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

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 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.

Keywords: MRI study; pharmacobezoars; preclinical testing; rodent stomach; spray-dried amorphous solid dispersions; viscosity.

Figure 1

Study design—dose finding study.

Figure 2

Study design—main study.

Figure 3

Visualization of transversal plane (left) and schematic MRI scan of the stomach in this plane (right). 1—spine; 2—forestomach; 3—limiting ridge; 4—glandular stomach.

Figure 4

Schematic evaluation of the maximum diameter of a pharmacobezoar in forestomach. ROI: green circle; green horizontal line = maximum diameter.

Figure 5

Ex vivo opened rat stomach of a female rat without pharmacobezoar (left) and of a rat from group DF 1 with pharmacobezoar (right) (1—cardia, 2—major solid pharmacobezoar with small hole at the upper left side, 3—non-rigid SD-ASD particles, 4—limiting ridge, 5—pylorus).

Figure 6

Total mass of all pharmacobezoars observed per rat in the dose finding study (♀: female; ♂: male).

Figure 7

At scheduled necropsy opened rat stomach of a male rat of DF 1 with multiple small to medium-sized pharmacobezoars accompanying the encircled major pharmacobezoar.

Figure 8

Pre-dose MRI image and MRI images of pharmacobezoars marked by red arrows at day 8 and day 16 in the stomach of a female rat after dosing of 2400 mg/kg/day SD-ASD in non-viscosity-enhanced vehicle (T1-weighted, transversal). Pre-dose MRI (left); onset of pharmacobezoar formation on day 8 with typical crescent shape of pharmacobezoar in the forestomach (middle) and pharmacobezoars observed on day 16 in the forestomach obtaining broken edges plus a smaller pharmacobezoar in the glandular stomach (right).

Figure 9

Incidence of pharmacobezoars observed at MRI measurements on day 8, 16 and 24 of the main study in Group A (non-viscosity-enhanced vehicle) and Group B (high-viscous vehicle); both groups n = 14.

Figure 10

Mass of pharmacobezoars at necropsy after 24 days dosing of 2400 mg/kg/day BI 1026706 SD-ASD suspended in non-viscosity-enhanced vehicle (Group A) and high-viscous vehicle (Group B); mean values are indicated by horizontal line.