Sustained-Release Solid Dispersions of Fenofibrate for Simultaneous Enhancement of the Extent and Duration of Drug Exposure

Abstract

Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and duration of drug exposure.

Methods: Fenofibrate-loaded solid dispersions (FNSDs) were prepared using poloxamer 407 and Eudragit^® RSPO at varied ratios via solvent evaporation. In vitro/in vivo characteristics of FNSDs were examined in comparison with untreated drugs.

Results: Based on dissolution profiles of FNSDs in aqueous media, the weight ratio of fenofibrate: poloxamer 407: Eudragit^® RSPO at 1:1:4 (FNSD2) was selected as the optimal composition for achieving sustained drug release while maximizing the drug dissolution. The enhanced and sustained drug release of FNSD2 was also confirmed in a buffer transition system mimicking the pH change in the gastrointestinal tract. FNSD2 achieved approximately 66% drug release over 12 h, while pure drug exhibited only 12%. Furthermore, FNSD2 maintained similar release rates under fed and fasted conditions, while the entire drug dissolution slightly increased in the fed state. Structural analysis by x-ray diffraction showed that fenofibrate remained crystalline in FNSD2. Pharmacokinetic studies in rats revealed that orally administered FNSD2 significantly improved the extent and duration of systemic drug exposure. Compared to pure drugs, the FNSD2 formulation increased the oral bioavailability of fenofibrate by 22 folds with the delayed T_max of 4 h in rats.

Conclusion: FNSD2 formulation is effective in improving the extent and duration of drug exposure simultaneously.

Introduction

Cardiovascular diseases (CVDs) are among the leading causes of mortality worldwide. Elevated blood lipid levels are associated with a high risk of CVDs, making the prevention and effective management of dyslipidemia essential for enhancing the quality of life and promoting healthy longevity [1]. Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, is used to treat patients with severe hypertriglyceridemia, primary hypercholesterolemia, or mixed dyslipidemia [2,3,4]. As a potent lipid regulator, fenofibrate lowers triglycerides, apolipoprotein B, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol [2,3,4]. However, the oral absorption of fenofibrate is limited due to its low solubility (<0.4 μg/mL, classified as Biopharmaceutics Classification System Class II), and its bioavailability is significantly affected by food intake [5,6]. To overcome this limitation, various formulation techniques, including micronization, nanoparticles, self-microemulsifying drug delivery systems, and solid dispersions, have been employed to improve the solubility and oral bioavailability of fenofibrate [2,6,7]. For example, a novel formulation containing fenofibrate nanoparticles (Tricor® 145 mg) and IDD-P (insoluble drug delivery-microparticle) fenofibrate tablets have been developed to improve the bioavailability of fenofibrate without the effect of food [8,9]. Recently, Kim et al. [10] reported that a supercritical fluid-assisted spray-drying process incorporating surface-active additives can efficiently micronize fenofibrate particles, improving drug dissolution. Alshamsan et al. [7]

also developed the self-nanoemulsifying formulation of fenofibrate using blended oils (Kollisolv MCT and Imwitor 742) and significantly improved the solubility and dissolution of fenofibrate. Although there was great success in improving the dissolution and bioavailability of fenofibrate via various formulations, most commercially available formulations of fenofibrate, with a few exceptions, are still recommended for use with a meal [2]. Accordingly, there is a need to develop a new formulation to maximize the therapeutic benefits of fenofibrate. Particularly, a sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal effects of food is crucial for enhancing oral bioavailability and reducing dosing frequency [9], ultimately improving patient compliance and offering additional benefits, such as cost savings and fewer side effects [6,11,12].

Among various formulation approaches, SDs within an insoluble polymer matrix provide a simple and effective technique for developing sustained-release oral dosage forms [13]. In SDs, the drug is uniformly distributed within the polymer matrix, with the release rate controlled by the polymer’s swelling or erosion [13,14]. A wide variety of hydrophilic and hydrophobic polymers are available commercially for SDs, each displaying distinct physicochemical properties. In preparing SDs, polymers are used alone or in combination with others to modulate the matrix’s permeability, thereby optimizing drug release rates. Polymethacrylate-based copolymers, derived from esters of acrylic and methacrylic acids, are among the most commonly used insoluble polymers for sustained drug release due to their high chemical stability, miscibility, compressibility, and versatility in diffusion control [15]. Specifically, Eudragit® RSPO, a poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, is insoluble with a pH-independent swelling, and thus it is suitable for sustained drug release across varied gastrointestinal pH [16,17,18]. In addition, given fenofibrate’s low solubility and resulting limited dissolution in intestinal fluids, enhancing its solubility and achieving controlled release are necessary to improve oral bioavailability and extend drug exposure. In this context, adding a solubilizer to the hydrophobic polymer matrix of SDs is advantageous. Poloxamer 407 is a hydrophilic and non-ionic surfactant. It is biocompatible, non-toxic, and has low immunogenicity [19,20,21].

Consequently, poloxamer 407 is widely used as a solubilizer and wetting agent across various drug delivery systems, including oral, parenteral, ocular, and rectal routes [19,20,21]. Taken together, poloxamer 407 and Eudragit® RSPO were selected to prepare solid dispersions of fenofibrate for not only enhancing drug dissolution rate but also sustaining drug release.

In this study, SDs were prepared using a solvent evaporation method with the blended mixture of poloxamer 407 and Eudragit® RSPO, and the in vitro and in vivo effectiveness of the developed SDs was evaluated.

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Materials

Fenofibrate, ketoprofen, poloxamer 407, and sodium taurocholate were obtained from Sigma-Aldrich (St. Louis, MO, USA). Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit® RSPO) powder was provided by Evonik Korea Ltd. (Seoul, Republic of Korea). Lecithin (soybean) was obtained from Daejung Chemicals & Metals Co., Ltd. (Siheung, Republic of Korea), while sodium oleate, inorganic salts, and polyethylene glycol sorbitan monooleate (Tween®80) were acquired from Junsei Chemical Co., Ltd. (Tokyo, Japan). Glyceryl monooleate was sourced from ABITEC Corporation (Columbus, OH, USA). All other chemicals were of analytical grade, and solvents, including acetonitrile and methanol, were HPLC grade.

Park, S.-J.; Kim, G.L.; Han, H.-K. Sustained-Release Solid Dispersions of Fenofibrate for Simultaneous Enhancement of the Extent and Duration of Drug Exposure. Pharmaceutics 2024, 16, 1617. https://doi.org/10.3390/pharmaceutics16121617

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