Biopolymer Microspheres by Supercritical

Article pubs.acs.org/IECR

Production of Luteolin/Biopolymer Microspheres by Supercritical Assisted Atomization Alessia Di Capua, Renata Adami,* and Ernesto Reverchon Department of Industrial Engineering. University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy ABSTRACT: Supercritical assisted atomization (SAA) was used to produce coprecipitated submicroparticles of luteolin (LUT)/poly(vinylpyrrolidone) (PVP) for pharmaceutical applications. LUT has antioxidant, antiinflammatory, and antitumoral properties but is poorly water-soluble, whereas PVP is highly water-soluble. This polymer can be used to protect the active molecule and to improve its bioavailability. Different LUT/PVP weight ratios were selected ranging between 1:4 and 1:8. SAA produced partly collapsed spherical particles with controlled particle size and mean diameters ranging between 0.22 and 0.33 μm. UV−vis analyses revealed very high loading efficiency of LUT in SAA particles (99−100%). The powders are amorphous, whereas the untreated material shows crystalline patterns. Fourier transform infrared revealed that hydrogen bonds were created between the drug and polymer. Drug-release analysis indicated that the supercritical processing was successful: the LUT dissolution rate in a phosphate-buffered saline solution was up to 9 times faster compared to that of an unprocessed drug.

1. INTRODUCTION Flavonoids are naturally occurring polyphenolic compounds found in several kinds of fruits, vegetables, and medicinal plants.1−4 Apart from their physiological roles in plants, flavonoids are relevant for human health because of their pharmacological properties, e.g., antiviral, antibacterial, antiinflammatory, vasodilatory, antiischemic, and anticancerous.5,6 They may block the proliferation of tumor cells, including metastatis and angiogenesis, by inhibiting kinase, reducing transcription factors, regulating cell cycles, and inducing apoptotic cell death.7,8 Luteolin (LUT) is one of the most common flavonoids present in plants, usually used in Chinese traditional medicine to treat a wide variety of diseases, such as hypertension, inflammatory disorders, and cancer.8,9 However, its instability, poor bioavailability, and hydrophobicity restrict its clinical applications. The reduction of the particle size (PS) of a drug can improve its bioavailability because the exposed surface in contact with the medium increases and, therefore, also its dissolution rate. However, the bioavailability can be improved also thanks to formulations based on a carrier in which the drug is finely dispersed. The carrier has to protect the active principle, inhibit crystallization, and improve dissolution.10−12 Several conventional micronization processes can be used: spray drying,13,14 jet milling,15 coacervation,16 and solvent evaporation.17,18 These techniques have some drawbacks: wide particle size distribution (PSD), high temperature, mechanical and thermal stresses for the product, and large use of organic and toxic solvents. In the case of LUT PS reduction, different techniques have been proposed. Dang et al.19 prepared solid lipid nanoparticles of LUT/soybean lecithin by a hot microemulsion technique at the laboratory scale, melting lecithin at 75 °C. They obtained © 2017 American Chemical Society

nanoparticles with an entrapment efficiency of about 75%, which were tested in vitro and in vivo on rats, demonstrating an increase of the LUT bioavailability of about 4.9 times with respect to a LUT suspension in water. Khan et al.20 prepared a laboratory recipe in which LUT was complexed with phospholipids, forming nanoparticles. They demonstrated that a faster dissolution rate of complexed LUT was possible, up to about 2.5 times that of pure LUT in water. The LUT complex was also successfully tested in animal studies. Puhl et al.21 prepared LUT + polymer particles [polycaprolactone and poly(lactic-co-glycolic acid)] by nanoprecipitation at small laboratory scale using, as the organic phase, oils like oleic acid and isodecyl oleate and obtained high encapsulation efficiencies (larger than 97%). This result is surprising because, in nanoprecipitation, particle formation is driven by nucleation and growth, and only a wrapping activity of the polymer can justify the formation of composite micro/nanoparticles instead of two separate precipitates. Success was possible because of the fact that very small quantities of LUT were used with respect to the polymer content; they used 75 mg of polymer versus 1.25 mg of LUT: it means a drug-to-polymer ratio of 1:60. In summary, the work found in the literature was successful in demonstrating the feasibility of the LUT bioavailability increase when LUT was coprecipitated and produced at a submicroscale. However, reliable, large-scale applicable processes have not been tested yet for LUT coprecipitation. Supercritical fluid (SCF)-based techniques are a good alternative to conventional processes and are able to overcome their limitations.22 Several materials have been processed using Received: Revised: Accepted: Published: 4334

