Beyond Dysphagia in Parkinson’s Disease: 3D Printing of Orally Disintegrating Tablets (ODTs) for Optimized Treatment

Abstract

Parkinson’s disease (PD) is frequently complicated by dysphagia, undermining timely and reliable oral dopaminergic medication. Levodopa’s short half-life and delayed gastric emptying in advanced PD result in inconsistent absorption, delayed “ON” periods, and challenges to adherence. Orally disintegrating tablets (ODTs) dissolve without water and can mitigate swallowing limitations. Research indicates that selegiline ODT achieves a faster time to peak and higher relative bioavailability via partial buccal absorption, whereas carbidopa/levodopa ODTs are bioequivalent to immediate release tablets (with similar AUC/C_max and approximately 1 h T_max) without consistent motor advantages but with higher patient acceptability. This review synthesizes the clinical burden of dysphagia in PD, pharmacokinetic constraints of current formulations, and the reasons for ODTs. We highlight 3D printing as a route to personalized, dysphagia friendly therapy, which enables dose individualization, polypills, engineered disintegration or release, and point-of-care production. Feasibility studies underscore stability considerations such as carbidopa, throughput and regulatory requirements (QbD/GMP), and bioequivalence information. We outline priorities to integrate 3D printed ODTs into PD care, aligning formulation, pharmacokinetics, and human factors to improve adherence and clinical outcomes.

1. Introduction

Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder that manifests with both motor and non-motor symptoms. Approximately 0.93 million people were living with PD in the United States in 2020, with projections of about 1.24 million by 2030 [1]. As more than half of the world’s elderly population resides in Asia, PD posing a significant public health challenge in countries such as Taiwan, China, and Japan [2]. As PD progresses, patients commonly develop dysphagia (swallowing difficulty), a non-motor symptom with severe health implications [3]. Dysphagia occurs in more than one-third of PD patients on average (pooled prevalence: 37%) and up to 70–87% in advanced cases depending on the assessment method [3,4]. This impairment leads to the malnutrition, dehydration, and aspiration of food or pills into the airway, often causing aspiration pneumonia. Aspiration pneumonia is the leading cause of death in PD, responsible for roughly 25% of PD-related mortality [5]. Difficulties in swallowing interfere with quality of life and limit medicine administration [4]. Managing motor symptoms typically requires multiple daily doses of immediate-release (IR) carbidopa/levodopa (approximately 5 times daily), which not only increases treatment complexity but also affects patient medication adherence [6]. Levodopa is a dopamine precursor that crosses the blood–brain barrier to alleviate motor symptoms, whereas carbidopa is a peripheral decarboxylase inhibitor given alongside levodopa to prevent its conversion to dopamine outside the brain. This combination increases the amount of levodopa reaching the central nervous system (CNS) and reduces peripheral side effects [7].

Oral levodopa remains the gold-standard therapy for PD motor control, but effective use of levodopa is challenged by late-stage disease progression and gastrointestinal dysfunction. In advanced PD, loss of physiologic dopamine buffering and delayed gastric emptying led to erratic absorption and motor response fluctuations [8,9]. Patients might experience a “delayed onset” condition, when the medication’s effects appear slowly or unpredictably, resulting in increased “OFF” periods due to the unstable pharmacokinetics of levodopa [7]. These problems are exacerbated by dysphagia, since patients who cannot swallow well may not take medications on time or at all. In late-stage PD, dysphagia amplifies these problems: patients who cannot swallow reliably delay or omit doses, undermining adherence and symptom control [4]. Because timely dopaminergic administration is critical, such delays are linked to worse motor outcomes in clinical settings [10]. There is a clear clinical urgency for dosage forms that can circumvent swallowing difficulties and improve the reliability of drug delivery in PD.

Orally disintegrating tablets (ODTs) are a patient-centric option for dysphagia. It is solid oral formulations that rapidly disintegrate in the mouth and can be administered without water [11,12]. For PD patients with dysphagia, ODTs offer easier self-administration and potentially faster absorption onset [13]. This review first examines the impact of dysphagia in Parkinson’s disease patients and evaluates how orally disintegrating formulations of antiparkinsonian drugs address these challenges. It further explores the emerging role of 3D printing technology in introducing innovative solutions for developing easy-to-swallow Parkinson’s disease treatments. We aim to clarify the urgent need for orally disintegrating formulations in Parkinson’s care and how 3D printed formulations can overcome existing limitations.

Table 1. Current and emerging formulations for Parkinson’s disease and their features. (click picture to enhance)

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4. Oral Disintegrating Tablet (ODT) Availability

For Parkinson’s disease patients, orally disintegrating tablets (ODTs) can help prevent swallowing-related difficulties and reduce delays in treatment caused by traditional formulation characteristics. Currently a limited number of ODT formulations for PD are commercially available, including ODTs carbidopa/levodopa [20] and selegiline [37]).

Selegiline ODT (Zelapar®) dissolves on the tongue and is absorbed through the oral mucosa, bypassing first-pass metabolism [37]. This pharmacokinetic advantage lowers the risk of certain side effects and potentially improves patient compliance. Compared to a conventional swallowable tablet, selegiline ODT’s time to peak concentration (Tmax) is markedly accelerated (approximately 10–15 min compared to 40–90 min), with higher relative bioavailability. Notably, a 1.25 mg Zelapar® ODT achieves plasma concentrations equivalent to 10 mg of traditional selegiline, with significantly reduced amphetamine metabolites [19,38].

Orally disintegrating tablets of carbidopa/levodopa may enhance the administration route but do not substantially modify the pharmacokinetic characteristics of levodopa. FDA bioequivalence studies show a Tmax of approximately 1 h, like standard release tablets, with standard bioequivalence in AUC and Cmax. Randomized crossover trials also found no significant differences in ON time [39]. A multicenter study found that the carbidopa/levodopa ODT was preferred by 45% of PD patients versus 20% for the standard tablet, with easier use and less swallowing concern cited as the main reasons [20]. Given the high prevalence of dysphagia in PD (~70%), these findings support ODTs’ suitability for patients with swallowing difficulties [4].

In the United States, there has not been a commercially available ODT for carbidopa/levodopa since the approval of the Parcopa® brand in 2004 but withdrawn by 2002, which is offered in dosages of 10/100, 25/100, and 25/250 mg. As of late 2023, no carbidopa/levodopa ODT remains on the US market, leaving a significant gap in care for PD patients with dysphagia. This gap matters because healthcare professionals may resort to crushing IR carbidopa/levodopa to administer with soft food, even though modified release products should not be crushed. In recent years, several “rescue” solutions that do not require swallowing have been introduced. Apomorphine sublingual film was approved by the FDA in 2020 but was voluntarily discontinued from the U.S. market in 2023. Inhaled levodopa powder was approved in 2018. Oral dispersible levodopa/benserazide (Madopar®) is still accessible outside of the U.S. Selegiline (Zelapar®) is still on the market as an ODT for PD in the U.S. However, no ODT formulation currently exists to substitute for daily levodopa tablets (Table 1). This persistent unmet need has prompted interest in novel fabrication methods, including 3D printing to create a swallow-friendly and patient-tailored PD therapeutics.

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Excipients mentioned in the study: POLYOX™ N80, Eudragit RSPO, Eudragit RL100, Eudragit EPO

Liao, Y.-J.; Liang, Y.-J. Beyond Dysphagia in Parkinson’s Disease: 3D Printing of Orally Disintegrating Tablets (ODTs) for Optimized Treatment. Pharmaceuticals 2025, 18, 1886. https://doi.org/10.3390/ph18121886