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Back to Journal »International Journal of Nanomedicine» Volume 13

Author Kankala RK, Chen BQ, Liu CG, Tang HX, Wang SB, Chen AZ 

Published on July 23, 2018, the 2018 volume: 13 pages 4227-4245

DOI https://doi.org/10.2147/IJN.S166124

Single anonymous peer review

Editor who approved for publication: Dr. Linlin Sun

Ranjith Kumar Kankala,1-3,* Biao-Qi Chen,1,2,* Chen-Guang Liu,1,2 Han-Xiao Tang,1,2 Shi-Bin Wang,1-3 Ai-Zeng Chen1-3 1College School of Chemical Engineering, Huaqiao University, Xiamen, People’s Republic of China; 2 Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen, People’s Republic of China; 3 Key Laboratory of Biochemical Technology of Fujian Province (Huaqiao University), Xiamen, China Abstract of equivalent contributions: In recent years, supercritical fluid (SCF) technology has aroused great interest among researchers in the manufacture of traditional medicines due to the environmental friendliness and economically promising properties of SCF. Among all the SCF-assisted processes used for particle formation, the solution-enhanced dispersion of the supercritical fluid (SEDS) process may be one of the most effective methods for manufacturing biomaterials and pharmaceutical compounds in any specification, ranging from micrometers to nanometers. The micro-particles produced by the SEDS process provide enhanced features regarding their physical properties, such as increased bioavailability due to their high surface area. First, we briefly describe SCF and its behavior as an anti-solvent in SCF-assisted processing. We then aim to provide a brief overview of the SEDS process and its modified prototype, focusing on the advantages and disadvantages of specific modifications. Then, we emphasized the influence of various processing constraints, such as temperature, pressure, SCF and organic solvent (if used) and its flow rate, as well as the concentration of drug/polymer, etc. The influence on particle formation is related to particle size distribution, Precipitation and morphological properties. Next, our goal is to systematically discuss the application of SEDS technology in the production of therapeutic nano-scale preparations. Through the use of drugs alone or in combination with biodegradable polymers, the application focuses on oral, pulmonary, and transdermal applications. And implanted drug delivery applications. example of. We conclude with the point of view at the end. Keywords: controlled release, antisolvent, nanometerization, drug delivery, polymer carrier, parametric effect

Recently, supercritical fluid (SCF) technology has attracted great attention from researchers in many fields, such as pharmaceuticals and food, as well as the health care industry for various applications. 1-3 This high-pressure technology has been widely adopted in the past decades due to the environmental friendliness and economically promising characteristics of SCF for obtaining products. 4 Although they have successfully formed particles during the processing of pharmaceutical active substances, various traditional methods (grinding, freeze-drying and spraying) are still subject to some limitations, such as unstable formulations, wide particle size distribution, low drug loading efficiency, etc. . 5 In some cases, the process of particle formation is extended to obtain a uniform particle size distribution through subsequent grinding and sieving, which usually results in sensitive biomolecules due to high shear forces. 6,7 In addition, most of these processes usually rely on the use of large amounts of organic solvents, which can lead to product damage, toxicity, flammability, and biocompatibility issues. 8 To this end, SCF uses benign solvents, namely CO2 and water, to circumvent the problems associated with traditional methods of precipitating drugs alone or in combination with biodegradable polymers. 9 Therefore, these SCFs can be used as effective substitutes for organic solvents when manufacturing pharmaceutical products. 4,6

More commonly, SCF as a benign solvent has aroused great interest in the pharmaceutical manufacturing process because of their ability to dissolve when separating components, and their physical and chemical properties have undergone significant changes beyond the critical point. 10 In addition, other benefits of SCF include solubilization ability and ease of recycling, among them. The physical properties (ie density, viscosity, solubility, and diffusivity) of SCF present in liquids and gases can be easily changed by adjusting the critical conditions (pressure and temperature) during solute processing. 8,9,11, 12 In this framework, other SCFs, such as water and solvents, such as CO2/ethanol mixtures, acetone, nitrous oxide, propane, ether, trifluoromethane and chlorodifluoromethane, are in their corresponding Operate under supercritical conditions. 10,12-18 These SCFs, including key parameters and other properties such as solubility, have been reported elsewhere. 19 Among all available SCFs, supercritical CO2 (SC-CO2) has attracted great interest from researchers due to its wide adaptability, safety, and low cost. Efficiency, and requires mild operating conditions under ambient conditions (temperature 304 K/31.1°C and pressure 7.38 MPa/73.8 bar). 10 In addition, it should be noted that SC-CO2 is a drug that is recognized as safe by the US Food and Drug Administration 20 because it is non-reactive, non-toxic, non-polluting, harmless, and non-flammable. 9,10 It also offers some advantages that are very conducive to particle manufacturing, such as high volatility, low cohesive energy density, and low polarization rate per unit volume. 12 In addition, the unique physical properties of SC-CO2, such as density, diffusion solubility and viscosity, can be adjusted by temperature and pressure. 10

There is an increasing demand for the manufacture of various active pharmaceutical ingredients (API) particles and their crystalline morphology research, while aiming to overcome the limitations of currently available traditional methods (ie, the destruction of particles by strong shear forces and the damage to biological activity , Different particle size distributions, etc.), 5 has attracted great attention from researchers to SCF technology. This technology may be one of the rapid development processes with many variants since the first report in 1879.22. The different variants of SCF technology used for particle manufacturing are classified according to the behavior of SCF, such as "solvent" (rapid expansion of supercritical solution), 23 "solute" (particles formed from a gas-saturated solution), 24 "antisolvent" (Supercritical anti-solvent [SAS], 25 and its variants 15, 26-31), "reagents", 32 and others such as supercritical-assisted atomization process 10, 33, 34 and expansion of the decompression of liquid organic solutions. 15.35 Despite the differences in behavior, SCF can be used as a fast, uniform and smooth solute (drug and/or polymer) in all of the aforementioned particle manufacturing processes. 10 In addition, the performance of these processes is entirely dependent on the selection of appropriate solvents and the fine-tuning of key parameters. twenty two

The SAS precipitation process has received extensive attention due to its unique advantages and its ability to circumvent the process limitations of traditional particle manufacturing methods and other SCF processes (such as the rapid expansion of supercritical solutions). 10,36 Since SC-CO2 is a relatively poor solvent, most pharmaceutical compounds and high molecular weight polymers can improve solubility and resistance to solvents under mild conditions (temperature <100°C, pressure <350 bar) and the use of co-solvents. Or the non-solvent properties become impractical12 This process is very suitable for making solutes that are hardly soluble in SCF. The name SAS was created based on the behavior of SCF, which acts as an antisolvent for the solute (API/polymer). 9 For the first time, Bleich et al. used SCF as an anti-solvent and encapsulated a mixture of solvents (methanol and dichloromethane [DCM]) used for butyl bromide into poly(L-lactic acid) (PLLA) particles through co-precipitation. 37 In the past two decades, SAS’s progress in manufacturing has proven tremendous progress in polymer-based micro- or nano-scale composite materials.

