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Dr. Konstantinos Kontogiannopoulos graduated from School of Chemical Engineering, Aristotle University of Thessaloniki - AUTh, Greece and holds a PhD (2011) in Chemistry and Technology of Natural Products and Pharmaceutical Technology, with emphasis on the utilization of bioactive natural products through innovative drug-delivery systems (DDS). He has worked in the Greek pharmaceutical industry, as well as in the National Centre for Research & Technological Development (CERTH), and since 2018 has been a Research assistant (Post-Doc researcher) in the Laboratory of Organic Chemistry / School of Chemical Engineering/AUTh. His research interests focus on innovative drug-delivery systems (liposomes, hyperbranched polymers and chimeric advanced DDS, cyclodextrines, and biodegradable polymeric patches) for bioactive compounds derived from natural products. Furthermore, his research expands on the utilization of natural products, as well as on advanced methods of management/processing and reuse of industrial water and wastewater streams, as well as the utilization/valorization of by- and co-products from agri-food industries. He has published 21 research articles in international peer-reviewed journals (seven as the first writer), and has participated in over 30 papers at international and Greek conferences (348 citations, h-index: 8). In addition, he has worked on 11 relevant research projects co-funded by the EU and Greece.
Although significant actions have been taken towards the utilization of poly(vinyl alcohol) (PVA) in the preparation of drug amorphous solid dispersions (ASDs) using fusion-based techniques (such as melt-quench cooling and hot-melt extrusion), several drawbacks regarding its rather high melting temperature and its thermal degradation profile make the use of the polymer extremely challenging. This is especially important when the active pharmaceutical ingredient (API) has a lower melting temperature (than PVA) or when it is thermally labile. In this vein, a previous study showed that newly synthesized polyester-based plasticizers may improve the processability and the thermal properties of PVA. However, the effects of such polyester-based plasticizers on the drug’s physicochemical and pharmaco-technical properties are yet unknown. Hence, the aim of the present study is to extend our previous findings and evaluate the use of poly(propylene succinate) (PPSu, i.e., the most promising plasticizer in regard to PVA) in the preparation of drug-loaded PVA-based ASDs. Dronedarone (DRN), a poorly water-soluble API, was selected as a model drug, and drug ASDs (using either neat PVA or PVA-PPSu) were prepared using the melt-mixing/quench cooling approach at low melting temperatures (i.e., 170 °C). DSC and pXRD analysis showed that a portion of the API remained crystalline in the ASDs prepared only with the use of neat PVA, while the samples having PPSu as a plasticizer were completely amorphous. Further evaluation with ATR-FTIR spectroscopy revealed the formation of significant intermolecular interactions between the API and the PVA-PPSu matrix, which could explain the system’s physical stability during storage. Finally, dissolution studies, conducted under nonsink conditions, revealed that the use of PVA-PPSu is able to maintain DRN’s sustained supersaturation for up to 8 h.
Afroditi Kapourani; Artemis Palamidi; Konstantinos N. Kontogiannopoulos; Nikolaos D. Bikiaris; Panagiotis Barmpalexis. Drug Amorphous Solid Dispersions Based on Poly(vinyl Alcohol): Evaluating the Effect of Poly(propylene Succinate) as Plasticizer. Polymers 2021, 13, 2922 .
AMA StyleAfroditi Kapourani, Artemis Palamidi, Konstantinos N. Kontogiannopoulos, Nikolaos D. Bikiaris, Panagiotis Barmpalexis. Drug Amorphous Solid Dispersions Based on Poly(vinyl Alcohol): Evaluating the Effect of Poly(propylene Succinate) as Plasticizer. Polymers. 2021; 13 (17):2922.
Chicago/Turabian StyleAfroditi Kapourani; Artemis Palamidi; Konstantinos N. Kontogiannopoulos; Nikolaos D. Bikiaris; Panagiotis Barmpalexis. 2021. "Drug Amorphous Solid Dispersions Based on Poly(vinyl Alcohol): Evaluating the Effect of Poly(propylene Succinate) as Plasticizer." Polymers 13, no. 17: 2922.
The amount of spent coffee grounds (SCGs) created, represents an environmental challenge worldwide. In this context, the aim of the present study was to exploit the potential of SCGs as a source of bioactive compounds that can be utilized in high value-added products. Thus, a cost-effective and environmentally friendly extraction technique was developed to ensure extracts with high total phenolic content and antioxidant activity, as well as significant amounts of caffeine and chlorogenic acid. Response surface methodology was implemented to evaluate the effects of the main extraction parameters (i.e., time, temperature, and ethanol-to-water ratio) and their interactions on the defined responses. The ethanol ratio was found to be the most significant variable. Then, a set of optimum values was determined (i.e., 7 min, 75 °C, and ethanol:water ratio 5:95), where the predicted values for responses were found to be 5.65% for the yield (Y1), 152.68 mg gallic acid equivalents per L for total phenolic content (Y2), 0.797 μmol Trolox equivalent per mL for the antioxidant activity (Y3), 30.5 ppm for caffeine concentration (Y4), and 17.4 ppm for chlorogenic acid concentration (Y5). Furthermore, the corresponding high experimental values from the validation experiment fitted well to these predictions, clearly clarifying the high potential of SCG extracts for use in high value-added applications.
Georgia-Christina Mitraka; Konstantinos Kontogiannopoulos; Maria Batsioula; George Banias; Andreana Assimopoulou. Spent Coffee Grounds’ Valorization towards the Recovery of Caffeine and Chlorogenic Acid: A Response Surface Methodology Approach. Sustainability 2021, 13, 8818 .
AMA StyleGeorgia-Christina Mitraka, Konstantinos Kontogiannopoulos, Maria Batsioula, George Banias, Andreana Assimopoulou. Spent Coffee Grounds’ Valorization towards the Recovery of Caffeine and Chlorogenic Acid: A Response Surface Methodology Approach. Sustainability. 2021; 13 (16):8818.
