Lipid Dispersions Research Articles

Characterization of solid lipid dispersions prepared by hot fusion containing a double-fixed dose combination of artemether and lumefantrine

Objective The World Health Organization has called for the development of novel drug delivery systems to combat malaria – the fourth most prevalent cause of death globally. The plausibility of utilizing hot fusion to prepare solid lipid dispersions containing the prescribed first-line, double-fixed dose combination (artemether and lumefantrine), proposed for inclusion in directly compressed lipid matrix tablets, was investigated. Significance: Currently, no anti-malarial product is commercially available that employs lipid technology in a solid oral dosage form that contains this double-fixed dose combination. Through developing lipid matrix tablets, the stability, solubility and subsequent bioavailability of these drugs could be significantly enhanced in the presence of lipids or oils. Methods Hot fusion encompasses encompassed melt mixing of a selected lipid base and the dispersion of the active ingredient(s) therein below their glass transition temperatures. Solid-state characterization, particle size analysis and pharmacotechnical properties were evaluated, with particular focus given to powder flowability. Results Stearic acid in a 0.5:1 lipid:drug ratio demonstrated the best powder flow properties of the investigated solid lipid dispersion for inclusion into prospective lipid–matrix tablets duly based on an increase in overall particle size, a more spherical particle shape and improved powder flow properties compared to the individual active ingredients. Conclusion Good powder flow is critical for powders destined for inclusion into tablets – especially when employing direct compression as method of manufacture – in this case, lipid matrix tablets, which have demonstrated huge promise as a prospective dosage form for future use in malarial treatment.

Effect of gangliosides on structure and integrity of polyethylene glycol (PEG)-stabilized liposomes

The in vivo efficacy and tolerance of polyethylene glycol (PEG)-decorated drug nanocarriers, such as liposomes, is compromised bytheir tendency to induce the generation of PEG-specific immunoglobulin M (IgM) antibodies. Recently, a number of independent studies have reported on an attenuated anti-PEG immune response upon incorporation of gangliosides in the membrane of PEGylated liposomes.In the present study we investigate the effect of gangliosides on the self-assembled structures found in lipid dispersions based on hydrogenated egg phosphatidylcholine (HEPC), cholesterol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG(2000)). Results from cryo-transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) investigations show that gangliosides promote structural transitions from liposomes to bilayer disks. In case of samples comprising 5 mol% PEG-conjugated lipids (PEG-lipid), inclusion of 2.5 mol% ganglioside (porcine ganglioside extract) results in the presence of a small but significant amount of disks. With increasing ganglioside content the population of disks grows at the expense of the liposomes. Comparative investigations using isolated ganglioside components reveal that disialoganglioside GD1a is more potent than monosialoganglioside GM1 in promoting disk formation. Experiments involving liposome encapsulated carboxyfluorescein confirm that the ganglioside-induced structural transformations have a detrimental effect on the total entrapped aqueous volume of the samples. The reported coexistence of liposomes and bilayer disks may if overlooked have important implications for the therapeutic efficacy and immunogenicity of ganglioside-supplemented liposomal formulations.

Toward a Spatiotemporal Model of Oxidation in Lipid Dispersions: A Hypothesis‐Driven Review

