(W1030-09-57) Improving PROTAC Dissolution via an Ionic Liquid API Approach with Enhanced Solid Handling

Purpose: PROTACs exist in the beyond rule of 5 (bRo5) chemical space and are classified as BCS class IV drugs. Their poor solubility is one of the leading challenges limiting the success of these targeted protein degraders (Garcia Jiménez et al., 2022). Active Pharmaceutical Ingredients based – ionic liquids (API-ILs) are well positioned to address this challenge but suffer from poor handling characteristics. Recently, spray encapsulation has emerged as a means to mitigate these challenges associated with processing and formulation of liquid/semi-solid API-ILs/or their lipid-based formulations (LBFs) (Stocker et al., 2020, Tsolaki et al., 2024). The spray encapsulated manufacturing process employed is known as SEncIL (spray encapsulation of innovative liquids). Through SEncIL, a powder comprising the API-IL can be prepared by forming a biphasic system with API-IL or API-IL/LBF encapsulated by a separate polymer phase. thus overcoming the handling issues associated with the API-IL.

Methods: ARV-110 was purchased from Kemprotec Ltd. (Cumbria, United Kingdom). Capryol® 90 and Transcutol® HP were a gift from Gattefossé (Saint-Priest, France), and Eudragit L100 was donated by Evonik (Essen, Germany). Docusic Acid was formed by mixing sodium docusate and HCl in acetone followed by filtration of the salt precipitate. The product obtained was a colourless liquid (98.6% yield). The docusate salt of ARV-110 (ARVDoc) was synthesised by mixing ARV-110 with docusic acid in a 90:10 DCM:methanol solvent mixture at room temperature. The solvent was evaporated to obtain a glassy yellow solid product (96.3% yield), namely ARVDoc. An LBF system composed of Capryol^® 90 (49.5%), Transcutol (49.5%) and hydrogenated castor oil (HCO, 1%) was assessed. a methanol solution composed ARVDoc was added to of Eudragit L-100, and LBF in the ratios illustrated in Table 1. The obtained solution was spray dried. Spray drying was carried out as previously described (Stocker et al., 2020). FaSSIF for dissolution studies was obtained from Biorelevant (London, United Kingdom). The potential of the developed systems to form nanoparticles was assessed using Dynamic Light Scattering (Zetasizer Ultra, Malvern Panalytical, UK). Samples were prepared in deionized water and analysed for particle size and zeta potential.

Results: To improve the in vitro dissolution characteristics of ARV-110, the following strategy was implemented. Firstly, a lipophilic API-IL was formed between ARV-110 and docusate ion to form ARVDoc. Whilst this improves aqueous solubility, forming a lipophilic salt significantly increases miscibility with LBFs. The API-IL/LBF mixture was spray encapsulated in a polymer (Eudragit L100) to obtain the product with the composition in Table 1 as a free-flowing powder. Dissolution studies indicated that the amount of ARV-110 dissolved after 4 hours was 800-fold higher for the PROTAC API-IL SEncIL formulation compared to the amorphous form of the API with the crystalline form being undetectable (Figure 1). These findings show the potential for the SEncIL strategy to dramatically improve the oral bioavailability of PROTACs when used in combination with conventional LBF approaches. Dynamic light scattering (DLS) data obtained for the spray encapsulated product indicates the formation of micelles with large negative zeta potential values (Table 2). The formulation may be classified as a self-emulsifying drug delivery system (SMEDDS) due to its particle size falling in the characteristic 100-250 nm range for such systems (Seo et al., 2022).

Conclusion: Encapsulation of a lipophilic API-IL of ARV-110 combined with a LBF has proven an effective strategy for improving both dissolution and processability of a challenging PROTAC molecule with the SEncIL formulation providing more than a 800-fold improvement over the amorphous drug. DLS data suggests that the formation of micelles from a SMEDDS system may be important in achieving the improvement in dissolution performance. This approach is successful in overcoming some of the key issues associated with both PROTACs and API-ILs or API-IL/LBFs. The SEncIL approach provides a promising platform for the formulation of bRo5 therapeutics, and the formation of a free-flowing powder product allows for the incorporation of the products into conventional manufacturing pipelines.

References: Shamshina, J.L., Rogers, R.D., 2023. Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties. Chem. Rev., 123(20), 11894–11953.
Stocker, M.W., Healy, A.M., Ferguson, S., 2020. Spray Encapsulation as a Formulation Strategy for Drug-Based Room Temperature Ionic Liquids: Exploiting Drug–Polymer Immiscibility to Enable Processing for Solid Dosage Forms. Mol. Pharm., 17(9), 3412–3424.
Tsolaki, E., McCartney, F., Healy, A.M., Brayden, D.J., Ferguson, S., 2025. Solidified ionic liquid-based formulations of metformin with enhanced GI epithelial permeability. Int. J. Pharm., 678, 125649.
García Jiménez, D., Rossi Sebastiano, M., Vallaro, M., Mileo, V., Pizzirani, D., Moretti, E., Ermondi, G., Caron, G., 2022. Designing soluble PROTACs: Strategies and preliminary guidelines. J. Med. Chem., 65, 12639–12649.
Seo, E.B., du Plessis, L.H., Viljoen, J.M., 2022. Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria. Pharmaceuticals, 15(2), 120.

Acknowledgements: This work has been supported by Research Ireland (RI) [18/EPSRC-CDT/3587]; and the Engineering and Physical Sciences Research Council [EP/S023054/1]. Additional support has been provided by RI co-funded by the European Regional Development Fund under grant number [12/RC/2275_P2] and Enterprise Ireland Commercialisation Fund Programme through project CF 2023 2109-I.

Fig. 1. Dissolution of SEncIL ARV-110, Amorphous ARV-110 and ARV-110 in FaSSIF.

Table 1. SEncIL ARV-110 Formulation Components.

Table 2. DLS data for SEncIL ARV-110 and ARVDoc in DI water.