Chicago/Turabian StyleGeorgia-Christina Mitraka; Konstantinos Kontogiannopoulos; Maria Batsioula; George Banias; Andreana Assimopoulou. 2021. "Spent Coffee Grounds’ Valorization towards the Recovery of Caffeine and Chlorogenic Acid: A Response Surface Methodology Approach." Sustainability 13, no. 16: 8818.
The aim of the present study was to prepare a leflunomide (LFD) sustained release transdermal delivery system for the treatment of psoriasis. In this context, LFD-loaded nanoparticles (NPs) based on either neat chitosan (CS) or CS modified with [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SDAEM, a sulfobetaine zwitterionic compound) were initially prepared via ionotropic gelation and characterized in terms of in vitro dissolution, physicochemical, and antibacterial properties. Results showed that the use of the SDAEM-modified CS resulted in the formation of LFD-loaded NPs with improved wetting and solubilization properties, better in vitro dissolution profile characteristics (i.e., higher dissolution rate and extent), and improved (enhanced) antibacterial properties. The resultant LFD-loaded NPs were then embedded in suitable thin-film skin patches, prepared via spin-coating, utilizing two different biodegradable polyesters, namely methoxy polyethylene glycol-b-poly(L-lactide) (mPEG-b-PLA, at a ratio of 25/75 mPEG to PLA) and poly(lactic-co-glycolic acid) (PLGA at a ratio of 75/25 DL-lactide/glycolide copolymer). Results showed the formation of polymeric thin-films with no agglomeration (or trapped air) and uniform structure in all cases, while the LFD-loaded NPs were successfully embedded in the polymeric matrix. Analysis of the obtained in vitro dissolution profiles revealed a sustained release profile of the drug for up to approximately twelve days, while between the two proposed systems, the use of CS-SDAEM NPs (independently of the polyester type) was the most promising formulation approach.
Stavroula Nanaki; Evi Christodoulou; Nikolaos Bikiaris; Afroditi Kapourani; Konstantinos Kontogiannopoulos; Souzan Vergkizi-Nikolakaki; Panagiotis Barmpalexis. Leflunomide Sustained Skin Delivery Based on Sulfobetaine-Modified Chitosan Nanoparticles Embedded in Biodegradable Polyesters Films. Polymers 2021, 13, 960 .
AMA StyleStavroula Nanaki, Evi Christodoulou, Nikolaos Bikiaris, Afroditi Kapourani, Konstantinos Kontogiannopoulos, Souzan Vergkizi-Nikolakaki, Panagiotis Barmpalexis. Leflunomide Sustained Skin Delivery Based on Sulfobetaine-Modified Chitosan Nanoparticles Embedded in Biodegradable Polyesters Films. Polymers. 2021; 13 (6):960.
Chicago/Turabian StyleStavroula Nanaki; Evi Christodoulou; Nikolaos Bikiaris; Afroditi Kapourani; Konstantinos Kontogiannopoulos; Souzan Vergkizi-Nikolakaki; Panagiotis Barmpalexis. 2021. "Leflunomide Sustained Skin Delivery Based on Sulfobetaine-Modified Chitosan Nanoparticles Embedded in Biodegradable Polyesters Films." Polymers 13, no. 6: 960.
The plasticizing effect of three low molecular weight oligomers of aliphatic poly(alkylene succinate) polyesters, namely poly(butylene succinate) (PBSu), poly(ethylene succinate) (PESu), and poly(propylene succinate) (PPSu), on partially hydrolyzed poly(vinyl alcohol) (PVA) used in melt-based pharmaceutical applications, was evaluated for the first time. Initially, the three aliphatic polyesters were prepared by the melt polycondensation process and characterized by differential scanning calorimetry (DSC), 1H NMR, intrinsic viscosity, and size exclusion chromatography (SEC). Subsequently, their effect on the thermophysical and physicochemical properties of PVA was thoroughly evaluated. According to the obtained results, PVA was completely miscible with all three polyesters, while PESu induced PVA’s thermal degradation, with the phenomenon starting from ~220 °C, in contrast to PBSu and PPSu, where a thermal profile similar to PVA was observed. Furthermore, molecular interactions between PVA and the prepared poly(alkylene succinate) polyesters were revealed by DSC, ATR-FTIR, and molecular dynamics simulations. Finally, melt flow index (MFI) measurements showed that, in contrast to PBSu, the use of PESu or PPSu significantly improved PVA’s melt flow properties. Hence, according to findings of the present work, only the use of low molecular weight PPSu is suitable in order to reduce processing temperature of PVA and improve its melt flow properties (plasticizing ability) without affecting its thermal decomposition.
Artemis Palamidi; Afroditi Kapourani; Evi Christodoulou; Panagiotis A. Klonos; Konstantinos N. Kontogiannopoulos; Apostolos Kyritsis; Dimitrios N. Bikiaris; Panagiotis Barmpalexis. Low Molecular Weight Oligomers of Poly(alkylene succinate) Polyesters as Plasticizers in Poly(vinyl alcohol) Based Pharmaceutical Applications. Polymers 2021, 13, 146 .
AMA StyleArtemis Palamidi, Afroditi Kapourani, Evi Christodoulou, Panagiotis A. Klonos, Konstantinos N. Kontogiannopoulos, Apostolos Kyritsis, Dimitrios N. Bikiaris, Panagiotis Barmpalexis. Low Molecular Weight Oligomers of Poly(alkylene succinate) Polyesters as Plasticizers in Poly(vinyl alcohol) Based Pharmaceutical Applications. Polymers. 2021; 13 (1):146.
Chicago/Turabian StyleArtemis Palamidi; Afroditi Kapourani; Evi Christodoulou; Panagiotis A. Klonos; Konstantinos N. Kontogiannopoulos; Apostolos Kyritsis; Dimitrios N. Bikiaris; Panagiotis Barmpalexis. 2021. "Low Molecular Weight Oligomers of Poly(alkylene succinate) Polyesters as Plasticizers in Poly(vinyl alcohol) Based Pharmaceutical Applications." Polymers 13, no. 1: 146.