AbstractUnsaturated lipids are prone to get oxidized through a sequence of reactions known as lipid oxidation. From a phenomenon considered at the beginning as a mere chemical process and described by the triptych of initiation, propagation, and termination, the vision of lipid oxidation has progressively evolved to further integrate the physical dimension of the phenomenon. Despite tremendous research efforts, however, this sequence of reactions is not yet well understood, especially in lipid dispersions where many facts are still inexplicable and unpredictable under the current paradigm. Here, the aim is to suggest that the main reason why a better understanding has not already been achieved is that the reactional network is not yet organized in a coherent spatiotemporal framework. The novel concepts and hypotheses proposed in this article may help redirecting a significant part of research efforts toward the establishment of a spatially and temporally resolved model of oxidation in dispersed lipids.Practical Application: Predicting how oxidation spreads in lipid dispersions represents a goal of crucial importance for academia but also for industry. Such prediction models would indeed greatly help food manufacturers prevent oxidation by using the most adapted antioxidative strategies for their specific products. To achieve such an objective, it is proposed that the first thing to do is to go beyond the extremely reductive and narrow framework in which this chemical process has been locked in. Indeed, while lipid dispersions are composed of a multitude of lipid colloids, researchers usually consider oxidation at the sole level of an individual droplet or membrane. Instead, lipid oxidation is advocated as a dynamic trafficking of chemical species within large communities of different colloidal objects such as droplets, membranes, or micelles dispersed in water—a system that dubbed “colloidal ecosystem”. This might represent a scale complementary to the scales of individual colloids or molecules that were the sole consideration so far to try to represent lipid oxidation. Only then can one hope to effectively apply modeling and “omics” approaches, as is explained in more details in this article.

Morphological Change and Cell Disruption of Haematococcus pluvialis Cyst during High-Pressure Homogenization for Astaxanthin Recovery

Haematococcus pluvialis accumulates astaxanthin, which is a high-value antioxidant, during the red cyst stage of its lifecycle. The development of a rigid cell wall in the cysts hinders the recovery of astaxanthin. We investigated morphological changes and cell disruption of mature H. pluvialis cyst cells while using high-pressure homogenization for astaxanthin extraction. When treated with French-press-cell (pressure, 10,000–30,000 psi; passage, 1–3), the intact cyst cells were significantly broken or fully ruptured, releasing cytoplasmic components, thereby facilitating the separation of astaxanthin by ethyl acetate. Fluorescence microscopy observations using three different fluorescent dyes revealed that a greater degree of cell breakage caused greater external dispersion of astaxanthin, chlorophyll, lipids, proteins, and carbohydrates. The mechanical treatment resulted in a high cell disruption rate of up to 91% based on microscopic cell typing and Coulter methods. After the ethyl acetate extraction, the astaxanthin concentration significantly increased by 15.2 mg/L in proportion to the increase in cell disruption rate, which indicates that cell disruption is a critical factor for solvent-based astaxanthin recovery. Furthermore, this study recommends a synergistic combination of the fast instrumental particle-volume-distribution analysis and microscope-based morphologic phenotyping for the development of practical H. pluvialis biorefinery processes that co-produce various biological products, including lipids, proteins, carbohydrates, chlorophyll, and astaxanthin.

Scale-up production, characterization and toxicity of a freeze-dried lipid-stabilized microbubble formulation for ultrasound imaging and therapy

Microbubble formulations have a long history for enhancement of ultrasound (US) imaging and recently also for therapeutic applications. Previously, a series of freeze-dried bubble formulations based on the lipids DSPC and DSPG were developed. Here, we have attempted to scale-up the production process for future more extensive studies. Bubbles were prepared by homogenization of a lipid dispersion in a perfluoropropane atmosphere in a medium size (300–500 mL) homogenizer and then freeze-dried for better storage stability. In total, 300 freeze-dried vials were prepared. The properties of the bubbles were similar to those previously prepared on a lab scale with the difference that they were slightly larger and also had a better stability. The re-entrapped gas concentration after re-constituted freeze-dried bubbles was 9.4 µL/µmol lipid. The re-entrapped rate was 72.3% of fresh bubble before freeze-drying (13.0 µL/µmol lipid). The half-life of US imaging signal of the re-constituted freeze-dried bubbles in water in vitro was shorter than that of the fresh bubbles (2.7 min vs. 3.3 min). A leak of Evans Blue, that binds to albumin, from mouse ear blood vessel was observed after combination of bubble and US irradiation of 1 MHz for 1 min. As a result of bubble vibration by US irradiation, vascular endothelial cell bond opened and Evans Blue leaked. Toxicity of bubble was tested in rats. No toxicity was found after a single injection in the dose range tested. No serious toxicity was seen after repeated injections (one daily injection during 15 days).

