Influence of polymer and surfactant-based precipitation inhibitors on supersaturation-driven absorption of Ibrutinib from high-dose lipid-based formulations

Abstract

There is a growing pharmaceutical interest in supersaturated lipid-based formulations (Super-LbF) as an innovative strategy to enhance drug loading capacities while simultaneously reducing pill burden. This approach involves increasing the drug concentration above its equilibrium solubility in a lipid solution, achieved through temperature-induced supersaturation or the dissolution of lipophilic ionic salts. However, the physical instability and potential drug precipitation upon the dispersion of LbF remain critical. The focus of this work was to assess the impact of polymer and surfactant as precipitation inhibitors (PIs) in Super-LbF and investigate whether PIs can effectively address the aforementioned challenges. Ibrutinib (Ibr) was selected as a model drug due to its limited solubility and dissolution characteristics. The optimized formulations were characterized with a focus on dispersibility, lipolysis-permeation, and physical stability during storage.
The inclusion of PIs in Super-LbF significantly enhanced physical stability by increasing viscosity and reducing the degree of supersaturation through elevated equilibrium solubility. During the dispersion and digestion study, varying levels of transient supersaturation were observed for both Super-LbF and PI-loaded Super-LbF. A noteworthy 2.5 to 3-fold increase in the solubilization ratio was observed for PI-loaded Super-LbF in comparison to Super-LbF without PI. This increase indicates a significant rise in transient drug supersaturation through kinetic and thermodynamic precipitation inhibition mechanisms. Moreover, lipolysis-permeation studies revealed increased flux values with enhanced solubilization, except in the case of Pluronic® F68, which exhibited a reduced free drug concentration near the Permeapad® barrier. Further, the in vivo absorption study confirmed that prolonged supersaturation, facilitated by PIs, contributed to enhancement in drug exposure in rats. PI-loaded Super-LbFs demonstrated a significant improvement (5.1 to 8.9-fold) in the absorption profile compared to Super-LbF without PI (p < 0.001). The study results indicate that incorporating PIs into Super-LbF enhances physical stability and maintains transient drug supersaturation under digestive conditions. Overall, this formulation approach shows promise for expanding the application of LbF to enable the successful oral delivery of high-dose regimen drugs.

Introduction

According to the lipid-based classification system consortium, lipid-based formulations (LbFs) typically contain drugs dissolved or suspended in oils (triglycerides or mixed glycerides), surfactants, or co-solvents (Pouton, 2006). LbFs have demonstrated efficacy in scientific, clinical, and regulatory domains. However, there have been several cases where dissolving the full therapeutic drug dose within the specified liquid fill volumes of pharmaceutical capsules is difficult (Ditzinger et al., 2019, Savla et al., 2017). To overcome these challenges supersaturated LbFs were introduced. The supersaturated state of the drug in LbFs is induced either by using ionic liquid or thermal treatment during solubilization (Michaelsen et al., 2016, Schultz et al., 2020, Thomas et al., 2013, 2012). In case of ibuprofen, celecoxib, halofantrine, and cinnarizine the supersaturation has increased the drug loading (∼2.5 times) as compared to the saturated drug loading at room temperature (Ilie et al., 2020b, Schultz et al., 2018, Thomas et al., 2012). However, the level of supersaturation used in the LbF significantly affects the product shelf life and in vivo performance (Holm et al., 2023).

Recently, Sirvi and co-workers developed the Super-LbF for Ibrutinib (Ibr) using the temperature-induced supersaturation method and observed a 2.5-fold increase in drug loading compared to conventional type III LbF (Sirvi et al., 2024b). However, the authors reported key limitations, noting that the biopharmaceutical performance of Super-LbF was hindered by physical instability and drug precipitation under digestive conditions. First, the physical stability of Super-LbF may raise concerns due to its unfavorable thermodynamic state, characterized by an increased chemical potential within the LbF (Ilie et al., 2020b). Second, drug precipitation during the dispersion and digestion conditions can manifest through two distinct processes: firstly, a reduction in solubilization capacity due to hydrophilic excipients and secondly, drug precipitation mediated by the endogenous digestion process (Suys et al., 2021, Stillhart et al., 2013). However, the in vivo impact of drug precipitation depends on the rate of drug precipitation, the solid form of the precipitate (amorphous or crystalline), and the permeability of the drug (Alskär et al., 2018).