This study examines the development of a nanocomposite consisting of iron oxy-hydroxides (FeOOH) embedded on magnetite (Fe3O4) nanocarriers, towards its application for the simultaneous uptake of As(V) and Sb(V) ionic forms at concentrations below drinking water regulation and its magnetically-assisted recovery at the end of the process. Considering Fe3O4 as the reductant assisting the transformation of highly mobile Sb(V) to Sb(III), and the high affinity of FeOOH to adsorb both As(V) and Sb(III), adsorption experiments carried out at equilibrium pH 7 indicated that a FeOOH/Fe3O4 composition of 50 %wt. is the optimum to establish a sufficient efficiency in the uptake of both pollutants . Particularly, the adsorption capacity for As(V) at residual concentration 10 μg/L is around 2.3 mg/g whereas around 0.4 mg/g of Sb(V) can be captured by the nanocomposite while keeping the residual concentration below 5 μg/L. Such efficiencies are preserved in the case of simultaneous adsorption of both pollutants without any appearance of cross-interference effects, at least for residual concentrations below 400 μg/L. The high magnetic response of Fe3O4 nanoparticles allows the application of the nanocomposite for water purification in an alternative setup, consisting of a contact stirring reactor and a magnetic separator constructed by permanent magnets. The dimensions and flowrates of the continuous-flow system were properly designed on the basis of theoretical calculations using the magnetization, adsorption efficiency and kinetics as input, to combine maximum purification and solid recovery. Suggestively, operation of the system using a natural water with pH 7 containing 50 μg/L As(V) and 10 μg/L Sb(V) showed successful decrease of residual concentrations below regulation limits for drinking water and 100 % recovery of the solid when a nanocomposite's dose of 20 mg/L was added.
M. Tzirini; E. Kaprara; T. Asimakidou; K. Kontogiannopoulos; E. Tzamos; I. Kellartzis; T. Samaras; Ll Balcells; M. Mitrakas; K. Simeonidis. Magnetically recoverable nanoparticles for the simultaneous removal of Sb and As from water. Environmental Advances 2020, 2, 100013 .
AMA StyleM. Tzirini, E. Kaprara, T. Asimakidou, K. Kontogiannopoulos, E. Tzamos, I. Kellartzis, T. Samaras, Ll Balcells, M. Mitrakas, K. Simeonidis. Magnetically recoverable nanoparticles for the simultaneous removal of Sb and As from water. Environmental Advances. 2020; 2 ():100013.
Chicago/Turabian StyleM. Tzirini; E. Kaprara; T. Asimakidou; K. Kontogiannopoulos; E. Tzamos; I. Kellartzis; T. Samaras; Ll Balcells; M. Mitrakas; K. Simeonidis. 2020. "Magnetically recoverable nanoparticles for the simultaneous removal of Sb and As from water." Environmental Advances 2, no. : 100013.
Coffee pulp, a by-product of coffee production, contains valuable compounds such as caffeine and chlorogenic acid with high antiradical activity. In this study, aqueous solutions of β-cyclodextrin (β-CD) were used as a non-conventional solvent for the extraction of targeted compounds from coffee pulp. The parameters of β-CD concentration (Cβcd), liquid-to-solid ratio (L/S), and temperature (T) were evaluated based on the antiradical activity (AAR) and the caffeine content (CCaf). The optimum operational conditions were found to be Cβcd: 9.25 mg/mL, L/S: 30 mL/g and T: 80 °C. The sensory profiles of brews prepared with coffee and coffee pulp with or without cyclodextrin were studied with quantitative descriptive analysis. The brew from the by-product had fruity, botanic, sweet and sourness sensory properties, and cyclodextrin was found to be able to affect the overall taste of the brew.
Anastasia Loukri; Petroula Tsitlakidou; Athanasia Goula; AndreAna N. Assimopoulou; Konstantinos N. Kontogiannopoulos; Ioannis Mourtzinos. Green Extracts from Coffee Pulp and Their Application in the Development of Innovative Brews. Applied Sciences 2020, 10, 6982 .
AMA StyleAnastasia Loukri, Petroula Tsitlakidou, Athanasia Goula, AndreAna N. Assimopoulou, Konstantinos N. Kontogiannopoulos, Ioannis Mourtzinos. Green Extracts from Coffee Pulp and Their Application in the Development of Innovative Brews. Applied Sciences. 2020; 10 (19):6982.
Chicago/Turabian StyleAnastasia Loukri; Petroula Tsitlakidou; Athanasia Goula; AndreAna N. Assimopoulou; Konstantinos N. Kontogiannopoulos; Ioannis Mourtzinos. 2020. "Green Extracts from Coffee Pulp and Their Application in the Development of Innovative Brews." Applied Sciences 10, no. 19: 6982.
Municipal Solid Waste (MSW) management has been a major problem of modern cities for many years. Thus, the development of optimal waste management strategies has been a priority for the European Commission, especially in the transition toward a circular economy. In this paper, an analysis of different MSW treatment methods that can be effectively implemented in the Region of Central Macedonia (RCM) is provided, and their comparison from an environmental point of view is performed. The assessment is based on real data indicated in the recently updated Greek National Waste Management Plan, whereas the different scenarios developed include landfilling without energy recovery, landfilling with energy recovery, recycling and secondary materials recovery, mechanical-biological treatment, bio-waste composting and anaerobic digestion with energy recovery, and incineration with energy recovery. The obtained results illustrate that efficient waste streams sorting is of vital importance for the effective implementation of an integrated waste management system toward the sustainable management of MSW.
Georgios Banias; Maria Batsioula; Charisios Achillas; Sotiris Patsios; Konstantinos Kontogiannopoulos; Dionysis Bochtis; Nicolas Moussiopoulos. A Life Cycle Analysis Approach for the Evaluation of Municipal Solid Waste Management Practices: The Case Study of the Region of Central Macedonia, Greece. Sustainability 2020, 12, 8221 .
AMA StyleGeorgios Banias, Maria Batsioula, Charisios Achillas, Sotiris Patsios, Konstantinos Kontogiannopoulos, Dionysis Bochtis, Nicolas Moussiopoulos. A Life Cycle Analysis Approach for the Evaluation of Municipal Solid Waste Management Practices: The Case Study of the Region of Central Macedonia, Greece. Sustainability. 2020; 12 (19):8221.
Chicago/Turabian StyleGeorgios Banias; Maria Batsioula; Charisios Achillas; Sotiris Patsios; Konstantinos Kontogiannopoulos; Dionysis Bochtis; Nicolas Moussiopoulos. 2020. "A Life Cycle Analysis Approach for the Evaluation of Municipal Solid Waste Management Practices: The Case Study of the Region of Central Macedonia, Greece." Sustainability 12, no. 19: 8221.
In this study, the potential of the co-generation of hydrolytic enzymes in the biorefinery plant for citric acid fermentation was investigated. Aspergillus niger B60 mycelium along with the solid residue after the recovery of sugars from white pomace (WP′) were recycled from citric acid fermentation. A mixture design was used to determine the optimum ternary feedstock mixture composed of WP′ (15%), red grape pomace (15%) and wheat bran (70%) that produced the target enzymes with high activities, which were compared to those from pure feedstocks. Maximum carboxymethyl cellulase, polygalacturonase, amylase, xylanase and acid protease activities obtained through solid-state fermentation (120 h, 30 °C) of the feedstock mixture were 668 IU/g, 3,151 IU/g, 1,099 IU/g, 579 IU/g and 204 IU/g (dry mass basis), respectively. The system was successfully simulated in SuperPro Designer. Results showed that the enzymes production process serves as the main contributor to the profitability of the biorefinery plant.
Eugenia Papadaki; Konstantinos N. Kontogiannopoulos; AndreAna N. Assimopoulou; Fani Mantzouridou. Feasibility of multi-hydrolytic enzymes production from optimized grape pomace residues and wheat bran mixture using Aspergillus niger in an integrated citric acid-enzymes production process. Bioresource Technology 2020, 309, 123317 .
AMA StyleEugenia Papadaki, Konstantinos N. Kontogiannopoulos, AndreAna N. Assimopoulou, Fani Mantzouridou. Feasibility of multi-hydrolytic enzymes production from optimized grape pomace residues and wheat bran mixture using Aspergillus niger in an integrated citric acid-enzymes production process. Bioresource Technology. 2020; 309 ():123317.
Chicago/Turabian StyleEugenia Papadaki; Konstantinos N. Kontogiannopoulos; AndreAna N. Assimopoulou; Fani Mantzouridou. 2020. "Feasibility of multi-hydrolytic enzymes production from optimized grape pomace residues and wheat bran mixture using Aspergillus niger in an integrated citric acid-enzymes production process." Bioresource Technology 309, no. : 123317.
A crucial step for the selection of proper amorphous solid dispersion (ASD) matrix carriers is the in-depth assessment of drug/polymer physicochemical properties. In this context, the present study extends the work of previously published attempts by evaluating the formation of simvastatin (SIM)–poly(vinylpyrrolidone) (PVP) ASDs with the aid of thermodynamic and molecular modeling. Specifically, the implementation of both Flory–Huggins lattice theory and molecular dynamics (MD) simulations was able to predict the miscibility between the two components (a finding that was experimentally verified via differential scanning calorimetry (DSC) and hot stage polarized microscopy), while a complete temperature-concentration phase-transition profile was constructed, leading to the identification of the thermodynamically metastable and unstable ASD zones. Furthermore, as in the case of previously published reports, the analysis of the ASDs via Fourier transform infrared spectroscopy did not clarify the type and extent of observed molecular interactions. Hence, in the present study, a computer-based MD simulation model was developed for the first time in order to gain an insight into the properties of the observed interactions. MD amorphous assemblies of SIM, PVP, and their mixtures were initially developed, and the calculated glass transition temperatures were in close agreement with experimentally obtained results, indicating that the developed models could be considered as realistic representations of the actual systems. Furthermore, molecular interactions evaluation via radial distribution function and radius of gyration analysis revealed that increasing SIM content results in a significant PVP chain shrinkage, which eventually leads to SIM–SIM amorphous intermolecular interactions, leading to the formation of amorphous drug zones. Finally, MD-based results were experimentally verified via DSC.
Afroditi Kapourani; Melina Chatzitheodoridou; Konstantinos N. Kontogiannopoulos; Panagiotis Barmpalexis. Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions. Molecular Pharmaceutics 2020, 17, 2703 -2720.
AMA StyleAfroditi Kapourani, Melina Chatzitheodoridou, Konstantinos N. Kontogiannopoulos, Panagiotis Barmpalexis. Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions. Molecular Pharmaceutics. 2020; 17 (7):2703-2720.
Chicago/Turabian StyleAfroditi Kapourani; Melina Chatzitheodoridou; Konstantinos N. Kontogiannopoulos; Panagiotis Barmpalexis. 2020. "Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions." Molecular Pharmaceutics 17, no. 7: 2703-2720.
The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett-Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde's concentration had a statistically significant impact on microsphere's final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug's release for up to 30 days, governed by a Fickian diffusion release mechanism.
Alexandros Nakas; Athanasia M. Dalatsi; Afroditi Kapourani; Konstantinos Kontogiannopoulos; AndreAna N. Assimopoulou; Panagiotis Barmpalexis. Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres. AAPS PharmSciTech 2020, 21, 127 -17.
AMA StyleAlexandros Nakas, Athanasia M. Dalatsi, Afroditi Kapourani, Konstantinos Kontogiannopoulos, AndreAna N. Assimopoulou, Panagiotis Barmpalexis. Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres. AAPS PharmSciTech. 2020; 21 (4):127-17.
Chicago/Turabian StyleAlexandros Nakas; Athanasia M. Dalatsi; Afroditi Kapourani; Konstantinos Kontogiannopoulos; AndreAna N. Assimopoulou; Panagiotis Barmpalexis. 2020. "Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres." AAPS PharmSciTech 21, no. 4: 127-17.
