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Keywords = pharmacobezoars

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15 pages, 3761 KiB  
Article
Evaluation of Pharmacobezoar Formation from Suspensions of Spray-Dried Amorphous Solid Dispersions: An MRI Study in Rats
by Hannes Gierke, Susan Mouchantat, Sabine Berg, Michael Grimm, Stefan Hadlich, Marie-Luise Kromrey, Thomas Nolte, Teresa Pfrommer, Vincent Rönnpagel, Adrian Rump, Kerstin Schaefer, Ann-Cathrin Willmann and Werner Weitschies
Pharmaceutics 2023, 15(3), 887; https://doi.org/10.3390/pharmaceutics15030887 - 9 Mar 2023
Cited by 1 | Viewed by 2154
Abstract
Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms [...] Read more.
Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)
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14 pages, 3094 KiB  
Article
An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars
by Hannes Gierke, Kerstin Schaefer, Lukas Gerlich, Ann-Cathrin Willmann, Verena Bialetzki, Georg Boeck, Teresa Pfrommer, Thomas Nolte and Werner Weitschies
Pharmaceutics 2022, 14(12), 2608; https://doi.org/10.3390/pharmaceutics14122608 - 26 Nov 2022
Cited by 2 | Viewed by 1841
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)
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