Comparison of the liquisolid technique and co-milling for loading of a poorly soluble drug in inorganic porous excipients

Abstract

Drug loading into mesoporous carriers may help to improve the dissolution of poorly aqueous-soluble drugs. However, both preparation method and carrier properties influence loading efficiency and drug release. Accordingly, this study aimed to compare two preparation methods: formulation into liquisolid systems (LSS) and co-milling for their efficiency in loading the poorly soluble model drug cyclosporine A (CyA) into mesoporous magnesium aluminometasilicate Neusilin® US2 (NEU) or functionalized calcium carbonate (FCC). Scanning electron microscopy was used to visualize the morphology of the samples and evaluate the changes that occurred during the drug loading process. The solid-state characteristics and physical stability of the formulations, prepared at different drug concentrations, were determined using X-ray powder diffraction. In vitro release of the drug was evaluated in biorelevant media simulating intestinal fluid. The obtained results revealed improved drug release profiles of the formulations when compared to the milled (amorphous) CyA alone. The dissolution of CyA from LSS was faster in comparison to the co-milled formulations. Higher drug release was achieved from NEU than FCC formulations presumably due to the higher pore volume and larger surface area of NEU.

Introduction

Low aqueous solubility and dissolution rate contribute to the insufficient bioavailability of many orally administered drugs (Amidon et al., 1995). Consequently, various techniques have been proposed to address these challenges, including chemical (Jornada et al., 2016; Park et al., 2019) or physical modifications of the drug substance itself, micronization (Loh et al., 2014) and co-milling (Brokešová et al., 2022, Liu et al., 2020), or the creation of specific pharmaceutical formulations through a variety of technological processes, such as preparation of amorphous solid dispersions (Laitinen et al., 2017), liquisolid systems (LSS) (Molaei et al., 2018, Vraníková et al., 2020a) and self-emulsifying systems (Kubackova et al., 2021).Table 1.

Recently, there has been increasing interest in the application of mesoporous inorganic materials, especially mesoporous silica materials such as mesoporous silicon dioxide (Syloid®, Sylisia®) (Takeuchi et al., 2005, Waters et al., 2018) and mesoporous magnesium aluminometasilicate (Neusilin®) (Grobelny et al., 2015, Vraníková et al., 2020b) as drug carriers to solve problems associated with low bioavailability. This is due to their unique features, such as high surface area, homogeneous pore structure and appropriate pore size for drug incorporation. For example, the high surface area increases the contact between the drug and the dissolution medium, which results in a proportional increase in the dissolution rate of the drug (Vraníková et al., 2020a). The spatial confinement of amorphous active ingredients in pores of certain sizes prevents their recrystallization, thus favouring dissolution, in contrast to the crystalline form (Vraníková et al., 2020b). High porosity also allows for drug sorption/retention from the liquid state (as in LSS or solidified lipid-based systems), leading to better wetting of the dosage form and a subsequent increase in drug release (Vraníková et al., 2020a, Yeom et al., 2016).

Similar results in drug stabilization and dissolution enhancement have also been reported using non-silicate porous materials. Among them, porous calcium carbonate and functionalized calcium carbonate (FCC) (Liu et al., 2020, Lundin Johnson et al., 2017, Preisig et al., 2014) are relatively new and promising. Lundin Johnson et al. (2017) studied the effects of FCC on the dissolution rate of poorly soluble flavouring compounds, curcumin and L-carvone, with possible application in food and pharmaceutics. By loading them into FCC, the release of the flavouring compounds was accelerated, and this result was mainly attributed to their increased contact area inside the FCC material and the release medium. Furthermore, the crystalline compound, curcumin, was found to remain amorphous in all FCC-loaded samples, even after 9 months of storage at room temperature and 30% relative humidity, due to confinement in small pores (Lundin Johnson et al., 2017).

Several approaches have been investigated for loading APIs into mesoporous carriers (Ahern et al., 2013, Dadej et al., 2022, Grobelny et al., 2015, Kinoshita et al., 2002, Lundin Johnson et al., 2017, Preisig et al., 2014). Solvent-based techniques that utilize organic solvents for drug loading are commonly employed, such as the solvent immersion method, which involves the suspension of the mesoporous carrier in a drug solution in an organic solvent or incipient wetness impregnation method, where a concentrated drug solution in a volatile solvent is continuously added to the mesoporous carrier (Lundin Johnson et al., 2017, Preisig et al., 2014). In these methods, it is usually necessary to remove the volatile solvent after drug loading. This step can contribute to an undesirable loss of a substantial part of the drug (Trzeciak et al., 2021). In addition, there is a potential risk of contamination of final products by solvent residues. To address this, an alternative based on a non-toxic solvent, such as supercritical carbon dioxide, has been investigated. This uses the high density and diffusivity of supercritical carbon dioxide to solubilize large amounts of drug molecules and to drive its high loading into mesopores (Ahern et al., 2013). Major issues with this method however are related to the high cost and specialized equipment required in the loading process.

