Generation and characterization of fine and stable powders suitable for pulmonary drug delivery using carbon dioxide-assisted nebulization with a Bubble Dryer (CAN-BD).

摘要

Fine particles of a proteins, sugars, surfactants, and small molecule drugs, can be rapidly made by a new patented drying process, known as CO 2-Assisted Nebulization with a Bubble-DryerRTM (CAN-BD). The primary advantages of this process are that it facilitates drying of microbubbles and microdroplets at lower temperatures (25--65°C) than those used in traditional spray drying processes and that no organic solvents are required. The compound(s) of interest are dissolved in water or an appropriate organic solvent, and mixed intimately with near-critical or supercritical CO 2 by pumping both fluids through a low volume tee at room temperature and about 100 bar. The mixture is then decompressed through a 10.0 cm long, 75 micrometer inner diameter (i.d.) flow restrictor into a low temperature drying chamber. The aerosol plume is mixed with preheated nitrogen and is dried at temperatures between 30 and 60°C in less than 5 seconds near atmospheric pressure. These particles (hollow or solid) are generally formed in the optimum size range for pulmonary delivery to the alveoli (1 to 3 mum in diameter). Aerodynamic diameters were measured using the Model 3225 Aerosizer RTM DSP. The stability of the proteins was determined using spectroscopic enzymatic activity measurements and by analyzing the secondary structure using Fourier Transform Infrared Spectroscopy (FTIR). Differential scanning calorimetry (DSC) was performed on the dry powders to determine the glass transition temperatures (Tg) of the particles. The CAN-BD process did not cause detectable damage to the proteins studied. With the optimum combination of sugars with the protein, full enzymatic activity of the protein after redissolution was observed.; Particles can also be made from compounds that have limited or no significant solubility in water. The compound of interest can be dissolved in an appropriate organic solvent and dried by the CAN-BD process. Particles have successfully been made from compounds dissolved in methanol, ethanol, or acetone.; It is also possible to make particles of two compounds that are soluble in different solvents. By using a low dead volume mixing cross, two liquid streams can be intimately mixed with CO2, nebulized and dried to form heterogeneous particles.