(T1230-12-79) P188 – Polymeric Carrier for Solid Dispersion Enabling Formulations of PROTACs

Purpose: The group of proteolysis targeting chimeras (PROTACs) comprises of large molecules, that act as degraders by engaging with the proteasome-ubiquitin system. Due to their hydrophobicity and size, solubility of these molecules is limited in biorelevant media, which may pose a challenge in formulation development¹. Therefore, solubility enhancing formulations of PROTACs are essential for future oral administration. In the present work, poloxamer P188 was evaluated as a solid dispersion carrier for several PROTACs. Based on screening results, a film formulation as enabling formulation of a model PROTAC was developed.

Methods: MS4078², ARV-110 and ARV-491 were purchased from medchemexpress.com (USA), compound 11³ from Pharmaron (China), Kolliphor P188 was obtained from BASF (Germany), SIAIS164018⁴ and the internal PROTAC were synthesized in-house. The miniaturized solvent-based screening and melt-based screening are described in detail elsewhere⁵. In brief, PROTAC-polymer solutions (10% (w/w) drug load) were prepared in a 96-well plate or alternatively DSC crucibles. The solvent was evaporated and for the melt-based approach, the resulting films were molten at 160°C using a DSC1 (Mettler Toledo, Germany). Fasted state simulated intestinal fluid pH 6.5 (FaSSIF) was added for a dissolution test. After 1 and 2 hours, samples were withdrawn and analyzed by liquid chromatography (UPLC, Aquity H-Class, Waters, Germany). MS4078-P188 films (10% (w/w) drug load) were prepared in a larger scale on aluminum foil by solvent evaporation (SE). For a SE-melting combination, part of the films was molten at 160°C in a vacuum oven (film_molten; Vacutherm, Thermo Scientific, USA). The films were cooled to -80°C and milled in two cycles at 15 Hz for 3 min using a Pulverisette 23 (Fritsch, Germany). In addition, a physical mixture was prepared by mixing the polymer and the API (active pharmaceutical ingredient) using a mortar and pestle. A small-scale non-sink dissolution assay of 400 µg/mL compound in 37°C FaSSIF was conducted: At defined time points, samples were centrifuged and 50 µL of supernatant were withdrawn for UPLC analysis.

Results: In the solvent-based screening, several PROTACs showed supersaturation from the P188 films containing 10% drug load compared to a reference film of pure API (Figure 1). Interestingly, a test of MS4078 in a melt-based approach provided a distinctive additional benefit. The manufacturing of a film prepared by solvent evaporation (fim_SE) on aluminum foil and a second one, which was additionally molten (film_molten), was feasible. Both films were milled prior to further experiments. The dissolution results of film_molten and film_SE compared to the physical mixture (PM-P) and the neat API are shown in Figure 2: The highest supersaturation, i.e. ~75fold the concentration of the neat compound, was provided by the molten film. In comparison, film_SE did not provide a stable supersaturation: After a maximum at the beginning, a decrease was observed and ~100 µg/mL were stabilized between 1 and 2 hours. From the physical mixture, however, a fast dissolution and stabilization of the dissolved drug was found. Nevertheless, PM-P only provided a ~10fold supersaturation compared to pure MS4078.

Conclusion: P188 is a suitable carrier to provide supersaturation from binary solid dispersion formulations of several PROTACs. One model compound (MS4078) showed a significantly higher supersaturation after dissolution from a molten film. A solid dispersion formulation of P188 and 10% MS4078, manufactured by SE and afterwards melting, was developed, and confirmed the results from the screening experiment. However, different dissolution performances dependent on the manufacturing technique of the formulation (physical mixture, film obtained by SE or SE-melting combination) were observed: After an initial maximum, film_SE was not able to stabilize the supersaturation and the compound precipitated slowly, whereas film_molten provided the same high but also stable supersaturation over 2 hours. The supersaturation exhibited by the physical mixture, which most likely originates from the solubilizing effect of the polymer, was exceeded by both films. The difference in the initial API concentration between film formulations and physical mixture can be explained by the distribution of the API in the polymeric matrix: A finer distribution in the matrix facilitates the congruent dissolution of the hydrophilic P188 and dispersed API, whereas clusters could lead to destabilization⁶. However, the reason for the great discrepancy in supersaturation stabilization between the two film formulations is still to be investigated. Possible explanations could be differences in interaction between the polymer and the API caused by the different preparation techniques – solution vs. heat. Additionally, the API might form less clusters in the matrix when a second amorphization step like melting is included after the solvent evaporation process.

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Figure 1. Dissolution results of different PROTAC reference films (100%, "API") and PROTAC-P188 films (10% drug load) from solvent-based ("P188") and melt-based screening ("P188molten").

Figure 2. Concentration of MS4078 after dissolution of the neat API, molten and unmolten P188-film and the physical mixture of P188 and MS4078 (10% drug load) in FaSSIF. (Mean ±SD (n=3)).