January 16, 2017 March 24, 2017 March 29, 2017 March 29, 2017 DOI: 10.1021/acs.iecr.7b00211 Ind. Eng. Chem. Res. 2017, 56, 4334−4340

Article

Industrial & Engineering Chemistry Research these techniques in different fields, such as micronization,23−27 membrane and scaffold production, 28−30 extraction of emulsions,31−33 impregnation,34 aerogel formation,35 and extraction of active compounds.36 Among these, supercritical assisted atomization (SAA)37 has been used to produce coprecipitates at the submicronic and micronic levels. In SAA, supercritical carbon dioxide (SC-CO2) is solubilized in a solution containing the compound to be micronized, forming an expanded liquid, characterized by reduced viscosity and surface tension, that is subsequently atomized. SAA produces controlled micro- and submicrodroplets that, upon drying, produce submicroparticles. It was used to reduce the PS of pure compounds38,39 but also to produce composite microparticles formed by a polymeric carrier in which a drug can be homogeneously dispersed.40−42 A polymer frequently used for the production of this kind of formulation is poly(vinylpyrrolidone) (PVP). It is a good carrier to enhance the dissolution rate of hydrophobic compounds43 because it is readily soluble in water and nontoxic. PVP can also be used to suppress the recrystallization44 of active molecules. It is accepted by the Food and Drug Administration, and it was found that PVP increases the activity of some active molecules, such as anticancer drugs.45 Because the LUT bioavailability increase by micronization has been proved but large-scale applicable processes have not yet been proposed, it could be relevant to study the applicability of SAA on systems LUT + polymer to produce composite micro/nanoparticles, in which the selected polymer is PVP. The ratio LUT/PVP should be the major parameter studied to establish its influence on the release rate of LUT. The microparticles obtained will be analyzed to control the effective formation of coprecipitates and measure the improvement of the release rate of LUT with respect to the starting material and its physical mixtures with PVP.

SON (Italy), and nitrogen (N2, 99%) was supplied by SOL (Italy). The SAA plant consists of two high pressure pumps (model 305, Gilson) delivering a liquid solution and CO2 to the saturator. The saturator is a high pressure vessel (50 cm3 internal volume) loaded with stainless steel perforated saddles to ensure a large contact surface between CO2 and the liquid solution. The expanded liquid is sprayed through a thin wall injection nozzle (80 μm internal diameter) into the precipitator (3 dm3 internal volume). A controlled flow of N2, heated in an electric heat exchanger (model CBEN 24G6, Watlow), is sent to the precipitator to allow droplet evaporation. The saturator and precipitator are electrically heated using thin band heaters (model STB3EA10, Watlow). The system is completed by a condenser that separates liquids from the gas stream at the exit of the precipitator. A stainless steel filter, located at the bottom of the precipitator, is used to collect powders. Further details and a schematic representation of the SAA plant were reported in previous works.37,38 The morphology of LUT/PVP produced particles was observed by FESEM (model LEO 1525, Carl Zeiss SMT AG, Oberkochen, Germany). Powders were dispersed on a carbon tab previously stuck to an aluminum stub (Agar Scientific, Stansted, U.K.). Samples were coated with gold (layer thickness 250 Å) using a sputter coater (model 108A, Agar Scientific). The PSD and PS were measured by a method based on FESEM photomicrographs: 1000 particles were measured for each PSD calculation, using Sigma Scan Pro Software (release 5.0; Aspire Software International, Ashburn, VA). Histograms, representing the PSD, were fitted using Microcal Origin Software (release 8.0; Microcal Software, Inc., Northampton, MA). Solid-state analysis of the precipitates was performed using powder X-ray diffraction (PXRD; model D8 Advance; Bruker AXS, Madison, WI) using a copper-sealed tube source. Samples were placed in the holder and flattened with a glass slide to ensure a good surface texture. The measuring conditions were nickel-filtered Cu Ka radiation, λ = 1.54 A, and a 2θ angle ranging from 4 to 50° with a scanning rate of 0.2 °C/step and a step size of 0.03°. Microparticle thermal characteristics were determined by differential scanning calorimetry (DSC; model TC11, Mettler Toledo, Inc., Columbus, OH). An accurately weighed amount of powder (±5 mg) was crimped in a standard aluminum pan that was pierced and heated from 25 to 350 °C at a scanning rate of 10 °C/min in a nitrogen atmosphere at a flow rate of 50 mL/min. Fourier transform infrared (FTIR) analysis was performed with a FTIR spectrophotometer (IRTracer100, Shimadzu). The samples were combined with a small amount of potassium bromide and pressed to 10 tons in a manual press. Analysis was performed at 25 °C, in the range 500−4000 cm −1 at a resolution of 1 cm −1 as the mean of 16 measurements. Drug loading and powder dissolution studies were performed using UV−vis spectrophotometry (model Cary 50, Varian, Palo Alto, CA). Drug loading into the coprecipitates was evaluated by measuring the UV−vis absorbance of LUT in ethanol at its characteristic wavelength of 275 nm. At this wavelength, PVP is not visible by the UV−vis spectrophotometer. The absorbance was then converted into the LUT concentration using a calibration curve. The loading efficiency was calculated as the ratio between the measured and theoretical drug contents. In dissolution tests, accurately weighed samples containing an equivalent amount of LUT (5 ppm), for each drug/polymer ratio (R), were incubated in 400 mL of phosphate-buffered

