Rational Design and Efficacy Evaluation of a Novel Solid Dispersion-Based Bempedoic Acid–Ezetimibe Fixed-Dose Combination Tablet Versus Nexlizet®

Abstract

Background/Objectives: For hyperlipidemic patients with statin resistance, a fixed-dose combination of a non-statin drug such as ezetimibe (EZT) and bempedoic acid (BA) provides a significant benefit. Although both drugs exhibit poor aqueous solubility, the oral bioavailability of EZT is more critically limited by dissolution, whereas BA maintains adequate absorption due to its high intestinal permeability. With regard to the reference product, Nexlizet^® (180/10 mg), our study focused on developing a novel tablet with superior in vitro performance without incorporating sodium lauryl sulfate (SLS), as it may potentially alter BA absorption.

Methods: The solid dispersion technique (co-precipitation) was applied using the Kollidon^® VA64 polymer, and the solid state was characterized through differential scanning colorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). The prepared solid dispersions (SDs) were formulated into film-coated tablets (FCTs) and were characterized physically and for drug performance, and an animal model study was also conducted.

Results: The solid-state analysis of the optimized SD formula (S30) revealed reduced drug crystallinity with no drug–carrier chemical interaction. The optimized formula (F30), a film-coated tablet, successfully achieved comparative in vitro dissolution versus Nexlizet^® and passed the accelerated stability study. Furthermore, in vivo evaluation revealed that F30 significantly reduced serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), with an increase in high-density lipoprotein (HDL), in an animal model.

Conclusions: These findings confirm that the SD technique is an effective one-step approach to co-formulating both APIs, simplifying manufacturing processes and optimizing the batch size.

Introduction

Dyslipidemia is a prevalent metabolic disorder marked by abnormal blood lipid profiles, primarily involving cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG). Over time, having unhealthy levels of blood fats can lead to fatty deposits building up inside the arteries, a condition called atherosclerosis, which increases the risk of heart problems. Management typically involves lifestyle changes, i.e., regular exercise and dietary adjustment, along with lipid-lowering medications—most commonly statins [1].

Statin drugs are used to treat and manage hypercholesteremia via the selective and competitive inhibition of the hydroxy methyl glutaryl-CoA (HMG-CoA) reductase enzyme, which reduces TG, LDL, and total cholesterol levels while increasing HDL levels [2,3]. Statins are generally regarded as well-tolerated medications. Statin intolerance is defined as any adverse event or abnormality not accepted by the patient and leading to the discontinuation of therapy [4,5]. Typically, musculoskeletal symptoms represent the predominant cause of therapy discontinuation, whereas laboratory abnormalities are comparatively infrequent [5,6,7]. Apart from statin-associated muscular symptoms (SAMS), additional side effects of statin therapy that may impair patient quality of life include erectile dysfunction, headache, nausea, dyspepsia, and alopecia [5,8]. Patients who are intolerant to statins are advised to switch to non-statin drugs.

Bempedoic acid (BA) is known chemically as 8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid. Its CAS number is [738606-46-7] and its molecular weight is 344.5 g per mole, and its chemical formula is C19H36O5. It is a white to off-white crystalline powder that is insoluble in water and aqueous solutions below pH 5 and highly soluble in ethanol, isopropanol, and pH 8.0 phosphate buffer. The structural formula is shown in Figure 1 [9].

Figure 1. Chemical structure of bempedoic acid.

Ezetimibe (EZT) is known chemically as 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. Its CAS number is [163222-33-1] and its molecular weight is 409.4 g per mole, and its molecular formula is C24H21F2NO3. It is a white, crystalline powder that is practically insoluble in water and freely to very soluble in ethanol, methanol, and acetone. The structural formula is shown in Figure 2 [9].

Figure 2. Chemical structure of ezetimibe.

Nexlizet® tablets were approved in the US in 2020 and are manufactured by the company Esperion Therapeutics, Inc. In addition to 180 mg of BA and 10 mg of EZT as active ingredients, each film-coated tablet also comprises many other inactive ingredients [10,11]. Bempedoic acid is a first-in-class adenosine triphosphate citrate lyase (ACL) inhibitor. It acts to reduce cholesterol production by blocking the ACL enzyme in the cholesterol biosynthesis pathway [11]. Ezetimibe acts by inhibiting the Niemann–Pick C1-like 1 (NPC1L1) transporter protein in the brush border of the small intestine; as a result, it prevents the absorption of dietary and biliary cholesterol into the bloodstream [12]. It is recommended as a dietary supplement and can be beneficial for adults who exhibit maximum tolerance to statin therapy. In Nexlizet®, sodium lauryl sulfate (SLS) is included as a surfactant to resolve the solubility issues of EZT, since EZT has poor water solubility beyond the physiological pH. Despite being pH-dependent, BA does not require a surfactant because its greater solubility is reached at a high (intestinal) pH, ensuring in vivo absorption and dissolution. Due to the distinct physicochemical properties of BA (poor flowability and stickiness), and considering that the potential impact of SLS on the dissolution behavior of BA remains unclear, a formulation strategy was adopted to avoid possible interference; the formulation was prepared as both monolayer and bilayer tablets. For the monolayer tablet, each active ingredient was granulated separately, mixed, compressed into a single layer, and coated. For the bilayer tablet, each active ingredient was prepared as two distinct layers, compressed into a bilayer tablet, and coated [9]. Nexlizet® contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, hydroxypropyl cellulose, colloidal silicon dioxide, and povidone K30. The film coating material, Opadry® AMB II, includes titanium dioxide, sodium lauryl sulfate, partially hydrolyzed polyvinyl alcohol (PVA), glyceryl monocaprylocaprate, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, and talc [9].

