Preparation of nanoparticle and nanoemulsion formulations containing repaglinide and determination of pharmacokinetic parameters in rats

Repaglinide (RPG) belongs to the class of drugs known as meglitinides and is used for improving and maintaining glycemic control in the treatment of patients with Type 2 diabetes. RPG is a Class II drug (BCS) because of its high permeability and low water solubility. It also undergoes hepatic first-pass metabolism. The oral bioavailability of RPG is low (about 56 %) due to these drawbacks. Our aim in this study is to prepare two different nano-sized drug carrier systems containing RPG (nanoparticle: RPG-PLGA-Zein-NPs or nanoemulsion: RPG-NE) and to carry out a pharmacokinetic study for these formulations. We prepared NPs using PLGA and Zein. In addition, a single NE formulation was developed using Tween 80 and Pluronic F68 as surfactants and Labrasol as co-surfactant. The droplet size values of the blank-NE and RPG-NE formulations were found to be less than 120 nm. The mean particle sizes of blank-Zein-PLGA-NPs and RPG-Zein-PLGA-NPs were less than 260 nm. The C_max and t_max values of RPG-Zein-PLGA-NPs and RPG-NE (523 ± 65 ng/mL and 770 ± 91 ng/mL; 1.41 ± 0.46 h and 1.61 ± 0.37 h, respectively) were meaningfully higher than those of free RPG (280 ± 33 ng/mL; 0.72 ± 0.28 h) (p < 0.05). The AUC_0-∞ values calculated for RPG-Zein-PLGA-NPs and RPG-NE were approximately 4.04 and 5.05 times higher than that calculated for free RPG. These nanosized drug delivery systems were useful in increasing the oral bioavailability of RPG. Moreover, the NE formulation was more effective than the NP formulation in improving the oral bioavailability of RPG (p < 0.05).

Introduction

Type 2 diabetes (T2D), which causes unusual blood glucose levels (elevated levels), is an increasingly common condition in adults and, in recent years, in children. Ineffective insulin use in T2D caused primarily by physical inactivity and obesity. Optimization of glycemic control is critical in the treatment of T2DM in minimizing the risk of diabetic complications (such as microvascular complications) (Kaplan et al., 2023).

RPG, a carbamoylmethyl benzoic acid derivative belonging to the class of drugs known as meglitinides, is used to improve and maintain glycemic control in the treatment of patients with T2D (Scott., 2012). RPG stimulates insulin secretion by blocking ATP-dependent potassium channels in pancreatic β-cells in order to lower blood sugar levels. RPG can be used alone (monotherapy) as an adjunct to dietary control and exercise or in combination with other antihyperglycemic agents (except sulfonylureas) (Milner and Akhondi, 2023).

RPG is classified as a “Biopharmaceutics Classification System (BCS)” Class II drug because of its high lipophilicity (logP 3.97), high permeability, and low water solubility (about 34 µg/mL at 37 °C). Drugs in Class II do not dissolve easily (Amidon et al., 1995; Albetawi et al., 2021) and, therefore, may not be adequately absorbed. RPG undergoes hepatic first-pass metabolism besides its high lipophilicity/low solubility, leading to poor oral bioavailability (about 56 %) (Kaplan et al., 2023; Milner and Akhondi, 2023). RPG has inconsistent pharmacokinetics, which makes it challenging to achieve optimal therapeutic outcomes. RPG is rapidly absorbed from the gastrointestinal tract (Milner and Akhondi, 2023). The hypoglycemic effect of RPG is rapid but short-lived because of its short plasma half-life (approximately one hour). Therefore, RPG is usually taken several times a day to improve glycemic control. However, increased frequency of dosing may result in poor patient compliance (Fouad et al., 2023).

