Eutectic mixture and amorphous solid dispersion: Two different supersaturating drug delivery system strategies to improve griseofulvin release using saccharin.

This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC -with the carrier that forms a eutectic mixture with GSF -provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment's hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.

The role of hydrophobicity in supramolecular polymer/surfactant catalysts: An understandable model for enzymatic catalysis.

Enzymes are highly significant catalysts, essential to biological systems, and a source of inspiration for the design of artificial enzymes. Although many models have been developed describing enzymatic catalysis, a deeper understanding of these biocatalysts remains a major challenge. Herein we detail the formation, characterization, performance, and catalytic mechanisms of a series of bio-inspired supramolecular polymer/surfactant complexes acting as artificial enzymes. The supramolecular complexes were characterized and exhibited exceptional catalytic efficiency for the dephosphorylation of an activated phosphate diester, the reaction rate being highly responsive to: (a) pH, (b) surfactant concentration, and (c) the length of the hydrophobic chain of the surfactant. Under optimal conditions (at pH > 8 for the more hydrophobic systems and at pre-micellar concentrations), enzyme-like rate enhancements of up to 6.0 × 109-fold over the rate of the spontaneous hydrolysis reaction in water were verified. The catalytic performance is a consequence of synergy between the hydrophobicity of the aggregates and the catalytic functionalities of the polymer and the catalytic mechanism is modulated by the nature of the hydrophobic pockets of these catalysts, changing from a general base mechanism to a nucleophilic mechanism as the hydrophobicity increases. Taken as a whole, the present results provide fundamental insights, through an understandable model, which are highly relevant to the design of novel bioinspired enzyme surrogates with multifunctional potentialities for future practical applications.

First report of electrospun cellulose acetate nanofibers mats with chitin and chitosan nanowhiskers: Fabrication, characterization, and antibacterial activity.

Physical adsorption has shown to be facile and highly effective to deposit chitosan nanowhiskers (CsNWs, 60 % deacetylated, length: 247 nm, thickness: 4-12 nm, width:15 nm) on electrospun cellulose acetate nanofibers (CANFs, 560 nm) to effect complete surface charge reversal from negatively charged CANFs (-40 mV) to positively charged CsNWs-adsorbed CANFs (+8 mV). The CsNWs coverage did not alter the smooth and homogeneous morphology of fibers, as observed from SEM images. Biological assays showed the CsNWs covered nanofibers were effective against the Gram-negative bacterium E. coli, reducing 99 % of colony forming units (CFU) in 24 h and atoxic to healthy Vero cells. The use of CsNWs to modify cellulose fiber surfaces has been proved to be efficient and may be applied to a broad scope of fields, especially as biomaterials and biomedical applications.

Liposome and polymeric micelle-based delivery systems for chlorophylls: Photodamage effects on Staphylococcus aureus.

Chlorophyll derivatives (Chls), loaded in F-127 polymeric micelles and DPPC liposomes as drug delivery systems (DDS), have been shown to be remarkable photosensitizers for photodynamic inactivation (PDI). Assays of photoinactivation of Staphylococcus aureus bacteria (as biological models) showed that the effectiveness of Chls in these nanocarriers is dependent on photobleaching processes, photosensitizer locations in DDS, singlet oxygen quantum yields, and Chl uptake to bacteria. These are factors related to changes in Chl structure, such as the presence of metals, charge, and the phytyl chain. The photodynamic activity was significantly greater for Chls without the phytyl chain, i.e., phorbides derivatives. Furthermore, the inactivation of S. aureus was increased by the use of liposomes compared to micelles. Therefore, this research details and shows the high significance of the Chl structure and delivery system to enhance the photodynamic activity. It also highlights the chlorophylls (particularly phorbides) in liposomes as promising photosensitizers for PDI.

Shielding effect of 'surface ion pairs' on physicochemical and bactericidal properties of N,N,N-trimethyl chitosan salts.

Different methodologies were employed in this study to synthesize N,N,N-trimethyl chitosan salts (TMC). TMC free of O-methylation and with partial O-methylation were obtained and characterized through 1H nuclear magnetic resonance, wide angle X-ray scattering, scanning electron microscopy coupled with X-ray energy dispersive spectroscopy, and thermogravimetric analysis. It was verified that the dialysis process allowed the removal of 'surface ion pairs' on TMC salt structure, increasing the mobility of TMC chains. The surface ion pairs considerably increased the material crystallinity, this property being independent of the used synthesis methodology. Biological tests showed that after dialysis, TMC salts free of 'surface ion pairs' kill Escherichia coli in only 6h of incubation. So, the increase in the mobility of dialyzed TMC chains allowed a strong interaction with the cell envelope and the good bactericidal activity of TMC was enhanced.