2. MATERIALS AND METHODS Poly(vinylpyrrolidone) (PVP; Mw = 10000 g/mol) was obtained from Fluka (Italy). Luteolin [LUT; its chemical structure and field-emission scanning electron microscopy (FESEM) images are reported in Figure 1] was supplied from Epitech Group Research Laboratories (code MP908, Italy). Ethanol (99%) was purchased from Sigma-Aldrich Chemical Co. (Italy) and carbon dioxide (CO2, 99.9%) from

Figure 1. FESEM image and chemical structure of untreated LUT. 4335

DOI: 10.1021/acs.iecr.7b00211 Ind. Eng. Chem. Res. 2017, 56, 4334−4340

Article

Industrial & Engineering Chemistry Research saline (PBS) at pH 7.4 and continuously stirred at 200 rpm and 37 °C. Each analysis was in triplicate.

Table 1. Ratios and Concentrations of LUT/PVP Used in Coprecipitation Experimentsa

3. RESULTS AND DISCUSSION First, LUT alone was micronized by SAA to evaluate its processability. The process conditions selected were 4 mg/mL LUT in ethanol, at 80 °C and 95 bar in the saturator with a gasto-liquid ratio (GLR; mass ratio between CO2 and the liquid solution) of 1.8 and 80 °C in the precipitator. These process conditions were selected to ensure a good solubility of CO2 in ethanol. The particles obtained showed an irregular morphology, as in the FESEM photomicrograph reported in Figure 2,

test code LUT01 PVP PVPL01 PVPL02 PVPL03

R (wLUT/wPVP)

1:8 1:6 1:4

Cpol (mg/mL)

C (mg/mL)

10 10 10 10

4.00 10.00 11.25 11.66 12.50

mean diameter (μm) 0.34 0.16 0.33 0.23 0.22

(±0.11)b (±0.11) (±0.12) (±0.11) (±0.09)

a

Cpol = polymer concentration; C = total concentration; R = LUT/ PVP (w/w); wLUT= LUT weight; wPVP = PVP weight. bSuperposition of the amorphous and crystalline products.