The manufacture of particles through the SAS process involves the following successive stages. Initially, after reaching a state of supersaturation, the mixing of the dispersed multiphase system leads to the nucleation of the solute. The molecules surrounding the solute in the medium then begin to accumulate on the nucleus, and crystal growth eventually ends with agglomeration. Since the nucleation phenomenon is very rapid in this process, the mixing stage is particularly important, which defines the morphological properties and particle characteristics of the final product in terms of particle size distribution. 1 The mechanism behind particle formation is the mixing of solvents, SCF and solute swell to a supersaturated state and cause rapid nucleation, indicating that due to the high diffusibility and low viscosity of SCF, there is a large amount of mass transfer between SCF and the solvent carrying the solute/API . 9,22 In addition, the high diffusion coefficient of SCF sequentially controls particle precipitation by initially increasing the volume of the solvent, which reduces its density, thereby reducing solvation capacity, and ultimately leading to solute precipitation. 9 Here, the solvent and SCF act as powerful driving forces in the solute nucleation process. Subsequently, high supersaturation and smaller particle size can be achieved by rapidly mixing the SCF-solution mixture. 9 In addition, the yield of this process mainly depends on the order of addition of SCF, solvent, and other substrates (if used). 10 In addition, various experimental properties need to be optimized systematically, such as critical conditions (ie pressure and temperature), the chemical composition of the solute (polymer and/or API), and the type of organic solvent, which have been discussed elsewhere. 9,10

Among all the SCF-based particle manufacturing processes, the SAS process has become the most effective and advantageous method for producing micro- and nano-sized structures with the desired morphology. 10 This process usually forms small-sized particles and produces a high specific surface area, which improves the release or solubility of API by increasing the mass transfer rate between the particles and the surrounding medium. 38 In addition, this process becomes very important due to the high drug loading efficiency and rapid precipitation of solutes. More commonly, the particle manufacturing process is carried out in an environmental environment, which is very suitable for processing heat-sensitive biomolecules such as genes and proteins. In addition, since it is easy to scale up fine particle production, this process is very suitable for performing continuous operations. Other processes similar to SAS technology include precipitation with compressed anti-solvent26 and gaseous anti-solvent. 27 Compared with traditional SAS processes, these methods have fewer operational problems; in addition, it is easy to implement these particle manufacturing strategies on an industrial scale. 10,27 Despite its significant advantages, the SAS process still has some shortcomings, such as larger droplets at the nozzle tip and longer cleaning time, which leads to particle aggregation. 9,25,39,40 However, this can be minimized by using a vibrating ultrasonic processor to enhance the mixing of the solution to break/atomize the solution jet under high turbulence into tiny droplets in the sub-micron range. 9 In addition, the micronization of SCF insoluble solutes has been further improved. 10 Various modifications have been made in the SAS process to improve its functional properties. The improved SAS process includes aerosol solvent extraction system, 15 supercritical antisolvent with enhanced mass transfer function, 31 supercritical fluid assisted emulsion extraction, 41 and supercritical fluid solution enhanced dispersion (SEDS). 28-30 Among all these SAS processes, SEDS is the most advanced particle precipitation anti-solvent process. In this review, we provide a comprehensive overview of this process based on the literature published in the past two decades related to administration through various routes of administration. In addition, this review highlights the impact of key parameters on particle size and provides a vision for the future of SCF technology.

The SEDS process was developed by York and Hanna of the University of Bradford in 1996 to improve the performance efficiency of the traditional SAS process. 42 On the other hand, this advanced process also minimizes the operating constraints of the aerosol solvent extraction system process and other processes. SAS process. 10 The SEDS process usually runs under a shorter drying time to increase the mass transfer rate, which is significantly different from the traditional SAS process that realizes micro-droplets. 14,42,43 The main goal of the SEDS process is to produce fine particles of uniform size in a single phase equilibrium, while removing organic solvents to provide them in a dry form. Generally, the ingredients (API and/or excipients) are first dissolved in a suitable organic solvent by vigorous mixing, and then they are quickly sprayed together with the SCF into a high-pressure vessel through a specially designed coaxial nozzle. As the jet at the nozzle tip breaks, the mixture produces small-sized droplets, which subsequently produce fine particles. Therefore, the nozzle and its specifications (mainly the inner diameter) play a crucial role in the final particle size distribution. In addition, various processing conditions, such as flow rates of SC-CO2 and drug solutions, and key parameters should be optimized to promote better control of particle size and morphology (Figure 1). 38 During the co-precipitation of drugs and drugs, the polymer composite particles in the process require that the components are insoluble in SCF, and they should have mutual compatibility and excellent thermodynamic properties. Otherwise, it will lead to serious consequences of phase separation, resulting in a single particle of drug and polymer instead of a drug-polymer composite.

Figure 1 Conceptual representation of the SEDS process and its various modifications. Abbreviations: SEDS, enhanced dispersion through supercritical fluid solution; SEDS-EM, enhanced solution dispersion through supercritical fluid with enhanced mass transfer; SEDS-PA, enhanced dispersion through supercritical fluid solution-pre-film atomization ; SpEDS, supercritical fluid suspension enhances dispersion.

As mentioned earlier, the formation of particles in the anti-solvent process depends entirely on the mass transfer ratio between the SCF and the solute containing the droplets, followed by the rate of solvent transfer to the SCF phase. 38,44 Therefore, spontaneous nucleation is allowed at high rates and results in no chance of agglomeration of small-sized particles. 28,38,44,45 In order to prove these facts, two possible mechanisms have been proposed, such as droplet dispersion, followed by SCF and the micromixing of droplets and solvent with SCF. 1,46 However, the miscibility between SCF and solvent mainly determines the type of mechanism involved in the particle formation process. 1

Among all available SAS-based particle manufacturing technologies, the SEDS process has many advantages, such as the production of ultrafine particles with a narrow and uniform particle size distribution, improved API dissolution rate, and high yield of polymer-based micron and nano-particles. The composite material, the smallest particle agglomeration, the acceptable limit of residual solvents when operating with reduced drying time, and the ease of polymer coating on APIs in various particle forms, resulting in a core-shell with sustained drug release capabilities Composite materials, etc. 47-50 In addition, this process is very suitable for manipulating water-soluble compounds by spraying aqueous and organic solvents separately through coaxial three-chamber nozzles. 10,51-55 However, there are still some problems, such as small processing capacity and easy nozzle clogging. In addition, a secondary disadvantage of this process is that the SCF is completely miscible with the solution feed above the critical pressure (exists as a single phase)1, which may result in a wider particle size distribution during the scale-up process. 46

One of the key steps for SEDS to make particles is to form smaller droplets at the tip of the nozzle. 56 Therefore, the nozzle and its specifications play a vital role in the SEDS process and can be modified to adjust the jet breaking for fine particle formation. In this regard, various atomizer designs have been developed, such as coaxial nozzles, internal two-fluid mixing nozzles, four pinhole nozzles, and annular gap nozzles. 55,57 In addition, huge progress is also reflected in the progress of the atomizer. SEDS improves the efficiency of particle formation and overcomes processing damage problems. Other variants of the SEDS process (Figure 1) include solution-enhanced dispersion of supercritical fluids—pre-film atomization, solution-enhanced dispersion of supercritical fluids with enhanced mass transfer, and suspension-enhanced dispersion of supercritical fluids (SpEDS) .

In the SEDS process, the bidirectional coaxial nozzle is usually used to spray SCF and the solution feed containing the active substrate into a high-pressure vessel under controlled critical conditions (Figure 1). 55 During particle formation, the turbulent SCF allows the solution containing the substrate to rapidly split into tiny droplets of partially mixed and highly supersaturated solutions, which are sprayed into the high-pressure vessel as a jet. Then the nucleation of the solute starts at the tip of the two-way nozzle chamber, and then the particles grow in the sedimentation vessel to end the process. 52,55

The coaxial three-channel system can be used for the micronization/nanoization of poorly water-soluble drugs or drug-polymer composite materials. This system is conducive to three solvents (SC-CO2, aqueous drug solution and polymers dissolved in organic solvents) to flow into the precipitation vessel significantly to overcome compatibility issues (Figure 1). 58 Generally speaking, a mixture of a drug and a polymer dissolved in an organic solvent. Polymers dissolved in the same solvent (such as acetone, DCM or solvent mixtures) are introduced through the two-way channel assisted spray method, which leads to the risk of organic solvents damaging biomolecules. In order to overcome this limitation, a multi-channel nozzle system is used to spray sensitive biomolecules (mainly peptides, proteins and genes) separately during the SEDS process. However, it should be pointed out that the geometry of the nozzle plays a crucial role in influencing the morphology of micro/nano particles in a three-channel nozzle system. 58 In one case, Zhang et al. produced particles by using three channels. Channel nozzle systems with different inner diameters in the range of 50-2,000 μm, and their ends are on the same plane. 58 The inner diameter of the different channels in the nozzle plays a crucial role in the size and mass diffusion of the initially formed droplets 59 However, in some cases, previous reports indicate that the initial droplet size is not significant to the final particle size Influence. 60

Another interesting nozzle type in SEDS processing is the annular gap nozzle. The nozzle system is clearly designed to increase the contact surface area between the solution and SC-CO2 (Figure 1). Here, SC-CO2 and the drug/polymer solution introduced through different channels are mixed in the annular gap of the nozzle, and then they are quickly sprayed into the high-pressure vessel to increase the feed of SCF and the solution containing the active substrate. . In addition, this method is more advantageous than other methods, because the distance within the nozzle annular gap can be adjusted according to the particle size requirements. 57

Supercritical fluid solution enhanced dispersion-pre-filming atomization

This process is different from the traditional SEDS process because it uses a special pre-filming two-fluid atomizer to increase the mass transfer rate between the SCF and the solution feed (Figure 1). The principle behind particle formation is that the fluid used for atomization is driven along the coaxial annular channel in the nozzle to form a thin vortex liquid membrane 61, which separates and produces fine droplets after interacting with the dense gas at the tip. In addition, the mixing of liquids (ie SCF and solution feed) is enhanced to increase the mass transfer rate, resulting in fine particles. 61-63 Previous reports have also indicated that the presence of atomizing air in the nozzle chamber may cause the split length to decrease more quickly, and this situation will become more intense when the atomizing air generates a vortex. 61,64

Enhanced dispersion of solutions with supercritical fluids that enhance mass transfer

The solution-enhanced dispersion of supercritical fluid with enhanced mass transfer process is an enhanced mass transfer precipitation technology, which was developed by combining the traditional SEDS process with an auxiliary ultrasonic treatment device (Figure 1). The operation of this process is similar to the traditional SEDS process, but the mixture of SCF and solution feed is sprayed on the vibrating surface at ultrasonic frequency, which increases the mass transfer between the solution and SCF, resulting in a significant reduction in particle size by approx. Several times. 65 In particular, the size of the droplet in the ultrasonic field decreases with the increase of the ultrasonic energy input, which subsequently increases the mass transfer rate and the mixing between the droplet and the SC-CO2.65. Therefore, this phenomenon indicates that the connection The ultrasonic transducer can effectively control the particle size.

Supercritical fluid suspension enhances dispersion

SpEDS is one of the most advanced processes developed to expand the application range of SEDS and overcome its processing damage problems. 29 The equipment setup of this process is almost similar to SEDS, but SpEDS has an auxiliary syringe equipped with a piston that can effectively pump the loaded drug suspension or drug-polymer mixture (Figure 1). 29,30 The use of a syringe setting in this process is very advantageous because it avoids the blockage of the one-way valve and the damage of the high-pressure pump during the process of pumping the particle suspension into the high-pressure container. 29,66,67 The process mainly produces core-shell structured drug polymer composites, with sizes ranging from micrometers to nanometers, with high drug encapsulation efficiency. In addition, these core-shell nanocomposites have significant advantages for sustained drug release from the core (discussed in the "Applications" section).

The influence of various process parameters on particle size

The SEDS process usually preferably precipitates particles in any size from micrometer to nanometer, with uniform size distribution and smooth surface. Due to their high surface area, these fine particles will ultimately increase the bioavailability of most APIs. More commonly, this process is used to manipulate poorly water-soluble drugs/biodegradable polymers designed to control drug release. To achieve this goal, the processing parameters of SEDS must be optimized with good care for fine particle formation, such as suitable operating conditions, appropriate selection of suitable polymers based on their solubility, and selection of the proper solvent. Here, we emphasize SEDS The influence of various operating parameters of the process, such as critical conditions (pressure and temperature), solute (drug or polymer) and solution concentration, an organic solvent and the flow rate and solution of SCF, SCF, and other factors, such as nozzle diameter , Atomization frequency and humidity are related to the size and morphological properties of the particles.

The key parameters that play a key role in the operation of SCF technology are pressure and temperature. These parameters are the main determinants of the existence of any supercritical solvent. Therefore, solvents above the critical condition exist in a single-phase form, and their physical properties are between liquid and gas, and can be easily controlled by adjusting the critical condition. Such adjustments are beneficial because they can be changed during the processing of pharmaceutical additives to obtain better product yields. However, it should be pointed out that changes in these conditions often not only have a significant impact on the difference in the physical properties of SCF, but also have a significant impact on the morphology and structural properties of the formulation.

Generally speaking, SCF auxiliary processing is under increased pressure, that is, above the critical point, due to the volume expansion of the solvent and its financing in the supply chain. On the contrary, it will cause irregular patterns below the critical point of the SCF. In addition, the increase in pressure will increase the diffusion of SCF into the solvent, leading to supersaturation and subsequent generation of small-sized particles. 68-70 However, changes in pressure have no significant effect on the biological activity of sensitive molecules, such as enzymes. 71

Temperature is another key parameter, which plays a very critical role in the particle manufacturing process. The SEDS process is usually run at around 40°C, and no significant impact on the particles is observed at this time. However, the density of the solute will only decrease as the temperature increases, which subsequently reduces its solubility in organic solvents. These results lead to slower supersaturation and longer growth time, resulting in large-sized particles. 72 Therefore, the balance between growth time and nucleation rate plays a crucial role in determining the final particle size of the product.

Similar to pressure, changes in temperature can also cause changes in the morphology and structural properties of particles. In some cases, due to collisions between particles, an increase in temperature can cause severe aggregation of particles with irregular surfaces, and vice versa. 68-70 For this reason, under these conditions, the drug loading efficiency in the polymer carrier will decrease due to phase separation, which is explained from the perspective of thermodynamics.

During processing, the primary consideration for any substrate (drug/polymer) is its solubility in SCF. Since SC-CO2 is a relatively poor solvent, organic solvents (such as acetone, DCM, dimethyl sulfoxide (DMSO) and other solvents) are used to dissolve the material, and the anti-solvent process is explored to operate SCF. The solute in which SCF acts as an anti-solvent for the substrate. In addition, it should be pointed out that the structure and properties of the drug/polymer and its physicochemical properties are important factors for the production of particles with the required drug encapsulation efficiency and particle size distribution using the SEDS process. For example, lipophilic drugs or SCF soluble drugs are extremely challenging due to their precipitation or encapsulation in polymers. On the other hand, compared with crystalline polymers or semi-crystalline polymers, amorphous polymers (for example, poly(lactic acid-glycolic acid copolymer) [PLGA]) are difficult to crystallize and precipitate in a high-pressure vessel. These consequences usually lead to lower drug loading efficiency and wider particle size distribution.

Previous reports have shown that it is easy to precipitate and produce small-sized particles from polymers in crystalline or semi-crystalline form (for example, PLLA). These forms of polymers are well recrystallized in the SEDS process through successive steps: initial nucleation, that is, the formation of the polymer core, and then the growth phase to produce the desired amorphous composite particles. 10 However, it is difficult to process polymers in amorphous forms, such as PLGA, because they eventually lead to undesirable aggregates. 10 In order to overcome this limitation, in some cases, a combination of biodegradable polymers (PLLA/PLGA) is preferred to produce particles within an acceptable average particle size range. 73 In addition, the crystallization of polymer particles The degree is reduced after SEDS processing, so the resulting particles in an amorphous state have a high degradation rate in the body.

In addition to the nature of the substrate, the concentration of the drug or polymer in the solvent also plays a vital role in determining the particle size and distribution during SEDS processing. 63 In the SCF-assisted process, the substrate usually increases with the increase of its concentration, which is related to the enhanced nucleation and growth process. In this framework, the injected dilute solution usually results in delayed saturation, followed by slower precipitation during droplet expansion. 63 These results will eventually lead to small size particles. Therefore, in these cases, nucleation is the main reasonable mechanism. Conversely, an increase in concentration will lead to an increase in surface tension and solution viscosity, which ultimately leads to the formation of large primary droplets. 9,74 Therefore, the mechanism behind particle growth is related to solute nucleation. To rapid supersaturation, resulting in large-sized particles. 56,63 Previous reports indicate that a lower concentration solution is very beneficial to the formation of particles with a uniform size distribution. However, the decrease in solution concentration will in turn affect the loading efficiency of the drug in the polymer. 68

In order to explore the influence of organic non-solvent and solution concentration on the particle size and shape in SEDS, Chen et al. proved that adding DCM to ethanol solution will cause the initial concentration to be highly saturated and produce small-sized particles with spherical shapes. 9,74 In this study, the authors describe that the solvent ratio has a dominant effect on particle size compared to the concentration of the solution. 74 In addition, they clarified that the solution concentration has a significant effect on the particle width. Together, they concluded that as the concentration of the solution decreases, the increase in saturation results in small-sized spherical particles. The strategy of using non-solvents is cost-effective because it can produce pellets with lower CO2 consumption. 74

In the anti-solvent process, various co-solvents are needed to increase the solubility of the solute. The most preferred solvents include acetone, DMSO, methanol, chloroform, ethanol, isopropanol, DCM and the like. However, when formulating a drug delivery system, choosing the right solvent plays a crucial role. The selection process mainly depends on the solubility of the solute (polymer/drug) in the solvent and its compatibility with SCF. In a few cases, combinations of solvents such as acetone/DMSO59 and DCM/DMSO47,59 are also used in certain ratios, so that one of them is highly volatile to cause significant swelling and easy removal, while the other The solvent enhances the solubility of the solute. 68 In addition, it should be noted that the choice of solvent is also based on the solubility ratio of the polymer to the drug, because the drug should be precipitated earlier to be encapsulated in the polymer. In addition, the embedded drug may also produce different polymorphs in different solvents, and ultimately guide the release of the drug. 75 In this case, some solvents may reduce the yield of the final product due to the following reasons: 1) the high viscosity of the solvent leads to insufficient diffusion between the solvent and the anti-solvent, and 2) the high solute in the solvent. Solubility makes it difficult to precipitate at low concentrations. 47 To overcome this limitation, high saturation is achieved by using a low concentration of solute in a non-solvent. Therefore, the solute can quickly precipitate and produce micro/nano-sized particles with uniform size distribution. 76 In addition, in some cases, heterogeneous emulsions can replace organic solvents to overcome the insolubility and inactivation of sensitive molecules, such as genes or peptides.

In addition to the solute concentration, the size of the substrate also depends on the solution flow rate during the SCF process. Generally speaking, due to the weak impact of SC-CO2 on the liquid film, the increase in solution flow rate leads to an increase in particle size. 56,72 However, it is also related to other parameters, such as surface tension and liquid viscosity. In one case, Chen et al. reported that the solution flow rate affects the shape of the particles. 74 As the flow rate increases beyond normal levels, the system causes the particles to take a pear shape, that is, extend more than the sphere. The effect of particles of different shapes on the flow rate can be well explained as related to the fluid dynamics of the liquid, that is, the change of kinetic energy per unit mass of the liquid. This is suitable for the precipitation of small-sized particles with a narrow particle size distribution at low flow rates, and vice versa. The same is true. 68 In addition to particle size, flow rate also affects drug loading efficiency in polymer-based delivery systems. To some extent, the increase in solution flow rate leads to an increase in its loading efficiency. In one case, the solution flow rate showed a combined effect on the particle size. 63 The particle size starts to increase, and then decreases with the increase of the flow rate, indicating the effect of the rapid atomization of the formed liquid sheet. He et al. clearly explained the effective mechanism that plays an important role in the atomization process. 63 They explained that there are two different but complementary mechanisms involved: 1) rapid atomization and 2) the wave mechanism in the atomization process. 63,70 Fast atomization mechanism Atomization is usually related to the velocity of the liquid sheet at the tip of the atomizer. Maintaining a lower velocity at a lower flow rate results in a strong equivalent momentum transfer between the solution and SC-CO2. Finally, the sheet is broken down into fine droplets. 63,70 Under these conditions, the energy per unit mass of liquid obtained from the dense gas will decrease with the increase of the solution flow rate, and the Vc will not change (that is, the CO2 under the standard state Flow rate [temperature 273 K, pressure 101, 325 Pa] (L/min), which increases the droplet size, which in turn increases the particle size of the final product. 63,70

In these anti-solvent processes, SCF not only acts as an anti-solvent, but also acts as a spray enhancer and reprecipitation aid. Generally speaking, SCF has no significant effect on the synthesis formula in the anti-solvent process. However, the average diameter of the particles produced by the semi-crystalline form of the polymer depends on the density of the SCF. 77 During the SEDS treatment of the substrate, the pumped SCF is completely miscible with the solution feed above the critical pressure, and the mixture exists as a single phase. The resulting particles produced by the SEDS process have attractive physicochemical properties, such as reduced tensile strength, which helps these easily dispersed fine particles to be used in aerosol formulations. 78 A wafer-like morphology with a higher surface area to improve the body Bioavailability, 79 and produce dosage forms with the following characteristics: Reduce dosage variability. 80

SCF technology usually operates with an available supercritical solvent. Interestingly, Ghaderi et al. improved the SEDS process by using a combination of SCF (N2 and CO2) to overcome the severe flocculation caused during the production of polymer particles. 81 Compared with the polymer dispersion obtained using gas combination, its size is smaller. Due to the enhanced plasticizing effect of SCF, the product obtained when only CO2 is used. These particles that successfully trapped the drug resulted in the controlled release of the drug. 81,82

Similar to the solution flow rate, the SCF flow rate has little effect on the particle size of the obtained product and can be adjusted by optimizing the conditions. 63 Generally speaking, the increase of SCF flow rate will cause the influence of surface tension and liquid viscosity to consolidate force. During the two-fluid atomization process, the damaging effect of external aerodynamic force is resolutely opposed. After that, the impact of the dense gas on the liquid film is strengthened and causes the formation of fine droplets. 63

The SEDS process involves spraying various components through a specially designed coaxial nozzle that facilitates the parallel flow of two liquids (ie SCF and a solution containing an active matrix). Despite these advantages, the use of coaxial nozzles still faces the limitation of generating high shear forces when discharging components from the pump, which can damage unstable biomolecules such as genes and peptides. This can be solved by using a three-channel nozzle system. In addition, it should be noted that the diameter of the nozzle plays a key role in the final size of the particles.

In addition, the atomization of the liquid in the nozzle is one of the key steps that play a key role in the particle formation process in the SEDS process. 56 These specially designed devices (ie, atomizers) effectively atomize the active substance solution and enhance its mixing with the solution. SCF in the nozzle and increase the mass transfer rate between them to form fine particles. 56,57,63 The solution to be atomized is initially driven along the coaxial annular channel, resulting in a thickness of 10 microns. The SC-CO2 stream used for atomization then hits the thin swirling film formed at the tip of the atomizer and generates shear force to break the film into ultra-fine droplets. Further intensification of mixing may result in the formation of uniformly sized particles. 56 However, high-quality atomization can produce ultra-fine primary droplets, thereby increasing the two-way mass transfer rate, and subsequently producing small-sized particles under significant conditions. Nucleation rate. 56,62

In SCF-assisted processing, humidity is another key factor that significantly affects the quality of the final product. Generally speaking, particle adhesion and wetting are the result of humidity, and they also vary with processing conditions. A study compared materials obtained through SEDS processing with products obtained through traditional micronization methods. 83 The survey showed that products processed through SEDS are more sensitive to humidity. Atomic force microscopy captured the influence of humidity on the morphology of particles, indicating that these changes are caused by surface chemical differences, including various factors such as static electricity, capillary and van der Waals forces, and surface free energy of particles, which play a key role in particle adhesion The role of. 83

Despite the efficiency and progress in the production of various polymer structures, the SEDS process still faces the small problem of low recovery rate as a single nanounit during the synthesis of nanoparticle preparations. 84 More commonly, nanoparticles in dry form tend to be dispersed in the sedimentation chamber and are difficult to collect. In order to overcome this limitation, Torino et al. proposed an innovative strategy that works by processing the collected soft aggregates of nanoparticles through ultrafiltration, ultracentrifugation, or ultrasound-based technology to separate them into individual nanometers. unit. 84

Drug delivery usually relies on various formulations and methods of delivering API (drug/protein/gene) to achieve the desired therapeutic effect. 10 The primary goal of any technology that produces these formulations/dosage forms is to effectively deliver the drug to the right target as far as the healthcare sector is concerned. SCF technology may be one of the technologies that have received great attention in the past few decades because of its many advantages and the ability to overcome the limitations of traditional methods, such as the physical instability of the resulting product, multi-step procedures, and often relying on a large number of Organic solvents, etc. 10,12,38,45,85–88 SCFs' unique adaptability characteristics, such as solubility, large compressibility, etc., provide many better methods for the manufacture of pharmaceutical particles 10,88,89 Another of this technology The significant advantage is that it allows single-step manufacturing of particles with uniform size distribution, which is difficult to achieve with traditional methods. In addition, the SCF auxiliary process has been used to synthesize various formulations of different categories and routes of administration, which have been discussed elsewhere. 10 This technology has been used to process API alone or in combination with various biodegradable polymers. 10 In this framework, the most advanced prototype SEDS process of SCF technology has been widely used in the pharmaceutical manufacturing process for the production of dosage forms for oral, pulmonary, and transdermal routes of administration. Here, we introduce in detail through a set of examples SEDS process processing API.

Micro-nanoization of pure drugs

Drug delivery is associated with some key challenges, such as solubility and diffusion, which need to be addressed in order to effectively transport therapeutic cargo. More commonly, new chemical entities also have poor solubility and stability problems. In addition, the dissolution rate after API administration is still an important issue for the formulation type, especially for drugs with a narrow therapeutic index. In order to overcome this limitation, a large number of studies have shown that reducing the particle size is one of the ways to improve the efficacy of such drugs. This has been well achieved by the micronization or nanonization of drugs, which leads to an increase in the available surface area exposed to solvents, which subsequently dissolve poorly water-soluble drugs and ultimately increase their therapeutic efficiency. In addition, these nano-sized products have been used in various biomedical applications, such as bioimaging, tissue engineering, in vitro diagnostics, and implants (Table 1). 3,10,88,90

Table 1 shows example abbreviations for nanonization/micronization of pure drugs using the SEDS process: DCM, dichloromethane; DMSO, dimethyl sulfoxide; EA, ethyl acetate; ethanol, ethanol; methanol, methanol; SEDS, supercritical The fluid solution enhances dispersion.

Various technologies, such as grinding, grinding, pulverizing, electrostatic spinning and spray drying, etc., can also be used to produce micron and nanometer particles of various pharmaceutical compounds. 10,74 However, the applicability of these traditional processes is limited due to the large amount of organic solvents required. In some cases, these processes can produce a wider particle size distribution in the final product, thermal denaturation due to high processing temperatures, and excessive surface changes or roughness of the product, thereby affecting the bioavailability of the drug. 10 In addition, this process may cause the product to be contaminated and damaged by the sensitive biomolecules due to the strong shear and heat generated by them in some cases. 59,90,91

Among all SCF-assisted processes, the SEDS technology is one of the effective methods for drug nanometerization, because the excessive mass transfer rate, enhanced mixing, and the formation of tiny droplets result in a very large range of fine particles. Ultrafine particles with narrow size distribution. 59,91 This process usually produces fine-sized drug particles with high efficiency because it uses an anti-solvent that acts as a spray enhancer through a mechanical effect. 65,92,93 The immediate high-speed liquid jet in contact with SCF will produce a uniformly dispersed mixture and eventually cause the rapid precipitation of nano-sized particles. The customization operation of the SEDS process is very fast, so it causes the physical state of the solute to change from the conventional crystalline state to the amorphous form. In this state, it has no opportunity and scope to consolidate the solute in its system crystallization mode 59,90,91 From a thermodynamic point of view, due to the regular arrangement of basic structural units, the solute happens to be in the lowest energy state in its crystal equivalents. 90 However, the transition of its physical state will lead to excess free energy and entropy, and these consequences will undoubtedly promote a surge in the dissolution rate of the drug and ultimately increase its bioavailability (Figure 2). 59,90

Figure 2 FE-SEM pictures of the pure (A) and SEDS process-assisted nanoparticle form (B) of methotrexate powder. Note: Reprinted from J Supercrit Fluids. Volume 67. Chen AZ, Li L, Wang SB, etc. Nanometerization of methotrexate by enhanced dispersion of supercritical CO2 solution. Page 7-13. Copyright 2012, with permission from Elsevier. 59 Abbreviations: FE-SEM, field emission scanning electron microscope; SEDS, supercritical fluid solution enhanced dispersion.

Generally speaking, the SEDS process is not only used to manipulate poorly water-soluble drugs, but also widely used to precipitate protein and peptide drugs, which are designed to be absorbed through non-invasive routes of administration (such as pulmonary and transdermal delivery). .96,97 Despite the success and reliability of formulating therapeutic proteins through the SEDS process, poor chemical degradation mechanisms and conformational changes may affect primary, secondary, and/or tertiary structures, so long-term stability may be impaired Affected 96 However, extensive research is needed to overcome these limitations and explore the separate treatment of sensitive biological macromolecules.

In recent years, various biodegradable and biocompatible polymers have attracted great attention from researchers in the preparation of controlled release systems, because they are easy to impregnate drugs, can deliver a large number of therapeutic drugs, and protect the drug to be released continuously from the matrix. drug. 10,104–106 In addition, incorporating the drug into a suitable carrier can help improve the fate of the drug by changing the way the drug is delivered. Mode (Figure 3). However, the ability to control various physical parameters (such as morphology, size, stimulus response, and desired release characteristics) is very challenging during the formulation of polymer carriers. By considering the thermal sensitivity and polarity of the polymer, these parameters completely depend on the choice of polymer. In addition, the key aspect that should be considered during the processing of polymer carriers is their solubility in SCF. However, in the SEDS process, it can be surpassed by dissolving them in the required organic solvents, which can eventually be removed by extraction after the particles are formed. These processes that use SCF as an anti-solvent to produce many drug products through co-precipitation or encapsulation strategies involve important solvation capabilities that are used to effectively separate the desired polymer and drug mixture as micron or nano-sized particles. In this case, various biodegradable micro/nanoparticles prepared by SEDS and its improved processes are used as potential delivery systems to complete therapeutic tasks (Figure 3; Table 2). 107 More commonly, active therapeutics, such as drugs, proteins, steroids, carotenoids, and organic pigments, have used various biodegradable polymer carriers (such as PLLA, PLGA, polyethylene glycol, chitosan, etc.). , Alginate, lactose, etc.) are incorporated to control delivery. 10,52,91, 92,108–110 This technology can adjust the size of polymer particles, which makes it very feasible to connect targeting ligands to achieve targeting efficacy, and their smaller size is conducive to high dissolution rate and improve the biologics of the drug Utilization. The high dissolution rate and increased bioavailability of these drugs subsequently promoted their therapeutic efficiency at low doses. 107,111 The controlled release of drugs can usually be achieved through different mechanisms, depending on the preparation method selected as the type of polymer selected. More commonly, drugs co-precipitated/encapsulated by SEDS and related processes are released by slow diffusion from the polymer matrix. In this framework, the interaction between the polymer and the drug usually constitutes an electrostatic or weak hydrogen bond interaction, which weakens and promotes the release of the drug when exposed to a solvent.

Figure 3 Schematic diagram of the formula synthesized by SEDS and its improved process. Abbreviations: SC-CO2, supercritical CO2; SEDS, supercritical fluid solution enhanced dispersion.

Table 2 Examples of drug-polymer conjugates obtained by SEDS treatment. Abbreviations: CD, cyclodextrin; DCM, dichloromethane; DMSO, dimethyl sulfoxide; EA, ethyl acetate; ethanol, ethanol; FA, folic acid ; HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; HPMC, hydroxypropyl methylcellulose; methanol, methanol; PCL, polycaprolactone; PEG, polyethylene glycol ; PLA, polylactic acid; PHBV, poly(3-hydroxybutyrate-co-hydroxyvalerate); PLGA, poly(lactic acid-glycolic acid copolymer); PVP, polyvinylpyrrolidone; SEDS, supercritical fluid solution Enhanced dispersion; SF, silk fibroin; THF, tetrahydrofuran; w/w, weight/weight; v/v, volume/volume.

In the traditional SEDS process, the composite micro/nanoparticles formed during the co-precipitation of drugs and polymers sometimes lead to low drug loading and reduced packaging efficiency due to decompression and washing during washing. In addition, the drug molecules dispersed in the polymer matrix are adsorbed on the surface of the polymer through weak binding interactions, which usually leads to the rapid release of the entire drug cargo. 66 In order to overcome these limitations, Chen et al. created an innovative core-shell preparation using an advanced SEDS process, namely SpEDS, which improved the drug loading efficiency and showed a sustained drug release effect. 29 In this process, drug nanoparticles are initially produced and then coated with polymers to produce core-shell composites. In addition, the authors proved that this treatment method has advantages over other SCF-assisted treatment methods because the drug molecules in the core diffuse slowly, after which the outer shell becomes porous or degraded by the surrounding fluid. In some cases, pH/thermosensitive polymers have also achieved rapid degradation, which is an explosive process. 10

Biomacromolecules such as proteins, genes and vaccines are the most promising therapeutic agents. They should be delivered to the desired site in an appropriate amount without losing their biological activity, thus having a higher curative effect and lower administration. Dosage requirements. 126,127 Pulmonary drug delivery is due to its high surface area, high vascularization, receiving the entire cardiac output, thin blood-alveolar barrier, and low enzyme activity. Therefore, it is an important alternative for the delivery of such therapeutically sensitive biomolecules. For example, the lung is a suitable site for absorbing various therapeutic agents. 10,122,128,129. More commonly, the pulmonary administration of various active parts for local and systemic treatments is accomplished through various delivery containers, such as dry powder inhalers, pressurized Metered-dose inhalers and nebulizers, loaded with powdered preparations. The size of the particles plays a crucial role in the manufacture of powders for inhalation and delivery. The acceptable size range for these powders should be <7 μm to allow them to be effectively deposited in the lungs. 42,45,87,129 Among all these SCF-based processes, the SEDS process is one of the most effective methods for synthesizing pharmaceutical preparations for inhaled administration. However, it should be noted that special care should be taken to avoid any residual amounts of organic solvents, as these residues may cause adverse and severe immune reactions in the lungs. In addition, another noteworthy issue that should be considered during the preparation of these delivery systems is to strictly optimize the formulation to maintain the biological activity of the therapeutic biomolecules. In one case, Tservistas et al. used mannitol as the main excipient and prepared a dry powder formulation of plasmid DNA through an improved SEDS process. 122 A significant improvement in this process is the use of a three-channel coaxial nozzle, which produces DNA-laden particles. Initially, nucleic acids processed by this high-pressure technique caused degradation of plasmid DNA. However, further studies have shown that the pH of the medium plays a crucial role in the recovery of intact DNA, and ultimately, the supercoiled ratio of DNA is restored (~80%). 122 Many other studies have also reported that the inhaled synthesis through SEDS and its improvement process, the delivery system of drugs and other therapeutic biomolecules (such as genes and proteins) is feasible. 78,80,122,130

Due to its potential advantages, such as bypassing the liver's first-pass metabolism, sustained drug release, and topical therapy, transdermal route administration has aroused increasing interest among researchers. 120,131-133 However, the effective penetration of drugs through the skin is highly restricted by a protective barrier called the stratum corneum. To overcome this limitation, some penetration enhancement techniques, including microneedles, 131 electroporation, 132 iontophoresis, 134 and ultrasonic pretreatment, 133, etc., 135 have been proposed for drug delivery and cosmetic applications. 135,136 However, the applicability of these methods is limited.120 For this reason, SCF adjuvant formulations have been transdermally administered to improve penetration efficiency because they have several advantages, such as high drug loading efficiency through diffusion in the matrix, plasticization Effect, high solubility, low residual solvent content and narrow and uniform particle size distribution, thereby improving the solubility and permeability of the drug. 137 In one case, Chen et al. used the SpEDS process to manufacture silk fibroin (SF) magnetic nanoparticles. 10,127 Transdermal drug delivery is effective through the use of SEDS process assisted SF nanoparticles combined with a fixed/alternating magnetic field. , Fully achieved this goal. It is worth noting that the synergistic combination of the magnetic field acting on the magnetic nanoparticles produces a massage-like effect on the skin to penetrate the carrier. 127

