(T1530-08-53) ASD Formulation to Unit Dosage Form: Integrated Drug Product Development with Dispersome

Purpose: Amorphous solid dispersions are a well consolidated technology to increase drug solubility, prompted by an ever-growing pipeline of new poorly soluble APIs [1-2]. ASDs are typically formulated with hydrophilic polymeric excipients [1]; however, recent efforts have been placed in identifying natural and more sustainable carriers which maintain manufacturability and address the solubility challenges particularly for high dose formulations. These formulations often require frequent dosing or large sized tablets, affecting patient compliance. β-lactoglobulin from whey protein (BLG) is a natural based excipient, which has been demonstrated to form stable ASDs, as well as increase dissolution performance at high drug loads [3]. This work focuses on the end-to-end product development strategy comprising formulation screening, spray drying process development and drug product development, using BLG as an alternative SDD carrier. Case-studies for BLG-based ASD formulations, from spray drying to tablet are presented.

Methods: In silico formulation screening for benchmark polymers selection was performed using computational models implemented in Python. Spray drying process development was performed in custom-made lab scale spray dryers, either equipped with two-fluid or pressure nozzle. Post drying of the spray dried powders was performed in a tray oven, using vacuum and temperature, until residual solvent content was below ICH limits. After blending, tablets were manufactured using compaction simulation, after slugging at a single solid fraction (0.60), and milling in a Frewitt unit equipped with an oscillating mill head. Compaction curves were established to compare the BLG-based SDDs with standard polymer SDDs.

Results: ASDs were prepared with two different model active drugs at 50% w/w drug load (DL): Ritonavir and Olaparib, a DCS II and a DCS IV compounds, respectively. PVP-VA 64 was selected as benchmark for Ritonavir and HPMCAS-L for Olaparib (based on Tg and thermodynamic miscibility, minimizing the risk for physical stability). Figure 1 shows the two-stage biorelevant dissolution profile obtained for spray dried dispersions (SDDs) made with BLG vs. the golden standard polymers. For Olaparib, BLG presented a higher amount of API dissolved in gastric media, which is maintained after pH shift and throughout at least 120 min. For Ritonavir, BLG allowed to increase C_max from 10% to 90% in fasted-state gastric media (FaSSGF), as well as from 10 to 30% in fasted-stated simulated intestinal media (FaSSIF) performing better than the benchmark. After proving the formulation advantage of BLG, the scalability of the technology was explored. Thus, the spray drying process design space was explored for the OLA-BLG formulation by varying outlet temperature (below T_denaturation = 70 ºC) and feed flow rate (up to 6 kg/h). No impact on the dissolution profile of Olaparib (up to 90% API dissolved) within the studied process parameters range. The feed solution was chemically stable for at least 14 days, and the wet material (prior to post-drying) was chemically and physically stable for at least 28 days. The resulting Olaparib-BLG SDD was also thermally stressed to evaluate product degradation rate, with no signs of physical or chemical degradation for at least 7 days at 60 ºC, under high relative saturation conditions. The processability of the BLG-based SDDs into tablets was compared with standard polymers by formulating them with standard tablet excipients (i.e. MCC/lactose-based). Ritonavir and Olaparib-based ASDs were blended with excipients at 50% SDD load. Adequate tabletability (2.0 MPa at 100 MPa for RIT and 200 MPa for OLA) and compactability (TS ≥ 2.0 MPa at SF = 0.85) and compressibility (SF > 0.75 at 100 MPa) for tablets of both ASDs, indicating that linearity is obtained up to 5 MPa for Ritonavir and up to 3 MPa for Olaparib (Figure 2). Low risk is foreseen for BLG-based SDDs are at typical Korsch XL100 (45 RPM) and Fette 1090i compression speeds (60 RPM) with no tablets and low friability (below 1.0%) / disintegration times for immediate release tablets (less than 10 min at SF~0.90).

Conclusion: The Dispersome® technology has previously been showcased as an alternative formulation platform for physical stability and performance increase at higher drug loads than conventional carriers. This work shows that these formulations are scalable beyond lab-scale manufacturing. In turn, it demonstrates the industrial viability of the technology, end-to-end, from screening / early-stage development to scale-up suitability considering the integration of spray drying and tableting processes. The spray drying design space was explored with stable dissolution performance for the model APIs tested while the processability of blends with up to 50% of BLG-based SDD load was also demonstrated. Particularly relevant for high dosage APIs, formulations with BLG have the potential to decrease pill burden and increase patient compliance with demonstrated manufacturability combining spray drying and tableting. (Dispersome® is a trademark of Zerion Pharma A/S, Denmark)

References: 1. Nunes, P. D. et al., Mol. Pharm., 2022, 19, 51–66.
2. Mosenson D.E. et al., Int. J. Pharm., 2024, In press (7).
3. Kebedev, A. et. al., Mol. Pharm. 19(11), 2022, 3922-3933.

Figure 1 - Biorelevant dissolution curves for Olaparib (OLA) and Ritonavir (RTV) against benchmark carriers.

Figure 2 - Compactability, compressibility and tabletability curves for Olaparib (OLA) and Ritonavir (RIT) BLG-SDD tablets (data generated for Fette 1090i simulated at 30 and 60 rpm, respectively, for OLA and RIT).