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Bioavailability of oral administration is quite limited due to hydrophobicity of most of cancer drugs. Emphasis has been placed on the development of oral drug delivery systems to enhance solubility and stability of chemotherapeutics. In this work, a novel oral drug delivery system based on emulsion was implemented to encapsulate curcumin, in which ethylcellulose was employed as oil phase polymer while gum arabic was selected as emulsifier and wall material. After processed by ultrasonic emulsification, oil-in-water emulsion loaded with curcumin was transformed from liquid state to solid particles by an improved supercritical CO 2 assisted atomization technique (SAA-HCM) to achieve its long-term stability. Effects of SAA-HCM operating conditions on sizes and distributions of microparticles were investigated in detail and particle formation mechanism was discussed. The chemical stability and amorphous form of microparticles were identified by solid characterization. In vitro drug release behavior of curcumin-loaded microparticles exhibited controlled release and enzyme triggered properties, which implies the potential in the application of colon targeted delivery. This work expands the application of SAA-HCM technique to emulsion, which will be of great importance in the design of water-insoluble drug loaded microparticles with elaborate structures. • Emulsion was micronized into particles by supercritical CO 2 assisted atomization. • Formation mechanism of curcumin-loaded microparticles from emulsion was explored. • Drug-loaded microparticles exhibited stability in simulated gastrointestinal fluids. • Cellulase-triggered drug release implies the potential in colon-targeted delivery. [ABSTRACT FROM AUTHOR]

Abstract: DsbA (disulfide bond formation protein A) is essential for disulfide bond formation directly affecting the nascent peptides folding to the correct conformation in vivo. In this paper, recombinant DsbA protein was employed to catalyze denatured lysozyme refolding and inhibit the aggregation of folding intermediates in vitro. Statistical methods, i.e., Plackett–Burman design and small central composite design, were adopted to screen out important factors affecting the refolding process and correlating these parameters with the refolding efficiency including both protein recovery and specific activity of refolded lysozyme. Four important parameters: initial lysozyme concentration, urea concentration, KCl concentration and GSSG (glutathione disulfide) concentration were picked out and operating conditions were optimized by introducing the effectiveness coefficient method and transforming the multiple objective programming into an ordinary constrained optimization issue. Finally, 99.7% protein recovery and 25,600U/mg specific activity of lysozyme were achieved when 281.35μg/mL denatured lysozyme refolding was catalyzed by an equivalent molar of DsbA at the optimal settings. The results indicated that recombinant DsbA protein could effectively catalyze the oxidized formation and reduced isomerization of intramolecular disulfide bonds in the refolding of lysozyme in vitro. [Copyright &y& Elsevier]

Abstract: The data of the liquid volume expansion could normally be used as one of the thermodynamic criteria to decide an appropriate process of supercritical fluid based micronization techniques. The liquid volume expansion data were predicted by the vapor–liquid phase equilibrium calculation of two binary systems (CO2/acetone and CO2/ethanol) using Peng–Robinson equation of state. The results indicated that the liquid volume expansion of CO2/acetone mixtures was much larger than that of CO2/ethanol mixtures at the specified temperature and pressure. According to the thermodynamic criterion, acetone was affirmed to be a good solvent for supercritical antisolvent process (SAS) due to the higher liquid volume expansion, while ethanol was suitable for supercritical assisted atomization (SAA). This thermodynamic criterion was applied to the micronization of cholesterol and spherical particles were prepared in various organic solvents by SAA with an enhanced mixer. When the liquid volume expansion was lower than 80%, SAA could be successfully conducted and the good morphology and size distribution of the cholesterol particles were obtained. If the liquid volume expansion was higher than 140%, the solute would precipitate in the mixer before the atomization leading to the blockage of nozzle due to the antisolvent effect. In that case, the cholesterol particles in the mixer maintained the same morphology and crystalline structure as the SAS processed. This criterion is a practical and accessible tool to successfully implement the SAA process avoiding undesirable precipitation in the mixer. [Copyright &y& Elsevier]