The present study evaluates the effect of several pharmaceutical plasticizers on the thermo-physical and physicochemical properties of partially hydrolyzed poly(vinyl alcohol) (PVA) used in fusion-based pharmaceutical formulation processes. Specifically, the effect of mannitol (MAN), sorbitol (SOR), sucrose (SUC), anhydrous citric acid (CA), triethyl citrate (TEC) and low-molecular weight polyethylene glycol (PEG400) on PVA’s melting properties, physical state and thermal degradation was evaluated via differential scanning calorimetry (DSC), powder X-ray diffractometry (pXRD) and thermo-gravimetric analysis (TGA). Results showed that the use of MAN, SOR, SUC and PEG400 led to the reduction of PVA’s melting onset temperature, while MAN, SUC, CA and SOR were amorphously dispersed within PVA’s matrix, and the addition of SUC and CA resulted in significant reduction of PVA’s crystallinity. TGA results showed the formation of thermally highly unstable PVA mixtures in the cases of CA and TEC (degradation started from ∼150 oC and ∼125 oC, respectively), while significant molecular interactions were identified by FTIR in the cases of PVA-MAN, PVA-SOR and PVA-SUC. Hot-stage polarized microscopy (HSM) revealed PVA’s melt miscibility only with MAN and SOR, while melt flow index (MFI) measurements showed that the use of MAN, SOR and PEG400 resulted in a significant improvement of PVA’s melt flow properties. Finally, MD simulations were in close agreement with the experimental observations, indicating that they can be considered as a promising tool for the theoretical modelling of such systems.
Konstantinos Katopodis; Afroditi Kapourani; Elisavet Vardaka; Anna Karagianni; Christina Chorianopoulou; Konstantinos Kontogiannopoulos; Dimitrios Bikiaris; Kyriakos Kachrimanis; Panagiotis Barmpalexis. Partially hydrolyzed polyvinyl alcohol for fusion-based pharmaceutical formulation processes: Evaluation of suitable plasticizers. International Journal of Pharmaceutics 2020, 578, 119121 .
AMA StyleKonstantinos Katopodis, Afroditi Kapourani, Elisavet Vardaka, Anna Karagianni, Christina Chorianopoulou, Konstantinos Kontogiannopoulos, Dimitrios Bikiaris, Kyriakos Kachrimanis, Panagiotis Barmpalexis. Partially hydrolyzed polyvinyl alcohol for fusion-based pharmaceutical formulation processes: Evaluation of suitable plasticizers. International Journal of Pharmaceutics. 2020; 578 ():119121.
Chicago/Turabian StyleKonstantinos Katopodis; Afroditi Kapourani; Elisavet Vardaka; Anna Karagianni; Christina Chorianopoulou; Konstantinos Kontogiannopoulos; Dimitrios Bikiaris; Kyriakos Kachrimanis; Panagiotis Barmpalexis. 2020. "Partially hydrolyzed polyvinyl alcohol for fusion-based pharmaceutical formulation processes: Evaluation of suitable plasticizers." International Journal of Pharmaceutics 578, no. : 119121.
The present study evaluates the preparation of systemic administrated NSAID gelatin nanoparticles with the aid of quality by design and artificial neural networks (ANNs). Specifically, two different preparation techniques (i.e. nanoprecipitation and two-step desolvation) were implemented for the formulation of diclofenac sodium (DLC) gelatin nanoparticles (GNs). Preliminary screening experiments showed that in the case of nanoprecipitation the best compromise (in terms of achieving both small particle size and high encapsulation efficiency) was the use of poloxamer 407 (as stabilizer) and acetone (as non-solvent), while in the case of two-step desolvation significant effect had the use of acetone, gelatin type and bloom number (type B with bloom 150 was selected for further evaluation). Implementation of a central composite experimental design (CCD), showed that in the case of nanoprecipitation the optimum formulation can be achieved at high poloxamer, high gelatin and moderate to high glutaraldehyde (GTA used for crosslinking) concentrations, while in the case of two-step desolvation high gelatin and GTA concentrations are needed. Artificial neural networks (ANN) implementation showed significantly improved prediction ability compared to MLR, while verification experiments showed good agreement between the ANN predicted and the experimentally obtained results. SEM analysis of the optimum suggested formulations showed nanoparticles with smooth surface, while powder X-ray diffraction (XRD) analysis showed the formation of amorphously dispersed systems, and Fourier transform infrared spectroscopy (FTIR) revealed the presence of molecular interactions irrespectively of the preparation method followed. A slightly faster release profile was observed in the case of nanoprecipitation based GNs, while all formulations followed biphasic release profile.
Antigoni E. Koletti; Efstathia Tsarouchi; Afroditi Kapourani; Konstantinos Kontogiannopoulos; AndreAna N. Assimopoulou; Panagiotis Barmpalexis. Gelatin nanoparticles for NSAID systemic administration: Quality by design and artificial neural networks implementation. International Journal of Pharmaceutics 2020, 578, 119118 .
AMA StyleAntigoni E. Koletti, Efstathia Tsarouchi, Afroditi Kapourani, Konstantinos Kontogiannopoulos, AndreAna N. Assimopoulou, Panagiotis Barmpalexis. Gelatin nanoparticles for NSAID systemic administration: Quality by design and artificial neural networks implementation. International Journal of Pharmaceutics. 2020; 578 ():119118.
Chicago/Turabian StyleAntigoni E. Koletti; Efstathia Tsarouchi; Afroditi Kapourani; Konstantinos Kontogiannopoulos; AndreAna N. Assimopoulou; Panagiotis Barmpalexis. 2020. "Gelatin nanoparticles for NSAID systemic administration: Quality by design and artificial neural networks implementation." International Journal of Pharmaceutics 578, no. : 119118.
