong signal, Schwarz initiated a pivotal multicentre phase III clinical trial which was randomised, as well as doubleblind and placebo-controlled with 277 patients lasting 27 weeks. This study demonstrated the efficacy of transdermal rotigotine when gradually increased to a dosage of 6 mg/24 h for the treatment of early-stage PD [12]. Nausea, drowsiness and application site reactions were the most common side effects reported (Fig. 2). The results of a required comparator trial, a double-blind, randomised, controlled study with placebo and with ropinirole, lasting 37 weeks, were reported by Giladi et al. [13]. Surprisingly, transdermal rotigotine at doses P8 mg/24 h did not show noninferiority to ropinirole at doses P24 mg/day. However, in a post hoc subgroup analysis, rotigotine P8 mg/24 h had a similar efficacy to ropinirole at doses P12 mg/day. As for the previous studies, the most common side effects were application-site reactions, nausea, and drowsiness. In executing their strategy for advanced PD, Schwarz initiated a randomised, double-blind, placebo-controlled trial with two transdermal doses of rotigotine in patients with advanced PD [14]. Patients received placebo patches or transdermal rotigotine (8 mg/24 h or 12 mg/24 h). There was a significant improvement in the ‘‘off’’ time of PD patients who did not respond optimally to L-dopa and patches were well tolerated. Among the side effects occurring more frequently in the rotigotine treated subjects were skin reactions, affecting 36% of the 8 mg/24 h rotigotine group, 46% of the 12 mg/24 h rotigotine group, and 13% of the placebo group. A randomised study conducted on patients with advanced PD and treated with L-dopa compared rotigotine as an adjunct therapy with placebo and oral pramipexole and was reported by Poewe et al [15]. The findings showed rotigotine to be non-inferior to pramipexole; rotigotine was also as efficacious as pramipexole in these patients over a six month period of treatment. In all, nearly 2000 patients at various stages of PD were studied in these highly controlled pivotal trials. While conducting these clinical studies, Schwarz also initiated a development programme for rotigotine as a therapy for restless legs syndrome (RLS) as other dopamine agonists had been shown to be efficacious in managing this condition. RLS is a common sensorimotor disorder characterised by an irresistible urge to move the legs and arms in order to ameliorate uncomfortable and unpleasant sensations in these limbs. Since this occurs more often at rest and in the evening, RLS is a major contributor to sleep disturbance, which is what drives most patients to seek therapy. Schwarz conducted an initial controlled 2 week phase II proof of principle study that demonstrated efficacy with doses considerably lower than those needed for control of parkinsonism [16]. A four week Phase II controlled study clearly demonstrated dose-dependent efficacy in 340 patients [16]. Two pivotal Phase III trials in nearly 1000 patients were conducted and submitted as part of the approval package. Trenkwalder et al. [17] reported the results of one of the studies conducted in subjects with moderate to severe RLS as a randomised, double-blind, placebo-controlled trial. Patients received transdermal rotigotine (1 mg/24 h, 2 mg/24 h or 3 mg/24 h) or placebo and patches were applied once daily for 6 months. The change in International RLS Study Group severity scale (IRLS score) from baseline after six months treatment with rotigotine is shown in Fig. 3. A significant lowering in IRLS sum scores was observed for all three doses of rotigotine compared with placebo (p < 0.001). The pivotal trials in PD and RLS have been continued in open label studies lasting for more than 5 years to

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3. Crystallisation and re-formulation of the rotigotine transdermal patch