Abstract: Supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to produce lysozyme microparticles with controlled particle size distribution in the range for aerosol drug delivery. The process is based on the atomization effect of carbon dioxide. The solubilization of certain amount of carbon dioxide in the solution plays the key role and the HCM can intensify mass transfer between carbon dioxide and liquid feedstock greatly. Water was used as the solvent to solubilize lysozyme and thus no organic residual was detected. The influences of process parameters on particle formation were investigated including temperature in the precipitator, pressure and temperature in the mixer, concentration of the solution and feed ratio CO2/solution. The particles were characterized with respect to their morphologies and particle size: well defined, spherical and separated particles with diameters ranging between 0.2 and 5μm could be always produced at optimum operating conditions. Bio-activity assay showed that good activity maintenance of higher than 85% for lysozyme was usually achieved. Solid state characterizations were further performed to investigate the changes of lysozyme in the process. Fourier transform infrared spectroscopy indicated that no change in secondary structure had occurred for processed lysozyme. X-ray diffraction analysis showed that the lysozyme particles produced remained similarly amorphous as the raw material. Differential scanning calorimetry and thermogravimetry analysis revealed that there was no significant difference in water association but with the increase of water content after processing. [Copyright &y& Elsevier]

Abstract: 11α-Hydroxylation of 16α,17-epoxyprogesterone (EP) by Rhizopus nigricans is an essential step in the synthesis of many steroidal drugs, while low conversion of the biohydroxylation is a tough problem to be solved urgently in industry. Two ionic liquids (ILs) of [BMIm][PF6] and [BMIm][NTf2] were used in the biotransformation of EP by R. nigricans. The results indicated that the conversion carried out in [BMIm][PF6]-aqueous biphasic system was greatly increased to above 90% at 18g/L feeding concentration. A simplified mechanism was proposed to explain the improvement of the bioconversion in a biphasic ionic liquid aqueous system. Besides, successive three batches of bioconversion were carried out in the biphasic system with a total conversion of 87% at phase ratio 10 and 75% at phase ratio 5, respectively. Since recycling of the [BMIm][PF6] is quite easy, there is a great potential for the application of ILs in fungi biotransformation to implement green production. [Copyright &y& Elsevier]

Abstract: Minichaperone sht GroEL191-345 was covalently coupled to NHS-activated Sepharose Fast Flow gel. Refolding of recombinant human interferon gamma (rhIFN-γ) was carried out on a chromatographic column packed with immobilized minichaperone. The effects of salt concentration, urea concentration gradient, elution flow rate and protein loading on the refolding efficiency were investigated. The results indicated that immobilized sht GroEL191-345 chromatography was an effective protocol for the refolding of rhIFN-γ. When loading 100μl denatured rhIFN-γ (17.8mg/ml), the protein mass recovery and total activity obtained in this optimal process reached 74.25% and 6.74×106 IU/ml, respectively with the immobilized minichaperone column which was reused for 10 times with 25% decrease of renaturation capacity. [Copyright &y& Elsevier]