The oral route is considered one of the most convenient and still preferred drug administration route due to factors such as patient compliance and ease of use. On the other hand, the challenges encountered in oral drug delivery include poor drug solubility in water, first-pass metabolism, and poor drug bioavailability. To overcome these limitations, nano-sized drug delivery systems (such as nanoemulsion, and polymeric nanoparticles) have been developed (Shrivastava et al., 2020; Alqahtani et al., 2021). In particular, the particle size (PS) and surface properties of nano-sized dosage forms have made them attractive because these properties provide them with advantages such as improving the solubility of poorly water-soluble drugs and enhancing their bioavailability (Demirtürk et al., 2022). Polymeric nanoparticles (NPs), colloidal particles with sizes less than 1000 nm, are prepared using natural polymers (chitosan, Zein, etc.) or synthetic polymers [poly(lactic-co-glycolide) (PLGA), poly(glycolic acid) (PGA), etc.]. The use of nanoparticles offers several advantages, including improved drug solubility, increased drug stability, sustained drug release, improved bioavailability, reduced side effects, and enhanced therapeutic efficacy (Zielińska et al., 2020; André de Almeida Campos et al., 2023).

Lipidic carrier systems (liposomes, microemulsions, nanoemulsions (NEs), etc.) have also been developed for oral administration of drugs with poor water solubility (BCS classes II and IV drugs) because these systems primarily increase the dissolution rate and solubility of these drugs in the gastrointestinal tract (Alqahtani et al., 2021).

NE formulations or polymeric NPs containing RPG have been prepared for oral use in the literature to overcome the drawbacks as mentioned above of RPG (Kaplan et al., 2023; Wadhwa et al., 2023; Akhtar et al., 2016; Karami et al., 2020). Wadhwa et al. (2023) prepared RPG-loaded poly(ethylene glycol)-poly- ε-caprolactone (PEG-PCL) NPs with a particle size of 112.5 nm and zeta potential of about -6 mV. They also carried out a pharmacokinetic study in Wistar rats. Compared to free RPG (at a dose of 4 mg/kg, p.o.), the use of NPs containing RPG (equivalent to 4 mg/kg RPG, p.o.) resulted in a 2.46-fold and 1.25-fold increase in tmax and Cmax, respectively (Wadhwa et al., 2023).

In another study, RPG-NEs [average droplet size (DS): 86.5 nm and zeta potential (ZP): -33.8 mV) or chitosan-coated RPG-NEs (average DS: 149.3 nm and ZP: + 31.5 mV] formulations were developed and pharmacokinetics parameters for these formulations after oral administration to Sprague–Dawley rats were evaluated. It has been emphasized that the use of chitosan-coated RPG-NEs may be a promising approach for the oral delivery of RPG (Karami et al., 2020).In this study, we aimed to develop RPG-NEs and RPG-Zein-PLGA NPs and to carry out a pharmacokinetic study of these formulations. We prepared RPG-Zein-PLGA NPs using PLGA (an FDA-approved biodegradable polymer) and Zein (a protein of natural origin that is “generally recognized as safe-GRAS” by FDA) polymers.

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Materials

The materials used in this study were as follows: RPG (as a generous gift; İlko İlaç San. Tic. A.S., Türkiye), PLGA (50:50, Resomer RG 502 H, Ave. Mw 7000-17000 Da; Sigma-Aldrich, Germany), Zein (Sigma-Aldrich, USA), Polyvinyl alcohol (PVA, MW 30000-70000; Sigma-Aldrich, USA) Labrasol (as a generous gift; Gattefosse, France), Ethyl oleate (Merck, Germany), Tween 80 (Merck, Germany), Pluronic F68 (BASF, Germany). All other materials used were analytical grade.

Esra Demirturk, Afife Busra Ugur Kaplan, Meltem Cetin, Meltem Dönmez Kutlu, Seda Köse, Kübra Akıllıoğlu, Preparation of nanoparticle and nanoemulsion formulations containing repaglinide and determination of pharmacokinetic parameters in rats, European Journal of Pharmaceutical Sciences, Volume 200, 2024, 106844, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106844.

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