A novel promising solvent-based method for drug loading is the utilization of liquisolid systems (LSS). Their preparation involves dispersing a drug in a hydrophilic non-volatile solvent (e.g., liquid polyethylene glycols, polysorbates, propylene glycol, Transcutol® HP), and the sorption of the resulting drug dispersion on the carrier, e.g., microcrystalline cellulose (Vraníková et al., 2020a). The obtained free-flowing powders are suitable for filling into capsules or compaction into tablets. Many studies have reported the application of this technique to improve the dissolution rate and bioavailability of poorly soluble drugs (Molaei et al., 2018, Tiong and Elkordy, 2009). A drawback of this method that is often highlighted is that poorly soluble compounds require a large amount of solvent to dissolve, leading to the need for large quantities of the carrier or an additional powder excipient known as the coating material to absorb the drug solution and maintain material free-flowable. To overcome this limitation, some carriers from the group of mesoporous silica, such as Neusilin® US2 (NEU), with a large specific surface area and high absorption capacity have been employed (Vraníková et al., 2021).

In contrast to the abovementioned methods, drug loading in mesoporous carriers has also been achieved through solvent-free methods. In this respect, the melt technique represents a rather simple approach in which the drug is heated in the presence of a carrier to fuse the molten drug into the carrier pores (Kinoshita et al., 2002). However, the impact of elevated temperatures on drug thermal stability is a major concern in this approach. A more suitable solvent-free alternative involves co-milling the drug with the mesoporous carrier. Milling is a well-known approach for particle size reduction and solid-state amorphization of drugs. Co-milling as a method of loading drugs into mesoporous carriers combines the drug amorphization step with its simultaneous embedding in the carrier (Liu et al., 2020, Zarinwall et al., 2022). This may aid the stabilization of the drug against recrystallization especially at high drug loads. Liu et al. (2020) reported that co-milling of the poorly water-soluble drug, carvedilol, using the mesoporous carrier, FCC, facilitated the amorphization of the drug, due to the accessibility of FCC pores and surfaces to the drug. In addition, the amorphous drug was stabilized for 19 weeks at drug concentrations of up to 30% w/w and the drug release was improved (Liu et al., 2020).

Despite numerous documented approaches, finding an optimal method for loading drugs into mesoporous carriers remains challenging. In addition, there is only a limited number of studies that have compared the efficiency of different loading methods (Ahern et al., 2013, Dadej et al., 2022, Grobelny et al., 2015, Limnell et al., 2011). Furthermore, to the best of the authors’ knowledge, there is no study comparing LSS with the formulations prepared by co-milling. Therefore, this study aimed to compare two different methods, preparation of liquisolid systems and co-milling, for the loading of a model poorly soluble drug, cyclosporine A (CyA), in mesoporous carriers. So far, mesoporous silica materials have been the most studied for drug loading, while porous calcium carbonate or FCC as a viable material for this purpose has only recently been introduced (Liu et al., 2020, Lundin Johnson et al., 2017, Preisig et al., 2014), thus their potential behaviour in different drug loading methods is less known. Hence, two mesoporous carriers, NEU, a mesoporous silica material, and FCC, a porous non-silica material, were used, and their drug loading and drug release performance were compared. Scanning electron microscopy was used to visualize the morphology of the carriers and evaluate the changes that occurred during the drug loading process. X-ray powder diffraction was used to observe the solid state after processing and to monitor possible phase transitions upon storage.

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Materials

The model drug cyclosporine A (CyA) was provided as a kind gift by Teva Czech Industries, s.r.o., Opava, Czech Republic. Neusilin® US2 (NEU) purchased from Fuji Chemical Industry Co., Ltd., Toyama, Japan, and functionalized calcium carbonate (FCC; Omyapharm® 500-OG with average particle size 6.6 µm) obtained from Omya International AG, Oftringen, Switzerland, were used as mesoporous carriers. Transcutol® HP (diethylene glycol monoethyl ether), purchased from Gattefossé, Saint-Priest, France

Chiazor Ugo Ogadah, Kristýna Mrštná, Ludmila Matysová, Anette Müllertz, Thomas Rades, Andreas Niederquell, Zdenka Šklubalová, Barbora Vraníková, Comparison of the liquisolid technique and co-milling for loading of a poorly soluble drug in inorganic porous excipients, International Journal of Pharmaceutics, 2023, 123702, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.123702.