Multiple Linear Regression Modeling To Predict the Stability of Polymer-Drug Solid Dispersions: Comparison of the Effects of Polymers and Manufacturing Methods on Solid Dispersion Stability.

Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray-drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 °C and 75% relative humidity (RH). Significant differences in times to crystallization (onset of crystallization) were observed between both the different polymers and the two processing methods. Stability from zero days to over one year was observed. The extensive experimental data set obtained from this stability study was used to build multiple linear regression models to correlate physicochemical properties of the active pharmaceutical ingredients (API) with the stability data. The purpose of these models is to indicate which combination of processing method and polymer carrier is most likely to give a stable solid dispersion. Six quantitative mathematical multiple linear regression-based models were produced based on selection of the most influential independent physical and chemical parameters from a set of 33 possible factors, one model for each combination of polymer and processing method, with good predictability of stability. Three general rules are proposed from these models for the formulation development of suitably stable solid dispersions. Namely, increased stability is correlated with increased glass transition temperature ( Tg) of solid dispersions, as well as decreased number of H-bond donors and increased molecular flexibility (such as rotatable bonds and ring count) of the drug molecule.

Support Tools in Formulation Development for Poorly Soluble Drugs.

The need for solubility enhancement through formulation is a well-known but still problematic issue because of the numbers of poorly water-soluble drugs in development. There are several possible routes that can be taken to increase the bioavailability of drugs intended for immediate-release oral formulation. The best formulation strategy for any given drug will depend on numerous factors, including required dose, shelf life, manufacturability, and the properties of the active pharmaceutical ingredient (API). Choosing an optimal formulation and manufacturing route for a new API is therefore not a straightforward process. Currently, there are several approaches that are used in the pharmaceutical industry to select the best formulation strategy. These differ in complexity and efficiency, but most try to predict which route will best suit the API based on selected molecular parameters such as molecular weight, lipophilicity (logP), and solubility. These methods range from using no tools, trial and error methods through a variety of complex tools from small in vitro or in vivo experiments or high throughput screening, guidance maps, and decision trees to the most complex methods based on computational modelling tools. This review aims to list available support tools and explain how they are used.

Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1ß.

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1ß has not been established in TAI. An IL-1ß-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n = 41) were compared with sham-injured controls (n = 20) and untreated, naive mice (n = 9). The anti-IL-1ß antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30 µg/brain tissue) at 24 h post-injury in both cFPI (n = 5) and sham-injured (n = 3) mice, with lower concentrations at 72 h post-injury (up to ~18 µg/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9 days post-injury, and the Morris water maze (MWM) at 14-21 days post-injury. Following TAI, the IL-1ß-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1ß-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1ß is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.