has sometimes been previously observed in SAA processing and can be due to the fragility of the solid structure.39,50,51 SAA particles collapses in a more evident manner as R increases. Because SAA shows many similarities with spray drying, the particle collapse can be explained by referring to this latter process. The theory of particle formation in spray drying52−54 claims that the particle morphology is influenced by the drying time, shell flexibility, and evaporation rate. When a dilute solution is processed, during drying, a thin layer of solid is formed. This shell can be fragile or flexible, and if the drying temperature is high, the solvent evaporation will be very fast and particles can deflate. This theory can also explain the morphology of LUT/PVP SAA produced particles. Figure 4 reports the PSDs in terms of the number of particles calculated from FESEM images, where the curves obtained at different LUT/PVP ratios are compared. The mean size of the coprecipitates depends on the LUT/PVP weight ratio (R): their mean diameter increases as R decreases. Submicroparticles were consistently obtained; the largest PSD covers the range from 0.1 to about 1.2 μm. 3.1. Solid State. PXRD analysis of coprecipitates and of pure LUT and PVP is reported in Figure 5. The analyses revealed that unprocessed LUT has a crystalline structure whereas untreated PVP shows the typical halos of an amorphous polymer. LUT processed by SAA, instead, shows only two enlarged peaks that might to be due to a partial recrystallization of LUT during droplet evaporation. This fact could explain the presence of the small needles, as seen in Figure 2. The diffractograms of all SAA coprecipitates show only PVP halos, while LUT peaks are not present. This result can be explained by a homogeneous dispersion of LUT in the polymer matrix. However, this result might be caused by a nonefficient coprecipitation and, therefore, it will be verified in the following part of this paper. All coprecipitates show an amorphous structure. FTIR analyses were performed to identify possible interactions between LUT and PVP in the composite particles. In Figure 6, FTIR spectra of unprocessed LUT and PVP, SAA coprecipitates, and a physical mixture are reported in the range 1750−500 cm−1. The spectrum of PVP shows a characteristic absorption band at 1653 cm−1, which corresponds to the stretching vibration of CO groups, a C−H stretching vibration at 2875 cm−1, and a −OH stretching vibration at 3469 cm−1. The spectrum of untreated LUT shows characteristic absorption bands at 1656 cm−1, which suggests the stretching vibration of a carbonyl group, at 1166 cm−1 related to C−O−C stretching vibration, and at 1266 cm−1 related to the bending of phenolic hydroxyl groups. The spectrum of the physical mixture LUT/PVP shows superimposition of the

Figure 2. FESEM image (Mag = 35 KX) of LUT particles produced by SAA.

with the formation of spherical particles from which small needles emerge. These results indicate that LUT has a very fast crystallization kinetics, and during the latter steps of droplet evaporation, it starts to crystallize. This particular tendency has been previously observed for other SAA processed materials.46−48 Each microsphere acts as an isolated precipitator and evidences the superposition of amorphous solidification and crystallization processes. PVP alone was also micronized by SAA, using ethanol as the solvent, in a previous work,49 perfectly spherical particles were obtained, and no problems were evidenced for its micronization. In a summary of these first results, LUT is not a perfect candidate for SAA micronization, whereas PVP gives no processing problems. The process conditions selected for coprecipitation experiments, on the basis of SAA experiments performed using LUT alone, were as follows: injection pressures ranging between 95 and 98 bar, a saturator temperature of 80 °C, and a precipitation temperature of 80 °C. The CO2 flow rate was set at 7.8 g/min, and the solvent flow rate was set at 5.4 mL/ min to obtain a GLR in the saturator of 1.8. LUT/PVP ratios of 1:8, 1:6, and 1:4 (w/w) were selected to study the influence of this parameter on the LUT release rate, using a constant concentration of the polymer (10 mg/mL). In Table 1, the ratios and concentrations of LUT/PVP used in selected coprecipitation experiments are summarized. Examples of FESEM images of the 1:8 and 1:4 LUT/PVP samples are reported in Figure 3. These particles consist of spherical and/or collapsed submicrospheres. This morphology 4336


Article

Industrial & Engineering Chemistry Research

Figure 3. FESEM images (Mag = 30 KX) of LUT/PVP microparticles produced at R = 1:4 (a) and 1:8 (b).

characteristic bands of LUT and PVP. All SAA coprecipitates show the presence of hydrogen bonding between the two compounds that have a significant influence on the peak shape and intensities. The interaction between the two compounds produces the shift of the LUT peak located at 1036 cm−1 to lower frequencies. Also, the absorption peak at 1377 cm−1 in the PVP spectrum is shifted to 1371 and 1361 cm−1 in the LUT/PVP spectrum respectively for R = 1:8 and 1:4, due to another interaction between the drug and polymer. Furthermore, there are two peak broadenings toward 1600 and 1260 cm−1 in the composite particle spectra, more evident at R = 1:4. These two changes in the LUT/PVP spectrum can be explained by the breakdown of the intermolecular hydrogen bonding of LUT and the creation of new hydrogen bonds between PVP and LUT. Therefore, higher R values lead to more hydrogen bonds and to more marked shifts of the characteristic peaks of LUT. DSC analyses (Figure 7) were performed to determine the changes in the thermal behavior of the drug and polymer in the

Figure 4. PSDs of LUT/PVP composite particles produced by SAA at different drug/polymer weight ratios.

Figure 5. PXRD related to the untreated PVP and LUT and SAA coprecipitates.

