Development of a Carvedilol-Loaded Solid Self-Nanoemulsifying System with Increased Solubility and Bioavailability Using Mesoporous Silica Nanoparticles

Abstract

This study developed a solid self-nanoemulsifying drug delivery system (S-SNEDDS) to improve the oral bioavailability of poorly soluble carvedilol using mesoporous silica nanoparticles (MSNs). The liquid self-nanoemulsifying drug delivery system (L-SNEDDS) consisted of carvedilol, Peceol, Tween 80, and Labrasol in a weight ratio of 10:25:50:25. The liquid SNEDDS was suspended in MSN at various ratios and spray-dried to produce S-SNEDDS. The emulsion size, PDI, solubility, and dissolution of various ratios of MSN were evaluated to make the optimal S-SNEDDS. The optimal S-SNEDDS, manufactured using a ratio of MSN to L-SNEDDS 1000 at 500, formed a nanoemulsion and achieved efficient supersaturation compared to carvedilol alone, which significantly improved drug solubility (approximately 400 times), dissolution (approximately 5.7 times at 60 min), area under the curve (AUC) (21.7 times), and maximum plasma concentration (Cmax) (15.7 times). In addition, the physicochemical properties of the optimal S-SNEDDS were evaluated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Fourier transform infrared (FT-IR), particle size, and scanning electron microscopy (SEM) images. S-SNEDDS showed a smaller particle size than MSN alone, and the crystalline drug was transformed into an amorphous substance, resulting in encapsulation in MSN. These results suggest that MSN can be a novel biocompatible carrier contributing to a safer and more effective delivery system.

Introduction

Carvedilol is a non-selective β-blocker with additional adrenergic receptor α1 blocking activity and is widely prescribed to manage hypertension, heart failure, and angina pectoris [1]. Although carvedilol has therapeutic efficacy, it is a class II drug in the biopharmaceutical classification. It has poor water solubility and low bioavailability, making it challenging to formulate and limiting its absorption and therapeutic effect. These characteristics may hinder clinical application, as patients may need higher doses or more frequent administration to achieve the desired effect, which may increase the risk of adverse effects [2].

Therefore, improving the solubility and bioavailability of drugs belonging to the BCS class II, such as carvedilol, is essential for optimizing therapeutic benefits. Various solubilization techniques have been developed to enhance the bioavailability of active drugs with limited solubility. These include particle size reduction techniques such as micronization and nanonization to increase the surface area, enhancing solubility [3,4]. Amorphous solid dispersions enhance solubility by inhibiting crystallization and creating supersaturated solutions. Polymeric carriers in solid dispersions and cyclodextrin complexes are also widely adopted to improve the solubility and stability of hydrophobic drugs [5]. Another strategy uses carriers and unique delivery systems to improve solubilization [6]. Lipid-based formulations such as SNEDDS are one of the most effective methods to enhance the bioavailability of hydrophobic drugs [7]. Encapsulation in liposomes, nanoparticles, and micelles can improve the solubility of poorly soluble drugs in aqueous environments [8]. SNEDDS are isotropic mixtures of oils, surfactants, and co-surfactants that spontaneously form nano-sized emulsions when exposed to gastrointestinal fluids. These systems enhance drug dissolution and absorption by providing a large surface area for drug release, increasing solubility, improving mucosal permeability, and improving overall bioavailability [9].

S-SNEDDS offers additional benefits by incorporating solid-state properties to improve the formulation’s stability, handling, and portability. Compared with conventional L-SNEDDS, S-SNEDDS can improve the drug’s physical and chemical stability, minimize leakage problems during storage and transportation, and control drug release, potentially improving dosing convenience. Solidification techniques such as spray drying, freeze drying, and adsorption onto solid carriers can convert L-SNEDDS into more convenient dosage forms, such as powders or tablets, while preserving their self-emulsifying properties to aid absorption [10].

The choice of solid carrier is critical for developing effective S-SNEDDS, as it directly affects the drug stability, release profile, and bioavailability. An ideal carrier should have the properties to ensure high drug loading, maintain the nano-emulsification potential of SNEDDS during reconstitution, and stabilize the drug and excipients within the solid matrix [11]. In particular, porous carriers are highly desirable, as they provide a large surface area for drug adsorption, which helps the uniform distribution of SNEDDS components and enhances the dissolution rate of drugs with low solubility [11].

MSN has been investigated as promising drug delivery systems due to their excellent biocompatibility and ideal porous structure for drug loading. They have also been used for drug delivery, such as anticancer drugs. In particular, the physicochemical properties of silica particles can be modified at the atomic level by introducing modifier cations into the Si–O network. For example, amorphous silica particles containing Ca2+, Na+, and phosphate have been used as excellent biodegradable biomaterials. Iron-doped silica particle nano-shells, Ca-doped silica nanoparticles, and manganese-doped silica nanoparticles have been used as magnetic resonance imaging contrast agents for anticancer drug delivery [12]. Recently developed zinc-doped silica-based mesoporous particles exhibit various bioactive activities [13]. In addition, S-SNEDDS using MSN can be used as a solubilizing carrier for insoluble substances. The high surface area and well-defined pore structure enable efficient loading of drug-SNEDDS mixtures. At the same time, the mesoporous nature can control the drug release by modulating the diffusion of encapsulated drug molecules. Therefore, using MSN particles in S-SNEDDS formulations can be a novel biocompatible carrier that enhances the solubility and bioavailability of carvedilol and contributes to an overall safer and more effective delivery system [14].
Compared with S-SNEDDS using conventional solid carriers, MSN can efficiently load drugs and be absorbed by the body. An important issue is determining the amount of MSN required to solidify L-SNEDSS and improve drug delivery efficiency [15,16].

This study aimed to develop an S-SNEDDS formulation using carvedilol as a poorly soluble model drug to improve solubility and bioavailability using various ratios of MSN particles. L-SNEDDS was prepared using selected oils, surfactants, and co-surfactants, and S-SNEDDS was prepared using various MSN through a spray dryer. The optimal MSN ratio that provides the smallest nanoemulsion particle size and improves solubility and dissolution rate was selected. The pharmacokinetic profiles of the S-SNEDDS were compared in rats administered compared to the carvedilol alone. Moreover, the physicochemical properties were evaluated using DSC, XRD, FT-IR, and SEM. The conceptual framework of the study is illustrated in Figure 1.

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Materials

MSN (SMB-7) was provided by CEN Co. (Miryang-si, Republic of Korea). Carvedilol was supplied by Cipla Ltd. (Mumbai, India). Peceol and Labrasol were supplied by Gattefossé (Saint-Priest, France). Tween 80 was purchased from Daejung Chemicals & Metals Co. (Siheung, Republic of Korea). All other chemicals and solvents used in this study were of reagent grade and were either used as received or further purified when necessary.

Jang, H.; Kim, N.; Jin, S.G. Development of a Carvedilol-Loaded Solid Self-Nanoemulsifying System with Increased Solubility and Bioavailability Using Mesoporous Silica Nanoparticles. Int. J. Mol. Sci. 2025, 26, 1592. https://doi.org/10.3390/ijms26041592