Self-Microemulsifying Drug Delivery System to Enhance Oral Bioavailability of Berberine Hydrochloride in Rats

Abstract

Berberine hydrochloride (BH) is a versatile bioactive compound derived from the plants of the Berberis genus, known for its various pharmacological effects. However, its oral bioavailability is low due to its high hydrophilicity and limited permeability. To enhance its clinical efficacy and oral bioavailability, this study designed and prepared a BH-loaded self-microemulsifying drug delivery system (BH-SMEDDS), and characterized its in vitro and in vivo properties. Firstly, the optimal formulation of BH-SMEDDS was selected using solubility evaluations, pseudo-ternary phase diagrams, and particle size analysis. The formulation containing 55% Capmul MCM, 22.5% Kolliphor RH 40, and 22.5% 1,2-propanediol was developed. BH-SMEDDS exhibited stable physicochemical properties, with an average particle size of 47.2 ± 0.10 nm and a self-emulsification time of 26.02 ± 0.24 s. Moreover, in vitro dissolution studies showed significant improvements in BH release in simulated intestinal fluid, achieving 93.1 ± 2.3% release within 300 min. Meanwhile, BH-SMEDDS did not exhibit cytotoxic effects on the Caco-2 cells. Additionally, BH-SMEDDS achieved a 1.63-fold increase in oral bioavailability compared to commercial BH tablets. Therefore, SMEDDS presents a promising strategy for delivering BH with enhanced oral bioavailability, demonstrating significant potential for clinical application.

Introduction

Berberine is a natural quaternary ammonium isoquinoline alkaloid extracted and isolated from plants of the Berberis genus, such as Coptis chinensis (Chinese goldthread) and Phellodendron amurense (Amur cork tree) [1]. In its natural state, berberine is commonly found as a chloride salt with low water solubility, belonging to the alkaloid family of protoberberine (5,6-dihydrodibenzo[a,g]quinolizinium). Berberine hydrochloride (BH) is produced by reacting berberine with hydrochloric acid, enhancing its water solubility and thereby improving its suitability for pharmaceutical formulation and application [2,3]. BH has various pharmacological effects including antidiabetic, antitumor, anti-inflammatory, antimicrobial, and antiatherosclerotic activities [4,5,6,7,8,9]. For instance, BH is utilized in the treatment of type 2 diabetes by activating AMP-activated protein kinase, thereby enhancing insulin sensitivity and reducing insulin resistance [5]. BH also modulates gut microbiota composition and metabolism, leveraging its antimicrobial properties against gut pathogens to potentially benefit the treatment of diarrhea and other digestive issues [7,9].

Oral administration is the preferred route due to its convenience and better patient compliance. Currently, BH is available in marketed formulations such as tablets and capsules. However, the oral administration of BH has demonstrated low bioavailability, mainly due to its strong hydrophilicity from the quaternary ammonium group, and low cell membrane permeability [10,11]. Fortunately, various formulation strategies have been explored to enhance the solubility and bioavailability of BH. The research indicates that the use of nanotechnology, such as nanoemulsions, nanoparticles and nanocrystals, appears to be an effective delivery system for improving solubility, absorption and oral bioavailability of BH [11,12,13].

Self-microemulsifying drug delivery systems (SMEDDS) are an ideal delivery strategy for improving the oral delivery of hydrophobic drugs [14,15]. Besides enhancing the bioavailability, SMEDDS offer other benefits such as increased solubility and dissolution rate, improved membrane permeability in the gastrointestinal tract, high drug loading efficiency, and ease of preparation [16,17]. SMEDDS consist of a drug, oil phase, surfactant, and co-surfactant. On the one hand, hydrophobic drugs can be encapsulated in solubilized microemulsions in the gastrointestinal tract, thereby enhancing their dissolution rate [18,19]. On the other hand, SMEDDS automatically form an oil-in-water (O/W) microemulsion under the digestive movements of the stomach and intestines, creating numerous emulsion droplets with particle sizes less than 100 nm. This small-sized microemulsion provides a large interfacial area, promoting gastrointestinal permeability of the incorporated drug and improving its absorption [20,21]. Therefore, SMEDDS represent a promising delivery system for transporting BH in the gastrointestinal tract, enhancing its solubility, membrane permeability, drug absorption, and ultimately, its bioavailability.

In this study, the BH-loaded SMEDDS was developed. Based on the solubilizing ability and pseudo-ternary phase diagrams, suitable oils, surfactants, and co-surfactants to prepare BH-SMEDDS were selected. The formulation was optimized using particle size and size distribution of the emulsions. Furthermore, the optimal formulation of BH-SMEDDS was characterized according to transmission electron microscopy, emulsification duration, and stability assessments. Subsequently, in vitro drug release and cytotoxicity studies were conducted. Finally, an in vivo pharmacokinetic study of the BH-SMEDDS was evaluated in rats.

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Reagents and Materials

Berberine hydrochloride was purchased from the Titan Technology Co., Ltd. (Shanghai, China, batch no. 0111043444). Berberine hydrochloride tablets were purchased from the Shanghai Xinyi Tianping Pharmaceutical Co. (Shanghai, China, batch no. 230302). Methanol, LC grade methanol, and acetonitrile were purchased from Starco High Purity Solvents Co. (Shanghai, China). Potassium dihydrogen phosphate dihydrate, OP-10, polyethylene glycol 400 (PEG 400), isopropyl alcohol, 1,2-propanediol, glycerol, and potassium dihydrogen phosphate dihydrate were purchased from Lingfeng Chemical Reagent Co. (Shanghai, China). Oleic acid, ethyl oleate, castor oil, and Tween 80 from Sinopharm Chemical Reagent Co. (Shanghai, China). Glyceryl monooleate (Peceol TM), medium chain triglycerides (MCT), glyceryl monolinoleate (Maisine CC), caprylic capric glycerol (Labrasol®), polyethylene glycerol laurate (Gelucire® 44/14), diethylene glycol monoethyl ether (Transcutol® HP), polyethylene glycerol oleate (Labrafil M1944 CS), propylene glycol monocaprylate (Capryol 90), and lauryl alcohol-90 (Lauraglycol-90) were purchased from Gatefosse (Saint-Priest, France). Caprylic mono/diglyceride (Capmul® MCM), propylene glycol mono octanoate (Capmul® PG8), and medium chain triglycerides (Captex 300 EP/NF) were supplied by Abitec (Janesville, WI, USA). Polyoxyethylene hydrogenated castor oil (Kolliphor® RH40) and polyoxyethylene 35 castor oil (Kolliphor® EL) were purchased from BASF AG (Frankfurt am Main, Germany) Heparin sodium was obtained from Yuan Ye Biotechnology Co. (Shanghai, China). Palmatine hydrochloride was purchased from Solebrite Technology Co. (Beijing, China, batch no. 2642332). All other chemicals used were of analytic grade. The human colon cancer cell line Caco-2.

Chen, X.; Yang, H.; Shi, L.; Mao, Y.; Niu, L.; Wang, J.; Chen, H.; Jia, J.; Wang, J.; Xue, J.; et al. Self-Microemulsifying Drug Delivery System to Enhance Oral Bioavailability of Berberine Hydrochloride in Rats. Pharmaceutics 2024, 16, 1116. https://doi.org/10.3390/pharmaceutics16091116

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