An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars

Abstract

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions. To verify that the pharmacobezoar formation potential can be assessed based on the observed agglomeration potential, we conducted a sequence of experiments with two HPMC-AS-based SD-ASD formulations. In vitro, we found their different in vivo pharmacobezoar formation potential reflected by a significantly increased agglomerated mass of formulation 1 per day compared to formulation 2. In order to find an approach to reduce the agglomeration potential of solid dispersion from suspensions, we further applied the model to investigate the impact of the viscosity of the vehicle used to prepare suspensions on agglomerate formation.

Evaluation of Pharmacobezoar Formation from Suspensions of Spray-Dried Amorphous Solid Dispersions: An MRI Study in Rats

“…It consisted of 70% BI 1026706 incorporated in a HPMC-AS (Shin-Etsu AQOAT ® AS-LG, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) polymer matrix and was spray-dried from the methanolic solution. Physicochemical properties of the crystalline NCE and the administered spray-dried formulation were described previously [ 9 ].…”

“…The preparation of the suspensions followed the same procedure as the preparation of the suspensions for in vitro tests [ 9 ]. Briefly, the required mass of SD-ASD was weighed into a glass beaker and wetted by a small amount of the respective aqueous vehicle before the remaining amount of aqueous vehicle was added under constant stirring.…”

“…Based on the significant reduction of SD-ASD agglomeration potential by viscosity increasement of the vehicle in vitro [ 9 ], a priori sample size calculation for the main study was carried out estimating an effect size (Cohens d) of 1, alpha error 0.05 and power set at 0.8: …”

“…However, their potential to impair animal wellbeing was observed in cases when pharmacobezoars were expelled to the small intestines [ 4 ]. We could demonstrate in vitro that an increase in the viscosity of the vehicle used to suspend the SD-ASDs effectively reduced the agglomeration potential of two HPMC-AS-based SD-ASD formulations [ 9 ].…”