(M1230-02-07) Dispersome® as an Advanced Platform for Oral Bioenhancement

Purpose: By incorporating poorly water-soluble active compounds into hydrophilic polymeric matrices, amorphous solid dispersions (ASDs) stand as a pivotal strategy to increase solubility and dissolution rates [1]. Up to 40% of commercialized drug products, along with 70-90% of drug candidates in development, suffer from poor solubility [2]. This results in diminished bioavailability, reduced therapeutic effects, and the necessity for dosage escalation. Additionally, the poor oral bioavailability of certain nutraceutical compounds renowned for their benefits is also a well-recognized challenge, significantly hampering their efficacy as health promoters [3]. Recent research has been focused on broadening the ASD formulation portfolio with natural carriers capable of physically stabilizing amorphous active compounds for ASD formulations and enhancing dissolution performance [4,5]. Dispersome®, a β-lactoglobulin (BLG) derived from whey protein, emerges as a particularly compelling ASD carrier due to its dual capacity, even at high drug loadings, of stabilizing amorphous active compounds while significantly improving dissolution performance [6]. The Dispersome® technology can be applied at any stage of the drug development cycle, including preclinical toxicology studies, first-in-human, replacement of existing drug formulations that present suboptimal bioavailability and/or dosage regimen, and life cycle management (LCM) of off-patent drugs. This versatility, coupled with the bioenhancement potential, positions Dispersome® as a differentiating platform applicable across the pharmaceutical and nutraceutical sectors. The value of Dispersome® as an oral bioenhancement platform is demonstrated herein through case studies.

Methods: ASDs were produced with two poorly soluble and permeable compounds – one nutraceutical (compound A) and one active pharmaceutical drug (compound B). For compound A, BLG was used as ASD carrier at 25 and 50% drug load. A commercial reference of Compound A served as the benchmark. For Compound B, BLG and HPMC-AS (benchmark) were used as ASD carriers at drug load of 50% to establish the advantage of replacing the gold standard polymer for LCM. Spray dried formulations were obtained using a customized lab-scale Spray-Drying unit. Post-drying of the spray dried powders was performed using a vacuum tray. Biorelevant dissolution testing (two-stage, pH shift approach from Fasted State Simulated Gastric Fluid - Fasted State Simulated Intestinal Fluid) was conducted to the different ASD prototypes and respective benchmarks. The Compound B spray-dried dispersions were then filled into capsules with disintegrant and submitted to a bioavailability study in beagles at the market target dose.

Results: Biorelevant dissolution results showed higher in vitro area under the curve (AUC) for BLG prototypes with Compound A and B, when comparing to the corresponding benchmark materials (Figure 1A and B). The in vivo study conducted with Compound B revealed that the pharmacokinetic parameters obtained for the BLG formulation were improved when compared to the benchmark material, highlighting its potential for enhanced bioavailability. BLG formulation displayed faster absorption (lower T_max), higher maximum concentrations, and greater exposure compared to the

Conclusion: This work underscores the significant potential of Dispersome® as an advanced platform for the bioenhancement of oral amorphous solid dispersions, leveraging BLG as a natural bioenhancer. Integration of BLG into ASDs not only demonstrates remarkable improvements in stabilizing amorphous APIs at high drug loads and enhancing dissolution rates, but also in improving the bioavailability of poorly soluble compounds. Actually, the case study presented further demonstrates an increase in the bioavailability of BLG formulation, surpassing the benchmark material. Ongoing research efforts, focusing on further understanding molecular interactions, evaluating BLG batch-to-batch consistency in final drug product intermediate performance, and refining formulation strategies, aim to fully exploit the potential of Dispersome®-based formulations. As a promising approach for overcoming bioavailability limitations and advancing drug delivery, Dispersome® holds promise for accelerating the development of effective pharmaceutical and nutraceutical products.

References: 1. Schittny, A., Huwyler, J., & Puchkov, M. (2020). Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery, 27, 110–127.
2. Kumari, L., Choudhari, Y., Patel, P., et al. (2023). Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Life (Basel), 13(5), 1099
3. Puri, V., Nagpal, M., Singh, I., et al. (2022). A Comprehensive Review on Nutraceuticals: Therapy Support and Formulation Challenges. Nutrients, 14(21), 4637.
4. Tambe, S., Jain, D., Meruva, S. K., et al. (2022). Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization. Pharmaceutics, 14, 2203.
5. Bennett-Lenane, H., O’Shea, J. P., O’Driscoll, C. M., et al. (2020). A Retrospective Biopharmaceutical Analysis of >800 Approved Oral Drug Products: Are Drug Properties of Solid Dispersions and Lipid-Based Formulations Distinctive? Journal of Pharmaceutical Sciences, 109, 3248–3261.
6. Kebedev, A., Donglei, L., Foderà, V., et al. (2022). Stabilizing mechanisms of β-lactoglobulin in Amorphous Solid Dispersions of Indomethacin. Molecular Pharmaceutics, 19(11), 3922–3933.


Figure 1. Biorelevant dissolution of ASD formulated with Compound A and B and BLG, and respective benchmarks. pH shift from fasted stated gastric to intestinal fluid is conducted at timepoint 30 min.