Development of Imeglimin Electrospun Nanofibers as a Potential Buccal Antidiabetic Therapeutic Approach

The prevalence of type 2 diabetes (T2D) has been growing worldwide; hence, safe and effective antidiabetics are critically warranted. Recently, imeglimin, a novel tetrahydrotriazene compound, has been approved for use in T2D patients in Japan. It has shown promising glucose-lowering properties by improving pancreatic beta-cell function and peripheral insulin sensitivity. Nevertheless, it has several drawbacks, including suboptimal oral absorption and gastrointestinal (GI) discomfort. Therefore, this study aimed to fabricate a novel formulation of imeglimin loaded into electrospun nanofibers to be delivered through the buccal cavity to overcome the current GI-related adverse events and to provide a convenient route of administration. The fabricated nanofibers were characterized for diameter, drug-loading (DL), disintegration, and drug release profiles. The data demonstrated that the imeglimin nanofibers had a diameter of 361 ± 54 nm and DL of 23.5 ± 0.2 μg/mg of fibers. The X-ray diffraction (XRD) data confirmed the solid dispersion of imeglimin, favoring drug solubility, and release with improved bioavailability. The rate of drug-loaded nanofibers disintegration was recorded at 2 ± 1 s, indicating the rapid disintegration ability of this dosage form and its suitability for buccal delivery, with a complete drug release after 30 min. The findings of this study suggest that the developed imeglimin nanofibers have the potential to be given via the buccal route, thereby achieving optimal therapeutic outcomes and improving patient compliance.

1. Introduction

Diabetes remains among the leading causes of morbidity and mortality, resulting in enormous burdens on healthcare systems worldwide [1]. The global prevalence of type 2 diabetes (T2D) has increased over the past few years [1]. A recent study has found that such an increase in the prevalence of T2D is mainly due to urbanization and improved socioeconomic status [2]. Although public health measures, such as education, public awareness, and implementation of healthy lifestyle changes, are critical for mitigating this global healthcare challenge, there is yet a need for the development of novel therapies for the treatment of T2D with better control of blood glucose levels and minimal adverse responses [3]. Furthermore, emerging perspectives are focused on tackling the challenge of obesity to treat T2D. Hence, unravelling novel therapeutics that could regulate blood glucose levels and improve cellular energetics is of utmost importance [4].

Several promising therapeutics for the treatment of T2D have been developed over the past recent years, and among these is imeglimin [3]. It is a tetrahydrotriazene-containing small molecule that belongs to a novel class of oral antidiabetics known as glimins [5]. In June 2021, imeglimin was approved for use in T2D patients in Japan, and several emerging research studies provided evidence for its efficacy as monotherapy or in combination with insulin in T2D patients [6,7,8]. Imeglimin mediates its glucose-lowering effect through multiple mechanisms, including enhancing pancreatic beta-cell function and preserving its integrity, suppressing liver gluconeogenesis, and improving insulin sensitivity in the liver and skeletal muscles [9]. The underlying molecular mechanism of imeglimin action is mainly mediated by improving mitochondrial function and suppressing mitochondrial-derived free radicals [9,10]. Interestingly, recent research demonstrates the protective properties of imeglimin beyond its glucose-lowering effect across various cell types and tissues, as demonstrated in several experimental disease models, such as cardiovascular and neurodegenerative [11,12,13]. Indeed, such findings may extend the future use of imeglimin beyond its current indication in T2D patients.

Treatment with imeglimin has demonstrated good safety and efficacy outcomes [6,7,14,15]. Nevertheless, several drawbacks have been reported, including reduced absorption with increased doses, potentially due to saturation of active transport and gastrointestinal (GI) discomfort, such as nausea and vomiting, constipation, and diarrhea [14,15,16]. On the other hand, the population of geriatric patients (aged 60 years and over) is growing worldwide, and it is estimated to be 1.4 and 2.1 billion by 2030 and 2050, respectively [17]. Multiple chronic diseases commonly occur in geriatric patients requiring various medications, which may lead to poor medication compliance [18]. In addition, geriatric patients may experience age-related issues concerning achieving optimal therapeutic outcomes, including difficulty swallowing and reduced GI function [19,20].

Similarly, the pediatric population may experience similar problems when achieving optimal therapeutic outcomes [19]. Such issues could be overcome by developing novel formulations via different routes of administration and utilization of advanced techniques in pharmaceutical technology, such as smart buccal delivery systems [19]. Furthermore, the emerging applications of imeglimin beyond its glucose-lowering properties, for example, the improvement of mitochondrial function and its consequent protection against different diseases, further emphasize the importance of developing novel formulations.

Oral and buccal delivery has several advantages, including ease of administration, fast absorption, bypassing first-pass metabolism, and low GI absorption [21,22]. Different fast-dissolving mucoadhesive pharmaceutical formulations have been established, such as transdermal patches, tablets, gels, and ointments, with the thin oral and buccal patches offering ease of administration and fast rate of absorption (i.e., seconds) [21,22]. Nevertheless, these thin oral films have limitations, including dose uniformity and film thickness, which could alter mechanical properties and drug release rates [23]. Smart buccal delivery systems utilize novel and advanced materials to achieve optimal absorption and drug delivery to its ultimate target [24,25]. Indeed, smart buccal delivery systems may overcome several limitations of thin oral and buccal film formulations [24,25].

Electrospun nanofibers are a key smart buccal delivery system with several advantages, including unique mechanical properties and ultra-rapid disintegration and drug release rates (≤2 s) [26]. Electrospinning is a widely used method to make nanofibers by applying high voltage to a capillary tube of polymer solution to form electrostatic repulsion between surface charges, eventually forming nanofibers [27]. Electrospun nanofibers have a wide range of applications, including biomedical applications such as drug delivery, wound dressing, and tissue engineering [27]. Electrospun nanofibers have high porosity and surface-to-volume ratio, allowing a large volume of drug loading and fast release and absorption of the loaded drug [26,28].

The current study is aimed to fabricate electrospun imeglimin nanofibers with the ultimate goal of having a novel imeglimin formulation that provides rapid disintegration and absorption rates via the buccal route. The imeglimin nanofibers will be prepared by the electrospinning technique and characterized for their fibrous diameter, drug-loading, disintegration and drug-release profile. The fabricated imeglimin-loaded nanofibers will have several advantages over conventional imeglimin, including ease of administration and patient compliance in geriatric and pediatric populations and avoidance of GI-related adverse responses. In addition, the nanofiber formulation will have other benefits, such as faster absorption rates, the onset of action, and bypassing drug first-pass metabolism in the liver.

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Alamer, A.A.; Alsaleh, N.B.; Aodah, A.H.; Alshehri, A.A.; Almughem, F.A.; Alqahtani, S.H.; Alfassam, H.A.; Tawfik, E.A. Development of Imeglimin Electrospun Nanofibers as a Potential Buccal Antidiabetic Therapeutic Approach. Pharmaceutics 2023, 15, 1208.
https://doi.org/10.3390/pharmaceutics15041208

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