PLGA and Eudragit-based long-acting microspheres for Parkinson's disease management

Abstract

Oral medications available for Parkinson’s disease require multiple administrations, which significantly affects the plasma concentration of the drug, and patients struggle to adhere to the treatment regimen due to the complexity of frequent dosing. Therefore, the idea of developing a long-acting biodegradable microsphere formulation was adopted. The biodegradable microspheres were prepared using a combination of PLGA_50:50 and Eudragit L-100. This combination incorporates the advantages of both PLGA_50:50 and Eudragit L-100 to achieve optimum drug release. The drug loaded was pramipexole. Since pramipexole is hydrophilic in nature, microspheres were fabricated using a double emulsion solvent evaporation process. The optimized microsphere formulation demonstrated an initial burst release of up to 24.18%, followed by a slow release of pramipexole for up to 18 days (93.78%) without the need to convert the drug into its salt form. The ex vivo drug release showed 78.96% release of pramipexole in 10 days. The optimized microspheres were further studied by DSC, FTIR, NMR, and SEM. The syringeability analysis of the microspheres, when suspended in sodium CMC solution, demonstrated an injectable force of 3.25 ± 0.24 N.

Introduction

The treatment strategies for Parkinson’s disease have developed considerably in recent years. Pharmacological therapies, including levodopa, dopamine receptor agonists, anticholinergic agents, monoamine oxidase B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors, remain the basis of symptomatic management and are widely reviewed in clinical practice.1

Levodopa is always given in combination with carbidopa to prevent its systemic adverse effects. Along with carbidopa, another class of drugs, COMT inhibitors (tolcapone and entacapone), has been added to the treatment regimen. They are approved for patients experiencing “wearing-off” phenomena, where the effect of levodopa diminishes before the next dose.2 Despite the well-established efficacy of levodopa as the most potent symptomatic treatment, increasing emphasis has been placed on “levodopa-sparing strategies” in early Parkinson’s disease. These approaches aim to delay the onset of long-term motor complications, particularly motor fluctuations and dyskinesias, which are strongly associated with chronic levodopa exposure and pulsatile dopaminergic stimulation. Another class of drugs, dopamine receptor agonists, mimics the natural action of dopamine and works by direct stimulation of dopamine receptors.1 Pramipexole and ropinirole are among the most frequently used dopamine agonists; pramipexole tends to be more potent.1

Pramipexole belongs to the non-ergot dopamine agonist class, which was first introduced in 1997 in the US, followed by European countries. It is currently prescribed as monotherapy and as adjunctive therapy with levodopa.3 In early-stage Parkinson’s disease, pramipexole can be prescribed as monotherapy, which delays the need for levodopa.4 Pramipexole is a synthetic non-ergot, aminothiazole dopamine agonist with affinity for dopamine D2 and D3 receptors.5–8 The higher affinity of pramipexole for the D3 receptor5 contributes to its efficacy against the psychiatric symptoms of Parkinson’s disease, such as depression.9 Pramipexole is presently available in the market as an oral immediate-release tablet, which is administered 3 times a day.10–12 The current immediate-release tablet formulation of pramipexole requires administration 3 times a day, resulting in fluctuations in the plasma concentration of pramipexole.10 Clinical studies demonstrate that pramipexole is effective both as monotherapy in early-stage Parkinson’s disease and as an adjunct to levodopa in advanced stages. In addition to improving motor symptoms such as akinesia, rigidity, and resting tremor, pramipexole has also been shown to alleviate depressive symptoms. It is generally well tolerated; however, compared with levodopa, it is associated with a higher incidence of certain dopaminergic adverse effects.3

Pramipexole is well absorbed when given orally;13 however, it still requires multiple administrations due to its short half-life. Additionally, many patients experience dysphagia with oral medication.14 To address these limitations, a sustained-release formulation is needed, which will enable slow release of the drug for a longer time. Long-acting injectables can be used as an alternative option, which will reduce the need for multiple administrations.

