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Laser scanning confocal microscopy combined with fluorescence recovery after photobleaching is an effective tool to measure the diffusion coefficients of macromolecules in cross-linked hydrogels and polymer solutions. In this study, the effects of enzyme treatment on the diffusion of macromolecules (FITC-dextran) in guar solutions and titanium-guar hydrogels are examined. Enzyme treatment with β-mannanase, a polymer backbone cleaving enzyme, quickly increases the diffusion coefficient of the probe molecules in both solutions and hydrogels to that in water. Enzyme treatment of guar solutions and hydrogels with α-galactosidase, a side chain cleaving enzyme, displays a unique behavior due to changes in the fine structure of guar. The removal of galactose branches from the mannan backbone of guar creates additional hyperentanglements (i.e., cross-links), which reduce the water holding capacity of guar and induce syneresis. If the depth at which the diffusion coefficient is measured remains constant, a minimum is observed in the diffusion coefficient as α-galactosidase enzyme treatment time increases. At the site of measurement, the sample changes from a homogeneous guar system to a phase-separated polymer-rich hydrogel and finally to a dilute polymer phase as the polymer-rich hydrogel phase precipitates below the site of measurement. The diffusion coefficient in the dilute polymer phase increases to that in water, while the diffusion coefficient in the hydrogel phase continues to decrease to a value of approximately 6 × 10-8 cm2/s.

Processing procedures for inducing domain size reduction and/or amorphous phase generation can be crucial for enhancing the bioavailability of active pharmaceutical ingredients (APIs). It is important to quantify these reduced coherence phases and to detect and characterize associated structural changes, to ensure that no deleterious effects on safety, function, or stability occur. Here, X-ray powder diffraction (XRPD), total scattering pair distribution function (TSPDF) analysis, and solid-state nuclear magnetic resonance spectroscopy (SSNMR) have been performed on samples of GSK2838232B, an investigational drug for the treatment of human immunodeficiency virus (HIV). Preparations were obtained through different mechanical treatments resulting in varying extents of domain size reduction and amorphous phase generation. Completely amorphous formulations could be prepared by milling and microfluidic injection processes. Microfluidic injection was shown to result in a different local structure due to dispersion with dichloromethane (DCM). Implications of combined TSPDF and SSNMR studies to characterize molecular compounds are also discussed, in particular, the possibility to obtain a thorough structural understanding of disordered samples from different processes.

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This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose‐escalation studies in healthy subjects which assessed single oral doses (5‐250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug‐related AEs. GSK2838232 tested fasted was quickly absorbed with a t max of 2‐3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and C max. Overall, following single doses GSK2838232 AUC and C max generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20‐200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and C max by 10‐ and 3‐fold, respectively. Half‐life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat‐dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once‐daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.

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