Improvement in Solubility–Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-β-cyclodextrin

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-β-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-β-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (K_c < 500 M⁻¹). PSO and 5-MOP permeability rate decreased after adding HP-β-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-β-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-β-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.     

Nanostructured lipid carriers for triamcinolone acetonide delivery to the posterior segment of the eye

Triamcinolone acetonide (TA) is a corticosteroid drug currently administered by intravitreal injection for a broad spectrum of inflammatory, edematous and angiogenic ocular diseases. To increase the drug's bioavailability by ocular instillation, TA was encapsulated in nanostructured lipid carriers (NLC), previously optimized by our group using a factorial design approach. In the present paper, nanometric (∼200 nm), unimodal and negatively charged NLC loaded with the fluorescent lipid marker Nile red (NR-NLC) and drug (TA-NLC) were produced by high pressure homogenization. Based on the selected formulations, in vivo tests were carried out by eye-drop instillation of NR-NLC in mice, revealing the systems’ ability of delivering lipophilic actives to the posterior segment of the eye via the corneal and non-corneal pathways. Short and long-term stability of TA-NLC was assessed by high performance stability analysis using the Turbiscan^®. The results showed a backscattering of less than 1.5% and during a period of 6 months, anticipated the low tendency of these particles for aggregation during shelf life when stored at room temperature.     

Physicochemical properties of mixed micellar aggregates containing CCK peptides and Gd complexes designed as tumor specific contrast agents in MRI

New amphiphilic molecules containing a bioactive peptide or a claw moiety have been prepared in order to obtain mixed micelles as target-specific contrast agents in magnetic resonance imaging. The first molecule, C(18)H(37)CONH(AdOO)(2)-G-CCK8 (C18CCK8), contains a C18 hydrophobic moiety bound to the C-terminal cholecystokinin octapeptide amide (CCK 26-33 or CCK8). The second amphiphilic compound, C(18)H(37)CONHLys(DTPAGlu)CONH(2) (C18DTPAGlu) or its gadolinium complex, (C18DTPAGlu(Gd)), contains the same C18 hydrophobic moiety bound, through a lysine residue, to the DTPAGlu chelating agent. The mixed aggregates as well as the pure C18DTPAGlu aggregate, in the presence and absence of Gd, have been fully characterized by surface tension measurements, FT-PGSE-NMR, fluorescence quenching, and small-angle neutron scattering measurements. The structural characterization of the mixed aggregates C18DTPAGlu(Gd)-C18CCK8 indicates a spherical arrangement of the micelles with an external shell of approximately 21 A and an inner core of approximately 20 A. Both the DTPAGlu(Gd) complexes and the CCK8 peptides point toward the external surface. The measured values for relaxivity in saline medium at 20 MHz proton Larmor frequency and 25 degrees C are 18.7 mM(-)(1) s(-)(1). These values show a large enhancement in comparison with the isolated DTPAGlu(Gd) complex.     

Enzymatic microreactors for the determination of ethanol by an automatic sequential injection analysis system

A sequential injection analysis system with two enzymatic microreactors for the determination of ethanol has been designed. Alcohol oxidase and horseradish peroxidase were separately immobilized on glass aminopropyl beads, and packed in 0.91-mL volume microreactors, working in line with the sequential injection analysis system. A stop flow of 120 s was selected for a linear ethanol range of 0.005-0.04 g/L +/- 0.6% relative standard deviation with a throughput of seven analyses per hour. The system was applied to measure ethanol concentrations in samples of distilled and nondistilled alcoholic beverages, and of alcoholic fermentation with good performance and no significant difference compared with other analytical procedures (gas chromatography and high-performance liquid chromatography).     

Unitary polarities in non commutative twisted field planes

In this paper the class of polarities in non commutative twisted field planes, defined in a paper of Biliotti, Jha and Johnson ([4]), is investigated. It is proved that these polarities are unitary and that the associated unitals have a collineation group that fixes a point and is transitive on the remaining ones. Received 9 October 1999; revised 8 January 2000.     

Ionic silica based hybrid material containing the pyridinium group used as an adsorbent for textile dye