Drug delivery is considered a mature scientific and technological platform for producing innovative medicines with nanosystems composed of intelligent bio-materials that carry active pharmaceutical ingredients forming advanced drug delivery systems (aDDnSs). Shikonin and its enantiomer alkannin are natural products that have been extensively studied in vitro and in vivo for, among others, their antitumor activity and various efforts have been made to prepare shikonin-loaded drug delivery systems. This study is focused on chimeric aDDnSs and specifically on liposomal formulations combining three lipids (egg-phosphatidylcholine, EPC; dipalmitoyl phosphatidylcholine, DPPC; and distearoyl phosphatidylcholine, DSPC) and a hyperbranched polymer (PFH-64-OH). Furthermore, pegylated liposomal formulations of all samples were also prepared. Calorimetric techniques and electron paramagnetic resonance (EPR) were used to explore and evaluate the interactions and stability of the liposomal formulations, showing that the presence of hyperbranched polymers promote the overall stability of the chimeric aDDnSs based on the drug release profile enhancement. Furthermore, results showed that polyethylene glycol (PEG) enhances drug stabilization inside the liposomes, forming a stable and promising carrier for shikonin with improved characteristics.
Konstantinos N. Kontogiannopoulos; Athanasia Dasargyri; Maria Francesca Ottaviani; Michela Cangiotti; Dimitrios Fessas; Vassilios Peter Papageorgiou; AndreAna N. Assimopoulou. Advanced Drug Delivery Nanosystems for Shikonin: A Calorimetric and Electron Paramagnetic Resonance Study. Langmuir 2018, 34, 9424 -9434.
AMA StyleKonstantinos N. Kontogiannopoulos, Athanasia Dasargyri, Maria Francesca Ottaviani, Michela Cangiotti, Dimitrios Fessas, Vassilios Peter Papageorgiou, AndreAna N. Assimopoulou. Advanced Drug Delivery Nanosystems for Shikonin: A Calorimetric and Electron Paramagnetic Resonance Study. Langmuir. 2018; 34 (32):9424-9434.
Chicago/Turabian StyleKonstantinos N. Kontogiannopoulos; Athanasia Dasargyri; Maria Francesca Ottaviani; Michela Cangiotti; Dimitrios Fessas; Vassilios Peter Papageorgiou; AndreAna N. Assimopoulou. 2018. "Advanced Drug Delivery Nanosystems for Shikonin: A Calorimetric and Electron Paramagnetic Resonance Study." Langmuir 34, no. 32: 9424-9434.
Liposomes are considered to be one of the most successful drug delivery systems. They apply nanotechnology to potentiate the therapeutic efficacy and reduce the toxicity of conventional medicines. Shikonin and alkannin, a pair of chiral natural naphthoquinone compounds, derived from Alkanna and Lithospermum species, are widely used due to their various pharmacological activities, mainly wound healing, antioxidant, anti-inflammatory and their recently established antitumor activity. The purpose of this study was to prepare conventional and PEGylated shikonin-loaded liposomal formulations and measure the effects of different lipids and polyethylene glycol (PEG) on parameters related to particle size distribution, the polydispersity index, the zeta potential, drug-loading efficiency and the stability of the prepared formulations. Three types of lipids were assessed (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DSPG)), separately and in mixtures, forming anionic liposomes with good physicochemical characteristics, high entrapment efficiencies (varying from 56.5 to 89.4%), satisfactory in vitro release profiles and good physical stability. The addition of the negatively charged DSPG lipids to DOPC, led to an increment in the drug’s incorporation efficiency and reduced the particle size distribution. Furthermore, the shikonin–loaded PEGylated sample with DOPC/DSPG, demonstrated the most satisfactory characteristics. These findings are considered promising and could be used for further design and improvement of such formulations.
Stella K. Tsermentseli; Konstantinos N. Kontogiannopoulos; Vassilios P. Papageorgiou; AndreAna N. Assimopoulou. Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin. Fluids 2018, 3, 36 .
AMA StyleStella K. Tsermentseli, Konstantinos N. Kontogiannopoulos, Vassilios P. Papageorgiou, AndreAna N. Assimopoulou. Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin. Fluids. 2018; 3 (2):36.
Chicago/Turabian StyleStella K. Tsermentseli; Konstantinos N. Kontogiannopoulos; Vassilios P. Papageorgiou; AndreAna N. Assimopoulou. 2018. "Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin." Fluids 3, no. 2: 36.
Wine waste lees are currently partly exploited for tartaric acid (TA) production, through an environment-offensive process, while concurrently occurring bio-active polyphenolic compounds are wasted. This paper, deals with the development of an integrated, environment friendly process, using mild conditions, for recovering TA with simultaneous exploitation of total polyphenols (TPP) from wine lees. A first process step, described in a previous publication, yields a liquid stream containing approx. 44.2 g L−1 TA and 323.3 mg GAE L−1 TPP. In the present study, various ultrafiltration and nanofiltration membranes are assessed, in bench-scale filtration tests, for their efficiency in separating the two main products (i.e. TA and TPP) from this stream. The most promising process configurations are also tested in a laboratory-scale cross-flow membrane filtration pilot plant and assessed concerning the separation efficiency and the membrane filtration performance, to determine process feasibility at industrial scale. The results show that a nanofiltration membrane with typical pore size approx. 1 kDa exhibits satisfactory separation and low-fouling filtration performance. The permeate, containing the bulk of TA (approx. 42.6 g L−1) could be used for TA recovery, whereas the concentrate, with antioxidant activity (EC50 = 10.0 mg sample mg−1 DPPH.), could be further purified to obtain polyphenolic-rich formulations. © 2017 Society of Chemical Industry
Konstantinos N Kontogiannopoulos; Sotiris I Patsios; Soultana T Mitrouli; Anastasios J Karabelas. Tartaric acid and polyphenols recovery from winery waste lees using membrane separation processes. Journal of Chemical Technology & Biotechnology 2017, 92, 2934 -2943.
AMA StyleKonstantinos N Kontogiannopoulos, Sotiris I Patsios, Soultana T Mitrouli, Anastasios J Karabelas. Tartaric acid and polyphenols recovery from winery waste lees using membrane separation processes. Journal of Chemical Technology & Biotechnology. 2017; 92 (12):2934-2943.
