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

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.

Keywords: dry powder inhaler (DPI); immunosuppression; lung surfactant; lung transplant; organic solution advanced spray drying; phospholipid colloidal self-assemblies; pulmonary nanomedicine; solid-state particle engineering design.

Figure 1

Chemical structures of (A) lung transplant immunosuppressant drug, tacrolimus, and lung surfactant mimic phospholipids, (B) dipalmitoylphosphatidylcholine, (DPPC), and (C) sodium dipalmitoylphosphatidylglycerol (DPPG).

Figure 2

Scanning electron micrographs of (A) raw unprocessed tacrolimus, (B) spray-dried tacrolimus prepared at 10% pump rate, (C) spray-dried tacrolimus prepared at 25% pump rate, (D) spray-dried tacrolimus prepared at 50% pump rate, and (E) spray-dried tacrolimus prepared at 75% pump rate.

Figure 3

Scanning electron micrographs of (A) raw unprocessed tacrolimus, (B) tacrolipo25, and (C) tacrolipo75.

Figure 4

Differential scanning calorimetry thermograms at 5.00°C/minute heating scan rate of raw tacrolimus and organic solution advanced spray-dried tacrolimus for dry powder inhalation. Abbreviations: SDT10, spray-dried tacrolimus prepared at 10% pump rate; SDT25, spray-dried tacrolimus prepared at 25% pump rate; SDT50, spray-dried tacrolimus prepared at 50% pump rate; SDT75, spray-dried tacrolimus prepared at 75% pump rate.

Figure 5

Differential scanning calorimetry thermograms at 5.00°C/minute heating scan rate of raw tacrolimus, pure dipalmitoylphosphatidylcholine (DPPC), pure sodium dipalmitoylphosphatidylglycerol (DPPG), and organic solution advanced co-spray-dried lung surfactant mimic inhalable particles (tacrolipo25 and tacrolipo75) for dry powder inhalation.

Figure 6

X-ray powder diffractograms of raw tacrolimus and organic solution advanced spray-dried tacrolimus for dry powder inhalation. Abbreviations: SDT10, spray-dried tacrolimus prepared at 10% pump rate; SDT25, spray-dried tacrolimus prepared at 25% pump rate; SDT50, spray-dried tacrolimus prepared at 50% pump rate; SDT75, spray-dried tacrolimus prepared at 75% pump rate.

Figure 7

X-ray powder diffraction patterns of raw tacrolimus, pure dipalmitoylphosphatidylcholine (DPPC), pure sodium dipalmitoylphosphatidylglycerol (DPPG), and organic solution advanced co-spray-dried lung surfactant mimic particles (tacrolipo25 and tacrolipo75) for dry powder inhalation.

Figure 8

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.

Figure 9

The effect of scanning rate on differential scanning calorimetry (DSC) thermograph of raw tacrolimus. Notes: The liquid crystal phase transition is highlighted in the black circle. It is shown that when a low scanning rate (2.50°C/min and 5.00°C/min) is used, the endothermic peak indicating the liquid crystal phase can be observed in the DSC thermograph. However, with a scanning rate of 10.00°C/minute, liquid crystal phase transition is not present in the DSC thermograph.

Figure 10

Cross-polarized light optical microscope images for the phase transitions of spray-dried tacrolimus prepared at 50% pump rate. The samples were heated from 25°C to 300°C at 5°C/minute. The temperature for each graph is (A) 25°C, (B) 85.1°C, (C) 92.1°C, (D) 94.1°C, (E) 98.6°C, (F) 100.6°C, (G) 120.4°C, and (H) 300.0°C. Note: Scale bar represents 0.2 mm.

Figure 11

Gravimetric water vapor absorption isotherms for raw tacrolimus versus organic solution advanced spray-dried dry powder inhalation tacrolimus at various spray-drying pump rates. Abbreviations: SDT10, spray-dried tacrolimus prepared at 10% pump rate; SDT25, spray-dried tacrolimus prepared at 25% pump rate; SDT50, spray-dried tacrolimus prepared at 50% pump rate; SDT75, spray-dried tacrolimus prepared at 75% pump rate.

Figure 12

Gravimetric water vapor absorption isotherms for raw tacrolimus, pure dipalmitoylphosphatidylcholine (DPPC), pure sodium dipalmitoylphosphatidylglycerol (DPPG) and organic solution advanced co-spray-dried lung surfactant mimic particles of tacrolimus for dry powder inhalation (tacrolipo25 and tacrolipo75).