• Separated nano-in-microparticles were fabricated by supercritical CO 2 -based technique. • Theoretical mass median aerodynamic diameter of nano-in-microparticles was 1∼2 μm. • Disintegration of nano-in-microparticles and release of nanoparticles were achieved. • Mechanism of aggregation and redispersibility of nanoparticles was revealed. Nano-in-microparticles used for inhalation lung cancer therapy combine the advantages of microparticles with aerodynamic diameters of 1∼5 μm for deep lung deposition and nanoparticles for long residence time in lung, high mucus penetrating and cancer cells uptake efficiency. In this work, nano-in-microparticles composed of chitosan nanoparticles and mannitol were prepared using a modified supercritical CO 2 assisted atomization (SAA-HCM) technique. Influences of process parameters of CO 2 /liquid mass flow ratio, total mass concentration and nanoparticles/mannitol ratio on size and morphologies of nano-in-microparticles were investigated in detail. Well-defined spherical nano-in-microparticles with theoretical mass median aerodynamic diameter of 1∼2 μm were obtained under optimized conditions. Fraction of about 40 % of nanoparticles was redispersed in deionized water at nanoparticles/mannitol ratio of 10:90. Meanwhile, quick disintegration of nano-in-microparticles was observed under conditions simulating high humidity in lung. In summary, dissociation of nano-in-microparticles and redispersibility of nanoparticles were determined by the structure of nano-in-microparticles according to particles formation mechanism. This work will expand the applicability of SAA-HCM to the preparation of nano-in-microparticles from nanosuspension and provide more references for designing of particles with elaborate structures. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Chemotherapeutics are used extensively in cancer and encapsulating the drug in nanoparticles is an effective method to enhance therapeutic efficacy and reduce side effect. In this work, DOX-loaded chitosan nanoparticles were prepared using supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) from aqueous solution. The influences of solution concentration, CO 2 /solution ratio, mixer pressure, chitosan/DOX ratio and chitosan molecular weight on particle morphologies and sizes were investigated in detail. Well defined spherical nanoparticles with average diameter ranging from 120 nm to 250 nm were obtained, and the loading efficiency was up to 90%. FT-IR result showed that the structure of DOX was not changed after the SAA-HCM process. Zeta potential of the nanoparticles was about +50 mV. The in vitro drug release behavior conducted in the media with pH of 4.5, 6.5 and 7.4 respectively showed strongly pH responsive. In vitro cytotoxicity profiles revealed that the activity of DOX was well maintained after loaded into chitosan nanoparticles. The SAA-HCM process was demonstrated to be a promising technique for one-step production of polymer/drug composite nanoparticles suitable for cancer drug delivery from aqueous solution. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Large pores increased in size with extended soaking time from 0.5 to 2 h. • Elongating holding time inceased mean size and decrease the density of large pores. • Pore size change patterns are distinct below and above 7 MPa intermediate pressure. • The pore growth profile in two-step depressurization sc-CO 2 foaming was unfolded. Abstract Bi-modal porous material is considered to have superior physical and tissue-inducing properties. This study reports on the fabrication of bi-modal porous poly(ε-caprolactone) (PCL) scaffolds using two-step depressurization supercritical CO 2 foaming process. In a single process, large pores over 100 μm nucleated in the slow depressurization step, and coalesced during holding stage; small pores below 40 μm were formed in the rapid depressurization step. Investigation on foaming parameters demonstrated that soaking time longer than 0.5 h was necessary to produce bi-modal pores. It was noted that the holding stage had a significant impact on the final pores. In particular, intermediate pressure would affect the plasticizing capabilities of CO 2 to increase (5–7 MPa) or decrease (7–12 MPa) pore size. In all, bi-modal porous PCL foams with around 80% porosity were produced, and this work provided a potential reference to efficient design of bone tissue engineering scaffolds. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH1–34)-loaded dry powders were fabricated from aqueous solution for pulmonary administration using supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM). Herein, chitosan oligosaccharide (CSO) was selected as a carrier in an effort to enhance transmucosal absorption of the drug. Well-defined, separated and spherical PTH(1–34)/CSO composite microparticles were obtained, and the particles size could be well controlled with narrow distribution. Aerodynamic performance was determined using next generation impactor (NGI), and the mass median aerodynamic diameter (MMAD) ranged strictly 1–5 μm range with fine particle fraction (FPF) up to 63.51%. The structural integrity of coprecipitated PTH(1–34) was validated by HPLC, FT-IR and circular dichroism, and a high loading efficiency up to 92.8% was obtained. TGA analyses revealed its thermal stability was preserved and XRD patterns showed amorphous structure of particles. The SAA-HCM process is proposed as a green technique for preparation of inhalable protein/polymer composite dry powders without use of any organic solvents. [ABSTRACT FROM AUTHOR]

