The challenge of aqueous solubility in pharmaceutical sciences is a significant obstacle, as a substantial proportion of approved molecules and emerging active candidates exhibit poor water solubility(1, 2). Despite the potent activity drugs at the forefront of industrial development may possess in terms of binding to specific receptors, their low solubility often results in inadequate absorption, leading to low drug concentrations in target tissues. This low solubility poses a considerable challenge for the pharmaceutical industry(3). Moreover, a notable percentage of approved drugs suffer from low water solubility, frequently associated with erratic absorption within the gastrointestinal tract. This frequently necessitates high doses and prolonged treatment regimens, which can be inconvenient for patients. As of 2015, reports indicated that 40% of marketed and 90% of drugs in the discovery phase encountered solubility challenges(4). Additional statistics suggest that 40% of all potential drug candidates were abandoned due to inherent aqueous solubility issues(5, 6).
In this context, harnessing nanotechnology is a pivotal strategy to tackle solubility issues and enhance drug release selectivity. Nanocrystals (NC) stands out as a frequently employed approach, yielding a significant impact on nanomedicine and becoming an integral component of the therapeutic arsenal against a spectrum of diseases(7, 8). By definition, NC refers to stabilized drug nanoparticles ranging in size from 10 to 1000 nm(9). The heightened specific surface area resulting from nanonization imparts distinct properties to these systems, including an accelerated dissolution rate, elevated saturation concentration (as deduced from Ostwald-Freundlich and Noyes-Whitney equations), and improved adherence to cell surface membranes(10).
Two methodological avenues exist for acquiring NC: the established "bottom-up" approach involves dissolving a drug under controlled conditions and precipitating it with a stabilizing agent, yielding small and uniform particles. However, this method carries several drawbacks, including the use of organic solvents, which diminishes its appeal to the pharmaceutical industry due to concerns over scalability and reproducibility and potential drug instability due to the lack of a protective material (polymer, lipid)(11). Conversely, the "top-down" approach begins with the suspension of a drug, applying substantial energy to achieve nanonization of the system. This results in a highly scalable, reproducible process favored by the pharmaceutical industry(12). Whereas the liquid suspensions resulting from the milling process are commonly named nanosuspensions (NS), water removal using spray- or Freeze-drying leads to the obtention of the solid NC(11). However, due to drug nanonization and its impact on increased solubility, the drug may dissolve entirely in the stomach, failing to reach the rest of the gastrointestinal tract. This could present an issue as the stability of drugs in the gastrointestinal tract can be influenced by an extremely acidic pH and enzymes. Furthermore, a considerable number of actives can irritate the gastric mucosa(13, 14).
The precise and effective delivery of drugs remains an ongoing challenge in pharmaceutical research, driven by the pursuit of more efficient and safer therapies. In this context, encapsulated drug delivery systems designed for intestinal release have emerged as promising strategies (15, 16). Encapsulation provides a protective barrier that shields the drug from enzymatic degradation and adverse gastrointestinal conditions, such as low pH and enzymatic activity(17). Furthermore, encapsulation can mask the unpleasant taste of certain drugs, enhancing patient acceptance and, thus, treatment adherence(18, 19). In this regard, Eudragit® polymers selectively target the entire gastrointestinal tract, including the small intestine, colon, and large intestine(20). In the past decade, Eudragit NPs have demonstrated the potential to encapsulate and enhance the solubility and bioavailability of poorly soluble drugs such as efavirenz(21), benznidazole(22), triclabendazole(23) and quercetin(24). These polymers can deliver drugs in a targeted manner through specific chemical modifications in their structure due to their differential solubility and release behavior at different pH values(25). Among these polymers, Eudragit® L is designed to release its content in the small intestine rather than the stomach(26). These polymers are insoluble in the acidic stomach environment, allowing them to resist dissolution until they reach the small intestine, where the pH is more alkaline. Once in this higher pH environment, Eudragit® L polymers become soluble, enabling the drug's or active substance's controlled release (20, 25).
Ivermectin (IVM) is a highly versatile antiparasitic agent belonging to the avermectin class, comprised of two components: 'a' (H2B1a, 80%) and 'b' (H2B1b, < 20%)(27, 28). FDA has approved its oral tablet form to address disorders such as intestinal strongyloidiasis and onchocerciasis. Recognized as an essential medicine endorsed by WHO since 1981, IVM stands out for its effectiveness and cost-effectiveness(29). In the Biopharmaceutical Classification System (BCS), ivermectin is categorized as Class II, exhibiting an aqueous solubility of approximately 1 µg/ml at room temperature(28). This classification poses formulation challenges due to its incomplete, fluctuating, and meal-dependent oral bioavailability(27, 30). These attributes make it a suitable candidate for developing pH-sensitive nanocrystals for intestinal release. To date, various articles have described the generation of drug nanocrystals in solid dosage forms(11, 31–33). However, the encapsulation of drug nanocrystals for targeted and controlled release has not been widely investigated. For instance, Muller et al. studied the production of pellets containing drug nanocrystals of hydrocortisone acetate by layering the freshly prepared nanosuspension(34). Subsequently, an enteric coating was applied to achieve pH-dependent drug release using the same equipment and Eudragit L 30 D-55. While they effectively achieved intestinal pH-dependent release, the system's drug loading percentage was deficient (1%).
This research aimed to develop pH-sensitive nanocrystals using Acryl-EZE, a pre-formulated dry acrylic coating system containing Eudragit L100 55 as the encapsulation agent and ivermectin as the prototype drug. This was achieved through easily scalable techniques with a high system loading capacity.