**1. Introduction**

Liposomes are one of the most studied drug delivery systems, owing to their ability to encapsulate various active substances of hydrophobic and hydrophilic nature, their biocompatibility, and design flexibility. Although liposomes were originally developed for parenteral drug delivery, their use for oral drug delivery has been a topic of research [1–4]. Liposomes are used for oral bioavailability enhancement of low-soluble or low-permeable active ingredients [4–7], as well as compounds with low stability in the gastrointestinal (GI) tract [2,8–11].

Compared to the widely used conventional solid dosage forms (i.e., tablets), production of liposomes is demanding due to production challenges, as well as physical and chemical stability issues. The production methods are optimized for small-scale production and are unlikely to qualify for oral dosage form production [12,13]. Moreover, liposomal dispersions that are stored in liquid form have a limited stability due to the risk of sedimentation, aggregation, and phospholipid hydrolysis [14]. It would also be beneficial to produce solid powders that can be processed using conventional tableting equipment.

Freeze-drying [15,16], spray-drying [17], spray freeze-drying [18], and supercritical fluid technology [19,20] are therefore used for producing solid liposomal formulations [21,22]. One of the methods for solidification of the oral liposomes is adsorption on solid inert carriers [23]. In 1986, Payne et al. [24] introduced dry and free-flowing liposomal formulations that could produce multi-lamellar liposomes upon hydration. These systems were given the name "proliposomal formulations" and have been a subject of various studies [5,25–29].

As adsorption carriers for dry liposomal formulations, water-soluble carriers such as sorbitol, mannitol, or cellulose derivatives have generally been used to enhance hydration of the phospholipids [27,30–34]. In this study, we propose the use of a pharmacologically inert porous carrier for a single-step production of solid proliposomal formulations. Porous materials offer various benefits for drug delivery, including their large surface area and large pore volumes that allow adsorption of materials and protection of the loaded material from harsh external conditions [35]. Additionally, porous media can facilitate the hydration of liposome-forming phospholipids by rapid water uptake due to the capillary action of the porous microstructure.

In the past years, we have focused on porous functionalized calcium carbonate (FCC) microparticles as a new carrier for drug delivery. FCC is a calcium carbonate that has undergone partial recrystallization to form a variable layer of lamellae of calcium phosphate (hydroxyapatite) on the surface of the particles. The particles have an average size of 10–20 µm and exhibit a specific surface area of 30–70 m<sup>2</sup> /g and roughly 60% intra-particulate porosity [36]. The intra-particulate pore sizes range from 500 nm to less than 100 nm and the pores can be loaded with different materials [37]. We have harnessed the capabilities of the internal porosity of FCC particles to hold small molecular compounds [38,39] and peptides [35]. Drug loading into FCC particles allows for convenient handling and processing of compounds that would otherwise be challenging to formulate as conventional oral dosage forms. We have also studied the behavior of FCC in direct compaction and granulation processes that have resulted in FCC tablets with high tensile strength and fast disintegration [40]. Such unique mechanical characteristics of this novel porous material have allowed the production of orally disintegrating and gastro-retentive tablets from FCC [41–43].

The goal of the present study was to produce dry powder proliposomal formulations using the inert porous material FCC as a carrier. The feasibility of this approach was demonstrated on the basis of spontaneous formation of liposomes during hydration, drug encapsulation efficiency of the emerged liposomes, and their potential to improve the dissolution performance of nifedipine as a model low-soluble drug. Ultimately, the factors influencing the formation of liposomes and liposomal drug encapsulation were studied in different simulated gastrointestinal fluids.
