Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras

Introduction

Traditionally, small-molecule drug discovery focused on structures that were able to occupy a functionally relevant and selective site of the target molecule. This limits novel drug discovery as only 25% of the human proteome is pharmaceutically accessible through tractable small-molecule binding sites. Ultimately, this would classify many disease-relevant proteins, such as transcription factors, scaffolding proteins or non-enzymatic proteins, as undruggable [1].

In the last decade, event-driven modes of action, such as proteolysis targeting chimeras (PROTACs), have emerged. PROTACs do not require functionally relevant binding sites, such as binding pockets, but are designed to target specific structures on the Protein of Interest (POI) and toward the structure involved for further degradation. They chemically induce the degradation of target proteins inside cells and, in turn, lead to the permanent inactivation of the entire protein [2].

These bifunctional molecules exhibit one ligand for the respective POI and another ligand that recruits an E3 ubiquitin ligase connected by a linker. A ternary complex between the POI and E3 ligase is formed. The POI is ubiquitinated, recognized and degraded by the 26S proteasome from the Ubiquitin Proteasome System (UPS) [3,4]. While the POI ligand is selective and unique for the specific target protein, two major compound classes for E3 ligases have emerged. While there are more than 600 E3 ligases known, PROTACs mainly address cereblon (CRBN, with Thalidomide as the lead structure) [5] or von Hippel–Lindau (VHL) as an E3 ligase [6]. There have also been reports on addressing the mouse double minute 2 homolog (MDM2) and the cellular inhibitor of apoptosis protein 1 (clAP1) [7].
However, the developability of PROTACs is challenging as these structures are well beyond the rule of five (bRo5), displaying a lower chance of desirable oral bioavailability. Lipinski‘s rule of five states that poor absorption or permeation behavior is more prevalent in molecules that exhibit more than five hydrogen bond donors (HBD > 5) and have a molecular weight greater than 500 Da (MW > 500) and a calculated logP greater than five (cLogP > 5) [8,9]. Yang et al. describe a typical PROTAC with a molecular weight > 800 Da and a predicted human dose of 200 mg [10]. In addition to being bRo5, these compounds are mostly classified in the Developability Classification System (DCS) as Class IIb or IV [10], which defines them as having poor solubility and good permeability (Class IIb) or poor solubility paired with poor permeability (Class IV). This classification system was developed as a derivative of the Biopharmaceutical Classification System (BCS) by Butler and Dressman to aid developability by incorporating biorelevant solubility while categorizing compounds regarding their solubility and permeability [11]. Due to their low solubility and non-specific binding, many of the well-established assays for the in vitro characterization of small molecules fail when applied in the evaluation and characterization of PROTACs. This also leads to challenges in permeability assays and in silico predictions that help find optimal clinical doses. Despite these undesirable properties, ARV-471 entered Phase III in clinical trials formulated as an oral solid dosage form [10], showing how high potency, as well as a prolonged pharmacodynamic effect, which might be able to counterbalance its poor solubility and permeability [9]. Additionally, several PROTACs targeting prostate cancer have entered clinical studies, including ARV-110, a further orally available PROTAC [12].

A very promising technology in the formulation of poorly soluble compounds and an opportunity for bRo5-classified PROTACs is the design of amorphous solid dispersion (ASD). ASD is composed of one or more Active Pharmaceutical Ingredients (APIs) in their amorphous forms, as well as one or more auxiliary materials, mostly polymers, that stabilize this high-energy state in a polymeric matrix. To obtain an amorphous state, the crystalline lattice needs to be disrupted either through melting or dissolving of the API. Spray drying is often used as a solvent-based technology to generate ASDs [13]. For the respective stabilizing matrix, formulators can choose from a vast variety of polymers that are mostly co-soluble with the API in a single organic solvent [14]. This set-up requires a two-fluid nozzle, where one channel forwards the organic feed containing the API and polymer, and the other forwards the spraying gas. In our previous work, we investigated the applicability of hydrophilic polymers, which require the use of a three-fluid nozzle as the API and polymer demand an individual solvent. An additional channel is present in the nozzle, which can forward the hydrophilic polymer dissolved in an aqueous liquid [15].

In this work, we follow up on our previous findings where we investigated PVA with a 30% w/w drug loading with small-molecule drugs from the BSC Classes II and IV to evaluate if our described protocol can be utilized for large and challenging structures, such as PROTACs [16]. Additionally, we follow up on experiments undertaken by Hofmann et al. In their research, they show the applicability of spray drying PROTACs and polymers to generate ASD containing the PROTAC MS4075 with Soluplus and E PO [17]. As a first step, they performed a polymer screening using a solvent-based 96 well plate set-up, which included the use of two PVA grades, PVA 4-88 and PVA 3-82. Both achieved high dissolution values in the screening but were not further investigated in spray drying, which might be due to the lack of three-fluid nozzle equipment. Here, we show the solubility enhancement of two PROTACs, the crystalline Arvinas 110 (ARV-110) and amorphous SelDeg51, using PVA 3-82 in a three-fluid nozzle spray drying set-up.

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Materials

Poly(vinyl alcohol) 3-82 (Parteck® MXP 3-82, EMPROVE® ESSENTIAL, Merck KGaA, Darmstadt, Germany), Bavdegalutamide (ARV-110) (MedChemExpress, Monmouth Junction, NJ, USA), SelDeg51 (TU Darmstadt, Darmstadt, Germany), acetonitrile (Sigma Aldrich, Taufkirchen, Germany), dimethylsulfoxide (Sigma Aldrich, Taufkirchen, Germany), ethanol (Sigma Aldrich, Taufkirchen, Germany), formic acid (Sigma Aldrich, Taufkirchen, Germany), methanol (Sigma Aldrich, Taufkirchen, Germany), phosphate buffer (pH 6.8) (protocol by USP), fasted-state simulated intestinal fluid and simulated gastric fluid (Biorelevant, London, UK) and Milli-Q® Water (Merck Millipore, Burlington, MA, USA).

Mareczek, L.; Mueller, L.K.; Halstenberg, L.; Geiger, T.M.; Walz, M.; Zheng, M.; Hausch, F. Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras. Pharmaceutics 2024, 16, 924. https://doi.org/10.3390/pharmaceutics16070924

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