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Transdermal Donepezil on the Treatment of Alzheimer's Disease

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Transdermal Donepezil on the Treatment of Alzheimer's Disease Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Transdermal donepezil on the treatment of Alzheimer’s disease Piera Sozio Abstract: Alzheimer’s disease (AD) is the most common type of senile dementia, characterized Laura S Cerasa by cognitive deficits related to degeneration of cholinergic neurons. The first anti-Alzheimer Lisa Marinelli drugs approved by the Food and Drug Administration were the cholinesterase inhibitors (ChEIs), Antonio Di Stefano which are capable of improving cholinergic neurotransmission by inhibiting acetylcholinesterase. The most common ChEIs used to treat cognitive symptoms in mild to moderate AD are Department of Pharmacy, University of “G. d’Annunzio,” Vai dei Vestini, rivastigmine, galantamine, and donepezil. In particular, the lattermost drug has been widely Chieti, Italy used to treat AD patients worldwide because it is significantly less hepatotoxic and better tolerated than its predecessor, tetrahydroaminoacridine. It also demonstrates high selectivity towards acetylcholinesterase inhibition and has a long duration of action. The formulations available for donepezil are immediate release (5 or 10 mg), sustained release (23 mg), and orally disintegrating (5 or 10 mg) tablets, all of which are intended for oral-route administration. Since the oral donepezil therapy is associated with adverse events in the gastrointestinal system and in plasma fluctuations, an alternative route of administration, such as the transdermal one, has been recently attempted. The goal of this paper is to provide a critical overview of AD therapy with donepezil, focusing particularly on the advantages of the transdermal over the oral route of administration. Keywords: Alzheimer’s disease, donepezil, transdermal, patch Introduction Alzheimer’s disease (AD) is the most common type of senile dementia, affecting 6%–8% of people over the age of 65 years and nearly 30% of people older than 85 years.1,2 In fact, it has been demonstrated that the number of people over 60 years old affected by AD doubles every 5 years.1,2 The common signs and symptoms of AD include apathy, agitation, irritability, disinhibition, delusions, mood disturbances, and aberrant motor behavior, as well as sleeping and eating abnormalities. Since this disease may progress in different ways, it has become difficult to make a precise diagnosis.3 AD is associated with reduced levels of a number of cerebral neurotransmitters such as acetylcholine (ACh), noradrenaline, serotonin, somatostatin, and corticotrophin- releasing factors, whereas the levels of glutamate increase.4 However, the cognitive deficits seem to be primarily related to the degeneration of cholinergic neurons that originate in the basal-forebrain-cholinergic system and innervate the neocortex, Correspondence: Department of hippocampus, and other brain areas.5 Thus, AD treatment entails the restoration of Pharmacy, University of “G. d’Annunzio,” Via dei Vestini, 66100 Chieti, Italy cholinergic pathway neurotransmitters through several approaches such as exploitation Tel +39 871 355 4708 of ACh precursors (eg, lecithin or choline), using muscarinic or nicotinic agonists Fax +39 871 355 4706 Email [email protected] (eg, bethanacol, arecoline, and milameline), as well as administering cholinesterase submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2012:8 361–368 361 Dovepress © 2012 Sozio et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/NDT.S16089 which permits unrestricted noncommercial use, provided the original work is properly cited. Sozio et al Dovepress inhibitors (ChEIs).6–8 ChEIs, the first class of anti-AD drugs of dementia of the Alzheimer’s type.12 Donepezil interacts approved by the United States Food and Drug Administration with AChE via hydrogen bonds and is demonstrated to be a (FDA), reduce the hydrolysis of acetylcholine in the synaptic reversible, non-competitive, and selective ChEI that produces cleft by inhibiting cholinesterase (acetylcholinesterase long-lasting inhibition of brain AChE without markedly [AChE] and/or butyrylcholinesterase [BuChE]). This affecting peripheral AChE activity.13 Due to properties inhibition increases the ACh levels and therefore improves such as low hepatotoxicity, high selectivity towards AChE neurotransmission.9 Since AChE is found predominantly in inhibition (IC50 AChE/IC50 BuChE = 6.7/7400 nM), and a the brain, striated muscle, and erythrocytes, while BuChE duration of action (t1/2 = 90 h) that is sufficiently long enough is mainly found in the periphery (skin, plasma, and cardiac to allow for convenient once-daily administration, donepezil