Three-Dimensional Screen Printing Technology Enables Sequential Release of Carbidopa and Levodopa—A New Approach Improving Levodopa Delivery for Treating Parkinson’s Disease

Abstract

Introduction: Levodopa (LD) is the most efficacious antiparkinsonian drug. However, long-term conventional LD treatment of Parkinson’s disease (PD) is frequently associated with motor complications. This can be attributed to pulsatile dopaminergic stimulation given the short LD half-life of conventional dosage forms. Tablets capable of delivering more stable and sustained dopaminergic stimulation would better mimic the brain’s natural dopamine activity.

Methods: In this study, 3D screen printing technology was used to manufacture oral dosage forms characterized by the sequential release of Carbidopa and Levodopa. This was achieved by separating the two compounds into different compartments within the same dosage form, which were arranged (LXM.5-1) or formulated (LXM.5-2) in a specific way. Both novel dosage forms were compared to conventional immediate release forms such as Sinemet^®. The physicochemical properties of the resulting tablets, LXM.5-1 and LXM.5-2, were assessed in accordance with the USP. Their pharmacokinetic profiles were defined in pigs.

Results: The physicochemical properties of LXM.5-1 and LXM.5-2 complied with regulatory requirements. Dissolution studies revealed sequential CD and LD release for both novel dosage forms. They differed regarding the interval between CD and LD release which was shorter for LXM.5-1. PK studies demonstrated that both novel dosage forms exhibited higher LD bioavailability in comparison to Sinemet^®, which was 211.36% and 383.64% for LXM.5-1 and LXM.5-2, respectively. Furthermore, blood levels were more stable and sustained, particularly for LXM.5-2.

Conclusions: We conclude that 3D screen-printed LXM.5-1 and LXM.5-2 and variations thereof have the potential to transform the pharmacotherapy of Parkinson’s disease.

Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, impacting approximately 0.3% of the population in Western countries. Its prevalence escalates with age, affecting about 1% of individuals aged 60 and reaching around 4% by age 80 [1]. It is estimated that PD cases will double within the next two decades [2,3].

PD is a progressive condition marked by a variety of motor and non-motor symptoms (NMSs). Its pathological hallmark is the accumulation of misfolded, fibrillar alpha-synuclein (aSyn) in neurons. Key motor symptoms include bradykinesia, rigidity, and resting tremor. NMSs also significantly impact those with PD. These include sleep disturbances, dysphagia, constipation, apathy, depression, pain, and autonomic dysfunctions, which collectively can severely affect the quality of life of patients and lead to disease-related complications. The severity of these symptoms often dictates the overall impact of the disease on the individual [4]. The clinical presentation and progression of PD can vary greatly among patients [5].

Levodopa (LD) is the most potent antiparkinsonian drug available. Ever since pioneering reports in the 1960s, it has represented the gold standard for the treatment of PD. It increases dopamine levels in the brain, alleviating motor symptoms like bradykinesia and rigidity. LD is combined with either a decarboxylase inhibitor (Carbidopa (CD), Benserazide) or a COMT inhibitor (Entacapone, Tolcapone) to prevent its peripheral degradation (after crossing the blood–brain barrier, Levodopa is transformed into dopamine by cerebral decarboxylases). These agents increase LD’s bioavailability and duration of action. Fixed combinations include LD/CD (added to the WHO list of essential medicines in 1977), LD/Benserazide, and LD/CD/Entacapone. Newer formulations such as Rytary® and Crexont® combine immediate-release (IR) LD/CD and extended-release (ER) LD/CD-containing beads (Rytary®) or ER LD pellets (Crexont®) in capsules. This keeps LD blood levels steady for longer periods of time. However, the LD bioavailability of Rytary® (70–80%) and Crexont® (88–99%) is reduced compared with IR LD/CD preparations (e.g., Sinemet®) necessitating higher doses. Of note, both the conventional and these newer LD dosage forms result in the concomitant release of LD and the decarboxylase inhibitor. To the best of our knowledge, there is currently no LD-containing dosage form available that would have been produced using additive manufacturing.

Despite its effectiveness, the chronic use of conventional oral Levodopa formulations is associated with significant long-term motor complications, notably motor fluctuations and dyskinesias. Within 5 years of conventional LD treatment, 40–50% of patients develop dyskinesias and motor fluctuations, increasing to 70–80% after 10 years [6]. Furthermore, LD’s effectiveness declines in advanced PD due to fluctuating medication periods and its short half-life. Patients often need to increase the dose and frequency of dosing, which in turn increases the incidence of dyskinesias [7]. These adverse effects are strongly correlated with pulsatile dopaminergic stimulation resulting from the pharmacokinetic profile of immediate-release levodopa, which leads to non-physiological oscillations in LD plasma and synaptic dopamine concentrations. They contribute to a 41% increase in direct medical costs [8].

Emerging evidence from both clinical and preclinical studies supports the hypothesis that the pattern of dopaminergic delivery, rather than the dose alone, plays a critical role in the development of these complications [9]. Non-pulsatile (continuous or sustained) dopaminergic stimulation (CDS) aims to more closely approximate endogenous dopaminergic neurotransmission by maintaining relatively stable plasma Levodopa levels and thereby achieving more uniform receptor activation in the striatum. Therapeutic strategies designed to implement CDS include Levodopa–Carbidopa intestinal gel (LCIG) infusion [10], controlled-release oral formulations, and the adjunctive use of enzyme inhibitors (e.g., COMT and MAO-B inhibitors) to extend the half-life of Levodopa. These approaches have demonstrated efficacy in reducing both motor fluctuations and dyskinesias, supporting the pathophysiological rationale underlying CDS [10].

Currently, 3D screen printing is a cutting-edge additive manufacturing technology [11,12]. It enables the production of pharmaceutical dosage forms of unprecedented complexity in large quantities. A single production run can produce units of different shapes and sizes [12]. The release of the active ingredient can be precisely controlled by defining the internal architecture, the size and geometry of the units, and the carrier materials used. As the 3D screen printing process does not involve high temperatures or significant pressure, it can be used with a wide range of substrates and drug substances.

Unlike other manufacturing technologies, 3D screen printing offers the possibility of separating drugs into different compartments of a given oral dosage form. This has the potential to differentially regulate the release of the different drugs. This is of particular interest to oral LD-containing dosage forms, as LD is combined with CD to increase its bioavailability. We hypothesized that the bioavailability of LD could be increased further if the CD were released before the LD, based on its inhibitory action against LD degradation. To this end, we harnessed the potential of additive manufacturing to design two novel dosage forms containing CD and LD in different compartments. Two principal strategies were followed, namely, controlled drug release by the architecture of the dosage form and controlled drug release as a function of the composition of the different compartments. In LXM.5-1 (LXM.5 is an internal project code referring to Laxxon’s novel LD/CD dosage forms; LXM.5-1/2 refers to specific prototypes as described in the manuscript), the release of both drugs was tailored through the geometry of the dosage form whereas in LXM.5-2 the release of the two drugs was controlled by the composition of the compartments, a key component being a pH-sensitive polymer built into the LD compartment. Their evaluation confirmed the concept of increasing the bioavailability of LD by sequentially releasing CD and LD, with CD preceding LD. Furthermore, not only were LD blood levels higher, but they also persisted for longer. These studies have several potential implications which range from practical consequences, such as reducing the number of daily intakes, to the potential to slow the progression of the disease.

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Chemicals

CD and LD were purchased from Divi’s Laboratories, Hyderabad, India. The various excipients were purchased from established providers: Klucel LF (Ashland, Covington, KY, USA), Avicel PH 105 (Dupont, Wilmington, DE, USA), starch 1500 (Colorcon, Harleysville, PA, USA), glycerol and triactin (AppliChem, Darmstadt, Germany), talc (Imerys, Paris, France), Silfar 350 and Silfar SE4 (Wacker Chemie, Munich, Germany), L-ascorbic acid and aqueous HCl (Carl Roth GmbH, Karlsruhe, Germany), citric acid (Honeywell FlukaTM, Charlotte, NC, USA), Ac-Di-Sol (IFF, Roquette, Lestrem, France), Mannogem Emerald (SPI Pharma, Wilmington, DE, USA), and Miglyol 812 N (IOI Oleo, Hamburg, Germany). Some materials were kindly provided by the respective manufacturers. This includes Shin-Etsu AQOAT® AS-LF provided by SE Tylose GmbH & Co.KG, Wiesbaden, Germany and RxCIPIENTS® FM 1000 by Evonik, Darmstadt, Germany. Demineralized water was used for all formulations and solutions. For HPLC measurements, sodium dihydrogen phosphate and HPLC-grade solvent Chemsolute (water and acetonitrile) from TH.Geyer, Renningen, Germany were used.

Enke, M.; Bünger, M.; Aedtner, E.; Kastner, S.; Gruschwitz, F.; Kühne, K.; Czernik-Schulz, D.; Greeley, D.R.; Volc, D.; Buzachnich-Ladinig, A.; et al. Three-Dimensional Screen Printing Technology Enables Sequential Release of Carbidopa and Levodopa—A New Approach Improving Levodopa Delivery for Treating Parkinson’s Disease. Pharmaceutics 2025, 17, 1507. https://doi.org/10.3390/pharmaceutics17121507