Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications

Abstract

During the past few decades, supercritical fluid (SCF) has emerged as an effective alternative for many traditional pharmaceutical manufacturing processes. Operating active pharmaceutical ingredients (APIs) alone or in combination with various biodegradable polymeric carriers in high-pressure conditions provides enhanced features with respect to their physical properties such as bioavailability enhancement, is of relevance to the application of SCF in the pharmaceutical industry. Herein, recent advances in drug delivery systems manufactured using the SCF technology are reviewed. We provide a brief description of the history, principle, and various preparation methods involved in the SCF technology. Next, we aim to give a brief overview, which provides an emphasis and discussion of recent reports using supercritical carbon dioxide (SC-CO₂ ) for fabrication of polymeric carriers, for applications in areas related to drug delivery, tissue engineering, bio-imaging, and other biomedical applications. We finally summarize with perspectives.

Keywords: bioavailability enhancement; biomedical applications; drug delivery; polymeric carriers; supercritical fluids; tissue engineering.

Figure 1

Schematic representation of CO₂ phase diagram elucidating CO₂ existence as various phases along with the supercritical phase beyond the critical point (T_c = 31.1 °C, P_c = 7.38 MPa) (Left). Graphic illustration elucidating the potential applications of SCF (Right).

Figure 2

Conceptual representation of various processes of particle formation using SC-CO₂. a) Particle formation from gas saturated solutions (PGSS). b) Rapid expansion of supercritical solutions (RESS). c) Rapid expansion of a supercritical solution into a liquid solvent (RESOLV). d) Precipitation with compressed anti-solvent (PCA)/Aerosol solvent extraction system (ASES). e) Supercritical antisolvent with enhanced mass transfer (SAS-EM). f) Solution enhanced dispersion by supercritical fluids (SEDS). g) Suspension enhanced dispersion by supercritical fluids (SpEDS).

Figure 3

SEM images showing microparticles prepared by the SEDS process. a) FA-PEG-PLA, b) PTX-loaded FA-PEG-PLA, c) PEG-PLA, and d) PTX-loaded PEG-PLA particles. Reproduced with permission.^[61b] Copyright 2015, Springer.

Figure 4

Celecoxib nanoparticles formation and characterization. a) Schematic representation of nanoparticle formation process. b) Particle size measurements in water by dynamic light scattering (DLS). c) SEM image of nanoparticles in powder. d) SEM image of nanoparticles embedded in hydrogel (dried). Reproduced with permission.^[31a] Copyright 2015, American Chemical Society.

Figure 5

Schematic mechanism of liposome formation by the modified supercritical method. a) Phospholipid curvatures present at ambient condition, b) formation of expanded phospholipid bilayers after pressurization and equilibration with CO₂, c) formation of an instantaneous dispersion of discrete phospholipid molecules during depressurization and release of CO₂, and d) formation of liposome vesicle due to hydrophobic interactions after depressurization. Reproduced with permission.^[105] Copyright 2015, Elsevier.

Figure 6

SEM images of (a) raw salmon calcitonin, (b) raw inulin, (c) raw trehalose, formulations prepared by (d,e) SD method, and (f, g) SASD method. Reproduced with permission.^[51] Copyright 2015, Elsevier.

Figure 7

The experimental setup of permeation studies. a) Diffusion cell with the stationary magnetic field. b) Diffusion cell with the alternating magnetic field. c) Diffusion cell with stationary/alternating magnetic fields. Reproduced with permission.^[61c] Copyright 2015, Dove Press.

Figure 8

Graphical illustration of drug impregnation into polymeric implants (SCL-Soft contact lens, CI- Conjunctival implants) by using SCF technology.

Figure 9

CA structures loaded with ibuprofen at 10% w/w, obtained at 250 bars and 35 °C, starting from different polymer concentrations. a–b) 5% w/w, c) 10% w/w, d) 15% w/w, and e) 20% w/w. Reproduced with permission.^[134b] Copyright 2016, Elsevier.