According to the BCS, APIs are classified based on their solubility and permeability into four classes [13,14]. BA and EZT are considered BCS Class II drugs of low solubility and high permeability. Their low solubility and slow dissolution in gastrointestinal fluids (acidic conditions) constitute the primary barriers to oral bioavailability. Therefore, improving their solubility and dissolution rates is crucial for their in vivo efficacy [13,15,16].

Solid dispersion is a strategy for drug solubility enhancement. In this approach, the drug can be distributed molecularly through a carrier matrix as amorphous particles (clusters) or in crystalline particles [17,18].

Relative to conventional methods such as spray drying or hot-melt extrusion, the co-precipitation method offers several distinct advantages, including simplicity, cost-effectiveness, and scalability, making it highly suitable for both laboratory-scale production and industrial manufacturing.

Nexlizet® presents significant formulation challenges relative to its physicochemical and biopharmaceutical characteristics. While BA is characterized by poor flowability and a sticky nature, EZT exhibits low aqueous solubility and dissolution-limited absorption, necessitating complex manufacturing approaches such as separate granulation. These constraints not only increase the process complexity but also limit the formulation flexibility and optimization potential; for example, the blending of separately processed granules may increase the risk of segregation arising from disparities in particle size distribution, density, and flow characteristics, potentially compromising content uniformity. In addition, variations in granule layer size may further complicate batch size determination and scale-up, introducing potential challenges in maintaining process consistency and reproducibility during the manufacturing of fixed-dose combinations of BA and EZT.

This study is the first to report a surfactant-free fixed-dose combination of BA/EZT (180/10 mg) prepared using a co-precipitation-based solid dispersion approach that was intentionally employed to induce the amorphization of both BA and EZT within a single composite system prior to tablet formulation—unlike Nexlizet® (180/10 mg), which uses an anionic surfactant (SLS) to resolve the solubility issue of EZT.

Although BA exhibits high oral bioavailability, the application of solid dispersion in this study was primarily intended to improve its physicochemical performance and constrain the potential risk within the fixed-dose combination excipients (SLS), rather than to enhance its absorption.

The proposed formula achieves rapid dissolution with a release profile comparable to Nexlizet® but without the use of SLS (SLS-free), which potentially improves formulation robustness, regulatory acceptability, and patient tolerability. In addition, this study overcomes the gelling effect associated with tablet-based solid dispersion. Accordingly, this study demonstrates an alternative manufacturing process to wet granulation and provides a unique formula with mechanical integrity, robustness, and downstream process suitability, including friability and coating performance. It passes the accelerated stability test and proves its antihyperlipidemic efficacy in a hyperlipidemic rat model with an improved lipid profile.

Download the full article as PDF here Rational Design and Efficacy Evaluation of a Novel Solid Dispersion-Based Bempedoic Acid–Ezetimibe Fixed-Dose Combination Tablet Versus Nexlizet®

or continue reading here

Materials

Bempedoic acid [Lee Pharma Limited, Telangana, India, purity of 99.6%]; ezetimibe [Glenmark Life Sciences Ltd., Maharashtra, India, purity of 99.3%]; copovidone, also known as PVP VA64 (Kollidon® VA64); crospovidone (Kollidon® CL); crospovidone (Polyplasdone® XL10); microcrystalline cellulose (Avicel® PH 102); colloidal silicon dioxide (Aerosil® 200); magnesium stearate; and Opadry® AMB II were obtained as gift samples from Future Pharmaceutical Industries (FPi), Badr City, Egypt. Nexlizet® 180/10 mg FCTs (lot number: 1750787) were purchased from the market. All other chemicals were of high analytical grade.

Heikal, M.; Ali, W.; Mahdy, M.A.; Gomaa, E. Rational Design and Efficacy Evaluation of a Novel Solid Dispersion-Based Bempedoic Acid–Ezetimibe Fixed-Dose Combination Tablet Versus Nexlizet^®. Pharmaceutics 2026, 18, 580. https://doi.org/10.3390/pharmaceutics18050580

Read also our introduction article on Magnesium Stearate here: