Design of Ionic Liquid Formulations with Azone-Mimic Structures for Enhanced Drug Skin Permeation.

Although laurocapram (Azone) significantly enhances the skin permeation of drugs, its development was hindered by its skin irritation. We then developed an Azone-mimic ionic liquid (IL-Azone), composed of less irritating cationic ε-caprolactam and anionic myristic acid. IL-Azone dissociates to the original cation and anion in the presence of water in the formulation. We tried to select a formulation suitable for IL-Azone in the present study. Each formulation contained 5 % of either Azone or IL-Azone along with the model drug antipyrine, and skin permeation experiments of the drug were conducted. The results revealed that IL-Azone did not enhance skin permeation when combined with most formulations tested. However, a notable and rapid enhancement in skin permeation was observed when combined with white petrolatum. This effect could be attributed to the minimal water content in white petrolatum, which prevented IL-Azone degradation. Furthermore, its permeation-enhancing effects from IL-Azone in white petrolatum were more pronounced and rapid than Azone. The rapid onset observed with IL-Azone can be attributed to its degradation into its original components at the interface between the stratum corneum and the living epidermis, which results in a shorter lag time before achieving a steady-state concentration in the SC compared to Azone.

Development and Evaluation of Biocompatible Topical Petrolatum-liquid Crystal Formulations with Enhanced Skin Permeation Properties.

Transdermal administration represents a major advancement over traditional pharmaceutical dosing methods. However, a frequent issue is inadequate penetration of the active medicinal component through the skin. As a result, in the current research, we assessed the utility of newly developed petrolatum-liquid crystal (LC) ointment formulations and characterized their biocompatibility and function in the transdermal drug delivery system. To begin, we made petrolatum-LC formulations using p-aminobenzoic acid (PABA) as a hydrophilic model molecule. The viscosity, small-angle X-ray scattering (SAXS), particle diameters, and z-potential were measured to assess the physicochemical properties of the formulations. A dialysis release technique was used to evaluate medication release from petrolatum-LC formulations. In vitro testing was performed to determine the potential to enhance skin penetration. The biocompatibility of the produced formulations was further tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and single-cell gel electrophoresis. According to the results, the novel petrolatum-LC formulations are biocompatible and effective in forming hexosomes. PABA skin penetration was significantly enhanced by the new petrolatum-LC formulations. According to this study, petroleum-LC formulations are more efficient than commercial petrolatum in terms of skin permeability improvement and PABA skin concentration.

The benefits of photoacoustics for the monitoring of drug stability and penetration through tissue-mimicking membranes.

The paper demonstrates the potential of photoacoustics for the identification of the mechanisms underlying drug transport through tissue-mimicking systems. Photoacoustic experiments were performed for a model transdermal delivery system, consisting of drug dithranol (in pharmaceutical form) and dodecanol-collodion (DDC) membrane. The spectroscopic data revealed a single-path photodegradation of dithranol in Vaseline (dithranol â†’ danthrone, characterized by the 1st order decay rate of (7.85 ± 0.31)·10-4 s-1), and a multipath degradation in the DDC system, involving danthrone and the unknown compound (characterized by the absorption band at ~400 nm) as the final products. The desorption experiments performed enabled the identification of the unknown compound as the photodegradation product of dithranol molecules bound to the membrane matrix. The result led to the incorporation of the adsorption effects and heterogeneous structure of the membrane into the hydrodynamical model of mass transport. The model was tested against the photoacoustic depth-profiling data for dithranol permeation through DDC. The analysis allowed the dispersion and advection coefficients to be determined (D' = (2.05 ± 0.03)⋅10-9 cm2 s-1 and va' = (-5.55 ± 0.05)⋅10-7 cm s-1, respectively). Moreover, it was found, that the dithranol photodegradation rate in the non-steady state system is slower compared to the steady-state case; the effect was attributed to different permeation rates of dithranol and mobile Vaseline particles through the membrane.

Integrating transient heterogeneity of non-photochemical quenching in shade-grown heterobaric leaves of avocado (Persea americana L.): responses to CO2 concentration, stomatal occlusion, dehydration and relative humidity.

Long-lived shade leaves of avocado had extremely low rates of photosynthesis. Gas exchange measurements of photosynthesis were of limited use, so we resorted to Chl fluorescence imaging (CFI) and spot measurements to evaluate photosynthetic electron transport rates (ETRs) and non-photochemical quenching (NPQ). Imaging revealed a remarkable transient heterogeneity of NPQ during photosynthetic induction in these hypostomatous, heterobaric leaves, but was adequately integrated by spot measurements, despite long-lasting artifacts from repeated saturating flashes during assays. Major veins (mid-vein, first- and second-order veins) defined areas of more static large-scale heterogeneous NPQ, with more dynamic small-scale heterogeneity most strongly expressed in mesophyll cells between third- and fourth-order veins. Both responded to external CO2 concentration ([CO2]), occlusion of stomata with Vaseline™, leaf dehydration and relative humidity (RH). We interpreted these responses in terms of independent behavior of stomata in adjacent areoles that was largely expressed through CO2-limited photosynthesis. Heterogeneity was most pronounced and prolonged in the absence of net CO2 fixation in 100 p.p.m. [CO2] when respiratory and photorespiratory CO2 cycling constrained the inferred ETR to ~75% of values in 400 or 700 p.p.m. [CO2]. Likewise, sustained higher NPQ under Vaseline™, after dehydration or at low RH, also restricted ETR to ~75% of control values. Low NPQ in chloroplast-containing cells adjacent to major veins but remote from stomata suggested internal sources of high [CO2] in these tissues.