Figure 7. DSC analysis related to untreated PVP and LUT and SAA coprecipitates.

coprecipitates LUT/PVP. They confirmed that untreated LUT is crystalline and its fusion temperature is 340 °C. Furthermore, LUT is a hygroscopic compound, as proven by the broad endothermic peak ranging from 90 to 100 °C. Unprocessed PVP shows a broad endothermic peak ranging between 50 and 130 °C. SAA processed LUT/PVP particles do not present any crystalline peak, and their DSC thermograms are very similar to that of PVP. In summary, all solid-state analyses suggest that the drug is homogeneously dispersed in the PVP matrix because each particle is the result of drying of a droplet containing LUT and PVP. Furthermore, these analyses evidence interactions between the drug and polymer.

Figure 6. FTIR analysis of raw materials and SAA coprecipitates.

4337


Article

Industrial & Engineering Chemistry Research 3.2. Drug Loading and Loading Efficiency. The loading efficiency of LUT in the composite submicroparticles is the major evidence of a successful coprecipitation. It was measured by UV−vis analysis, as previously described, and was over 99% for all drug/polymer weight ratios studied, as summarized in Table 2. This result is not surprising because the mechanism of

dissolution rate increases when the relative quantity of the polymer decreases.50 This behavior was expected also in this case because the polymer (PVP) is highly water-soluble, and at higher polymer contents, smaller LUT nanoparticles should be formed inside the coprecipitate. Several parameters usually influence drug release from the coprecipitates. Our hypothesis, to explain the trend of the LUT/PVP dissolution behavior, is that the main role is taken by the interactions between the two compounds that reduce the dissolution rate of PVP, and, consequently, the release rate of LUT is slower in the liquid medium. These results were expected because the solid state analyses showed that LUT is uniformly dispersed in PVP microparticles.

Table 2. LUT Loading and Loading Efficiency for Particles Produced by SAA test code

R (wLUT/wPVP)a

theoretical loading (%)

effective loading (%)

loading efficiency (%)

PVPL01 PVPL02 PVPL03

1:8 1:6 1:4

11.1 14.2 20.0

11.0 (±0.18) 14.2 (±0.15) 19.9 (±0.22)

99.0 100.0 99.4

a

4. CONCLUSIONS This work has shown that it is possible to improve the LUT dissolution rate and bioavailability by preparing SAA nanodispersed LUT/PVP submicroparticles: the corresponding dissolution rate is up to 9 times faster than that of the untreated drug. The dissolution time is reduced from the scale of days to only several hours. An unexpected result is that small quantities of PVP are enough to obtain excellent results for coprecipitation and for an increase of the release rate. The formation of the LUT/PVP bonds gives an account of the apparently anomalous trend of the drug release rate curves, showing that the LUT release rate increases reducing the PVP percentage used in the coprecipitate, up to the largest drug/polymer ratio tested in this work (R = 1:4).

R = LUT/PVP (w/w), wLUT = LUT weight, and wPVP = PVP weight.

SAA microparticle formation is atomization of the solution and droplet drying; therefore, the components of the starting solution tend to remain together in the final particles. However, this result is particularly relevant for the fact that practically all LUT is entrapped in the final product; perhaps, the interactions LUT/PVP, evidenced in the previous analysis, play a role in further stabilizing the composite particles. Therefore, all analytical indications converge toward the conclusion that coprecipitated submicroparticles LUT-PVP were efficiently produced. At this point of the work, dissolution tests were performed to evaluate the improvement of the dissolution rate of LUT in PBS at pH 7.4; this pH simulates blood system. Figure 8 shows the measured dissolution profiles,

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Web site: www. supercriticalfluidgroup.unisa.it. ORCID

Renata Adami: 0000-0001-9467-2630 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Ministero dell’Istruzione dell’Università e della Ricerca is acknowledged for financial support. The authors gratefully acknowledge Epitech Group SpA for supplying the LUT used for the experiments reported in this work and Dr. Mario Bancone for help in performing the dissolution tests.

Figure 8. Dissolution profiles of LUT in PBS at 37 °C and pH 7.4.

plotting the percentage of dissolved LUT as a function of time. It is possible to observe that untreated LUT and the physical mixture at R = 1/4 show a complete dissolution time in about 70 and 57 h, respectively. The coprecipitate produced at R = 1/ 8 totally dissolves in 17 h; whereas, the one produced at R = 1/ 4 completely dissolves in about 8 h: 9 times faster than untreated LUT. The dissolution rate of SAA produced microparticles increases with an increase of the drug/polymer ratio, and all SAA coprecipitates show a faster release than those of untreated LUT. This result confirms that the drug bioavailability is influenced by several factors, like the reduction of PS, morphology, and solid state of the material.10,11,50 When the drug/polymer ratio is increased, larger drug release rates are obtained (Figure 8). This trend seems unusual when compared to other coprecipitated systems tested by SAA, in which the

■

REFERENCES

(1) Lotito, S. B.; Frei, B. Relevance of apple polyphenols as antioxidants in human plasma: contrasting in vitro and in vivo effects. Free Radical Biol. Med. 2003, 36, 201−211. (2) Zheng, W.; Wang, S. Y. Antioxidant Activity and Phenolic Compounds in Selected Herbs. J. Agric. Food Chem. 2001, 49, 5165− 5170. (3) Mustafa, R. A.; Hamid, A. A.; Mohamed, S.; Bakar, F. A. Total phenolic compounds, flavonoids, and radical scavenging activity of 21 selected tropical plants. J. Food Sci. 2010, 75, 28−35. (4) Yao, L. H.; Jiang, Y. M.; Shi, J.; Tomás-Barberán, F. A.; Datta, N.; Singanusong, R.; Chen, S. S. Flavonoids in food and their health benefits. Plant Foods Hum. Nutr. 2004, 59, 113−122. (5) Procházková, D.; Boušová, I.; Wilhelmová, N. Antioxidant and prooxidant properties of flavonoide. Fitoterapia 2011, 82, 513−523.

4338


Article

Industrial & Engineering Chemistry Research

supercritical antisolvent process. Ind. Eng. Chem. Res. 2014, 53, 4318− 4327. (28) Baldino, L.; Cardea, S.; Reverchon, E. Production of antimicrobial membranes loaded with potassium sorbate using a supercritical phase separation process. Innovative Food Sci. Emerging Technol. 2016, 34, 77−85. (29) Baldino, L.; Sarno, M.; Cardea, S.; Irusta, S.; Ciambelli, P.; Santamaria, J.; Reverchon, E. Formation of cellulose acetate-graphene oxide nanocomposites by supercritical CO2 assisted phase inversion. Ind. Eng. Chem. Res. 2015, 54, 8147−8156. (30) Tsivintzelis, I.; Pavlidou, E.; Panayiotou, C. Porous scaffolds prepared by phase inversion using supercritical CO2 as antisolvent. I. Poly(l-lactic acid). J. Supercrit. Fluids 2007, 40, 317−322. (31) Della Porta, G.; Falco, N.; Giordano, E.; Reverchon, E. PLGA microspheres by Supercritical Emulsion Extraction: a study on insulin release in myoblast culture. J. Biomater. Sci., Polym. Ed. 2013, 24, 1831−1847. (32) Campardelli, R.; Della Porta, G.; Gomez, V.; Irusta, S.; Reverchon, E.; Santamaria, J. Encapsulation of titanium dioxide nanoparticles in PLA microspheres using supercritical emulsion extraction to produce bactericidal nanocomposites. J. Nanopart. Res. 2013, 15, 1−11. (33) Shekunov, B. Y.; Chattopadhyay, P.; Seitzinger, J.; Huff, R. Nanoparticles of poorly water-soluble drugs prepared by supercritical fluid extraction of emulsions. Pharm. Res. 2006, 23, 196−204. (34) Duarte, A. R. C.; Simplicio, A. L.; Vega-González, A.; SubraPaternault, P.; Coimbra, P.; Gil, M. H.; de Sousa, H. C.; Duarte, C. M. M. Supercritical fluid impregnation of a biocompatible polymer for ophthalmic drug delivery. J. Supercrit. Fluids 2007, 42, 373−377. (35) Caputo, G.; Scognamiglio, M.; De Marco, I. Nimesulide adsorbed on silica aerogel using supercritical carbon dioxide. Chem. Eng. Res. Des. 2012, 90, 1082−1089. (36) Marques, J. L.; Porta, G. D.; Reverchon, E.; Renuncio, J. A. R.; Mainar, A. M. Supercritical antisolvent extraction of antioxidants from grape seeds after vinification. J. Supercrit. Fluids 2013, 82, 238−243. (37) Reverchon, E. Supercritical Assisted Atomization to produce micro and nano particles of controlled size and distribution. Ind. Eng. Chem. Res. 2002, 41, 2405−2411. (38) Reverchon, E.; Spada, A. Erythromycin microparticles produced by supercritical fluid atomization. Powder Technol. 2004, 141, 100− 108. (39) Liparoti, S.; Adami, R.; Reverchon, E. PEG micronization by supercritical assisted atomization, operated under reduced pressure. J. Supercrit. Fluids 2012, 72, 46−51. (40) Adami, R.; Reverchon, E. Composite polymer-Fe3O4 microparticles for biomedical application, produced by supercritical assisted atomization. Powder Technol. 2012, 218, 102−108. (41) Reverchon, E.; Adami, R. Supercritical assisted atomization to produce nanostructured chitosan-hydroxyapatite microparticles for biomedical application. Powder Technol. 2013, 246, 441−447. (42) Labuschagne, P. W.; Adami, R.; Liparoti, S.; Naidoo, S.; Swai, H.; Reverchon, E. Preparation of rifampicin/poly(d,l-lactice) nanoparticles for sustained release by supercritical assisted atomization technique. J. Supercrit. Fluids 2014, 95, 106−117. (43) Kanaze, F. I.; Kokkalou, E.; Niopas, I.; Barmpalexis, P.; Georgarakis, E.; Bikiaris, D. Dissolution rate and stability study of flavanone aglycones, naringenin and hesperetin, by drug delivery systems based on polyvinylpyrrolidone (PVP) nanodispersions. Drug Dev. Ind. Pharm. 2010, 36, 292−301. (44) Crowley, K. J.; Zografi, G. The effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) on indomethacin crystallization from the amorphous state. Pharm. Res. 2003, 20, 1417− 1422. (45) Kamada, H.; Tsutsumi, Y.; Yamamoto, Y.; Kihira, T.; Kaneda, Y.; Mu, Y.; Kodaira, H.; Tsunoda, S. I.; Nakagawa, S.; Mayumi, T. Antitumor activity of tumor necrosis factor-α conjugated with polyvinylpyrrolidone on solid tumors in mice. Cancer Res. 2000, 60, 6416−6420.

(6) Sharma, D. Pharmacological properties of flavonoids including flavonolignans-Integration of petrocrops with drug development from plants. J. Sci. Ind. Res. 2006, 65, 477−484. (7) Neuhouser, M. L. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr. Cancer 2004, 50, 1−7. (8) Sulaiman, G. M. In vitro study of molecular structure and cytotoxicity effect of luteolin in the human colon carcinoma cells. Eur. Food Res. Technol. 2015, 241, 83−90. (9) Lin, Y.; Shi, R.; Wang, X.; Shen, H. M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets 2008, 8, 634−646. (10) Martín, Á .; Cocero, M. J. Micronization processes with supercritical fluids: fundamentals and mechanisms. Adv. Drug Delivery Rev. 2008, 60, 339−350. (11) Merisko-Liversidge, E. M.; Liversidge, G. G. Drug nanoparticles formulating poorly water-soluble compounds. Toxicol. Pathol. 2008, 36, 43−48. (12) Dizaj, S. M.; Vazifehasl, Z.; Salatin, S.; Adibkia, K.; Javadzadeh, Y. Nanosizing of drugs: Effect on dissolution rate. Res. Pharm. Sci. 2015, 10, 95−108. (13) Paudel, A. T.; Worku, Z. A.; Meeus, J.; Guns, S.; Van den Mooter, G. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations. Int. J. Pharm. 2013, 453, 253−284. (14) Khadka, P.; Ro, J.; Kim, H.; Kim, I.; Kim, J. T.; Kim, H.; Cho, J. M.; Yun, G.; Lee, J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. 2014, 9, 304−316. (15) Joshi, J. T. A review on Micronization Techniques. J. Pharmaceut. Sci. Technol. 2011, 3, 651−681. (16) Thomasin, C.; Merkle, H. P.; Gander, B. Drug Microencapsulation by PLA/PLGA Coacervation in the Light of Thermodynamics. 2. Parameters Determining Microsphere Formation. J. Pharm. Sci. 1998, 87, 269−275. (17) Iqbal, M.; Zafar, N.; Fessi, H.; Elaissari, A. Double emulsion solvent evaporation techniques used for drug encapsulation. Int. J. Pharm. 2015, 496, 173−190. (18) Frizon, F.; Eloy, J. D. O.; Donaduzzi, C. M.; Mitsui, M. L.; Marchetti, J. M. Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid dispersions by solvent methods. Powder Technol. 2013, 235, 532−539. (19) Dang, H.; Meng, M. H. W.; Zhao, H.; Iqbal, J.; Dai, R.; Deng, Y.; Lv, F. Luteolin-loaded solid lipid nanoparticles synthesis, characterization, & improvement of bioavailability, pharmacokinetics in vitro and vivo studies. J. Nanopart. Res. 2014, 16, 2347. (20) Khan, J.; Alexander, A.; Ajazuddin; Saraf, S.; Saraf, S. Luteolinphospholipid complex: preparation, characterization and biological evaluation. J. Pharm. Pharmacol. 2014, 66, 1451−1462. (21) Puhl, A. C.; Fagundes, M.; dos Santos, K. C.; Polikarpov, I.; das Graças Fernandes da Silva, M. F.; Fernandes, J. B.; Vieira, P. C.; Rossi Forim, M. Preparation and characterization of polymeric nanoparticles loaded with the flavonoid Luteolin, by using factorial design. Int. J. Drug Delivery 2011, 3, 683−698. (22) Campardelli, R.; Baldino, L.; Reverchon, E. Supercritical fluids applications in nanomedicine. J. Supercrit. Fluids 2015, 101, 193−214. (23) Prosapio, V.; Reverchon, E.; De Marco, I. Formation of PVP/ nimesulide microspheres by supercritical antisolvent coprecipitation. J. Supercrit. Fluids 2016, 118, 19−26. (24) Prosapio, V.; De Marco, I.; Scognamiglio, M.; Reverchon, E. Folic acid−PVP nanostructured composite microparticles by supercritical antisolvent precipitation. Chem. Eng. J. 2015, 277, 286−294. (25) Campardelli, R.; Reverchon, E. α-Tocopherol nanosuspensions produced using a supercritical assisted process. J. Food Eng. 2015, 149, 131−136. (26) Martín, Á .; Mattea, F.; Gutiérrez, L.; Miguel, F.; Cocero, M. J. Co-precipitation of carotenoids and bio-polymers with the supercritical anti-solvent process. J. Supercrit. Fluids 2007, 41, 138−147. (27) Fraile, M.; Buratto, R.; Gómez, B.; Martín, Á .; Cocero, M. J. Enhanced delivery of quercetin by encapsulation in poloxamers by 4339


