DRUG PROFILE Selegiline orally disintegrating tablet in the treatment of Parkinson’s disease Anthony Clarke & Mono- and adjunctive therapy with the oral monoamine oxidase B inhibitor selegiline has Joseph Jankovic† been used to treat motor complications resulting from long-term treatment of Parkinson’s †Author for correspondence disease. However, oral selegiline undergoes extensive first-pass metabolism resulting in low Parkinson’s Disease Center and Movement Disorders bioavailability and production of amphetamine and other metabolites, as well as Clinic, Baylor College of compromised efficacy and tolerability. An orally disintegrating tablet of selegiline utilizing Medicine, Department of Zydis® technology undergoes markedly reduced presystemic metabolism, thus providing Neurology, The Smith Tower, Suite 1801 higher plasma concentrations and lower levels of amphetamine metabolites. As an adjunct 6550 Fannin, Houston, to levodopa, selegiline orally disintegrating tablet has been found to significantly reduce TX 77030, USA ‘off’ time, increase ‘on’ time, and improve motor function in Parkinson’s disease patients Tel.: +1 713 798 5998 Fax: +1 713 798 6808 experiencing ‘wearing off’ episodes. This article provides an overview of the Zydis [email protected] technology, the rationale for its application in delivering selegiline, and results from clinical trials of selegiline orally disintegrating tablet in patients with Parkinson’s disease. Although conventional oral administration is study was carried out in part to evaluate poten- the preferred and more convenient route of tially neuroprotective effects of selegiline in drug delivery, it has some disadvantages. Phar- patients with early PD. While results demon- macokinetic limitations to conventional oral strated that selegiline conferred some clinical administration can include poor absorption and benefit, they did not permit any conclusions enzymatic degradation of the drug within the regarding the medication’s neuroprotective effects gastrointestinal tract. Also, reduced bioavaila- [18]. Selegiline has been used most extensively for bility may result from the intestinal Phase I the treatment of wearing-off symptoms, and sev- metabolism and the active extrusion of eral studies have demonstrated modest decreases absorbed drug by cytochrome P450 enzymes in symptoms, duration of ‘wearing-off’ and and P-glycoprotein. Bioavailability is also lim- ‘on–off’ episodes, levodopa dose, and disability ited by hepatic first-pass metabolism, which [10–15]. The benefit of selegiline in reducing gives rise to metabolites that do not contribute motor fluctuations has also been demonstrated in greatly to clinical benefit and may even produce a meta-analysis of clinical trial results for this substantial toxicity [1–7]. In some patients, con- MAO-B inhibitor [14]. However, it is important ventional oral delivery is not possible because of to note that some studies have shown minimal or gastric mucosal irritation, bowel obstruction, no benefit long-term from adjunctive selegiline in frequent emesis, or severe dysphagia [8]. In addi- patients with PD [19]. The role of selegiline as tion, an estimated 50% of the general popula- adjunctive therapy in the treatment of patients tion reports difficulty swallowing tablets and with PD has also been controversial because of hard gelatin capsules, which results in a high results reported by the Parkinson’s Disease Study incidence of noncompliance and the conse- Group of the United Kingdom indicating that quent compromises in efficacy [9]. This is most long-term exposure to this agent was associated common among pediatric and geriatric with increased mortality risk, particularly in Keywords: adjunctive patients, but also occurs in those who are ill or patients with a history of dementia or falls [20]. therapy, CNS, dyskinesia, monoamine oxidase who are busy or traveling and do not have While these results may be troubling, it is impor- inhibitors, orally convenient access to water [9]. tant to note that long-term follow-up of sele- disintegrating tablet, The monoamine oxidase type B (MAO-B) giline-treated patients in other studies has failed Parkinson’s disease, selegiline, Zydis fast-dissolve drug- inhibitor selegiline has been shown to be clini- to detect any mortality [21,22]. delivery technology cally effective for the treatment of patients with The maximum dose of selegiline is limited Parkinson’s disease (PD) [10–16]. Laboratory because the drug undergoes extensive hepatic experiments have also shown that selegiline pro- first-pass metabolism, which leads to high levels vides protection against apoptosis and may have of amphetamine metabolites and ultimately Future Drugs Ltd neuroprotective properties [17]. The DATATOP compromises