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Two polymorphic forms of rotigotine are now known [18]. These can be distinguished by their melting points and with other techniques such as Differential Scanning Calorimetry, X-Ray diffraction and Raman spectroscopy. At room temperature form II is more stable than form I; form II also has a higher melting point (97 ± 2 °C) than form I. The existence of form II only became known when stability problems were reported with the patch formulation in 2008 [19]. Crystallisation was evident in patches and concerns were raised over the possibility that crystallization might affect drug release from the patch and change the amount of drug which permeated through skin and hence drug systemic levels. The crystals present were identified as the more stable form II of rotigotine. The discovery of this second crystalline rotigotine polymorph was surprising as no indication of the presence of other polymorphs was observed in earlier preformulation screening. The torsion angle of the thiophene ring relative to the CH2–CH2 chain in form II is significantly different than for form I Because of this 100° torsional difference form II has a denser packing and different crystal symmetry compared with form I [18]. Consequently the patch was withdrawn from the US market in 2008 but in Europe stock was replaced and a cold chain manufacture, distribution and storage process was implemented. European Medicines Agency (EMA) treatment restrictions between July 2008 and August 2009 limited prescribing to one month’s supply of patches and prevented new patients from being initiated on rotigotine. Clearly, a new formulation was required and a room temperature stable patch using polymorphic form II, adapted not to crystallise, was developed, and was approved by both the FDA and the EMA in 2012. Rotigotine was re-launched in the US market in July 2012. In the EU, the room temperature stable patch was introduced to replace the cold chain supply patch. In 2013 the patch was approved in Japan for idiopathic PD and RLS and is marketed by UCB’s partner, Otsuka Pharmaceuticals. The currently marketed adhesive matrix patch contains the active component rotigotine and the following inactive components: ascorbyl palmitate, povidone, silicone adhesive, sodium metabisulfite, and dlalpha-tocopherol. This would suggest that the patch needs to be protected from oxidation and may be the reason that the initial patches manufactured by Cygnus used the salt form rather than the free base. A number of studies have been conducted to determine whether the new room temperature stable patch had similar bioavailability and adhesiveness to the original and cold chain patches [20]. Two bioequivalence (BE) studies were performed in healthy individuals and a patch adhesion study was performed in patients with PD. Volunteers received a single-dose application of each formulation of rotigotine, in randomised order. Patches were worn for 24 h, with a wash-out period of at least 5 days between applications. The smallest patch size developed for the treatment of early-stage PD (2 mg/24 h, 10 cm2) was used, as results from phase 1 clinical trials had indicated that this dose is well tolerated in healthy individuals. Plasma concentration–time curves were very similar for the original and cold chain patches and for the cold chain and new room temperature stable patches. For the BE studies, the 90% Confidence Intervals for ratios of area under the plasma concentration–time curve from zero until the last analytically quantifiable concentration [AUC(0–tz)] and the maximum plasma concentration (Cmax) was within the bioequivalence acceptance range (0.80–1.25). The overall median adhesiveness scores were similar for cold chain and room temperature stable formulations.

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Coughing Insomnia Somnolence Skeletal pain Back pain Arthralgia Diarrhea Dyspepsia Conspaon Voming Nausea Parkinson aggravated Tremor Headache Dizziness Leg pain Pain Fague Accident NOS Applicaon site disorders

0

5

10

15

20

25

30

35

40

45

50

Percentage (%) Fig. 2. Summary of most common treatment emergent adverse events for randomised, blind controlled trial of transdermal rotigotine in early PD (Placebo group n = 95; Rotigotine n = 181). Adapted from Ref. [12]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

-5

-10

*

g/ da y m 2

1

m

g/ da y

-20

Pl ac eb o

*

*

ay

-15

3m g/ d

Change in IRLS Score

0

Fig. 3. Effect of rotigotine on IRLS score (1–40); 100 pts/group with moderate to severe symptoms, 6 month study. Adapted from Ref. [17].

268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286

provide a clear understanding of the safety and efficacy over longterm therapy. However, Schwarz Pharma was purchased by UCB (Brussels, Belgium) in 2006 and UCB assumed responsibility for the regulatory submissions and follow on studies. Based on these studies, rotigotine transdermal patches were approved for use in all stages of PD in Europe in 2006 and the US in 2007 and for RLS in Europe in 2007. Typical doses for RLS range from 1 to 3 mg/day and for PD, 2–8 mg/day. Branded as Neupro™, rotigotine patches are supplied in six sizes or doses ranging from 5 to 40 cm2 capable of delivering 200 lg/cm2/day or 1, 2, 3, 4, 6 and 8 mg/24 h. In order to sustain that flux for 24 h, the patches are actually loaded with more than twice the rated dose so that an adequate concentration gradient is maintained to drive passage of rotigotine through the skin. Unlike oral medications in which the dose is the amount administered, for transdermal drugs the labelled dose is the amount normally delivered over a defined period of time regardless of the amount in the patch administered. These doses have been established by the metabolism and pharmacokinetic studies described in Section 4.

