(T0930-03-16) Natural-Based ASD Platforms: Enhancing Stability and Bioavailability

Purpose: Nearly 70% of molecules in the discovery pipeline and about 40% of active pharmaceutical ingredients (API) in the market are poorly water soluble1,2. To address this, recent research has shifted towards the development of more sustainable, excipients (EXC) for the creation of amorphous solid dispersions (ASD). This serves as an alternative to conventional golden standard polymers (i.e. cellulose-based, polyvinylpyrrolidone (PVP)-based), leveraging on their ability to stabilize the amorphous active pharmaceutical ingredients (API) while improving bioavailability to widen the ASD formulation design space2,3,4. Aligned with that trend, this work explores new excipients among naturally derived compounds (e.g. proteins, polysaccharides, other natural polymers) for oral ASD formulation, , through small scale prototyping via melt quenching (MQ) and spray drying (SD). These new excipient-based formulations were tested for their ability to prevent API recrystallization and sustain API supersaturation with impact on in vitro dissolution performance at high drug loads.

Methods: Literature search to identify new excipients was performed with emphasis on relevant features for ASD formulation (e.g. solubility in aqueous solutions/organic solvents, relevant molecular features, glass transition temperature, and sustainability). Preliminary formulation screening of new excipient matrices was conducted by melt quenching (MQ) using differential scanning calorimetry (DSC). SD prototyping of natural-based ASD formulations was conducted using a Buchi B290 (Buchi, CH). Spray dried intermediates underwent a 24h post-drying process using a vacuum tray oven, followed by Karl Fisher (KF) characterization and gas chromatography (GC) analysis to ensure low water content and residual solvent levels below ICH limits. SD prototypes were compared with preliminary MQ results regarding their thermal transitions (e.g. glass transition (Tg) and melting temperatures (Tm)) and their molecular arrangement was studied by x-ray powder diffraction (XRPD). Furthermore, two-stage biorelevant dissolution (pH shift approach from fasted state simulated gastric fluid (FaSSGF, pH = 1.6) to fasted state simulated intestinal fluid (FaSSIF, pH = 6.5) media) were conducted using a USP II dissolution apparatus (Copley Scientific, UK).

Results: Prior to the screening phase, an extensive literature search was performed to create a database comprising over 100 new natural-based alternative excipients and to narrow down the number of excipients to test in vitro. From this database, 15 alternative excipients were selected to be tested with a poorly soluble – DCS class IIb API, in terms of physical stability and bioavailability against benchmark polymers identified using Hovione’s in silico models. Small scale prototyping via MQ at 50% API drug load allowed for a rapid assessment of miscibility and glass transition temperature increase (Tg) of the formulations, having EXC 1, 4, 7, 13, and 15 attained a Tg increase higher than 35ºC in relation to the API alone, thus reducing the risk for API recrystallization and improving shelf-life stability. Based on these findings, SD prototypes at the same API load were produced with EXC 1, 2, 3, 4, 5 and 6, with yields higher than 78% for all formulations. XRPD analysis indicated that SD prototypes with EXC 1, 3 and 4 were amorphous at 50% drug load. Moreover, DSC data showed that EXC 1, 3, and 4 based SD formulations prevented API recrystallization (see Table 1). Biorelevant dissolution data demonstrated that EXC 1 and 3 significantly increased API dissolution performance by 31 and 71% (expressed in area-under-curve), respectively, when compared to the API alone (see Figure 1). In vitro dissolution data generated with different media composition will be compared for a deeper understanding of the excipient properties’ influence on drug product performance when natural-based excipients are used.

Conclusion: This study allowed for the rapid screening and SD prototyping of ASD formulations using new excipients, yielding promising data regarding excipient:API compatibility at high drug loads (the proof-of-concept with DCS class IIb APIs). Herein, five formulations demonstrated to have superior stability compared to non-formulated API, attaining an increase in Tg exceeding 35ºC. Furthermore, biorelevant dissolution data demonstrated that EXC 1 and 3 significantly increased API availability when compared to API alone, with EXC 3-based SDD showing enhanced dissolution under fasted state simulated gastric fluid (FaSSGF). By tailoring biorelevant dissolution media compositions, this research will foster a deeper comprehension on the excipient’s influence on drug product intermediate performance, thus contributing for more rational and robust development and design of ASD formulations with APIs beyond the current technology fit space. Moreover, the exploration of these excipients not only presents opportunities for life cycle management of currently marketed ASDs but also for the formulation of new chemical entities.

References: 1. Nunes, P. D. et al., Mol. Pharm., 2022, 19, 51–66.
2. Pas, T. et al., Int. J. Pharm., 2018, 535, 47–58.
3. Xie, T. et al., J. Pharm. Sci., 2017, 106, 100–110.
4. Shah, B. et al., AAPS PharmSciTech., 2022, 113, 19-23

Acknowledgements: This work was funded by Hovione under the doctoral fellowship PBDL/BDE/18


Figure 1 – Area under the curve for natural-based amorphous solid dispersions (ASDs) formulations produced via spray drying (SD) tested using a two-step biorelevant dissolution (FaSSGF and FaSSIF) in an USP II dissolution apparatus.


Table 1 – DSC data regarding the glass transition temperatures obtained for amorphous solid dispersions (ASD) produced via melt quenching (MQ) and spray drying (SD); XRPD data regarding the molecular arrangement of the spray dried dispersions (SDD) formulations.