The drug precipitation during dispersion and digestion can be prevented by utilizing the appropriate approach including the use of non-digestible lipids, lipolysis inhibitors, steric hindrance by stealth-LbF, and the use of precipitation inhibitors (PIs) (Alskär et al., 2018, Feeney et al., 2014, Paulus et al., 2024a). Particularly, PIs have been added to conventional LbFs to stabilize the metastable state generated during dispersion and digestion. It has been demonstrated that PIs may sustain a supersaturated metastable state for a considerable amount of time, which boosts the absorption of drugs that are PWSDs (Mondal et al., 2023, Suys et al., 2018). Both kinetic and thermodynamic inhibition mechanisms provide explanations for drug precipitation inhibition. Drug precipitation from a supersaturated solution is often delayed by PIs through a kinetic inhibitory mechanism, which includes interaction with dissolved drug molecules that subsequently prevent crystal nucleation and/or growth. They can also alter the pH and viscosity of the medium to prevent drug precipitation (Price et al., 2019, Sodhi et al., 2019). Additionally, drug precipitation can be thermodynamically prevented by increasing the solubility of the drug in the dispersion medium (Dai et al., 2007).

Common polymeric PIs include cellulosic polymers like hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose phthalate (HPMCP), as well as Eudragit-based polymers. Additionally, different grades of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), and polyvinyl alcohol (PVA) are frequently used as PIs (Holm et al., 2023, Price et al., 2019). However, the solubility of these PIs in LbF is a crucial element for formulation development (Ilie et al., 2021, Suys et al., 2018). Gao et al. developed paclitaxel-LbF using hydroxypropyl methylcellulose (HPMC) as a PI. Contrary to the traditional formulation with its rapid precipitation, in vitro results revealed that the developed supersaturable self-emulsifying formulation generated a prolonged supersaturated state of paclitaxel (Gao et al., 2003). Similarly, in quercetin-loaded supersaturable LbFs with and without PIs, Sirvi and colleagues observed that the formulations with PIs exhibited enhanced water solubilization in mixed bile-lipid aggregates, leading to improved pharmacokinetic characteristics (Sirvi et al., 2022).

Surfactant-based PIs, including Soluplus®, vitamin E TPGS (tocopheryl polyethylene glycol succinate), Kolliphor® HS15, Kolliphor® RH40, and different grades of Pluronic®, were studied for their potential in stabilizing the drug supersaturation (Ilie et al., 2021, Rao et al., 2015, Raut et al., 2015). Recently, Koehl and coworkers assessed surfactant-based PIs for their ability to sustain supersaturation in LbFs for venetoclax (Koehl et al., 2021a). A range of PIs were evaluated using solvent shift-based supersaturation techniques and molecular dynamics simulation; the most promising PIs (HPMC, HPMCAS, PVP, Eudragit® EPO, and Pluronic® F108) were subsequently identified. Despite the superior performance of PI-laden LbFs in in vitro settings, pharmacokinetic results showed that adding PIs to LbFs did not enhance oral bioavailability, and in some cases, it even decreased it (Koehl et al., 2021a). The published literature on PI-loaded Super-LbF highlights that their performance depends on the specific drug, lipid composition, and nature of PI (Ilie et al., 2021, Paulus et al., 2024b). So far, few studies have explored the use of polymer or surfactant-type PIs to maintain drug supersaturation and their subsequent impact on drug absorption (Holm et al., 2023, Price et al., 2019). Thus, there is a need for further investigation into the influence of these PIs to develop improved Super-LbF and fully utilize their benefits.

The purpose of this study was to assess the impact of different PIs incorporation in Super-LbF and understand their complex characteristics in both in vitro and in vivo contexts. Different PIs were comprehensively screened based on their ability to stabilize supersaturation and the chosen PIs were further used to prepare the PI-loaded Super-LbF. A previously developed prototype type III Super-LbF of Ibr was used as a control formulation, with a drug loading of 250 % w/w relative to its equilibrium solubility in the lipid preconcentrate at ambient temperature (Sirvi et al., 2024b). The prepared PI-loaded Super-LbFs were directly compared to the control formulation to assess physical stability, emulsification, and solubilization. This study also aimed to evaluate the potential of PIs to enhance drug diffusion across a biomimetic membrane, based on prior evidence indicating that PIs can sustain drug supersaturation. Lastly, in vitro findings were compared with pharmacokinetic outcomes to provide insights into the relationship between the influence of PIs on liquid Super-LbF, and its in vivo performance.

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Materials

Ibr, a weakly basic BCS Class II compound, was received as a gift sample from MSN Laboratories Pvt. Ltd. in Hyderabad, India. Capmul® MCM EP (Glycerol Monocaprylocaprate) was also provided as a gratis sample by Abitec Corporation in Columbus, Ohio; Labrasol® was received from Gattefossé, Co., (France); and Polyethylene glycol was sourced from Thermo Fisher Scientific India Pvt. Ltd. (Mumbai, India).

Following excipients are mentioned in the study besides other: Soluplus®, vitamin E TPGS (tocopheryl polyethylene glycol succinate), Kolliphor® HS15, Kolliphor® RH40, Eudragit® EPO

Arvind Sirvi, Akash Janjal, Shubham Debaje, Abhay T. Sangamwar, Influence of polymer and surfactant-based precipitation inhibitors on supersaturation-driven absorption of Ibrutinib from high-dose lipid-based formulations,
International Journal of Pharmaceutics, Volume 669, 2025, 125079, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125079.


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