The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability

Abstract

Enzalutamide (ENZ), marketed under the brand name Xtandi^® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development.

Introduction

Oral administration is the most frequently used route for drug delivery. However, approximately 40% of the drugs currently on the market and approximately 70% of new drug candidates are known to be poorly water-soluble [1,2,3]. These poorly water-soluble drugs exhibit reduced oral absorption rates due to their low solubility. This leads to increased dosages, decreased patient compliance, and the need for alternative delivery routes [4,5]. Therefore, enhancing the solubility of poorly soluble drugs for oral administration represents a significant challenge [6].

Enzalutamide (ENZ) is an androgen receptor signaling inhibitor that both inhibits the proliferation and induces the death of prostate cancer cells [7,8,9]. Despite these therapeutic advantages, ENZ exhibits low water solubility (Biopharmaceutics Classification System, BCS class II) due to its lipophilic properties. Additionally, even when dissolved in an amorphous form in aqueous solutions, it tends to quickly recrystallize [10,11]. In a previous study, a self-nanoemulsifying drug delivery system (SNEDDS), which is a lipid-based drug delivery system, was applied to reflect the characteristics of ENZ and develop a liquid SNEDDS formulation (Labrafac PG, Solutol HS15, and Transcutol P at a weight ratio of 1:8:1), achieving approximately a twofold improvement in oral absorption compared to commercial products [12]. However, the liquid SNEDDS generally has stability issues because of precipitation or phase separation due to the agglomeration of particles. Furthermore, limitations, such as the limited storage conditions, complex process control, and high manufacturing costs of soft capsules, must be addressed [13,14,15,16,17].

To overcome these challenges, research on SNEDDS solidification using methods such as melt extrusion, adsorption to solid carriers, wet granulation using a high-speed mixer, spray drying, and supercritical fluid-based methods is actively ongoing [17,18,19,20,21,22]. In this study, a solid form of liquid SNEDDS (S-SNEDDS) was developed using spray drying, incorporating a solidification carrier and a polymer to restrain recrystallization. This polymer helps ENZ remain either molecularly dissolved or in an amorphous state in the S-SNEDDS directly after spray drying. Subsequently, it helps to induce and maintain a supersaturated solution, preventing rapid recrystallization of the drug and thereby enhancing drug absorption in vivo [10]. Consequently, the physicochemical properties of the S-SNEDDS formulation with added polymer were evaluated, and improvements in bioavailability were assessed through in vivo rat pharmacokinetics (PK) studies.

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Materials

ENZ was purchased from MSN Laboratories Private Ltd. (Telangana, India). Copovidone (Abbreviated as Kollidon VA64) and colloidal silica were supplied by Boryung Pharmaceutical. Co., Ltd. (Seoul, Republic of Korea). Hydroxypropylcellulose (Abbreviated as HPC-L) was supplied by Cosmax Pharmaceutical. Co., Ltd. (Cheongju, Republic of Korea). Hydroxypropylmethylcellulose phthalate (HPMCP HP55) was provided by Hanmi Pharmaceutical. Co., Ltd. (Seoul, Republic of Korea). N,N-dimethylaminoethyl methacrylate (abbreviated as Eudragit E PO) was obtained from Evonik (Essen, Germany). Propylene glycol dicaprylocaprate (abbreviated as Labrafa PG) and Diethylene glycol monoethyl ether (abbreviated as Transcutol P) were acquired from Gattefosse (St. Priest, France). Macrogoli 15 hydroxystearas (abbreviated as Solutol HS15) was sourced from BASF (Ludwigshafen, Germany). Sodium carboxymethyl cellulose was purchased from Duksan Chemicals (Ansan, Republic of Korea). Acetonitrile, ammonium acetate, and acetone were purchased from Daejung Chemicals (Siheung, Republic of Korea). Other chemicals used were of the appropriate class for analysis.

Lee, S.-M.; Lee, J.-G.; Yun, T.-H.; Kim, C.-H.; Cho, J.-H.; Kim, K.-S. The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability. Pharmaceutics 2024, 16, 457. https://doi.org/10.3390/pharmaceutics16040457

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