The implantable drug delivery system is an incredible medical device that is pre-loaded with drugs or other biomolecules and inserted into the body through surgical procedures for long-term treatment. More commonly, these systems are used to treat postoperative complications, such as infections and immune reactions. 10,138 In addition, these systemic drug delivery systems are considered to be potential solutions to the problems associated with various other systemic delivery routes, such as frequent dosing. 10,118,138 Various methods have been considered to produce implantable systems, such as solvent casting and hot melt extrusion. 10 However, these methods still face certain problems. Limitations, such as high processing temperatures and organic solvent residues, can cause undesirable immune responses during implantation. For this reason, SCF technology overcomes the limitations of the above-mentioned traditional manufacturing methods and has attracted great interest from researchers in synthesizing these implants. This technology is very conducive to API processing, and its applicability is limited due to its poor pharmacokinetic behavior, such as low solubility and subsequent low bioavailability. 118 Interestingly, Xie et al. developed an implantable polymer nanofiber drug delivery platform to enhance the bioavailability of the natural polyphenol compound curcumin (CM) for effective cancer treatment. 138 This active part is known for its effects on many cancers. In this study, the nanofiber implantable matrix of the SF carrier incorporated into the CM by the SEDS process resulted in a controlled release of CM for local cancer treatment (Figure 4). 117,138

Figure 4 Schematic diagram showing the mechanism of using the SEDS processing method to improve the cell uptake efficiency of the implantable nanofiber drug delivery platform. Note: Reprinted from biological materials. Volume 103. Xie Min, Fan Ding, Chen Yi, etc. An implantable and controllable drug release silk fibroin nanofiber matrix can promote the treatment of solid tumors and cancers. Pages 33-43. Copyright 2016, with permission from Elsevier. 138 Abbreviations: CM-SF, curcumin-silk fibroin; SEDS, supercritical fluid solution to enhance dispersion.

Due to its environmentally harmless nature, SCF technology has been widely used in various applications in the healthcare field except for drug delivery. 6,10 One of them is the processing of various biologically active substances, namely proteins and carotenoids, for nutraceutical applications and their encapsulation in biodegradable polymers to produce particles for effective nutrient delivery. 101 In addition, biodegradable polymers coated on biomolecules provide them with significant protection from the harsh environment in physiological fluids. Carotenoids, commonly referred to as nutraceutical compounds, are the most common group of pigments widely used in the food and health product industries. 101 More commonly, the presence of carotenoids can inhibit the oxidation of food ingredients because of its singlet oxygen quenching activity. 109 In addition, these substituents are used to improve the aesthetics of food. However, the color intensity of pigments depends entirely on their physical and chemical properties, such as particle size and its distribution and morphology. 101,109 More commonly, these water-insoluble commercial carotenoids exist in their crystalline form and are usually processed using oils and organic solvents, which may cause contamination of food and nutrients. For this reason, this environmentally friendly process can overcome the limitation of food contamination. The SEDS process is the most effective method to treat carotenoids, because the strategy is operated in close to environmental conditions and in an inert environment, and sensitive carotenoids have no thermal degradation range. 65,139 Unlike other traditional methods, the process on which SCF is based does not rely on organic solvents. Due to the increased surface area exposed to the solvent, SEDS micronizes or nanosizes these nutrients, thereby increasing their solubility. 6,10 However, it is clear that the applicability of synthetic colors is limited due to their health hazards in the food, cosmetics and pharmaceutical industries. In one case, Hong et al. micronized the natural pigment astaxanthin by using a supercritical fluid solution-enhanced dispersion-pre-filming atomization method. 139 The author proves that this natural pigment has different biological functions, such as UV protection, so it is the first choice. 139 In addition, the author claims that various experimental variables such as the initial concentration of the solute, the solution flow rate and the critical condition are important for determining the shape and particle size. Have a significant impact. Astaxanthin granules. 70

Due to the presence of double bonds in the molecular chain of carotenoids, processing these nutrients through traditional manufacturing methods usually produces adverse effects. 109 In this framework, exposure of these sensitive molecules to heat, light, and acid may result in the isomerization of trans carotenoids (stable form) into the cis form, which is relatively inferior to the trans form (i.e., reduced color). , The activity of provitamins is reduced, ultimately reducing its efficacy) 109,140,​​141 Encapsulation and co-precipitation of these proteins/carotenoids in biodegradable polymers through the SEDS process is the most effective way to maintain the effect and increase its efficiency. 109,119 In addition, further progress has been made in formulating nano-sized inclusions using the SEDS process to compound with β-cyclodextrin. 140 Under optimized conditions, 40 nm lycopene/β-CD nanoparticles are obtained at high temperature and the solution flow rate under pressure is low, thereby improving the solubility and stability of lycopene.

In summary, this review provides insights into the SEDS process in generating micro/nano-sized APIs or their polymer conjugates, which can be administered by oral, pulmonary, and transdermal routes. In addition, specialized formulations such as core-shell formulations and implantable nanofiber delivery systems have been systematically reviewed. Compared with products obtained through other processing technologies of SCF technology, the delivery system produced by this process has higher advantages, resulting in products with better performance. In addition, we emphasized the influence of various parameters on particle morphology during SEDS processing.

Despite its success and significant advantages, the SEDS method still faces major obstacles in its scale-up processing due to the lack of basic research to accurately describe the phase behavior and performance of multi-component mixtures. In addition, the certainty of particle properties, including increased solubility of the particles produced by this process, remains an obstacle. Therefore, we envision that the combination of traditional technology and SCF technology may lead to further advances in the carrier. In addition, it may go beyond the complexity of processing and be able to better understand the behavioral characteristics of the product. However, with continuous innovation, we believe that promising formulations of biodegradable micro/nanoparticles from these SCF-assisted processes will soon be commercialized.

Thanks to the National Natural Science Foundation of China (U1605225, 31570974, 31470927), the Marine Public Science and Technology Research Fund Project (201505029), the Science and Technology Research Promotion Program for Young and Middle-aged Teachers, Huaqiao University (ZQN-PY107), and the Youth Research Initiative Fund (Project No. 16BS803) ).

The authors report no conflicts of interest in this work.

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