In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A

Abstract

In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation principles in mice are still lacking. The development of novel in vitro and in silico models supported the preclinical formulation evaluation for the anti-infective corallopyronin A (CorA). To this end, CorA and solubility-enhanced amorphous solid dispersion formulations, comprising povidone or copovidone, were evaluated regarding biorelevant solubilities and dissolution in mouse-specific media. As an acidic compound, CorA and CorA-ASD formulations showed decreased solubilities in mice when compared with human-specific media. In biorelevant biphasic dissolution experiments CorA-povidone showed a three-fold higher fraction partitioned into the organic phase of the biphasic dissolution, when compared with CorA-copovidone. Bioavailabilities determined by pharmacokinetic studies in BALB/c mice correlated with the biphasic dissolution prediction and resulted in a Level C in vitro–in vivo correlation. In vitro cell experiments excluded intestinal efflux by P-glycoprotein or breast cancer resistance protein. By incorporating in vitro results into a physiologically based pharmacokinetic model, the plasma concentrations of CorA-ASD formulations were predicted and identified dissolution as the limiting factor for bioavailability.

Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations

“…By using the mesoporous silica formulation, it was possible to achieve increased solubility values for CorA tested in biorelevant media (FaSSIF: 0.835 ± 0.002 mg/mL; FeSSIF: 0.615 ± 0.031 mg/mL) [ 13 ]. Furthermore, in vitro dissolution indicated a fast dissolution rate.…”

“…Data were analyzed using the Empower 3 software FR2, and quantified using an external reference standard. A solvent gradient was used comprising mobile phase A (acetonitrile/water 5/95 with 5 mM ammonium acetate and 40 μL acetic acid per liter) and mobile phase B (acetonitrile/water 95/5 with 5 mM ammonium acetate and 40 μL acetic acid per liter) with a gradient of 70% A/30% B to 20% A/80% B, added stepwise within 30 min at a flow rate of 0.3 mL/min [ 7 , 13 ]. For toxicokinetic analysis, the plasma concentrations of each dog were analyzed with the PK-Plus ® software (Simulations-Plus, Lancaster, CA, USA) using a non-compartmental model.…”

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

“…In addition to the investigation of biodistribution towards tissues, organ concentrations were assessed in further organs after PO administration. Although in this study only low bioavailability was seen after PO administration compared to the IP and SC routes, recent studies have shown and predicted good bioavailability using a povidone-based amorphous solid dispersion method, paving the way to deploy this formulation for additional efficacy studies [ 23 , 29 ]. Whereas high rectum and pharynx concentrations of CorA might be attributed to the administration route, it was surprising to find CorA in the vaginal tract tissue as well as in tibia.…”

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

“…However, it has been proven that in terms of increasing solubility and dissolution, formulating ASDs is not only beneficial for crystalline drugs but also for poorly soluble drugs of amorphous nature [ 17 , 18 ]. Numerous ASDs have been demonstrated to improve dissolution properties by generating an aqueous supersaturated solution of the drug and stabilizing this state for a sufficient time, causing an increase in the bioavailability [ 15 , 19 , 20 , 21 , 22 ].…”