efficacy and tolerability [23,24]. To 10.1586/14750708.3.3.349 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(3), 349–356 349 DRUG PROFILE – Clarke & Jankovic overcome these problems, selegiline was formu- decreased dosing restrictions with respect to lated in an orally disintegrating tablet (ODT) meals, which can potentially improve the balance using Zydis® technology. This new formulation of efficacy and safety of orally delivered medica- is awaiting approval by the US FDA for use as tions, increase tolerability and compliance, and adjunctive therapy to levodopa in the enhance therapeutic outcomes [1,25,26]. management of PD. Two distinct types of preparations that permit This article describes the Zydis fast-dissolve absorption of medication through the oral drug delivery system, introduced more than a mucosa are in relatively wide clinical use: rapidly decade ago [9], which eliminates many of the disintegrating tablets and soft gelatin capsules problems associated with traditional oral drug filled with liquid drug [1]. The current discussion formulations. The article also presents the focuses on the Zydis fast-dissolve drug delivery rationale for its application in the formulation of system (Cardinal Health Oral Technologies, NJ, selegiline for the treatment of PD, and discusses USA) and its application to improve delivery of the results of clinical trials of selegiline ODT. selegiline given as adjunctive therapy with levodopa in patients with PD. Alternatives to conventional oral drug delivery Zydis formulation for oral drug delivery Limitations of conventional oral drug administra- Zydis technology is used to create a rapidly disin- tion have prompted intensive exploration of alter- tegrating dosage form in a freeze-dried medicinal native delivery vehicles that use transdermal tablet that differs qualitatively from conventional administration or transmucosal drug delivery oral dosage forms [9]. The production sequence through the nasal, rectal, vaginal, ocular, and oral begins with the bulk preparation of an aqueous cavities [1,7]. Drug preparations that permit drug solution or suspension into preformed blis- absorption through the oral mucosa have a ters in the shape of the tablet. The filled blisters number of potential advantages over conventional are rapidly frozen and transferred to large-scale oral preparations. Pharmacokinetic and pharma- freeze dryers for a sublimation process, during codynamic benefits may include more rapid onset which the remaining moisture is removed. This of action, avoidance of presystemic metabolism to leaves a matrix composed of microspindles of gel- provide higher and steadier drug levels than stand- atin and large spaces (where the ice once resided) ard formulations, and decreased levels of and allows for rapid disintegration on contact unwanted metabolites that may result from with moisture (Figure 1). Finally, tablets are heat hepatic first-pass metabolism. Benefits may also sealed in the blisters to ensure the product include reduced risk of interaction with food and remains stable and is protected from varying environmental conditions. Figure 1. Electron micrograph (×50) of a Zydis orally disintegrating tablet demonstrating its porous architecture. Drug candidates for Zydis formulation Numerous criteria are evaluated when consider- ing a drug for Zydis formulation. Both water- soluble and insoluble agents can be formulated using Zydis technology, but compounds must be absorbable through the mucosa [9]. Upper dose limits are generally higher for water-insolu- ble drugs than for water-soluble drugs. The drug should also have an acceptable taste. Cur- rent approaches to improving the taste of a rap- idly disintegrating tablet, not generally a significant consideration in the development of conventional oral tablets, include addition of sweeteners and flavors. If these additives do not mask a bitter taste, drug particles may also be coated [101]. A drug that meets these criteria and is hindered by one or more of the common drawbacks of conventional oral formulation that limit its clinical use is the best candidate for the Reprinted with kind permission from J. Pharm. Pharmacol. [9]. Zydis formulation. 350 Therapy (2006) 3(3) Selegiline orally disintegrating tablet – DRUG PROFILE Actions & advantages of the neurons in the substantia nigra pars compacta, Zydis formulation and this cell death is thought to be the key factor When Zydis tablets are placed in the mouth, the leading to the major clinical symptoms of this porous structure disintegrates and instantane- disease [33,34], which include resting tremor, ously releases the drug to dissolve or disperse in rigidity, bradykinesia, and postural disturbances the saliva. When the patient swallows this saliva, [34,35].