ABSTRACT
The particle engineering process, thin film freezing (TFF), was used to produce particulate voriconazole (VRC) formulations with enhanced properties. The effect of various processing parameters on the solid state properties and aerodynamic performance of the TFF-processed powders was investigated in order to evaluate the suitability of these formulations for dry powder inhalation and to optimize the aerodynamic properties. Thin film freezing of VRC solution without stabilizing excipients resulted in microstructured, crystalline low density aggregate particles with specific surface areas of approximately 10m(2)/g. Thin film freezing of VRC-PVP solutions produced nanostructured, amorphous low density aggregate particles with specific surface areas ranging from 15 to 180m(2)/g, depending on the solvent system composition, polymer grade, and drug to polymer ratio utilized. VRC formulations manufactured with 1,4-dioxane, with and without PVP K12, resulted in the lowest specific surface areas but displayed the best aerodynamic properties. Using a Handihaler(®) dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K12 (1:2) displayed total emitted fractions of 80.6% and 96.5%, fine particle fractions of 43.1% and 42.4%, and mass median aerodynamic diameters of 3.5 and 4.5µm, respectively.
Subject(s)
Antifungal Agents/chemistry , Excipients/chemistry , Polymers/chemistry , Pyrimidines/chemistry , Triazoles/chemistry , Administration, Inhalation , Antifungal Agents/administration & dosage , Crystallization , Dioxanes/chemistry , Dry Powder Inhalers , Freezing , Nanostructures , Particle Size , Povidone/chemistry , Powders , Pyrimidines/administration & dosage , Solvents/chemistry , Technology, Pharmaceutical , Triazoles/administration & dosage , VoriconazoleABSTRACT
Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.
