Enhanced stability of levodopa and benserazide fixed-dose combination tablets through optimized production processes

Abstract

Parkinson’s disease is a debilitating neurodegenerative disorder that is primarily characterized by dopamine deficiency, which significantly impairs motor function and quality of life. Levodopa remains the gold standard treatment due to its efficacy in replenishing dopamine levels. However, its combination with decarboxylase inhibitors such as benserazide is necessary to increase bioavailability and reduce peripheral side effects. Despite this advantage, the inherent instability of benserazide under changing environmental conditions presents a significant challenge in formulating effective and long-lasting fixed-dose combinations. The objective of this study is to develop a stable fixed-dose tablet composition of levodopa and benserazide by formulating their granules separately to prevent degradation, an approach underexplored in existing literature. By granulating these active ingredients separately, the formulation exploits the stability and process advantages of both techniques while addressing the risks of degradation associated with their direct interaction. The wet granulation of levodopa ensures homogeneity and optimized powder compressibility, while the dry granulation of benserazide avoids moisture-induced instability. Extensive stability studies under accelerated and long-term conditions have demonstrated the superiority of this dual granulation strategy. These findings suggest that separate granulation improves the stability and efficacy of levodopa-benserazide formulations, offering a promising strategy for the long-term management of Parkinson’s disease and addressing a critical gap in current pharmaceutical research. The formulation demonstrated consistent active ingredient content over time, minimized impurity formation, and exhibited stable physicochemical properties, going far beyond conventional single granulation methods.

Introduction

Parkinson’s disease is a neurodegenerative disorder that is characterized by the progressive degeneration of the dopaminergic pathway, which ultimately results in a reduction of dopamine concentration in the brain. This deficiency is manifested in the form of symptoms such as bradykinesia (slowness of movement), rigidity, tremor, and poor balance (Bergman et al., 1990; Mayeux et al., 1995; Smith et al., 2020). Levodopa, an immediate metabolic precursor of dopamine, is capable of crossing the blood-brain barrier, thereby making it a crucial treatment for the restoration of dopamine levels within the brain (Nagatsu and Sawada, 2009; Fahn et al., 2004; Kim and Park, 2019). Although levodopa is an effective treatment for the early stages of Parkinson’s disease, the majority of administered levodopa is metabolized before reaching the brain. This necessitates the use of large doses, which can cause significant side effects such as nausea (Hauser and Zesiewicz, 2007).

To enhance the bioavailability of levodopa and mitigate the adverse effects associated with its administration, it is combined with decarboxylase inhibitors, such as carbidopa or benserazide. These inhibitors compete with levodopa for the metabolizing enzyme dopadecarboxylase (DDC), thereby allowing a greater quantity of levodopa to reach the brain before conversion to dopamine. This combination therapy markedly reduces the required dose of levodopa by 60-80 %, thereby minimizing peripheral side effects while maintaining therapeutic efficacy (Brown and Green, 2021; Marsden and Parkes, 1976; Williams et al., 2022).

Comparative studies have demonstrated the advantages of combining levodopa with benserazide over carbidopa, with fewer peripheral side effects and similar clinical improvements. For example, Madopar® tablets, which contain levodopa and benserazide, are commonly used to treat Parkinson’s disease and restless leg syndrome (RLS) (Olanow et al., 1993). They offer improved tolerability and effectiveness compared to levodopa alone. Combination therapies, have become a cornerstone in managing Parkinson’s disease by ensuring a more stable release of dopamine in the brain and better patient compliance (Schapira, 2009; Varga et al., 2019; Wang and Sun, 2021).

Benserazide plays a pivotal role in this combination, as it inhibits the premature conversion of levodopa to dopamine outside the brain, thereby increasing the amount of levodopa that reaches the brain. This process not only enhances the therapeutic effects but also reduces peripheral adverse effects, such as nausea and orthostatic hypotension. A number of studies, including those conducted by Da Prada (1987) and Rinne (1979), have demonstrated that benserazide is more potent than carbidopa in inhibiting peripheral aromatic L-amino acid decarboxylase, which has been linked to improved clinical outcomes (Da Prada and Burkard, 1987; Rinne, 1979).