Drug-loaded hydrogels with wound environment stimuli-responsive property can significantly promote wound healing and are widely applied in dressings. Two natural polymers, i.e. sodium alginate and sodium hyaluronate, were modified by 3-aminophenylboric acid and then cross-linked with polyvinyl alcohol to prepare ROS responsive hydrogels. Doxycycline hydrochloride was loaded onto hydrogels using supercritical solvent impregnation (SSI) technology, and the effects of immersion time, pressure and temperature on drug loading capacity (DLC) were investigated. DLC firstly increased and then decreased with the elevation of supercritical CO 2 pressure, and maximum value was up to 11 mg/g at 15 MPa and 50 °C. In the in vitro drug release study, doxycycline hydrochloride was controllably released from hydrogels for 10 h via the sensitivity of boronate ester bonds to ROS. This work expands the application of SSI in wound dressing, which provides a new approach for the design of composite hydrogel formulations with uniform drug distribution. [Display omitted] • ROS-responsive hydrogels were fabricated via crosslinking Alg-PBA, HA-PBA and PVA. • Doxy was loaded onto hydrogels using supercritical solution impregnation. • The dynamic mechanical properties of drug-loaded hydrogels can be adjusted. • Dug-loaded hydrogels exhibited excellent in vitro antibacterial properties. [ABSTRACT FROM AUTHOR]

Abstract: This work concentrates on a chiral separation technology named biphasic recognition applied to resolution of α-cyclohexylmandelic acid enantiomers by high-speed counter-current chromatography (HSCCC). The biphasic chiral recognition HSCCC was performed by adding lipophilic (−)-2-ethylhexyl tartrate in the organic stationary phase and hydrophilic hydroxypropyl-β-cyclodextrin in the aqueous mobile phase, which preferentially recognized the (−)-enantiomer and (+)-enantiomer, respectively. The two-phase solvent system composed of n-hexane-methyl tert-butyl ether–water (9:1:10, v/v/v) with the above chiral selectors was selected according to the partition coefficient and separation factor of the target enantiomers. Important parameters involved in the chiral separation were investigated, namely the types of the chiral selectors (CS); the concentration of each chiral selector; pH of the mobile phase and the separation temperature. The mechanism involved in this biphasic recognition chiral separation by HSCCC was discussed. Langmuirian isotherm was employed to estimate the loading limits for a given value of chiral selectors. Under optimum separation conditions, 3.5–22.0mg of α-cyclohexylmandelic acid racemate were separated using the analytical apparatus and 440mg of racemate was separated using the preparative one. The purities of both of the fractions including (+)-enantiomer and (−)-enantiomer from the preparative CCC separation were over 99.5% determined by HPLC and enantiomeric excess reached 100% for the (±)-enantiomers. Recovery for the target compounds from the CCC fractions reached 85–88% yielding 186mg of (+)-enantiomer and 190mg of (−)-enantiomer. The overall experimental results show that the HSCCC separation of enantiomer based on biphasic recognition, in which only if the CSs involved will show affinity for opposite enantiomers of the analyte, is much more efficient than the traditional monophasic recognition chiral separation, since it utilizes the cooperation of both of lipophilic and hydrophilic chiral selectors. [Copyright &y& Elsevier]

Abstract: (1→3)-β-d-Glucans have received increasing attentions with respect to their biological functions. Previously, a method combining cellular induced autolysis with subsequent oxidation by sodium hypochlorite to prepare (1→3)-β-d-glucan from Saccharomyces cerevisiae was developed. However, the poor aqueous solubility of the resultant polysaccharide was a huge hindrance to its application especially in pharmaceuticals. Herein, a novel glucan sulphation process, also a heterogeneous reaction system, composed of sulfuric acid and n-propanol with a molar ratio of 1.4, is proposed to improve polysaccharide polarity and its aqueous solubility. After the heterogeneous sulphation at -6°C for 90min, (1→3)-β-d-glucan sulphate yield was about 37.4% (w/w), the degree of sulphation 0.36, and its empirical formula was (C6H10O5)25·9SO3·7H2O according to elemental analysis. In addition, sulphation made the polysaccharide morphologically loosened according to observation under scanning electron microscopy. The presence of characteristic absorptions at 1246 and 813cm-1 in the FTIR spectrum, as well as the 1H NMR spectrum demonstrated that the material was a sulphate ester of glucan. [Copyright &y& Elsevier]