muscle), AD treatment strategies are mainly directed towards has been widely used to treat AD patients worldwide.14 The the inhibition of AChE.10,11 It is worth mentioning that these long-term benefits and good safety profile of AChEIs shown agents may not be effective in all patients because only 50% by extended post-marketing studies allowed for the approval of AD patients have cholinergic deficits. Indeed, 30% of AD of donepezil for the treatment of the entire clinical spectra patients are also characterized by noradrenaline deficits.10 of the disease in 2007.15,16 Four ChEIs are commonly used to treat cognitive The recommended dosage for donepezil IR is 5 mg/day symptoms in mild to moderate AD: Exelon® (rivastigmine for the first 4 weeks and 10 mg/day thereafter.17 Inactive tartrate; Novartis AG, Basel, Switzerland); Reminyl® ingredients in 5 and 10 mg tablets are lactose monohydrate, (galantamine hydrobromide; Johnson and Johnson Inc, New corn starch, microcrystalline cellulose, hydroxypropyl Brunswick, NJ); Aricept® (donepezil hydrochloride; Pfizer cellulose, and magnesium stearate. The film coating contains Inc, New York, NY; Eisai Inc, Tokyo, Japan); and the rarely talc, polyethylene glycol, hypromellose, and titanium prescribed Cognex® (tacrine hydrochloride; First Horizon dioxide.13 The efficacy of donepezil was demonstrated both in Pharmaceutical Corp., Roswell, GA) (Figure 1). a 24-week, double-blind study and in a placebo-controlled trial The goal of this paper is to provide a critical overview (the AD2000 study).18 In the former study, patients with mild of donepezil as an AD therapy, focusing particularly to moderate AD were randomly treated with donepezil 5 mg/ on the advantages of transdermal over the oral route of day, 10 mg/day, or placebo. Patients’ cognition and clinicians’ administration. global ratings (AD Assessment Scale [ADAS-cog] and the Clinician’s Interview Based Assessment of Change-Plus Oral donepezil therapy [CIBC], respectively) were significantly improved in patients Immediate-release tablets treated with the drug compared with placebo, whereas no Donepezil immediate-release (IR) tablets (5 or 10 mg) were improvement was noted on patient-related quality of life.19,20 approved for use in the US in November 1996 for the treatment In the latter study, 565 patients with mild to moderate AD were H OH O H ON O N O N Rivastigmine Galantamine O NH2 O N H O N Donepezil Tacrine Figure 1 Structure of ChEIs. Abbreviation: ChEIs, cholinesterase inhibitors. 362 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2012:8 Dovepress Dovepress Transdermal donepezil and Alzheimer’s disease enrolled; in both the presence and absence of cerebrovascular which depends on the chosen dose.26,27 Less common disease, donepezil has been shown to improve cognition adverse effects are vagotonia (eg, bradycardia, syncope), compared with placebo. In particular, the ratio of “improved” and central nervous system (eg, aggression, sleep patients (as judged by the clinicians) across the presence disturbance) and parasympathetically mediated (eg, urinary of hallucinations, delusions, wandering, and aggression at incontinence) AEs.28 last observation carried forward among patients receiving The incidence of AEs increases with oral administration donepezil, and ranged between 59.6% and 65.6%.21 For these due to the large and frequent plasma fluctuations. In fact, reasons, donepezil may be a useful treatment not only for the when donepezil is administered orally, it is rapidly absorbed behavioral and psychological symptoms of dementia (BPSD), through the gastrointestinal wall thus reaching its peak but also for cognitive dysfunction. plasma level (Cmax). The drug levels then decrease until the 9 next dose is admnistered. In order to decrease both the Cmax Sustained-release tablets level and the rate of Cmax achievement so as to attenuate the In 2010, the FDA approved sustained-release (SR) tablets AEs, the alternative route of transdermal administration was containing 23 mg of donepezil to provide a higher once- attempted. daily dose while avoiding a sharp daily increase in peak concentration. Inactive ingredients in the 23 mg tablets are Transdermal route versus oral route ethylcellulose, hydroxypropyl cellulose, lactose monohydrate, The transdermal drug delivery route has several advantages magnesium stearate, and methacrylic acid copolymer, type C. compared to the parenteral and oral routes of administration, 29 The film coating is composed of ferric oxide, hypromellose especially in the elderly. Indeed, this type of administration 2910, PEG 8000, talc, and titanium dioxide. These film- is particularly useful when a chronic neurological disorder coated tablets were compared with the marketed formulation
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