Article

Industrial & Engineering Chemistry Research (46) Martin, L.; Liparoti, S.; Della Porta, G.; Adami, R.; Marques, J. L.; Urieta, J. S.; Mainar, A. M.; Reverchon, E. Rotenone coprecipitation with biodegradable polymers by supercritical assisted atomization. J. Supercrit. Fluids 2013, 81, 48−54. (47) Reverchon, E.; Adami, R.; De Marco, I.; Laudani, C. G.; Spada, A. Pigment Red 60 micronization using supercritical fluids based techniques. J. Supercrit. Fluids 2005, 35, 76−82. (48) Adami, R.; Liparoti, S.; Izzo, L.; Pappalardo, D.; Reverchon, E. PLA−PEG copolymers micronization by supercritical assisted atomization. J. Supercrit. Fluids 2012, 72, 15−21. (49) Liparoti, S.; Adami, R.; Reverchon, E. Supercritical Assisted Atomization: effect of operative conditions PVP microparticles size and morphology. J. Supercrit. Fluids 2015, 97, 31−35. (50) Adami, R.; Di Capua, A.; Reverchon, E. Supercritical Assisted Atomization for the production of curcumin-biopolymer microspheres. Powder Technol. 2017, 305, 455−461. (51) Adami, R.; Liparoti, S.; Della Porta, G.; Del Gaudio, P.; Reverchon, E. Lincomycin hydrocloride loaded albumin microspheres for controlled drug release, produced by Supercritical Assisted Atomization. J. Supercrit. Fluids 2017, 119, 203−210. (52) Eslamian, M.; Ahmed, M.; Ashgriz, N. Modeling of Solution Droplet Evaporation and Particle Evolution in Droplet-to-Particle Spray Methods. Drying Technol. 2009, 27, 3−13. (53) Vicente, J.; Pinto, J.; Menezes, J.; Gaspar, F. Fundamental analysis of particle formation in spray drying. Powder Technol. 2013, 247, 1−7. (54) Junyaprasert, V. B.; Morakul, B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J. Pharm. Sci. 2015, 10, 13−23.

4340


Biopolymer Microspheres by Supercritical

Recommend Documents