Chicago/Turabian StyleKonstantinos N Kontogiannopoulos; Sotiris I Patsios; Soultana T Mitrouli; Anastasios J Karabelas. 2017. "Tartaric acid and polyphenols recovery from winery waste lees using membrane separation processes." Journal of Chemical Technology & Biotechnology 92, no. 12: 2934-2943.
A crucial first step in developing a novel cost-effective and environment-friendly process for recovering tartaric acid and bioactive polyphenolic compounds from wine lees involves tartrates dissolution by mild means, aiming to maximize tartaric acid recovery, while minimizing the concentration of undesirable potassium. Such a processing step, using cation exchange resin, has been systematically assessed to obtain a set of near-optimum values of the key variables (i.e. pH, water dosage and cation exchange resin dosage). An experimental design was carried out based on Central Composite Design (CCD) with Response Surface Methodology (RSM) to evaluate the effects of process parameters and their interaction towards the attainment of optimum conditions. All three variables considered were found to be significant; however, the most influential factor for maximum tartaric acid concentration was the volume of added water, whereas for potassium removal the cation exchange resin dosage. A quadratic model was developed that fitted well to the experimental data confirmed by the high R2 values, greater than 0.98. A set of optimum values of the three main variables was determined to be pH = 3.0, water dosage 10 ml/g dry lees and resin dosage 3.5 g/g dry lees. Under these optimum conditions, the predicted tartaric acid and potassium concentration were 43,143 ppm and 178 ppm, respectively, which correspond to 74.9% tartaric acid recovery and 98.8% potassium removal. Furthermore, the corresponding experimental values, from the validation experiment, fitted well to these predictions. This work clearly shows that the recovery of tartaric acid from wine lees can be achieved using cation exchange resin, under mild conditions (ambient temperature) avoiding the waste calcium sulfate sludge of the conventional process.
Konstantinos N. Kontogiannopoulos; Sotiris I. Patsios; Anastasios J. Karabelas. Tartaric acid recovery from winery lees using cation exchange resin: Optimization by Response Surface Methodology. Separation and Purification Technology 2016, 165, 32 -41.
AMA StyleKonstantinos N. Kontogiannopoulos, Sotiris I. Patsios, Anastasios J. Karabelas. Tartaric acid recovery from winery lees using cation exchange resin: Optimization by Response Surface Methodology. Separation and Purification Technology. 2016; 165 ():32-41.
Chicago/Turabian StyleKonstantinos N. Kontogiannopoulos; Sotiris I. Patsios; Anastasios J. Karabelas. 2016. "Tartaric acid recovery from winery lees using cation exchange resin: Optimization by Response Surface Methodology." Separation and Purification Technology 165, no. : 32-41.
The ability of pegylated liposomes (sterically stabilized liposomes-SSL) to localize in solid tumors via the enhanced permeability and retention (EPR) effect, partly depends on their long circulating properties which can be achieved by grafting polyethylene glycol (PEG) to the liposomes' surface. Alkannin and shikonin (A/S) are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant, and recently established antitumor activity. The purpose of this work was to prepare and characterize shikonin-loaded pegylated liposomes as a new drug carrier for shikonin, as a continuation of authors' previous work on conventional shikonin-loaded liposomal formulations. Three new pegylated liposomal formulations of shikonin (DSPC-PEG2000, EPC-PEG2000, and DPPC-PEG2000) were prepared and characterized in terms of physicochemical characteristics, pharmacokinetics, and stability (at 4 °C, for 28 d) and compared with the corresponding conventional ones. Particle size distribution, ζ-potential, entrapment efficiency, and release profile of the entrapped drug were measured. Results indicated the successful incorporation of shikonin into liposomes alongside with their good physicochemical characteristics, high entrapment efficiency, satisfactory in vitro release profile, and good physical stability. The results are considered promising and could be used as a road map for designing further in vivo experiments.
Konstantinos Kontogiannopoulos; S. K. Tsermentseli; A. N. Assimopoulou; V. P. Papageorgiou. Sterically stabilized liposomes as a potent carrier for shikonin. Journal of Liposome Research 2014, 24, 230 -240.
AMA StyleKonstantinos Kontogiannopoulos, S. K. Tsermentseli, A. N. Assimopoulou, V. P. Papageorgiou. Sterically stabilized liposomes as a potent carrier for shikonin. Journal of Liposome Research. 2014; 24 (3):230-240.
Chicago/Turabian StyleKonstantinos Kontogiannopoulos; S. K. Tsermentseli; A. N. Assimopoulou; V. P. Papageorgiou. 2014. "Sterically stabilized liposomes as a potent carrier for shikonin." Journal of Liposome Research 24, no. 3: 230-240.
The interest of drug delivery has focused on the creation of new formulations with improved properties, taking much attention to the drug release from the carrier. Liposomes have already been commercialized, while dendrimers and hyperbranched polymers are emerging as potentially ideal drug delivery vehicles. Chimeric advanced drug delivery nano systems (chi-aDDnSs) are mixed nanosystems combining different biomaterials that can offer advantages as drug carriers. Alkannin and shikonin (A/S) are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant and recently established antitumor activity. In this work three generations of hyperbranched aliphatic polyesters were used for the first time to form complexes with shikonin, as well as liposomal chi-aDDnSs. Characterization of the shikonin-loaded chi-aDDnSs was performed by measuring their particle size distribution, ζ-potential, drug encapsulation efficiency and the in vitro release profile. The analysis revealed sufficient drug encapsulation and appropriately featured release profiles. Chi-aDDnSs were also examined for their physical stability at 4°C. The results are considered promising and could be used as a road map for designing in vivo experiments.
Konstantinos N. Kontogiannopoulos; Andreana Assimopoulou; Sophia Hatziantoniou; Kostas Karatasos; Costas Demetzos; Vassilios P. Papageorgiou. Chimeric advanced drug delivery nano systems (chi-aDDnSs) for shikonin combining dendritic and liposomal technology. International Journal of Pharmaceutics 2012, 422, 381 -389.
