Development of Orodispersible Tablets with Solid Dispersions of Fenofibrate and Co-Processed Mesoporous Silica for Improved Dissolution

Introduction

Poor aqueous solubility of many pharmaceutical compounds represents an important challenge in the development of solid dosage forms intended for oral use. It has been estimated that as much as 90% of newly discovered compounds are poorly water-soluble and belong to either Class II or Class IV according to the Biopharmaceutical Classification System (BCS) [1,2]. Preparation of amorphous solid dispersions (SDs) has been recognized as one of the promising approaches to enhance the apparent solubility and dissolution rate of such compounds, because the amorphous state exhibits a disordered structure and possesses higher free energy [3]. In recent years, there has been an increasing research focus on mesoporous materials, especially mesoporous silica materials, as carriers for SDs. Due to their high surface area and high pore volume, the drug can adsorb inside the pores in an amorphous state and spreads over a large surface, which makes it available for subsequent dissolution in the aqueous environment [4]. This concept has already been proven successful on many model drugs and the detailed mechanism for it has also been thoroughly discussed [5].

However, the use of such SDs to produce final dosage forms is often limited by their poor powder flow and compression properties, making them inappropriate for capsule filling or tableting. To overcome these challenges, high proportions of excipients such as fillers, binders and disintegrants are needed to prepare a suitable powder blend [6]. Consequently, the mass and size of a final dosage form have to be relatively high to ensure sufficient drug content, which is undesired by patients, especially children and the elderly. As these patient groups are particularly challenging regarding patient compliance, there have been many incentives to promote the development of more patient-friendly dosage forms [7]. While dosage forms such as granules, pellets and mini-tablets are easier to swallow due to their small size, (oro)dispersible and effervescent dosage forms are produced and supplied as a solid, but ingested as a liquid dispersion [8]. Among the latter, orodispersible tablets (ODTs) are especially convenient, since they disintegrate rapidly in the oral cavity upon contact with the saliva, which makes them considered as the first choice for patients with swallowing dysfunction or dysphagia [9].

Direct compression is the most common method to produce ODTs due to its ease of use and a greater cost effectiveness compared to methods such as lyophilization, molding, etc. [10]. However, since poor compressibility of the tablet ingredients can limit its applicability, one must choose the excipients wisely. One possibility is to include co-processed excipients, which are defined as a combination of two or more excipients designed to physically alter their properties in a manner not achievable by physical mixing, and without any significant chemical changes [11]. Co-processed excipients, when used in direct compression, can have a role of a filler and/or binder and can improve powder flow properties of a tableting blend. In some cases, they can even include a superdissintegrant, thereby being functionalized especially for ODTs [12]. In our previous study, we developed a co-processed excipient consisting of mesoporous silica and a sugar alcohol isomalt, which is appropriate for direct compression and has a sufficiently large specific surface area to make it suitable for drug loading and formulation of amorphous SDs [4]. In this study, our objective was to prepare SDs by loading a model BCS Class II drug fenofibrate (FF, Figure 1; log P = 5.24, aqueous solubility less than 0.1 mg/L, Tg < −20 °C) [13,14] onto this excipient, and then use these SDs to produce ODTs. Due to its physicochemical properties, FF is regarded as challenging for drug dissolution improvement, and the incorporation into a mesoporous silica material has been proven successful for it in the previously published studies [15,16,17]. Since the aim was to transform FF from crystalline to amorphous state, pure SDs as well as ODTs should have improved dissolution rate compared to crystalline FF or physical mixtures of FF and co-processed excipient.

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Materials

Mesoporous silica (Syloid^® 244 FP) was obtained from Grace Davison, Grace GmbH & Co. KG (Worms, Germany), and isomalt (GalenIQ^® 800) was obtained from Beneo (Mannheim, Germany). FF was obtained from Biosynth^®, Carbosynth (Berkshire, UK). Magnesium stearate and mannitol (Parteck ^® M) were obtained from Merck KGaA (Darmstadt, Germany). Sodium croscarmellose (Ac-Di-Sol^®) was obtained from IFF’s Pharma Solutions (New York, NY, USA). Sorbitol (Neosorb^® P 300 DC) was obtained from Roquette (Lestrem, France). Low-substituted hydroxypropylcellulose (L-HPC) was obtained from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). All other materials used in the study were of reagent grade. Water was purified by reverse osmosis.

Baumgartner, A.; Planinšek, O. Development of Orodispersible Tablets with Solid Dispersions of Fenofibrate and Co-Processed Mesoporous Silica for Improved Dissolution. Pharmaceutics 2024, 16, 1060. https://doi.org/10.3390/pharmaceutics16081060