Nevertheless, the formulation of a stable levodopa and benserazide tablet is impeded by the instability of benserazide hydrochloride. This compound is particularly susceptible to degradation under light, moisture, and varying pH conditions, which can lead to the formation of impurities that may affect the drug’s safety and efficacy. The primary degradation products are benserazide impurities A, B, and C, which are formed as a result of oxidation and other chemical processes (Mehetre et al., 2024; Pahwa et al., 2017).

Stability-related issues not only reduce the shelf life of the formulation but also diminish the efficacy of the medication. Degraded benserazide can impede the inhibition of peripheral decarboxylase, limiting the penetration of levodopa into the brain and reducing its therapeutic benefits. Therefore, addressing these stability concerns is essential for developing a reliable and effective long-term medication (Brown and Green, 2021; Garcia et al., 2017; Jankovic and Poewe, 2012; Kim and Park, 2019).

In the absence of comprehensive studies on the degradation of compositions containing both levodopa and benserazide, there remains a significant need for the development of novel formulations. It is imperative that these formulations guarantee the stability of the active ingredients throughout the product’s shelf life, ensuring that they retain their therapeutic efficacy and safety (Fahn, 2008; Gasser et al., 2013). Fixed-dose combination (FDC) tablets are widely employed in chronic disease management to enhance patient adherence. Among these, bilayer tablet technology is a commonly used approach to physically separate incompatible active pharmaceutical ingredients. However, bilayer tablets often require more complex and expensive manufacturing processes, and their layer adhesion and uniformity pose additional formulation challenges. In the present study, a single-layer formulation with separate granulation of the APIs was chosen as a simpler and more scalable alternative, capable of improving the chemical stability of benserazide without requiring structural separation. This approach enables efficient production and robust performance under stability conditions. This article explores the formulation development of a tablet containing levodopa and benserazide, with a particular focus on surmounting the challenges associated with stability in order to provide a consistent and effective treatment for Parkinson’s disease.

The objective of the present research is to develop a stable pharmaceutical tablet composition containing pharmaceutically effective amounts of levodopa and benserazide, or their pharmaceutically acceptable salts, in conjunction with suitable excipients. In order to achieve a stable tablet composition, the levodopa and benserazide granules are formulated separately. This separation is intended to prevent interaction between the two active ingredients, which can lead to degradation, and is designed to optimize the stability and effectiveness of each component (Connolly and Lang, 2014; Lin and Chen, 2018; Singh and Kumar, 2017; Taylor et al., 2018; Zhang and Liu, 2019).

The granulation processes for both levodopa and benserazide are meticulously detailed to ensure stability and efficacy. The preparation of levodopa granules involves a wet granulation process followed by drying in a fluid bed dryer, whereas benserazide granules are prepared through dry granulation and sieving. The formulation strategy also includes specific dosage combinations, such as 200 mg to 100 mg of levodopa and 50 mg to 25 mg of benserazide. These dosage ranges are designed to provide effective treatment while minimizing side effects (Smith et al., 2012).

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Materials

The developed formulation comprised the following ingredients: levodopa, benserazide hydrochloride, mannitol, microcrystalline cellulose, pregelatinized starch, calcium hydrogen phosphate, ethyl cellulose, docusate sodium, colloidal silicon dioxide, crospovidone, and magnesium stearate. Throughout the formulation studies, the tablets were subjected to rigorous quantification and impurity analyses employing the most appropriate analytical techniques. The aforementioned analyses employed the use of sodium heptanesulfonate monohydrate, potassium dihydrogen phosphate, ultra-pure water, orthophosphoric acid and methanol.

All excipients included in the formulation are widely recognized in the field of pharmaceutical technology and conform to the standards outlined in the European Pharmacopoeia and the United States Pharmacopeia (USP) monographs. This ensures compatibility with relevant specifications. The selection of excipients was guided by the example of the reference product, Madopar® Tablet, reflecting their common use in oral pharmaceutical formulations. Furthermore, all chemicals used were of analytical grade and sourced from reputable commercial suppliers. This approach maintains consistency and reliability throughout the formulation process, which is crucial for ensuring the quality and efficacy of the final pharmaceutical product.

Onur Pinarbasli, N. Egesen Kok, Feristah Bilgin, Nagehan Sarracoglu, Enhanced stability of levodopa and benserazide fixed-dose combination tablets through optimized production processes, European Journal of Pharmaceutical Sciences, Volume 211, 2025, 107134, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107134.