AMA StyleKonstantinos N. Kontogiannopoulos, Andreana Assimopoulou, Sophia Hatziantoniou, Kostas Karatasos, Costas Demetzos, Vassilios P. Papageorgiou. Chimeric advanced drug delivery nano systems (chi-aDDnSs) for shikonin combining dendritic and liposomal technology. International Journal of Pharmaceutics. 2012; 422 (1-2):381-389.
Chicago/Turabian StyleKonstantinos N. Kontogiannopoulos; Andreana Assimopoulou; Sophia Hatziantoniou; Kostas Karatasos; Costas Demetzos; Vassilios P. Papageorgiou. 2012. "Chimeric advanced drug delivery nano systems (chi-aDDnSs) for shikonin combining dendritic and liposomal technology." International Journal of Pharmaceutics 422, no. 1-2: 381-389.
Alkannin and shikonin are naturally occurring hydroxynaphthoquinones with a well‐established spectrum of wound healing, antimicrobial, anti‐inflammatory, and antioxidant activities. Recently, extensive scientific effort has been focused on their effectiveness on several tumors and mechanism(s) of antitumor activity. Liposomes have been proved as adequate drug carriers offering significant advantages over conventional formulations, such as controlled release and targeted drug delivery, leading to the appearance of several liposomal formulations in the market, some of them concerning anticancer drugs. The aim of the present study was to prepare shikonin‐loaded liposomes for the first time in order to enhance shikonin therapeutic index. An optimized technique based on the thin film hydration method was developed and liposomes characterization was performed in terms of their physicochemical characteristics, drug entrapment efficiency, and release profile. Results indicated the successful incorporation of shikonin into liposomes, using both 1,2‐dipalmitoylphosphatidylcholine and egg phosphatidylcholine lipids. Liposomes presented good physicochemical characteristics, high entrapment efficiency and satisfactory in vitro release profile. In vitro cytotoxicity of liposomes was additionally tested against three human cancer cell lines (breast, glioma, and non‐small cell lung cancer) showing a moderate growth inhibitory activity. Practical applications: Shikonin is a naturally occurring hydroxynaphthoquinone and extensive scientific research (in vitro, in vivo, and clinical trials) has been conducted during the last years, focusing on its effectiveness on several tumors and mechanism(s) of antitumor action. The purpose of this work was to prepare and characterize shikonin‐loaded liposomes as a new drug delivery system for shikonin. Liposomal formulations provide significant advantages over conventional dosage forms, such as controlled release and targeted drug delivery for anticancer agents. Thus, liposomes could reduce shikonin's side effects, enhance selectivity to cancer cells and protect shikonin from internal biotransformations and instability matters (oxidization and polymerization). Furthermore, liposomal delivery helps overcome the low aqueous solubility of shikonin, which is the major barrier to its oral and internal administration, since it cannot be dissolved and further absorbed from the receptor.
Konstantinos N. Kontogiannopoulos; AndreAna N. Assimopoulou; Konstantinos Dimas; Vassilios P. Papageorgiou. Shikonin-loaded liposomes as a new drug delivery system: Physicochemical characterization and in vitro cytotoxicity. European Journal of Lipid Science and Technology 2011, 113, 1113 -1123.
AMA StyleKonstantinos N. Kontogiannopoulos, AndreAna N. Assimopoulou, Konstantinos Dimas, Vassilios P. Papageorgiou. Shikonin-loaded liposomes as a new drug delivery system: Physicochemical characterization and in vitro cytotoxicity. European Journal of Lipid Science and Technology. 2011; 113 (9):1113-1123.
Chicago/Turabian StyleKonstantinos N. Kontogiannopoulos; AndreAna N. Assimopoulou; Konstantinos Dimas; Vassilios P. Papageorgiou. 2011. "Shikonin-loaded liposomes as a new drug delivery system: Physicochemical characterization and in vitro cytotoxicity." European Journal of Lipid Science and Technology 113, no. 9: 1113-1123.
Alkannin, shikonin (A/S) and their derivatives are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant and antitumor activity. Clinical studies over the years revealed that A/S derivatives-based wound healing preparations (such as HELIXDERM(®)) are among a very small group of therapeutics that modulate both the inflammatory and proliferative phases of wound healing and present significant tissue regenerative activity. The purpose of the present work was to combine the biological properties of A/S and the advantages of electrospun meshes to prepare a potent topical/transdermal biomaterial for A/S. Four biocompatible polymers (cellulose acetate, poly(L-lactide), poly(lactide-co-glycolide) LA/GA:50/50 and 75/25) were used for the first time, to produce electrospun fiber mats containing either shikonin or A/S mixture in various amounts. Both drugs were effectively loaded into the above biomaterials. The incorporation of drugs did not considerably affect fibers morphology and their mean diameter size varied from 315 to 670 nm. High drug entrapment efficiencies (ranged from 74% to 95%) and appropriate release profiles were achieved, that render these fibers as potential A/S topical/transdermal wound healing dressings. Given the multifunctional activity of the natural products alkannins and shikonins, their consideration as bioactive constituents for tissue engineering scaffolds seems a promising strategy for repairing and regenerating tissues and mainly skin.
Konstantinos N. Kontogiannopoulos; Andreana Assimopoulou; Ioannis Tsivintzelis; Costas Panayiotou; Vassilios Papageorgiou. Electrospun fiber mats containing shikonin and derivatives with potential biomedical applications. International Journal of Pharmaceutics 2011, 409, 216 -228.
AMA StyleKonstantinos N. Kontogiannopoulos, Andreana Assimopoulou, Ioannis Tsivintzelis, Costas Panayiotou, Vassilios Papageorgiou. Electrospun fiber mats containing shikonin and derivatives with potential biomedical applications. International Journal of Pharmaceutics. 2011; 409 (1-2):216-228.
Chicago/Turabian StyleKonstantinos N. Kontogiannopoulos; Andreana Assimopoulou; Ioannis Tsivintzelis; Costas Panayiotou; Vassilios Papageorgiou. 2011. "Electrospun fiber mats containing shikonin and derivatives with potential biomedical applications." International Journal of Pharmaceutics 409, no. 1-2: 216-228.