Limits...
Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation.

Wu X, Hayes D, Zwischenberger JB, Kuhn RJ, Mansour HM - Drug Des Devel Ther (2013)

Bottom Line: Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size.Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung.These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

View Article: PubMed Central - PubMed

Affiliation: University of Kentucky, College of Pharmacy, Department of Pharmaceutical Sciences-Drug Development Division, Lexington, KY 40536-0596 , USA.

ABSTRACT
The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

Show MeSH

Related in: MedlinePlus

Cross-polarized light optical microscope images of the phase transitions for raw tacrolimus. The samples were heated from 25°C to 300°C at 5.00°C/minute. The temperature for each graph is (A) 24.9°C, (B) 133.8°C, (C) 137.1°C, (D) 139.3°C, (E) 140.9°C, (F) 142.8°C, (G) 150.3°C, and (H) 300.0°C.Note: Scale bar represents 0.2 mm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3569053&req=5

f8-dddt-7-059: Cross-polarized light optical microscope images of the phase transitions for raw tacrolimus. The samples were heated from 25°C to 300°C at 5.00°C/minute. The temperature for each graph is (A) 24.9°C, (B) 133.8°C, (C) 137.1°C, (D) 139.3°C, (E) 140.9°C, (F) 142.8°C, (G) 150.3°C, and (H) 300.0°C.Note: Scale bar represents 0.2 mm.

Mentions: Figure 8 shows the polarized optical microscope images for the phase transitions of raw tacrolimus. At room temperature, raw tacrolimus exhibited crystal forms, as shown in Figure 8A. When temperature increased to 133.8°C, tacrolimus started to melt (Figure 8B). The onset temperature coincided with its melting recorded by DSC. Figure 8C–F shows the melting process. Before tacrolimus transformed into a liquid state, it also displayed a liquid crystal state, as shown in Figure 8D–F. The endothermic peak of crystalline transformation into liquid crystal was also present in the DSC thermograph of tacrolimus at slow heating scan rates of 2.50°C/minute versus 5.00°C/minute, as shown in Figure 9. At 2.50°C/minute and 5.00°C/minute, DSC thermograms show a small endothermic peak at ~147°C following the main phase transition, indicative of the liquid crystal state. This is the first time that such a thermal event in tacrolimus has been reported. However, interestingly, the small peak was not readily observed at a heating scan rate of 10.00°C/minute. This indicates that only a slow scan rate of 2.50°C/minute can reveal this important liquid crystalline material property involved in the phase transition of crystalline tacrolimus. Figure 8G shows the liquid state of tacrolimus after melting. At 225°C, tacrolimus started to degrade (Figure 8H), which was consistent with the DSC thermal analysis (Figures 4 and 9).


Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation.

Wu X, Hayes D, Zwischenberger JB, Kuhn RJ, Mansour HM - Drug Des Devel Ther (2013)

Cross-polarized light optical microscope images of the phase transitions for raw tacrolimus. The samples were heated from 25°C to 300°C at 5.00°C/minute. The temperature for each graph is (A) 24.9°C, (B) 133.8°C, (C) 137.1°C, (D) 139.3°C, (E) 140.9°C, (F) 142.8°C, (G) 150.3°C, and (H) 300.0°C.Note: Scale bar represents 0.2 mm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569053&req=5

f8-dddt-7-059: Cross-polarized light optical microscope images of the phase transitions for raw tacrolimus. The samples were heated from 25°C to 300°C at 5.00°C/minute. The temperature for each graph is (A) 24.9°C, (B) 133.8°C, (C) 137.1°C, (D) 139.3°C, (E) 140.9°C, (F) 142.8°C, (G) 150.3°C, and (H) 300.0°C.Note: Scale bar represents 0.2 mm.
Mentions: Figure 8 shows the polarized optical microscope images for the phase transitions of raw tacrolimus. At room temperature, raw tacrolimus exhibited crystal forms, as shown in Figure 8A. When temperature increased to 133.8°C, tacrolimus started to melt (Figure 8B). The onset temperature coincided with its melting recorded by DSC. Figure 8C–F shows the melting process. Before tacrolimus transformed into a liquid state, it also displayed a liquid crystal state, as shown in Figure 8D–F. The endothermic peak of crystalline transformation into liquid crystal was also present in the DSC thermograph of tacrolimus at slow heating scan rates of 2.50°C/minute versus 5.00°C/minute, as shown in Figure 9. At 2.50°C/minute and 5.00°C/minute, DSC thermograms show a small endothermic peak at ~147°C following the main phase transition, indicative of the liquid crystal state. This is the first time that such a thermal event in tacrolimus has been reported. However, interestingly, the small peak was not readily observed at a heating scan rate of 10.00°C/minute. This indicates that only a slow scan rate of 2.50°C/minute can reveal this important liquid crystalline material property involved in the phase transition of crystalline tacrolimus. Figure 8G shows the liquid state of tacrolimus after melting. At 225°C, tacrolimus started to degrade (Figure 8H), which was consistent with the DSC thermal analysis (Figures 4 and 9).

Bottom Line: Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size.Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung.These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

View Article: PubMed Central - PubMed

Affiliation: University of Kentucky, College of Pharmacy, Department of Pharmaceutical Sciences-Drug Development Division, Lexington, KY 40536-0596 , USA.

ABSTRACT
The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

Show MeSH
Related in: MedlinePlus