Please cite this article in press as: D.A. McAfee et al., Rotigotine: The first new chemical entity for transdermal drug delivery, Eur. J. Pharm. Biopharm. (2014), http://dx.doi.org/10.1016/j.ejpb.2014.08.007

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4. Pharmacokinetics and metabolism

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It is important to conduct Absorption Distribution Metabolism Excretion (ADME) studies for any new chemical entity but it is especially difficult to do them under transdermal conditions. Accordingly, most studies involve intravenous administration to establish a more rigorous reference point, and then transdermal studies for comparison where the variability and uncertainty are likely to be greater. Early studies were conducted on the racemic mixture N-0437. The disposition and metabolic fate of N-0437 was reported in rats following intravenous (i.v.) and oral administration [21,22]. The drug was cleared very rapidly for both routes of administration with excretion predominantly via bile. The primary metabolite was formed by glucuronidation of the phenolic group with this conjugate accounted for 50% and 65% of the metabolites for the i.v. and oral routes, respectively. Ocular administration of N-0437 in monkeys was also investigated [23]. Approximately 66% of the dose applied to the eye was accounted for in bile (35%) and urine (31%) after 7 h. Swart and De Zeeuw also reported significant gastrointestinal metabolism of rotigotine following oral administration in rats; the maximum fraction of the drug reaching the portal vein was 1% of the administered dose [24]. The racemic mixture was also applied to the skin of rats [25]. The drug was dissolved in ethanol, water and polyethylene glycol (3:1:1) and a dose of 10 lmol/kg was applied to the hairless skin of the rat neck. Microdialysis indicated that a sustained decrease in dopamine release was achieved following delivery via the skin (13 h) compared with oral dosing (5 h). Calabrese et al. [9] conducted an open-label study of rotigotine in nine PD patients. Initially, rotigotine was administered in a doseescalation regime as sequential 30 min intravenous infusions. Subsequently the highest tolerated dose was given as a loading infusion followed by a maintenance infusion. Improvements in patient symptoms were manifest within minutes of the infusion commencing. A two-compartment model was used to calculate distribution and elimination half-lives (2.7 and 71 min respectively). Values for clearance and volume of distribution were reported as 61.2 ± 4.7 ml/min per kg and 3.6 ± 0.7 l/kg. Cawello et al. [26] reported the findings of a study where transdermal patches containing radiolabelled and unlabelled rotigotine were applied to six healthy males for 24 h. The patches were manufactured under special conditions by Lohmann to match the 10 cm2 patches to be generated on the commercial fabrication line. Unused patches, used patches and washings from the skin after the 24 h application period were analysed. Skin tape strips, plasma, urine and faeces samples were also taken for up to 96 h after patch application. Based on the measured amount of radioactivity remaining in patches it was estimated that 51% of the patch content was released. Radioactivity values for skin wash samples were 4.8 ± 1.5% with 0.1% in the upper skin layers. However, among the 6 subjects, the absorbed dose ranged from 35% to 60%, suggesting significant inter-individual variability. Even though the mass balance was reported to account for 96% of the applied dose, the radioactivity recovered in urine and faeces was 30.4% and 10.2%, amounting to about 88% of the systemic load. The 12% discrepancy is not large for mass balance studies of this type, but it raises important questions as to the degree and variety of metabolic products that contributed to the radioactivity. To address the question of disposition, metabolism, elimination, and absolute bioavailability of rotigotine, six healthy male subjects were examined following administration of a single radiolabeled i.v. infusion (1.2 mg rotigotine) compared with a 10 cm2 transdermal patch (4.5 mg rotigotine) in a randomised crossover design study [27]. The infusion was administered for 12 h and the patch

