(T1130-01-05) Recent Advances in ASD Formulations: HIPROS and Dispersome

Purpose: 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. Recent research efforts on this field have focused on improving screening methodologies, bioavailability, drug loads and the search for alternate carriers. This work focuses on two aspects to obtain optimal formulations: high throughput screening and the use of a natural carrier (BLG protein - Dispersome) for ASD formulations. A description of the requirements and outputs of a HTS formulation is given, as well as the improvements obtained in specific ASD formulations obtained with Dispersome.

Methods: Spray dried formulations were obtained using a Buchi B290, Buchi, and a customized lab-scale 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. Computational methods were implemented in Python.

Results: Traditional screening of ASD formulations either requires the use of proxy methods such as solvent casting, with significant physical and performance differences to spray dried material, or extensive testing in laboratory spray drying equipment, which is time and material consuming. Given the large number of variables in optimizing an ASD formulation (drug load, polymer, surfactant), the number of prototypes to be tested must be reduced. In our high throughput screening platform (HTS) the first step consists in a computation screening phase based on the Flory-Huggins equation coupled with a drying kinetics and particle formation model. This stage allows the elimination of prototypes that have a high probability of failing and therefore will focus all development efforts on prototypes that are likely viable. The production of prototypes is done using a custom-built high throughput spray dryer and submitted to a streamlined analytical characterization package that includes physical stability and performance. Up to 24 prototypes can be produced and characterized in a limited timeframe. The number of tested prototypes and the fact that actual spray dried material is produced greatly ensures that an optimal formulation is obtained without compromises. This technique coupled with the Dispersome technology further allows the screening of innovative formulations with improved drug loading. This technology relies on the use of spray dried dispersions with BLG protein (by-product from cheese production, widely used for food applications). The use of this natural occurring polymer has been shown to improve the solubility performance of BCS class II drugs both in-vitro and in-vivo, but also the possibility of increasing drug loads ( >50% for indomethacin) of existing ASD formulations. The increase in drug load contributes to improved performance and patient compliance through reduction of tablet burden.

Conclusion: ASDs have become an established platform for BCS class 2 drugs. The use of computational methods coupled with high throughput screening in a streamlined platform, HIPROS, can significantly improve the ASD screening step and reduce development time and effort. Coupled with innovative formulation technologies such as Dispersome, improved formulations (higher performance and drug load) can be developed with minimum time and reduced risk. BLG was demonstrated as a viable carrier for ASDs with the potential to significantly increase both drug loadings and bioavailability.

Output of Flory-Huggins application to ASD screening



Illustration of the integration of Flory-Huggins with kinetic model



Relevance of SD attributes for dissolution performance