The design of a long-acting formulation depends on the physicochemical properties of the API including molecular weight, log P, solubility, and hydrophobicity. In addition, safety, therapeutic area, administration needs, pharmacokinetics, and pharmacodynamics of the API are crucial factors in the design of the long-acting formulation.15 Multiple methods of controlling release duration have been developed as a result of the range of potential drug features and applicable disorders. Numerous drug delivery systems, including microencapsulation,16,17 oil-based solutions and suspensions,18,19 in situ forming implants,20,21 nanocrystal suspension,22 long-acting hydrogels, long-acting microneedles,23 and long-acting implants,24 have been developed to maintain drug release.25 Based on the physicochemical data, pramipexole is highly hydrophilic in nature, so controlling the release of hydrophilic drugs requires encapsulation of the drug or conversion into a less soluble pro-drug form. Nevertheless, for hydrophilic drugs, a microsphere formulation is the best approach for sustaining drug release due to its flexibility in modifying drug release.26 In addition, microspheres can increase the efficiency and the duration of action of drugs, along with the prevention of drug degradation after administration. Different strategies for encapsulation are applied according to the drug’s solubility and inherent properties.27 For example, solvent evaporation, oil-in-water (o/w) emulsion for hydrophobic drugs, and water-in-oil-in-water (w/o/w) double emulsion for water-soluble drugs are employed.27–29

Various pramipexole formulations have been developed by researchers. For example, in 2018, Raj et al.30 formulated pramipexole dihydrochloride loaded nanoparticles for nose-to-brain delivery of pramipexole. However, the in vitro release and ex vivo studies showed drug release for up to 24 hours. Hence, this formulation cannot be used for achieving sustained drug release for a longer period. In 2023, Pamlenyi et al.31 developed pramipexole-loaded buccal films for improving the absorption of the drug. The in vitro release showed up to 80% drug release in 20 minutes.

The literature on pramipexole long-acting formulations includes a study by Li et al., 2019,32 which reported a near-infrared light-responsive microsphere for pramipexole; however, this formulation requires external light stimulation to achieve drug release, which reduces its practicality for continuous use. Another study by Ban et al., 2025,33 involves the conversion of pramipexole into its xinafoate salt form, which adds a layer of manufacturing complexity. Additionally, the xinafoate salt form has not been approved by the FDA for injectables to date.

In this study, we explored the double emulsion (W/O/W) solvent evaporation method for pramipexole microsphere preparation using a combination of polymers, namely PLGA and Eudragit L-100. This method is simple compared to the tedious method of converting the drug into a lipophilic form, which adds to the complexity of scale-up. This is the first study to discuss long-acting injectable microspheres for pramipexole using a combination polymer, PLGA and Eudragit L-100. The optimized microspheres were also characterized for in vitro drug release, drug loading, encapsulation efficiency, syringeability, viscosity, XRD, DSC, and particle size distribution.

Download the full article as PDF here PLGA and Eudragit-based long-acting microspheres for Parkinson’s disease management

or continue reading here

Materials

PLGA_50:50 (inherent viscosity 0.17 dl g⁻¹, acid terminated) was obtained from Nomisma Healthcare (Gujarat, India). Polyvinyl alcohol (87–90% hydrolysed, MW: 30000–70000) was procured from Sigma (the Netherlands). Sodium phosphate dibasic was purchased from Sigma (Germany). Potassium phosphate monobasic, Tween 80 and dimethyl sulfoxide (DMSO) were procured from Chemsupply (Gillman, Australia). Ethyl acetate was procured from Merck (South Africa). Dichloromethane was purchased from Sigma-Aldrich (MO, USA). Eudragit L-100 was procured from Evonik (Darmstadt, Germany). Acetonitrile was obtained from Sigma-Aldrich (NSW, Australia). Pramipexole was acquired from BLD Pharma Tech Ltd (China).

Deepa D. Nakmode, Haripriya Koppisetti, Weranga Rajapaksha, Yunmei Song, Sanjay Garg; PLGA and Eudragit-based long-acting microspheres for Parkinson’s disease management. RSC Pharm. 2026; https://doi.org/10.1039/d6pm00029k