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was applied for 24 h. The decay in plasma rotigotine had similar time constants when infusion was halted or the patch was removed. Of interest was the determination of the metabolic pathway for rotigotine in these patients. In contrast to the studies in rats and monkey described above, it was clear that metabolism proceeded mainly in the liver by phase II conjugation with sulphate followed by renal excretion, and, to a much lesser extent, by glucuronidation and excretion in the bile. These metabolites reportedly have no affinity for dopamine receptors, while phase I metabolites do have dopamine receptor affinity; they are at 10-fold lower plasma concentrations and thus exert no pharmacological action. As might be expected, unconjugated rotigotine is not excreted by the liver. This study suggested that special patient population studies be conducted in patients that have renal or hepatic impairment. A study was conducted in 17 subjects, 9 of whom had moderate hepatic impairment (class B Child-Pugh scores) over a period of 3 successive days of treatment with a 2 mg/24 h patch [28]. On the fourth day the patch was removed. Blood and urine samples were taken at regular intervals over days 3 and 4. Surprisingly, there was no difference in the pharmacokinetic profile between the liver impaired patients and the healthy control subjects although total rotigotine (conjugated and unconjugated) was higher in the hepatic impaired group. Thus dose adjustment does not seem to be required at least in those with moderate hepatic impairment. The pharmacokinetics of transdermal rotigotine in patients with impaired renal function have also been studied by Cawello et al. [29]. Patches (10 cm2, 4.5 mg drug content) were applied to healthy patients and patients with mild, moderate, severe or end-stage renal insufficiency. Blood samples were taken during the period of application and up to 60 h after the initial application. Analysis of the pharmacokinetic parameters, including AUC, Cmax, clearance and total volume of distribution indicated that values were similar across the groups, although high inter-patient variability was noted. The authors concluded that no dose adjustment of rotigotine was required for patients with varying stages of renal disease. More recently Cawello and colleagues [30] investigated the pharmacokinetics of transdermal rotigotine in Japanese and Caucasian subjects. Healthy subjects were recruited (24 Caucasian, 24 Japanese) and patches (10 cm2, 4.5 mg drug content) were applied to the abdomen for 24 h. Comparable pharmacokinetic profiles were obtained for both groups and patches were generally well tolerated. Drug interaction studies in patients with RLS indicate that there appear to be no interactions between rotigotine and levodopa–carbidopa pharmacokinetics [31]. The administration of domperidone, in healthy subjects, does not change the steady-state concentrations of rotigotine [32] and rotigotine does not interfere with the efficacy of oral contraceptives [33]. The steady state pharmacokinetic parameters of transdermal rotigotine, as well as dose proportionality and influence of patch application site were evaluated in three highly focused clinical studies [34]. In two studies early stage Parkinson’s patients were up titrated to steady state plasma levels over a period of 20 days to 8 mg/24 h using either one 40 cm2 patch in one trial or 2  20 cm2 patches in the other. During the following maintenance period, each patient rotated through a 6 day period in which the patch or patches were placed in 6 different areas: Shoulder, upper arm, abdomen, flank, and thigh. In the third study healthy volunteers were up titrated to 3.5 mg/24 h over 12 days with a 15 cm2 patch or a combination of one 10 and one 5 cm2 patch. The actual amount of drug delivered was estimated by assaying the contents of the patch remaining upon removal 24 h after its application. The results were informative. The 40 cm2 patches which contained