Antiadhesive and antibacterial multilayer films via layer-by-layer assembly of TMC/heparin complexes.

N-Trimethyl chitosan (TMC), an antibacterial agent, and heparin (HP), an antiadhesive biopolymer, were alternately deposited on modified polystyrene films, as substrates, to built antiadhesive and antibacterial multilayer films. The properties of the multilayer films were investigated by Fourier transform infrared spectroscopy, atomic force microscopy, scanning electron microscopy, and Kelvin force microscopy. In vitro studies of controlled release of HP were evaluated in simulated intestinal fluid and simulated gastric fluid. The initial adhesion test of E. coli on multilayer films surface showed effective antiadhesive properties. The in vitro antibacterial test indicated that the multilayer films of TMC/HP based on TMC80 can kill the E. coli bacteria. Therefore, antiadhesive and antibacterial multilayer films may have good potential for coatings and surface modification of biomedical applications.

Properties of chlorophyll and derivatives in homogeneous and microheterogeneous systems.

Chlorophyll (Mg-Chl) and its derivatives, zinc chlorophyll (Zn-Chl), copper chlorophyll (Cu-Chl), pheophytin (Pheo), pheophorbide (Pheid), and zinc chlorophyllide (Zn-Chld), were studied as to their acid-base equilibrium properties, hydrophobicity, stability, binding, and relative localization in neutral surfactant micellar systems. The stability order of metalochlorophyll (pH(M)) in acidic medium was found to be Cu-Chl > Zn-Chld > Zn-Chl > Mg-Chl. The apparent pK(a) for protonation of porphyrin ring nitrogens was around 1.0 for all derivatives. The pK(a) for protonation of carboxylate phorbide was 5.9 for Pheid and 2.4 for Zn-Chld. This difference was attributed to complexation of carboxylate with zinc. The hydrophobicity of chlorophyll in relation to the ability of partitioning the cell membrane lipid layer was estimated in the octanol/water biphasic system. Pheo, a more hydrophobic molecule, presented the highest partition coefficient (K(P)) in the organic phase, followed by Cu-Chl, Mg-Chl, Zn-Chl, Pheid, and Zn-Chld. The hydrophobic character was the key to relative drug location in the micellar systems. All studied derivatives interacted strongly with Tween 80 micellar systems, and particularly with P-123. For both surfactants, the order followed by binding constant (K(b)) was Zn-Chld > Pheo > Cu-Chl > Mg-Chl > Zn-Chl > Pheid, while binding constants estimated for the Chl containing the phytyl group correlated with K(P). Fluorescence quenching studies have shown that phorbides are located in a less hydrophobic region than the phytyl chain-containing derivatives, which are located preferentially in a deeper micellar microenvironment. Thus, the association of the chlorophylls with specific binding sites of micellar systems is strongly modulated by the presence of phytyl chains and metal coordinated to the porphyrinic ring.

Effects of metal and the phytyl chain on chlorophyll derivatives: physicochemical evaluation for photodynamic inactivation of microorganisms.

Chlorophyll compounds and their derivatives containing metal or phytyl chain can be used as photosensitizer in photodynamic inactivation of microorganisms (PDI). So, the physicochemical properties and antimicrobial effect of chlorophyll derivatives were investigated: Mg-chlorophyll (Mg-Chl), Zn-chlorophyll (Zn-Chl), Zn-chlorophyllide (Zn-Chlde), Cu-chlorophyll (Cu-Chl), pheophytin (Pheo) and pheophorbide (Pheid). The photobleaching experiments showed photostability according to Cu-Chl > Pheo ∼ Pheid ≫ Zn-Chl ∼ Zn-Chlde > Mg-Chl. This order was discussed in terms of metal and the phytyl chain presences. Pheid and Zn-Chl in aqueous Tween 80 solution exhibited highest singlet oxygen yield compared with the other derivatives. Chlorophyll derivatives (CD) with phytyl chain was limited by the self-aggregation phenomenon at high concentrations, even in micellar systems (Tween 80 and P-123). The antimicrobial effect of CD derivatives was investigated against Staphylococcus aureus, Escherichia coli, Candida albicans and Artemia salina. Pheid showed the best results against all organisms tested, Zn-Chlde was an excellent bactericide in the dark and Cu-Chl had no PDI effect. No correlation with CD uptake by microorganisms and darkness cytotoxicity was found. The physicochemical properties allied to bioassays results indicate that Mg-Chl, Pheo, Zn-Chl and Pheid are good candidates for PDI.