Chemical and microbial community analysis during aerobic biostimulation assays of non-sulfonated alkyl-benzene-contaminated groundwater.

A chemical and microbial characterization of lab-scale biostimulation assays with groundwater samples taken from an industrial site in which the aquifer had been contaminated by linear non-sulfonate alkyl benzenes (LABs) was carried out for further field-scale bioremediation purposes. Two lab-scale biodegradability assays were performed, one with a previously obtained gas-oil-degrading consortium and another with the native groundwater flora. Results for the characterization of the groundwater microbial population of the site revealed the presence of an important LAB-degrading microbial population with a strong degrading capacity. Among the microorganisms identified at the site, the detection of Parvibaculum lavamentivorans, which have been described in other studies as alkyl benzene sulfonates degraders, is worth mentioning. Incubation of P. lavamentivorans DSMZ13023 with LABs as reported in this study shows for the first time the metabolic capacity of this strain to degrade such compounds. Results from the biodegradation assays in this study showed that the indigenous microbial population had a higher degrading capacity than the gas-oil-degrading consortium, indicating the strong ability of the native community to adapt to the presence of LABs. The addition of inorganic nutrients significantly improved the aerobic biodegradation rate, achieving levels of biodegradation close to 90%. The results of this study show the potential effectiveness of oxygen and nutrients as in situ biostimulation agents as well as the existence of a complex microbial community that encompasses well-known hydrocarbon- and LAS-degrading microbial populations in the aquifer studied.

[Evaluation of the effect of various methods of oil-polluted soil bioremediation on micromycete complexes].

The influence of remediation of oil-contaminated gray forest, dark gray forest, and black soils by biological preparations Bacispecin, Devoroil, and Belvitamil on the population of opportunistic and phytotoxic fungi was studied. It was found that this population increased after oil pollution and decreased after three months of remediation. The latter is a sign of gradual recovery of soil microbiota.

Lipid uptake and skin occlusion following topical application of oils on adult and infant skin.

BACKGROUND: Topical application of oils and oil-based formulations is common practice in skin care for both adults and infants. Only limited knowledge however is available regarding skin penetration and occlusive potential of oils and common methods for measuring skin moisturization fall short when it comes to the moisturizing effect of oils. OBJECTIVE: In this study we used in vivo confocal Raman microspectroscopy to test the efficacy of paraffin oil (mineral oil) and two vegetable oils in terms of skin penetration and occlusion. Petrolatum was used as a positive control. METHODS: The products were applied topically on the forearms of nine volunteers and seven infants and Raman spectra were acquired before and at 30 and 90 min following application. Depth concentration profiles for lipid and water were calculated from the Raman spectra. Skin occlusion was assessed from the amount of stratum corneum (SC) swelling measured from the water concentration profiles. RESULTS: The paraffin oil and the vegetable oils penetrate the top layers of the SC with similar concentration profiles, a result that was confirmed both for adult and infant skin. The three oils tested demonstrated modest SC swelling (10-20%) compared to moderate swelling (40-60%) for petrolatum. CONCLUSION: These data indicate that there is no statistical difference between the paraffin oil and vegetable oils in terms of skin penetration and skin occlusion. The results for petrolatum show that in vivo confocal Raman microspectroscopy is sensitive and specific enough to measure both lipid uptake and skin occlusion events following topical application.

Specificity of Ca2+-dependent protein interactions mediated by the C2A domains of synaptotagmins.

