Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia

Discover Nano Research Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia Swagata Sinha1 · Punna Rao Ravi1 · Makarand Somvanshi1 · S. R. Rashmi1 Received: 18 August 2024 / Accepted: 28 November 2024 © The Author(s) 2024  OPEN Abstract Acalabrutinib (ACP) is a first-line treatment for chronic lymphocytic leukemia but suffers from poor and variable oral bioavailability due to its pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. Thus, the objective of this study was to improve the solubility and dissolution behaviour, in turn enhancing bioavailability, by formulating solid lipid nanoparticles (SLNs). ACP loaded SLNs (ACP-SLNs) were prepared via solvent-free hot emulsification followed by a double sonication process. A combination of glyceryl di-behenate and stearyl palmitate along with Tween 80 was used as the lipid phase to dissolve ACP. A 1% w/v Poloxomer188 solution served as the aqueous phase. The optimized ACP-SLNs were spherical in shape and had particle size of 234.7–257.5 nm, PDI of 0.261–0.320 and loading efficiency of 18.70 ± 1.78%. A typical biphasic release pattern was observed from ACP-SLNs in the in vitro dissolution studies under gastrointestinal and plasma pH conditions (> 90% drug release at pH 4.5 ± 0.2, 6.8 ± 0.2 (representing GIT), and 7.4 ± 0.2 (representing plasma) at 8, 16 and 24 h, respectively). The freeze-dried product was stable when stored at 5 °C for over 6 months. Compared with the bulk drug suspension, the ACP-SLNs suspension resulted in 2.29-fold increase in oral bioavailability and more importantly 2.46-fold increase in the distribution of drug to spleen. Additionally, inhibition of lymph production and flow by administering cycloheximide resulted in 46.01% decrease in the overall absorption of ACP-SLNs, indicating the significance of lymphatic uptake process in the oral absorption of ACP-SLNs. Keywords Tyrosine kinase inhibitor · Solvent-free hot emulsification · Biphasic release systems · Spleen distribution · Lymphatic uptake 1 Introduction Chronic lymphocytic leukaemia (CLL) is a slow-progressing heterogeneous neoplastic disorder characterized by abnormal B lymphocyte proliferation (> 5,000 cells per μL of blood) and is usually diagnosed around the age of 55–65 years in humans [1]. The development of CLL, like other cancers, primarily depends on the microenvironment consisting of cellular elements, generation of new vessels, availability of growth factors, immunogenic protection of neoplastic cells, etc.. The T cells, stromal cells, and macrophages fuel the proliferation and survival of neoplastic cells. A previous study revealed that tyrosine kinases, specifically the B-cell receptor (BCR) pathway, play a significant role in the development of CLL and maintenance of its microenvironment via various antigen interactions [2–4]. In addition to conventional therapies with chlorambucil, bendamustine, and fludarabine, which have several severe side effects, various tyrosine kinase inhibitors (TKis), such as ibrutinib, acalabrutinib, venetoclax, and dasatinib, provide targeted therapy and improved * Punna Rao Ravi, | 1Department of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana 500078, India. Discover Nano (2024) 19:218 | https://doi.org/10.1186/s11671-024-04157-8 Vol.:(0123456789) Research Discover Nano (2024) 19:218 | https://doi.org/10.1186/s11671-024-04157-8 tolerance [4–6]. In the entire cascade of tyrosine kinases in the B-cell receptor (BCR) axis, Bruton’s tyrosine kinase (BTK) is a key target, whose activation leads to consecutive phosphorylation and activation of other kinase pathways. Thus, molecules such as ibrutinib, acalabrutinib, bosutinib, and zanubrutinib, which specifically inhibit the phosphorylation of BTK, are the first-line therapies [7, 8]. BTK inhibitors (BTKis) share similar overall structural patterns, with highly hydrophobic substituent groups such as aromatic amines, heterocyclic aromatics, and biaryl groups [9, 10]. Thus, most BTKIs belong to either BCS class II (low solubility and high permeability) or BCS class IV (low solubility and low permeability). Acalabrutinib (ACP), a type of selective irreversible BTKi, belongs to BCS class II. It is marketed as Calquence, 100 mg capsules and tablets (active ingredient in the form of acalabrutinib maleate), by AstraZeneca, Cambridge, UK [11, 12]. The molecule shows pH-dependent solubility- ACP is practically insoluble above pH 6 [11, 12]. Zhou D. et. Al, 2022, reported that, the dynamic gastrointestinal pH influences the pH at the surface which ultimately affect the solubility of ACP (a weakly basic compound having a maximum basic pKa at 5.77) [13]. The gradual increase in the pH from 1 to 7, perilously impacted both C max and AUC ultimately resulting in an oral bioavailability of 25 ± 11%. The low and variable bioavailability is also the result of its extensive metabolism by CYP3A enzymes and efflux by P-gp systems in the small intestine [11, 12, 14]. The metabolism of the drug was also assessed as part of its elimination profile, revealing that unchanged ACP accounted for less than 2% of the total amount eliminated (84% excreted in faeces and 12% in urine) [12, 14]. Thus, the formulation of a nanoparticulate drug delivery system may increase the bioavailability of the drug not only by direct uptake of the formulation into the systemic circulation, circumventing the need for drug dissolution in small intestinal lumenal fluids but also by preventing the exposure of the drug to P-gp and CYP3A enzymes in enterocytes. A population PK study by Edlund H. et. Al, 2018, revealed that ACP showed a two compartmental oral pharmacokinetic model- a fast absorption phase ( Tmax = 0.5 to 0.75 h) followed by a bi-exponential elimination phase (a rapid decline followed by a slower phase) [15]. Lipid-based drug delivery systems such as solid lipid nanoparticles (SLNs), composed of a solid core (0.1 to 30% w/w; made of either triglycerides, fatty acids, or wax alone or in combination) coated with an amphiphilic stabilizer or surfactant (0.5 to 5% w/w; such as poloxamers, lecithin, or polysorbates) [16], may offer an improved delivery of ACP. The lipophilic core, which is solid at both room temperature and physiological temperature, enhances drug loading and facilitates controlled release of the entrapped lipophilic drug. Additionally, the presence of lipids affects the gastric emptying time, allowing the formulation to be present for a longer duration. The interaction between SLNs and enterocytes could lead to increased chylomicron production, facilitating the uptake of the SLN lipid matrix through lymphatic drainage [17, 18]. The suitability and increased chances of uptake of SLNs by the lymphatic system was well proven and reported by Ravi P. et. Al, 2014 for BCS class II molecules like lopinavir and ra (...truncated)