Development of taste-masked enteric granules containing diclofenac sodium utilizing Eudragit® E PO as a taste-masking agent

ABSTRACT

This study aimed to develop a taste-masking method for Eudragit® L 100-based enteric microparticles containing diclofenac sodium (DS) using Eudragit® E PO and to determine the optimal polymer ratio for effective taste-masking. The taste-masked enteric granules (TEGs) were fabricated via rotary evaporation with dichloromethane as the solvent, with enteric microparticle-to-Eudragit® E PO weight ratios of 1:0.1, 1:0.25, 1:0.5, and 1:1. Reducing the polymer ratio to 0.1 caused enteric microparticles to disperse independently from the polymer, while higher ratios embedded them in the polymeric carrier. To evaluate the taste-masking efficiency of TEGs, drug release in 10-mL simulated salivary fluid (SSF) was tested. The results revealed that increasing the polymer ratio enhanced the inhibition of drug release in SSF, indicating improved taste masking. However, in the in vitro drug dissolution in a two-stage biorelevant medium, TEGs with high polymer ratios of 1 and 0.5 released only 69.80±1.47% and 78.87±1.21% of DS after 3 h in the buffer stage dissolution, while TEGs with lower polymer ratios of 0.25 and 0.1 exhibited higher drug release percentages of 92.61±1.23% and 97.14±0.58%, respectively. From this study, the optimal enteric particle-to-Eudragit® E PO ratio was 1:0.25, effectively masking the bitter taste of DS while minimally affecting drug release in a gastrointestinal-mimicking environment.

INTRODUCTION

Taste masking plays a crucial role in the formulation design of pharmaceuticals, especially those intended for oral administration, due to the fact that numerous active pharmaceutical ingredients (APIs) have unpalatable tastes. To mask the bitter taste, three major approaches were utilized to prevent the APIs from interacting with taste buds. These strategies comprised the utilization of flavoring agents, chemical modifications, and employing physical barriers. Utilizing flavoring agents is a common and widely used method. Sweeteners, flavoring agents, and additional pharmaceutical excipients are employed to disguise the bitter taste of drug substances (Lenik et al., 2016). Nevertheless, this technique is constrained in its ability to mask the taste of highly potent drugs and may not entirely eliminate strong taste and odor. Chemical modification for taste masking involves transforming the drug structure into a prodrug. Alternatively, drug substances may be formulated as complex compounds, such as inclusion complexes with cyclodextrins (Adamkiewicz and Szeleszczuk, 2023). Taste masking of drugs occurs due to decreased dissolution of drugs in saliva, resulting in a reduced amount of drug stimulating taste receptors. The final method employed for taste masking utilizes a physical barrier by coating a drug with polymers to prevent its dissolution in the oral cavity (Felton, 2018). These polymers have limited or no solubility in saliva, thus preventing direct contact of the drug with taste receptors on the tongue. Various techniques for polymer coating include extrusion-spheronization, hot-melt extrusion, granulation, coacervation, emulsion solvent diffusion, and spray drying (Petrovick et al., 2016; Maniruzzaman et al., 2012; Nishiyama et al., 2016; Comunian et al., 2013; Gao et al., 2006; Yi et al., 2014).

Polymers utilized in taste masking may include water-soluble polymers, water-insoluble polymers, or polymers with solubility dependent on pH. Polymers with pH-dependent solubility are widely favored for taste masking applications. These polymers contain functional groups that ionize differently across varying pH levels, resulting in distinct solubility profiles in different solutions. This characteristic renders them effective in preventing drug dissolution in the oral cavity (pH = 6.97–7.40), while ensuring adequate dissolution in acidic gastric conditions. Commonly utilized polymers include Eudragit® E, a cationic copolymer featuring dimethyl aminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (Nollenberger and Albers, 2013). Eudragit® E, which incorporates tertiary amine functional groups, rapidly ionizes under acidic conditions, allowing for dissolution in gastric fluids while maintaining insolubility in the oral cavity. Consequently, the thickness of the coating layer does not affect drug release kinetics in the stomach (Joshi and Petereit, 2013). Eudragit® E is marketed in different formulations, including granules (Eudragit® E 100) and powder (Eudragit® E PO), both of which are colorless to yellow-tinged and have a characteristic amine-like odor. Additionally, Eudragit® E 12.5 is an organic solution of Eudragit® E 100, containing 12.5% w/w dry substance in a mixture of 60% w/w isopropyl alcohol and 40% w/w acetone. This solution appears as a light yellow, low-viscosity liquid that is clear to slightly cloudy, with a distinctive solvent odor. Eudragit® E demonstrates solubility in acetone and alcohols, as well as in solutions with pH levels lower than 5 (Rowe et al., 2012).

Several studies have documented the utilization of Eudragit® E PO in taste masking of drug particles through various techniques. Spray-drying is a widely employed method. This technique involves dispersing or dissolving the drug and polymer in a dispersion medium, typically including additional additives to prevent particle aggregation and achieve a more uniform coating on the drug particles. Yan et al. (2010) successfully prepared taste-masked microparticles of donepezil hydrochloride via spray-drying and found that the optimal drug-to-polymer ratio for taste masking using Eudragit® E PO was 1:2. Georgieva et al. (2020) also reported the same optimal ratio of 1:2 for taste masking, achieving a drug loading of approximately 24% in their study. In contrast, Bora et al. (2008) reported a similar optimal drug-to-polymer ratio with higher drug loading when using an organic solvent, dichloromethane, as the dispersion medium for Eudragit® E PO without the addition of other additives.

Fluid bed coating is another technique utilized for taste-masking drug particles. In this approach, a dispersion of Eudragit® E PO is sprayed onto drug particles suspended in air. Drašković et al. (2017) prepared Eudragit® E PO in an aqueous medium containing sodium lauryl sulfate, stearic acid, and talc, which acted as a wetting agent, plasticizer, and glidant, respectively. This method successfully masked the bitter taste of the drug, with the drug content of the coated microparticles reported to be approximately 70%. Fluid bed coating has also been utilized in the preparation of enteric taste-masked pellets, as demonstrated in the study by Alotaibi et al. (2019). This study employed fluid bed coating to create enteric taste-masked pellets containing diclofenac sodium (DS). The drug was initially layered onto sugar spheres before being enteric-coated with Eudragit® L 100 using a layering technique. Subsequently, the enteric-coated pellets were taste-masked by coating them with Eudragit® E 100, also via a layering method. This approach effectively produced enteric taste-masked pellets that could prevent drug release in both the oral cavity and the stomach. However, this method requires the use of several additional additives, such as inert cores, anti-adherents, and plasticizers like talc and PEG 6000.

The potential applications of taste-masked microparticles and pellets extend to drug administration for patients with dysphagia, including pediatric and geriatric populations, due to their small size and ease of swallowing (Liu et al., 2014). Similar to pellets, taste-masked granules are also suitable for drug administration in these populations because of their manageable size and ease of ingestion. Furthermore, taste-masked granules can be formulated into oral dispersible dosage forms, such as orally disintegrating tablets (ODTs), due to their suitable flow properties. Taste-masking granules have been developed in various studies, employing techniques such as melt granulation (Forster and Lebo, 2021), coating by fluid bed granulation (Nishiyama et al., 2016), dispersion (Sangnim and Huanbutta, 2019) and granulation by high shear mixer (Albertini et al., 2004).

In this study, taste-masked enteric granules (TEGs) were developed to encapsulate Eudragit® L 100-based enteric microparticles loaded with DS, fabricated as described in our prior work (Burapapadh et al., 2024). DS, a potent non-steroidal anti-inflammatory drug (NSAID), was chosen as the model drug in this study due to its intense bitterness and potential to cause local stomach irritation as a side effect. The primary objective of formulating the TEGs was to mask the drug’s bitter taste while preserving the enteric properties of the enteric microparticles, thus improving both acceptability and therapeutic efficacy. Figure 1 presents a schematic representation of the composition of TEGs. Taste-masking was achieved through the dispersion of enteric microparticles in Eudragit® E PO to hinder the dissolution of Eudragit® L 100 in the oral cavity. Various amounts of Eudragit® E PO, as the taste-masking polymer, were utilized in the preparation of TEGs through solvent evaporation employing a rotary evaporator. A thorough investigation was carried out to ascertain the optimal polymer ratio. The morphology of TEGs was investigated through SEM, and the physicochemical properties of the TEGs were analyzed by FT-IR, DSC, and PXRD analysis. Furthermore, simplified drug release and biphasic dissolution tests were performed to assess the taste-masking efficiency and drug release characteristics of the TEGs in a simulated gastrointestinal environment, respectively.

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Materials

Diclofenac sodium (Batch no. DFS/19050129) was obtained from Aarti Drugs Limited, India. Eudragit® E PO (Batch no. G180631579) and Eudragit® L100 (Batch no. 190303201), which were sourced from Evonik Nutrition & Care GmbH, Germany, were generously donated by Jebsen & Jessen Ingredients (Thailand). HPLC-grade methanol was purchased from Fischer Scientific, Korea, and ultrapure water was employed as the mobile phase. Reference standard dichloromethane (Lot no. G1257711) for the residual solvent analysis was from Dr. Ehrenstorfer GmbH, Germany. All chemicals, unless otherwise stated, were of analytical grade and were utilized without additional purification.

Burapapadh, K., Warintaksa, P., Ruksapram, S., and Saokham, P. (2024). Development of taste-masked enteric granules containing diclofenac sodium utilizing Eudragit® E PO as a taste-masking agent. Science, Engineering and Health Studies, 18, 24050016.

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