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. 2022 Nov 26;14(12):2608.
doi: 10.3390/pharmaceutics14122608.

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

Hannes Gierke  1 , Kerstin Schaefer  2 , Lukas Gerlich  1 , Ann-Cathrin Willmann  2 , Verena Bialetzki  2 , Georg Boeck  3 , Teresa Pfrommer  2 , Thomas Nolte  2 , Werner Weitschies  1
Affiliations

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

Hannes Gierke et al. Pharmaceutics. .

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.

Keywords: in vitro model; pharmacobezoars; preclinical testing; rodent stomach; spray dried amorphous solid dispersions.

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Conflict of interest statement

Kerstin Schaefer, Thomas Nolte, Georg Boeck, Ann-Cathrin Willmann, Verena Bialetzki and Teresa Pfrommer are at the time of submission employees at Boehringer Ingelheim Pharma GmbH & Co. KG. The authors declare no conflict of interest. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic illustration of the rat stomach’s anatomy (1—cardia; 2—nonglandular stomach; 3—limiting ridge; 4—glandular stomach; 5—pylorus).
Figure 2
Figure 2
Schematic top view on the in vitro model.
Figure 3
Figure 3
Schematic top view on the in vitro model (top). Cross section of the in vitro model with one unit displayed (below). (1—movement transmission bar; 2—disk; 3—spring; 4—spindle; 5—scale; 6—connector; 7—plunger endcaps; 8—recesses for syringe plungers; 9—retainer bar; 10—holder bars; 11—syringe plunger; 12—U-rail; 13—cavity of the syringe cylinder; 14—media reservoir).
Figure 4
Figure 4
Volume in the syringe cavities over time.
Figure 5
Figure 5
Graphical illustration of dosing procedure 1—transferring suspensions to syringe; 2—placing syringe in the in vitro model; 3—repeating daily dosing procedure (steps 1 and 2) including completion of the volume pattern until agglomerate formation is completed and agglomerates can be extracted by cutting the syringe cylinder with a scalpel.
Figure 6
Figure 6
Agglomerate of formulation 1 in the opened syringe cylinder (top) and following drying on a microscopic slide (below).
Figure 7
Figure 7
Volume pattern with marked photo and scotophase (left) and one hour kinetics of emptying derived from in vivo data [16,20,21,22] (right).
Figure 8
Figure 8
Top view on two units in the in vitro model—completion of agglomerate formation in the right syringes is indicated by the compression of the spring (indicated by green cycle).
Figure 9
Figure 9
In vitro agglomerated masses per day of formulation 1 (yellow) and formulation 2 (blue) from suspensions without (n = 9), with 0.5% and 1% (w/w) hydroxyethyl cellulose (HEC) added to the vehicle as viscosity-enhancer (both n = 3).
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