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18 mg on average released 7.7 mg while a pair of 20 cm2 released 7.1 mg with a S.D. of 2 mg for both populations. Similarly, the 15 cm2 patch released 3.5 mg as did the combination of 5 and 10 cm2 patches with a S.D. of 0.8–0.9 mg, demonstrating dose-proportionality. By measuring the AUC of the plasma levels of unconjugated rotigotine, the investigators were able to confirm this bioequivalence as the dose ratios were within the accepted standard ratio of 0.80–1.25. With one exception, the bioavailability at each of the six application sites was within this standard. The exception was the shoulder to thigh ratio which was 1.46. Apparently this difference is considered small enough to be ignored as the prescribing information for Neupro™ does not caution switching from shoulder to thigh. In fact, it recommends that the application site be ‘‘moved on a daily basis (for example from the right side to the left side and from the upper body to the lower body)’’. Finally, these studies demonstrated that each day, 2 h after patch application the plasma levels begin a steady monotonic rise from the trough to a peak at 16 h which is 50% greater than the mean plasma level. These once a day peak and trough fluctuations are considerably smaller and less frequent than the multiple peaks and troughs of L-dopa taken two or three times a day even with adjunct COMT and MAO inhibitors [35].

5. Novel formulation strategies for transdermal delivery of rotigotine Bouwstra and co-workers have investigated a number of alternative formulation strategies for transdermal delivery of rotigotine as the base or hydrochloride salt. Honeywell-Nguyen et al. [36] prepared rigid or elastic vesicles based on combinations of the sucrose laurate ester (L-595) and octaoxyethylene laurate ester (PEG-8-L). Rotigotine penetration from these vesicles in vitro was determined using human skin mounted in diffusion cells. Maximum flux values were obtained for the formulation containing L-595:PEG-8-L (50:50) and were reported as 214.4 ± 27.8 ng/ (h  cm2) which the authors characterised as the most elastic vesicle formulation. Iontophoretic transport of rotigotine HCl in vitro with human stratum corneum has also been studied by the same group [37]. Experiments were conducted in diffusion cells with an initial period of passive diffusion, followed by iontophoresis (current density of 0.5 mA cm 2) and then passive diffusion over a total time period of 20 h. The value of pH in the donor compartment was 4, 5 or 6 and the drug concentration was either 0.5 or 1.4 mg ml 1 for each pH value studied. The NaCl concentration in the donor phase was also alternated between 0.07 and 0.14 M at pH 5. Phosphate buffered saline (PBS) at a pH of 7.4 or 6.2 was used as the receptor phase. For applied drug concentrations of 0.5 mg ml 1 significantly higher iontophoretic flux values were observed for experiments where the donor compartment was maintained at pH 6 compared with other pH values (p < 0.05). However, although significant differences were observed for the higher drug concentration between donor compartments maintained at pH 4 versus 5 (p < 0.001), no differences in flux were evident for experiments conducted at pH 5 versus 6 (p < 0.05). Higher amounts of NaCl present in the donor chamber significantly reduced drug flux (p < 0.05) and also suppressed drug solubility. Maximum flux values observed were 60 nmol cm 2 h 1 for the higher drug concentration, with the donor compartment maintained at pH 5 and with a receptor pH value of 6.2. In a related study [38] the authors investigated whether the use of dermatomed skin versus stratum corneum impacted on drug iontophoretic flux. Drug concentration in the donor phase was either 0.5, 1.0 or 1.4 mg ml 1 and the influence of tetra ethyl ammonium (TEA) or tetra butyl ammonium (TBA) as alternative co-ions to NaCl was also investigated with the donor

compartment maintained at either pH 5 or 6. The applied current density was varied over the range of 0.125–0.500 mA cm 2. Increasing drug concentration in the donor phase resulted in a 2.4-fold increase in flux values. Replacing Na with TEA resulted in increased flux values (p < 0.05) but a similar increase was not evident for TBA (p > 0.05). Slower and reduced overall drug permeation was observed for the thicker skin samples compared with stratum corneum. Flux increased proportionally with current density. The maximum flux value reported was 80.2 ± 14.4 nmol cm 2 h 1, an input rate which suggests that an iontophoretic patch should achieve adequate therapeutic plasma levels. Alternative salt forms of rotigotine for iontophoretic transport were investigated in a more recent study [39]. The H3PO4 salt form of rotigotine was 2–10-fold more soluble than the HCl form at pH values of 4, 5 and 6, in the presence and absence of NaCl. Comparable iontophoretic flux values were obtained for the HCl (3.77 mM) and H3PO4 (3.74 mM) salt forms for a donor compartment of pH 5 (70 nmol cm 2 h 1). Application of higher concentrations of the H3PO4 salt for the same pH conditions in the donor compartment resulted in flux values of 140 nmol cm 2 h 1, significantly higher than the maximum flux values that could be achieved for the HCl salt. The preparation of film-forming gel formulations of rotigotine using hydroxypropyl cellulose (HPC) and Carbomer 934 was reported by Li et al. [40]. In vitro permeation studies were conducted with nude mouse skin and pharmacokinetic studies were conducted with rabbits. As these models over predict likely permeation of the drug from transdermal formulations in humans it is difficult to determine whether the flux values reported are meaningful for the development of clinically useful gel formulations.