Synaptotagmins represent a family of neuronal proteins thought to function in membrane traffic. The best characterized synaptotagmin, synaptotagmin I, is essential for fast Ca2+-dependent synaptic vesicle exocytosis, indicating a role in the Ca2+ triggering of membrane fusion. Synaptotagmins contain two C2 domains, the C2A and C2B domains, which bind Ca2+ and may mediate their functions by binding to specific targets. For synaptotagmin I, several putative targets have been identified, including the SNARE proteins syntaxin and SNAP-25. However, it is unclear which of the many binding proteins are physiologically relevant. Furthermore, more than 10 highly homologous synaptotagmins are expressed in brain, but it is unknown if they execute similar binding reactions. To address these questions, we have performed a systematic, unbiased study of proteins which bind to the C2A domains of synaptotagmins I-VII. Although the various C2A domains exhibit similar binding activities for phospholipids and syntaxin, we found that they differ greatly in their protein binding patterns. Surprisingly, none of the previously characterized binding proteins for synaptotagmin I are among the major interacting proteins identified. Instead, several proteins that were not known to interact with synaptotagmin I were bound tightly and stoichiometrically, most prominently the NSF homologue VCP, which is thought to be involved in membrane fusion, and an unknown protein of 40 kDa. Point mutations in the Ca2+ binding loops of the C2A domain revealed that the interactions of these proteins with synaptotagmin I were highly specific. Furthermore, a synaptotagmin I/VCP complex could be immunoprecipitated from brain homogenates in a Ca2+-dependent manner, and GST-VCP fusion proteins efficiently captured synaptotagmin I from brain. However, when we investigated the tissue distribution of VCP, we found that, different from synaptic proteins, VCP was not enriched in brain and exhibited no developmental increase paralleling synaptogenesis. Moreover, binding of VCP, which is an ATPase, to synaptotagmin I was inhibited by both ATP and ADP, indicating that the native, nucleotide-occupied state of VCP does not bind to synaptotagmin. Together our findings suggest that the C2A-domains of different synaptotagmins, despite their homology, exhibit a high degree of specificity in their protein interactions. This is direct evidence for diverse roles of the various synaptotagmins in brain, consistent with their differential subcellular localizations. Furthermore, our results indicate that traditional approaches, such as affinity chromatography and immunoprecipitations, are useful tools to evaluate the overall spectrum of binding activity for a protein but are not sufficient to estimate physiological relevance.

Effect of vehicle on topical liposomal drug delivery: petrolatum bases.

Liposornes used for topical applications are often incorporated into a vehicle to achieve suitable viscosity and application properties. The effect of incorporation of liposomes into white petrolatum as a possible dermatological base was investigated. A number of formulae were developed to determine the type of petrolatum base that would be compatible with the liposomes. The physical appearance and stability of the vaseline-liposome (VL) preparations were determined by organoleptic analysis and microscopy. The effect of petrolatum base on the drug release from the liposomes was determined in a flow-through diffusion cell system using a model silastic polymer membrane as barrier. A base containing white petrolatum 46.7% (w/w), stearyl alcohol 6.7% (w/w), cholesterol 13.3 (w/w), Tween 80 16.7% (w/w) and Span 16.7% (w/w) was selected for diffusion studies, since the mixture of this base and liposome preparation, at 1:1.9 (w/w) ratios, provided a stable, dermatologically acceptable dosage form, in which the liposomes were uniformly distributed and their structures were preserved. Diffusion studies showed that the drug release rate decreases 2.5x when the liposomes are incorporated into the vaseline base; however, after a temporary decrease they seem to extend the duration of release beyond that of the original liposomal formula. These studies revealed a possibility of using white petrolatum in the topical application of liposomes.

The effect of some ointment bases on the systemic absorption of tobramycin from various wound surfaces of burned patients.

Three kinds of 0.2 per cent tobramycin ointment were prepared with tobramycin and 3 ointment bases (cream, polyethylene glycol and hydrophilic petrolatum), and applied to the various wound surfaces of 5 burned patients. The systemic absorptions of tobramycin were compared with the values of the tentative AUC (area under the curve of tobramycin blood level, micrograms.h/ml.g) until 12 hours after the applications, by determining tobramycin level in blood. Similar values of AUC from the cream and polyethylene glycol ointments were obtained, while that of hydrophilic petrolatum ointment was very low. The systemic absorption of tobramycin from the polyethylene glycol ointment was studied when the ointment was applied to the wound surfaces of 7 patients with partial-thickness burn, 9 patients with full-thickness burn and 6 patients with burn ulcer. The mean values of the tentative AUC of patients with partial-thickness burn, full-thickness burn and burn ulcer were found to be 0.06, 0.03 and 0.15, respectively. These results showed that cream and polyethylene glycol bases should be used carefully as a vehicle of tobramycin ointments because of the rapid systemic absorption of tobramycin from human burn wounds, especially burn ulcer.

Effects of drug vehicles on ocular uptake of tetracycline.

Varying concentrations of tetracycline hydrochloride were topically applied to the rabbit eye in several ophthalmic vehicles. The antibiotic levels in the corneal epithelium, aqueous humor, and lens were markedly elevated by increasing the drug concentration and the drug contact time with the eye. The ocular levels of tetracycline were increased by the vehicle in this ascending order: isotonic saline, 1.4% polyvinyl alcohol, 1% alpha-methylcellulose, and a 6:4 mixture of white petrolatum-mineral oil ointment. Tetracycline hydrochloride as a 2.0% suspension in ointment produced anterior chamber and corneal concentrations for several hours in the range of bacteriostasis for many gram-negative bacteria that occasionally invade the eye.