Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion.

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting.

AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution.

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.

Alternating current electrospinning for preparation of fibrous drug delivery systems.

Alternating current electrospinning (ACES) was compared to direct current electrospinning (DCES) for the preparation of drug-loaded nanofibrous mats. It is generally considered that DCES is the solely technique to produce nanofibers using the electrostatic force from polymer solutions, however, less studied and also capable ACES provides further advantages such as increased specific productivities. A poorly water-soluble drug (carvedilol) was incorporated into the fibers based on three different polymeric matrices (an acid-soluble terpolymer (Eudragit(®) E), a base-soluble copolymer (Eudragit(®) L 100-55) and a nonionic homopolymer (polyvinylpyrrolidone K90)) to improve the dissolution of the weak base drug under different pH conditions.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as P(eff), flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as Peff, flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB.

Prediction of blood-brain barrier penetration of poorly soluble drug candidates using surface activity profiling.

The aim of this study was to determine whether transepithelial transport across the blood-brain barrier (BBB) [expressed as the logarithm of blood/brain partitioning coefficient (logbb)] could be correlated to surface tension properties for a series of new chemical entities (NCEs) having extremely low solubility in aqueous media. Surface tension data were generated by the "Du Nouy maximum pull force method" using an automated, small volume Kibron Delta 8 Multi-channel tensiometer. Using the surface pressure/concentration profiles, parameters such as the maximum surface pressure, cross-sectional area and the air-water partitioning coefficient were calculated for the individual compounds and correlated with their in vivo logbb values.

Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability.

The Parallel Artificial Membrane Permeability Assay (PAMPA) has been successfully introduced into the pharmaceutical industry to allow useful predictions of passive oral absorption. Over the last 5 years, researchers have modified the PAMPA such that it can also evaluate passive blood-brain barrier (BBB) permeability. This paper compares the permeability of 19 structurally diverse, commercially available drugs assessed in four different PAMPA models: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (Double Sink) model, (3) a PAMPA-BBB model and (4) a PAMPA-BBB-UWL (unstirred water layer) model in order to find the most discriminating method for the prediction of BBB permeability.

In vivo, in vitro and in silico methods for small molecule transfer across the BBB.

The inability of molecules to permeate the BBB is a significant source of attrition in Central Nervous System (CNS) drug discovery. Given the increasing medical drivers for new and improved CNS drugs, small molecule transfer across the BBB is attracting a heightened awareness within pharmaceutical industry and medical fields. In order to assess the potential for small CNS molecules to permeate the BBB, a variety of methods and models, from in silico to in vivo going through in vitro models are developed as predictive tools in drug discovery.

Novel generic UPLC/MS/MS method for high throughput analysis applied to permeability assessment in early Drug Discovery.

A novel generic ultra performance liquid chromatography-tandem mass spectrometric (UPLC/MS/MS) method for the high throughput quantification of samples generated during permeability assessment (PAMPA) has been developed and validated. The novel UPLC/MS/MS methodology consists of two stages. Firstly, running a 1.

Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds.

A simple, reliable, and user friendly system was established to cultivate Caco-2 cell monolayer for epithelial transport studies. After an initial growth period of 1 week in a CO(2) incubator, Caco-2 cells were cultivated in an automated continuous perfusion system (Minucells and Minutissue, Germany). Medium was constantly renewed at the apical and basal side of the monolayers, which resulted in a continuous supply of nutrients as well as in a continuous removal of metabolite wastes.

Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer.

Electrostatic spinning was applied to the preparation of drug-laden nonbiodegradable nanofiber for potential use in topical drug administration and wound healing. The specific aim of these studies was to assess whether these systems might be of interest as delivery systems for poorly water-soluble drugs. Itraconazole and ketanserin were selected as model compounds while a segmented polyurethane (PU) was selected as the nonbiodegradable polymer.