(W0930-03-21) Dispersome^® a Viable Alternative toward Enhanced Drug Load and Bioavailability

Purpose: Amorphous solid dispersions (ASDs) of poorly water soluble active pharmaceutical ingredients (APIs) in hydrophilic polymeric matrices are a commonly used strategy to increase the solubility and dissolution rate of oral-dosage forms [1]. To successfully formulate a growing solubility-impaired pipeline of APIs (i.e. more than 75% of the development pipeline are poorly soluble), recent research efforts on this field have been focused on expanding the toolbox with natural carriers with the ability of physically stabilizing amorphous APIs for ASD formulation while boosting dissolution performance [2,3]. β-lactoglobulin (BLG) from whey protein – widely known as Dispersome^® technology - is a particularly interesting ASD carrier due to the ability of stabilizing amorphous APIs, as well as increasing dissolution performance at high loadings [4]. Molecular dynamics indicate that stabilization mechanisms are API-load related with hydrogen-bond networks beyond the first API layer allowing to reach promising stability above 40% drug loads due to reduced molecular mobility [4]. This work focuses on 3 fundamental aspects to obtain optimal ASD formulations: i) the use of BLG protein (Dispersome^®) as an alternative excipient to broad the formulation design-space, ii) produce high drug load ASD formulations with improved dissolution performance, iii) understand the impact of API properties on formulation outputs.

Methods: Spray dried formulations were obtained using a customized lab-scale Spray-Drying unit. Post-drying of the spray dried powders was performed using vacuum tray ovens until residual solvent levels were below ICH limit by gas chromatography. ASDs were produced with four poorly soluble APIs with different chemical properties and consequently different protonation profiles across gastrointestinal pH (Figure 1). BLG and HPMC AS (benchmark) were used as ASD carriers with drug loads ranging from 50 to 70 %. ASDs were physically characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Biorelevant dissolution (FaSSGF-FaSSIF, pH shift approach, USP II apparatus) was conducted to the different produced ASD prototypes.

Results: ASDs were prepared with four different APIs with drug load (DL) ranging from 50% to 70% by spray-drying. XRPD analyses indicated that all ASDs produced with both Dispersome^® and HPMC AS were fully amorphous. DSC results showed similar or higher glass transition temperatures (Tgs) for ASD prototypes produced with BLG as a result of BLG higher Tg in comparison with benchmark polymer (240ºC vs 120°C, respectively). Biorelevant dissolution results showed higher in vitro area under the curve (AUC) for BLG prototypes with APIs 1 and 2 (week acid APIs) and similar/lower performance with API 3 (week base) and API 4 (neutral), respectively. BLG is not an enteric carrier unlike HPMC AS and therefore, for weak bases, such as API 3, higher API release observed in gastric media may be an advantage for APIs absorbed in the duodenum / proximal regions of the intestine. The improvement of dissolution performance for API 1 and 2 might be related to stronger hydrogen-bond networks between these 2 APIs and BLG, stabilizing these ASDs to drug load fractions up 70 % [4]. These interactions are being further characterized by spectroscopic characterization, as an ongoing work.

Conclusion: ASDs are an established solubility enhancement platform for poorly soluble drugs. BLG, which is obtained naturally and in a sustainable way, showed to be a viable carrier to significantly increase drug load, Tg and bioavailability of ASDs, especially with weekly acid drugs. As depicted in this work, BLG accommodates API molecular variability expanding the current formulation design-space typically applicable to gold standard polymers (PVP-VA, HPMC AS). This Dispesorme ® platform is being successfully used at Hovione as part of a high-throughput screening platform (AD-HIPROS) to maximize the probability of ASD success and accelerate first-in-human. As ongoing work, molecular interactions, batch-to-batch consistency, and the impact of BLG purity in dissolution performance is being studied. Moreover, formulation robustness studies will be conducted to understand the drug load edge of failure comparing to benchmark polymers.

References: 1.Schittny, A., Huwyler, J. & Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Deliv. 27, 110–127 (2020).
2. Tambe, S., Jain, D., Meruva, S.K., et al. Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization. Pharmaceutics 14, 2203 (2022).
3. Bennett-Lenane, H., O’Shea, J. P., O’Driscoll, C. M. & Griffin, B. T. A Retrospective Biopharmaceutical Analysis of >800 Approved Oral Drug Products: Are Drug Properties of Solid Dispersions and Lipid-Based Formulations Distinctive? J. Pharm. Sci. 109, 3248–3261 (2020).
4. Kebedev, A.,Donglei, L., Foderà, V. et al. Stabilizing mechanisms of β-lactoglobulin in Amorphous Solid Dispersions of Indomethacin. Mol. Pharmaceutics. 19(11), 3922-3933 (2022).

Figure 1: Protonation plot API 1 and 2 (week acids); API 3 (week base) and API 4 (neutral).

Figure 2 – Biorelevant dissolution of ASD formulated with 4 APIs with BLG and benchmark polymer HPMC AS.