E. coli and S. cerevisiae were encapsulated within alginate/cellulose sulphate–CaCl2/poly(methylene-co-guanidine) (SA/CS–CaCl2/PMCG) capsules. Although PMCG inhibited strongly the growth of E. coli and S. cerevisiae in free cultivation, PMCG coated capsules had no negative effects on the growth of free E. coli and S. cerevisiae or on the consumption of glucose in the cultivation of S. cerevisiae. If commercial PMCG agent was pre-treated by the method specified in this paper, E. coli and S cerevisiae immobilised in the SA/CS–CaCl2/PMCG capsules grew almost as normally as in free cultivation. Thus, PMCG was shown to be a suitable membrane material for microorganism encapsulation after it was purified under appropriate conditions. [Copyright &y& Elsevier]

Natural polymers like polysaccharides, polypeptides and their derivatives are broadly applied in drug delivery due to excellent biocompatibility and biodegradability. In this study, the dissolving tablets, formed with carboxymethylcellulose/poly- l -lysine/tripolyphosphate (CMC/PLL/TPP) complex, were prepared using metformin hydrochloride (MetHCl) as model drug. Confocal laser scanning microscopy observation manifested that FITC-labeled PLL interacted with CMC and formed a uniform interior microstructure. Scanning electron microscope images showed the drug-loaded tablets had well-formed shapes with smooth surfaces. MetHCl embedded interior the microstructures of the tablets and represented in a crystal form. Thermo-gravimetric analysis and differential scanning calorimetry indicated that the drug-loaded tablets had stable thermal properties with less moisture content (3.52%). Fourier transform infrared spectrometer confirmed that the CMC/PLL/TPP complex was fabricated via the electrostatic interactions between -NH 3 +, -COO− and -[P 2 O 5 4-]− groups. The drug-loaded tablets had a high drug loading efficiency of 85.76% and drug encapsulation efficiency of 81.47%, and a shorter wetting time of 2.16 min in SSF (pH 6.8) and lower swelling ratio of 233.34%. The drug loaded in the samples could be released completely within 10 min in simulated saliva fluid (SSF pH 6.8), indicating a rapid drug release and dissolving profile in the environment, which could be developed for dissolving tablets. • Novel carboxymethylcellulose/poly- l -lysine/tripolyphosphate tablets were prepared. • FITC-labeled PLL interacted with CMC and formed a uniform interior microstructure. • The drug-loaded tablets had a higher drug loading efficiency of 85.76%. • The drug released completely within 10 min in simulated saliva fluid (SSF pH 6.8). • CMC/PLL/TPP complex could be used to develop dissolving tablets as drug vehicles. [ABSTRACT FROM AUTHOR]

Abstract: Supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to prepare chitosan microparticles with the well-defined spherical morphology and the controlled particle size distribution as a promising carrier for drug delivery system. Chitosan with different molecular weights (3kDa, 50kDa, 300kDa) was successfully micronized, in which water was used as the solvent for 3kDa chitosan, while 1.0% (v/v) acetic acid aqueous solution was used for 50kDa and 300kDa chitosan, respectively. The process parameters including operating pressure and temperature in the mixer, mass flow ratio of CO2/solution, precipitator temperature and solution concentration were explored to evaluate their influences on the morphologies and size distributions of precipitated particles. Results showed that particle size tailoring (ranging between 0.2 and 5μm) could be achieved through modulation of the process parameters. After processing by SAA-HCM, Fourier transform infrared spectroscopy did not indicate significant change in the main structure of chitosan microparticles. Compared with raw materials, a decrease in crystallinity and thermal stability was observed for the SAA-HCM processed chitosan microparticles, as demonstrated by X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. [Copyright &y& Elsevier]

Highlights: [•] Separated and spherical chitosan oligomers microparticles were produced from water. [•] Particle size could be tailored and distribution was narrow in the range of 0.5–3μm. [•] FTIR, TGA and DSC results confirmed chitosan oligomers molecular structure stability. [•] Mass median aerodynamic particle size ranged inside 1–2μm suitable for inhalation. [ABSTRACT FROM AUTHOR]