The present study reports the development of an ionic silica based hybrid material containing the cationic pyridinium group, which was employed for the removal of the Reactive Red 194 textile dye from aqueous solution. Three hybrid material samples were prepared with planned textural and chemical properties, varying the inorganic precursor molar percentage in the sol-gel synthesis. The obtained samples were defined as Py/Si-90, Py/Si-92 and Py/Si-94, where the number specifies the inorganic molar percentage. The hybrid samples were characterized by elemental, infrared, (13)C and (29)Si NMR, N(2) adsorption-desorption isotherms and thermogravimetric analyses. The dye-removing ability of these adsorbents was determined by the batch contact adsorption procedure. Effects such as pH value and adsorbent dosage on the adsorption capacities were studied. Four kinetic models were applied. The adsorption was best fitted to Avrami fractional-order kinetic model for the three hybrid material samples. The kinetic data were also adjusted to an intra-particle diffusion model resulting three linear regions, indicating that the adsorption kinetics follows multiple sorption rates. The equilibrium data were fitted to Langmuir, Freundlich and Liu isotherm models. The maximum adsorption capacities were 165.4, 190.3 and 195.9 mg g(-1) for Py/Si-90, Py/Si-92 and Py/Si-94, respectively. Simulated dye-house effluents were used to check the applicability of the proposed adsorbents for effluent treatment. Dye loaded adsorbents were regenerated (>98.2%) by using 0.4 mol L(-1) of NaOH solution as an eluent.     

High Relaxivity Supramolecular Adducts Between Human‐Liver Fatty‐Acid‐Binding Protein and Amphiphilic GdIII Complexes: Structural Basis for the Design of Intracellular Targeting MRI Probes

Gadolinium complexes linked to an apolar fragment are known to be efficiently internalized into various cell types, including hepatocytes. Two lipid‐functionalized gadolinium chelates have been investigated for the targeting of the human liver fatty acid binding protein (hL‐FABP) as a means of increasing the sensitivity and specificity of intracellular‐directed MRI probes. hL‐FABP, the most abundant cytosolic lipid binding protein in hepatocytes, displays the ability to interact with multiple ligands involved in lipid signaling and is believed to be an obligate carrier to escort lipidic drugs across the cell. The interaction modes of a fatty acid and a bile acid based gadolinium complex with hL‐FABP have been characterized by relaxometric and NMR experiments in solution with close‐to‐physiological protein concentrations. We have introduced the analysis of paramagnetic‐induced protein NMR signal intensity changes as a quantitative tool for the determination of binding stoichiometry and of precise metal‐ion‐center positioning in protein–ligand supramolecular adducts. A few additional NMR‐derived restraints were then sufficient to locate the ligand molecules in the protein binding sites by using a rapid data‐driven docking method. Relaxometric and ¹³C NMR competition experiments with oleate and the gadolinium complexes revealed the formation of heterotypic adducts, which indicates that the amphiphilic compounds may co‐exist in the protein cavity with physiological ligands. The differences in adduct formation between fatty acid and bile acid based complexes provide the basis for an improved molecular design of intracellular targeted probes.     

High relaxivity supramolecular adducts between human-liver fatty-acid-binding protein and amphiphilic Gd(III) complexes: structural basis for the design of intracellular targeting MRI probes

Gadolinium complexes linked to an apolar fragment are known to be efficiently internalized into various cell types, including hepatocytes. Two lipid-functionalized gadolinium chelates have been investigated for the targeting of the human liver fatty acid binding protein (hL-FABP) as a means of increasing the sensitivity and specificity of intracellular-directed MRI probes. hL-FABP, the most abundant cytosolic lipid binding protein in hepatocytes, displays the ability to interact with multiple ligands involved in lipid signaling and is believed to be an obligate carrier to escort lipidic drugs across the cell. The interaction modes of a fatty acid and a bile acid based gadolinium complex with hL-FABP have been characterized by relaxometric and NMR experiments in solution with close-to-physiological protein concentrations. We have introduced the analysis of paramagnetic-induced protein NMR signal intensity changes as a quantitative tool for the determination of binding stoichiometry and of precise metal-ion-center positioning in protein-ligand supramolecular adducts. A few additional NMR-derived restraints were then sufficient to locate the ligand molecules in the protein binding sites by using a rapid data-driven docking method. Relaxometric and (13)C NMR competition experiments with oleate and the gadolinium complexes revealed the formation of heterotypic adducts, which indicates that the amphiphilic compounds may co-exist in the protein cavity with physiological ligands. The differences in adduct formation between fatty acid and bile acid based complexes provide the basis for an improved molecular design of intracellular targeted probes.     

Activity of Spray-dried Microparticles Containing Pomegranate Peel Extract against <em>Candida albicans</em>

Pomegranate has attracted interest from researchers because of its chemical composition and biological properties. It possesses strong antioxidant activity, with potential health benefits, and also antimicrobial properties. The aim of this study was to produce microparticles containing pomegranate extract by the spray-drying technique, utilizing alginate or chitosan as encapsulating agents. Characterization and antifungal assays were carried out. Production yields were about 40% for alginate microparticles and 41% for chitosan. Mean diameters were 2.45 μm and 2.80 μm, and encapsulation efficiencies were 81.9% and 74.7% for alginate and chitosan microparticles, respectively. The spray-drying process preserved the antifungal activity against Candida albicans. These results could be useful for developing dosage forms for treating candidiasis, and should be further investigated in in vivo models.