Comparative interaction of 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions.

Cyclodextrins can increase the apparent solubility and dissolution rate of poorly water-soluble drug candidates improving their biopharmaceutical performance. The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth. To these points, the effects of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutylether-beta-cyclodextrin (SBEbetaCD) on equilibrium solubility was assessed via phase-solubility analysis as were the interactions of these excipients on drug solubility under conditions favoring supersaturation. Phase-solubility analysis indicated that different profiles were generated as a function of the cyclodextrin examined and the pH of the complexing medium. When kinetic solubility measurements were completed, the cyclodextrins were found to stabilize concentrations of itraconazole significantly in excess of their equilibrium solubility when supersaturated solutions were formed using the co-solvent/solvent quench approach. These solutions were stable over 240 min falling in concentration at the 24 h time point of the experiment unlike those formed using surfactants and other polymers which demonstrated a rapid decrease in concentration over time. These data suggest that hydrophilic cyclodextrins might be useful formulation adjuncts in supersaturating drug delivery systems.

Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design.

Assessing the effect of excipients on the ability to attain and maintain supersaturation of drug-based solution may provide useful information for the design of solid formulations. Judicious selection of materials that affect either the extent or stability of supersaturating drug delivery systems may be enabling for poorly soluble drug candidates or other difficult-to-formulate compounds. The technique suggested herein is aimed at providing a screening protocol to allow preliminary assessment of these factors based on small to moderate amounts of drug substance. A series of excipients were selected that may, by various mechanisms, affect supersaturation including pharmaceutical polymers such as HMPC and PVP, surfactants such as Polysorbate 20, Cremophor RH40 and TPGS and hydrophilic cyclodextrins such as HPbetaCD. Using a co-solvent based method and 25 drug candidates, the data suggested, on the whole, that the surfactants and the selected cyclodextrin seemed to best augment the extent of supersaturation but had variable benefits as stabilizers, while the pharmaceutical polymers had useful effect on supersaturation stability but were less helpful in increasing the extent of supersaturation. Using these data, a group of simple solid dosage forms were prepared and tested in the dog for one of the drug candidates. Excipients that gave the best extent and stability for the formed supersaturated solution in the screening assay also gave the highest oral bioavailability in the dog.

The use of three different solid dispersion formulations--melt extrusion, film-coated beads, and a glass thermoplastic system--to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor.

A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies.