Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

Heat-induced formulation inhomogeneity of a three-component suspension.

A suspension formulation containing sarafloxacin HCl, triamcinolone acetonide, and clotrimazole was developed for the treatment of otitis externa in dogs. The potency for the three active ingredients in this suspension was monitored at 25 degrees C and 40 degrees C for up to 3 months. The potencies of triamcinolone and clotrimazole were found unchanged, but the potency of sarafloxacin HCl in the samples stored at 40 degrees C for 1 month varied significantly between samples. However, assay inconsistency for sarafloxacin HCl was not seen in samples stored at 25 degrees C. Under an optical microscope, large crystals were found in the 40 degrees C stability samples but not in the 25 degrees C samples. The large crystals in 40 degrees C samples were identified as sarafloxacin by high-performance liquid chromatography (HPLC). This finding suggests that crystal growth of sarafloxacin took place at 40 degrees C during storage, leading to the formation of larger crystals and the consequent sampling nonuniformity and assay inconsistency. The solid-state properties of these crystals were further evaluated using hot-stage microscopy and Fourier transform infrared (FTIR) analysis. The results indicate that the crystal growth of sarafloxacin was most likely attributed to a change in the hydration form of sarafloxacin.

Formulation and characterization of bupivacaine lipospheres.

Bupivacaine lipospheres were prepared as a parenteral sustained-release system for post-operative pain management. Bupivacaine free base was incorporated into micron-sized triglyceride solid particles coated with phospholipids, which were formed via a hot emulsification and cold resolidification process. The bupivacaine liposphere dispersions were characterized with respect to drug loading, particle-size distribution, and morphology. Gelation of the fluid liposphere dispersions was observed at different time intervals upon storage. The type of phospholipids used in the formulation was found to have a major impact on the gelation of the dispersion. The use of synthetic phospholipids instead of the natural phospholipids in the formulation yielded bupivacaine liposphere dispersions exhibiting prolonged gelation time. The addition of a hydrophilic cellulosic polymer can further improve the physical stability of the dispersion.