Fabrication and Evaluation of Isomalt-Based Microfibers as Drug Carrier Systems

Abstract

Background/Objectives: The melt-spinning process has seen limited application in the pharmaceutical industry. However, nano- and microfibrous structures show significant potential for novel drug delivery systems, due to their high specific surface area. To facilitate broader adoption in pharmaceutical technology, critical parameters influencing fiber quality and yield must be investigated. In this study, we aimed to develop an isomaltbased microfibrous carrier system for active pharmaceutical ingredients.

Methods: The effects of different isomalt compositions—specifically, varying ratios of GPS (6-O-α-Dglucopyranosyl-D-sorbitol) and GPM (1-O-α-D-glucopyranosyl-D-mannitol)—as well as key process parameters, were systematically investigated to optimize fiber formation. The prepared fibers underwent different treatments. Morphological changes were monitored with a microscope, and microstructural changes were studied using a differential scanning calorimeter and X-ray diffractometer. The macroscopic behavior of the fibers was evaluated by image analysis under monitored conditions.

Results: Statistical analysis was used to determine the optimal setting to produce isomalt-based fibers. We found that storage over ethanol vapor has a positive effect on the stability of the fibers. We successfully prepared ibuprofen sodium-containing fibers that remained stable after alcohol treatment and enabled drug release within 15 s.

Conclusions: It was found that the applied GPS:GPM isomalt ratio significantly influenced fiber formation and that storage over ethanol positively influenced the processability and stability of the fibrous structure. An isomalt-based microfibrous system with advantageous physicochemical and structural properties was successfully developed as a potential drug carrier. The system is also resistant to the destructive effects of ambient humidity, enabling preparation of suitable dosage forms.

Introduction

Isomalt has been extensively utilized for decades, particularly in the formulation of sugar-free or reduced-calorie confectionery items such as toffees, hard candies, chocolates, chewing gums, and baked goods [1–4]. Beyond its role in food applications, its relevance in the pharmaceutical field has grown steadily, owing to its versatility across various dosage forms and its suitability for sugar-free formulations. Consequently, isomalt is recognized as an official excipient in several pharmacopeias [5,6].

The production of this excipient consists of two main steps. Firstly, an enzymatic transglucosidation process converts the non-reducing sucrose molecule into the reducing molecule α-D-glucopyranosyl-1,6-D-fructose, generically called isomaltulose. The 1-6 bond formed between the glucose and fructose molecule is much more stable than the 1-2 bond in the sucrose molecule, making isomaltulose more resistant to acids and microbial agents. The next step is catalytic hydrogenation (with Raney nickel), which results in the formation of the stereoisomers 6-O-α-D-glucopyranosyl-D sorbitol (1,6-GPS) and 1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM) in almost equal proportions. GPM crystallizes into two molecules with water, while GPS crystallizes in anhydrate form [7,8]. The ratio of GPS to GPM can be varied by a special crystallization process. As a result, the GPS-rich end product has better water solubility than the GPS poor end product [5]. From a pharmaceutical perspective, isomalt exhibits several advantageous properties compared to sucrose. In addition to being non-cariogenic (tooth-friendly) and suitable for diabetic patients, it exhibits lower hygroscopicity [9,10]. It also has half the sweetening power of sugar and has no unpleasant taste or aftertaste [8].

Isomalt is a pharmaceutical excipient suitable for use in various dosage forms, commercially available in different particle sizes and with varying GPS and GPM ratios. Langer produced solid dispersions containing various active ingredients and used four types of sugar alcohol as excipients in the study, with results showing that isomalt was the most suitable carrier [11]. Isomalt has been shown to enhance the solubility of certain active pharmaceutical ingredients (APIs) [12]. As an inert pellet core, it serves as a seed for multiparticulate systems [13–16]. Isomalt can be used for the production of oromucosal films due to its sweet taste [17,18]. It is suitable for the development of 3D printed printlets [19,20]. Tuderman showed that isomalt is suitable as a protein-stabilizing excipient in lyophilization [21]. Isomalt is also suitable as an excipient for granule formation. In a 2011 publication, Sáska et al. performed agglomeration using isomalt (galenIQ™ 801) and water without any additional binders [22]. Several research groups have successfully used isomalt to produce co-processed excipients by combining it with other materials [23,24].

Several studies have been published in which authors have investigated the compressibility of isomalt [25–27]. The commercially available aggregated isomalt is suitable for direct compression due to its good granule flowability and good compressibility. It can be used for the production of tablets, chewable tablets, and—when combined with suitable excipients—mini-tablets and orally dispersible tablets (ODTs) [28–30]. Unlike conventional direct compression methods used in ODT production, the patented FlashDose® technology employs a preliminary melt-spinning process to create a fibrous matrix, which is then formed into rapidly disintegrating tablets. Developed by Fuisz Technologies, this approach uses sugars such as sucrose, sucrose, lactose, or fructose as the spinning material. To condition the amorphous fibrous structure and ensure its stability, ethanol is sprayed onto the cotton candy-like fibers. The resulting fibers exhibit good adhesion and improved flow properties, making the fibrous structure suitable for the production of orodispersible tablets [31–34].

In this manuscript, we have investigated a novel use of isomalt. The applicability of different commercially available isomalt compositions with varying GPS and GPM ratios for melt fiber formation was investigated, as well as the stability of the fibers. For optimal production, a two-variable three-stage factorial design was applied to investigate the effect on yield of two main independent variables used in pre-production. In order to improve the pharmaceutical processability and environmental stability of the fibers, ethanol vapor treatment was employed. Unlike the previously described patented method involving direct ethanol spraying, our approach introduces a novel strategy by storing the fibers in an ethanol-saturated vapor environment. By leveraging the high specific surface area of the fibers, this method allows for uniform ethanol exposure while avoiding local dissolution or deformation that can occur with liquid application. To our knowledge, the use of ethanol vapor for fiber treatment in this context has not been previously reported, making this a potentially advantageous and innovative alternative.

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Materials

2.1. Materials

For the comparison, two types of isomalt were used as raw materials and as starters for fiber-forming and preparation of melted samples, specifically galenIQ ™ 720 and galenIQ ™ 721 (BENEO-Palatinit GmbH, Mannheim, Germany). Currently, only two types of isomalt with different GPS:GPM ratios are commercially available from the manufacturer for pharmaceutical use. The properties of the isomalt types used are described in Table 1, based on the manufacturer’s specifications [35]. As a reference, crystalline saccharose was chosen (Molar Chemicals Ltd., Halásztelek, Hungary), and for the alcoholic treatment of the prepared fibers, ethanol (Molar Chemicals Ltd., Halásztelek, Hungary) was used. The model drug was ibuprofen sodium (I1892-500; Sigma-Aldrich; Supelco, Bangalore, India).

Table 1. Physicochemical properties of the excipients used in this study based on Ref. [35].

Kovács, A.; Kecskés, B.A.; Filipszki, G.; Farkas, D.; Tóth, B.; Antal, I.; Kállai-Szabó, N. Fabrication and Evaluation of Isomalt-Based Microfibers as Drug Carrier Systems. Pharmaceutics 2025, 17, 1063. https://doi.org/10.3390/pharmaceutics17081063