Alendronate is a hydrophilic, amphiprotic drug administered orally to treat various diseases including postmenopausal osteoporosis, metastatic bone diseases, malignant hypercalcemia, Paget's disease, and primary hyperparathyroidism [[1], [2], [3], [4]]. The bisphosphonate alendronate is also one of the most popular antiresorptive agents for the prevention and treatment of postmenopausal osteoporosis [5,6]. It promotes bone formation by inducing the proliferation and maturation of osteoblasts and preventing their apoptosis [4]. However, alendronate has very low oral bioavailability (0.6 %), which decreases further when taken with meals or beverages other than water [7,8]. Owing to its hydrophilicity and negative charge, it cannot pass through the lipid membrane of the gastrointestinal tract and is classified as BCS class III. Additionally, oral administration of alendronate can lead to gastrointestinal intolerance, with reports of gastric and esophageal lesions, such as erosions and ulcers, owing to the local irritant effects [[9], [10], [11]]. Patients must remain upright for at least 30 min without consuming food or drinks after each dose. As a result of its side effects and complex dosing requirements, up to 60 % of patients discontinue alendronate within the first year [12].

Permeation enhancers (PEs) have emerged as a new strategy for orally administered drugs with poor absorption rates. The FDA approved oral semaglutide tablets formulated with SNAC as a permeation enhancer (Rybelsus®, Novo Nordisk) in 2019, in which SNAC improved the bioavailability of semaglutide [13]. SNAC can be combined with various drugs and formulations [14,15]. In addition, oral octreotide capsules approved in 2020 contained sodium caprylate (C8) as a chemical PE in an oily suspension (Mycapssa®, Chiasma).

Intestinal PEs, temporarily increase the permeability of co-administered compounds across the small intestinal epithelium via the paracellular route by opening tight junctions, the transcellular route by increasing plasma membrane permeability, or a combination of both. Several studies have been conducted on the various PEs and their modes of action [[16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]]. These enhancers span a wide variety of substances, including natural, semi-synthetic, and synthetic compounds, such as chelating agents [27], surfactants [28], bile salts [29], acetylsalicylic acid [30], and polysaccharides [31]. The majority of PEs that have advanced to the clinical trial stage are chemical PEs, including SNAC and medium-chain fatty acids (C8 and C10), which are generally recognized as safe (GRAS) and have obtained safety status as food additives, respectively, are lead PEs [32].

Several alendronate delivery systems have been created in order to get around these restrictions, including solid lipid nanoparticles (SLNs), liposomes [[33], [34], [35]], microformulations [8,36], polymeric micelles [37], hydrogel-based systems [38], and niosomes [39]. SLNs are colloidal dispersions of non-polar lipids that stay solid at body temperature, like fatty acids and triglycerides [40]. The main benefit of SLNs is that they considerably lower the mobility of the medications incorporated into the lipid matrix, which stops particle aggregation, improves stability, and permits long-term drug release. Furthermore, SLNs can be absorbed by the reticuloendothelial system when taken orally, avoiding first-pass metabolism and boosting drug bioavailability [41]. SLN excipients are classified as GRAS and are inherently non-toxic. Because of their sustained drug release properties, SLNs are especially useful for treating diseases like osteoporosis that need long-term treatment. Currently, there is an ongoing discussion on methods for preparing SLNs using hydrophilic drugs, and examples exist where SLNs have been successfully formulated with BCS Class III drugs, similar to alendronate [42]. There are several examples of SLNs prepared using hydrophilic drugs [[43], [44], [45], [46], [47], [48], [49], [50], [51]].

Therefore, we designed a strategy to reduce the gastrointestinal side effects of alendronate, while stably transporting it to the intestine and increasing intestinal permeation. Therefore, the purpose of this study was to optimize the composition of alendronate SLNs to increase their intestinal transport and maximize their bioavailability by formulating them with an effective PE. First, various PEs were screened for alendronate permeability using Caco-2 cell transport assays, and SNAC was selected as the best PE. We also evaluated several solid lipids and surfactants to identify the optimal formulation of alendronate/SNAC co-loaded SLNs. In addition, the formulation was powdered by lyophilization and demonstrated superior storage stability. The dissolution profile of powdered alendronate/SNAC co-loaded SLNs was evaluated under simulated gastric and intestinal conditions. In addition, the formulation showed excellent results compared to the free drug state in transport assays. Scheme 1 illustrates the conceptual framework of the study.