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It has become apparent that the pharmacology and efficacy of rotigotine in the treatment of PD and RLS is comparable with that of the other two marketed non-ergot dopamine agonists, pramipexole and ropinirole, and none of the agonists are as efficacious as L-dopa in late stage disease. What then, is the advantage of a formulation that is considerably more expensive to manufacture than oral tablets, and causes skin irritation in up to 40% patients in some populations? The most obvious issue to consider is gastrointestinal disturbances (GID) because this is a serious issue and can affect delivery and absorption of oral medications. A retrospective study of nearly 1000 Parkinson’s patients, sponsored by UCB, confirmed that GID is the most common non-motor dysfunction [41]. Within 4 years of developing Parkinson’ disease 50–70% of the patients will develop GID depending on age. Interestingly, patients with GID were more likely to have psychological problems and suffer from falls, than patients without GID. It seems clear that patients with GID will derive more benefit from transdermal rotigotine than from oral antiparkinson agents. Furthermore, patients on transdermal rotigotine have 24 h therapy while patients on oral drugs begin to loose efficacy overnight. The RECOVER trial investigated the response of nearly 300 Parkinson patients on immediate release L-dopa with unsatisfactory early-morning motor symptom control to treatment with rotigotine versus a placebo patch [42]. Nocturnal sleep disturbance and motor function were significantly improved. There is considerable literature that asserts continuous dopaminergic drug delivery should provide superior control of Parkinson’s symptoms compared to the pulsatile delivery of oral agents [43]. Continuous infusion of L-dopa in animal models and Parkinson’s patients can effectively reduce motor fluctuations and dyskinesias, but this is not practical in the long run because of the high volumes

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and low pH required in the formulation. However, rotigotine as a transdermal agent should provide continuous dopaminergic stimulation. It is indeed, efficacious as monotherapy in earlier stages of the disease but eventually, as with all of the dopamine agonists, L-dopa must be added. The dopamine agonists delay the onset of Ldopa dyskinesias and by reducing the dose of L-dopa needed to control the symptoms reduce the movement disorders associated with higher doses of L-dopa. However, it is not clear that transdermal delivery is superior to oral delivery of the agonists because a controlled trial has never been conducted. Meanwhile new formulations of L-dopa are being tested that provide super extended release times and one that is being used for continuous duodenal infusion.

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Transdermal rotigotine has come of age as a patient-friendly, safe and effective medicine for use in patients with PD. As with many transdermal patch formulations, skin irritation is the most commonly reported side effect associated with use of the product. Development of a NCE for transdermal delivery was an important milestone in the history of transdermal formulation. The transdermal formulation provides a clear therapeutic advantage over oral agonists, at least for some patients. The story of rotigotine should give impetus to the pharmaceutical industry to look towards other NCEs for transdermal administration, especially given the advantages of this route when compared with more conventional routes of drug delivery.

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Conflict of interest statement

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D.M. was the VP Research at Nelson Research and Development Company and Whitby Pharmaceuticals. He was the founder and CEO of Discovery Therapeutics. J.H. was a consultant to Nelson Research and Development Company, Whitby Pharmaceuticals, and Discovery Therapeutics.

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References

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