The modulation of drug-loading stability within lipid membranes via medium chain triglycerides incorporation

The current research aimed to explore medium chain triglycerides (MCT) incorporation in liposomes to overcome stability challenges when drugs with high molecular weight and payload are loaded within lipid membranes. A model drug clarithromycin was loaded in lipid dispersions with various MCT/phospholipids ratios (RM/P = 0, 0.5, 1.75 and 7.5 w/w). TEM images demonstrated a liposome-to-emulsion structural transformation by MCT incorporation to cause increased particle size (104.3–167.7 nm) but decreased zeta potential (−63.6 to −44.4 mV) of lipid particles. MCT incorporation produced biphasic release in PBS and accelerated released in plasma. The tolerance of liposomes for thermal sterilization, high temperature test and freeze-thaw cycles were significantly improved by MCT incorporation. However, MCT incorporation produced adverse effects on colloidal stability in plasma and pharmacokinetics behavior in vivo to some extent. MCT stabilizing mechanism attributes to the modulation of drug loading area and stability improvement of lipid carriers. MCT incorporated liposomes achieved 2–3 fold cellular uptake level than traditional liposomes without significant cytotoxicity. These results indicated that MCT incorporation could be a promising strategy to apply in liposome production to achieve stable drug loading.

Supramolecular Nanotube Reactors for Production of Imine Polymers with Controlled Conformation, Size, and Chirality.

A series of supramolecular nanotubes with inner diameters of 1, 4, 9, 12, 16, and 29 nm are prepared from amino acid lipids. The hydrophobic channels of the nanotubes act as reactors for the formation of imine polymers by not only effectively encapsulating the benzaldehyde and diacetyleneamine precursors of the imine monomers but also markedly accelerating imine formation. The nanotube inner diameter determines whether the imine monomers self-assemble into nanoparticles, nanotapes, nanocoils, or twisted nanofibers in the channels. UV-induced polymerization of the diacetylene units in the imine nanostructures followed by decomposition of the nanotubes into molecular dispersions of the constituent amino acid lipids results in expulsion of the polymerized imine nanostructures with retained conformation. The isolated nanocoils and twisted nanofibers retain the helicity and circular dichroism induced by the nanotubes, which exhibits supramolecular chirality, even though the components of the imine monomers are achiral. These supramolecular nanotubes with tunable diameters and functionalizable surfaces can be expected to be useful for the production of polymers with controlled conformation, size, and chirality without the need for rational design or chemical modification of the monomers or optimization of the polymerization conditions.

Solvent accessibility in interdigitated and micellar phases formed by DPPC/Lyso-PPC mixtures: D2O-ESEEM of chain labeled lipids.

Electron spin echo envelope modulation (ESEEM) spectroscopy was used to investigate binary mixtures of single-chain micelle-forming lipids and diacyl bilayer-forming lipids dispersed in D2O at 77 K. Mixtures of dipalmitoylphosphatidylcholine (DPPC) and lyso-palmitoylphosphatidylcholine (Lyso-PPC) over the entire composition range (0-100 mol%) and phosphatidylcholine spin-labeled at selected carbon atom position along the sn-2 chain (n-PCSL) were considered. On increasing the content of the lysolipids incorporated in DPPC, the lipid bilayers are first transformed in interdigitated lamellae and then converted in micelles of Lyso-PPC. In the interdigitated phase, the profile of translamellae water accessibility is rather uniform as all the hydrocarbon segments are equally exposed to the solvent. In Lyso-PPC micelle, water penetrates at any depth of the hydrocarbon region with a tendency to increase toward the chain termini. The extent of water penetration is higher in the interdigitated DPPC/Lyso-PPC dispersions than in Lyso-PPC micelles. The profiles of water permeation revealed directly by D2O-ESEEM are also confirmed by more indirect evaluation of the polarity profiles based on the 14N-hyperfine splitting in the conventional electron paramagnetic resonance spectra of n-PCSL in frozen DPPC/Lyso-PPC mixtures at 77 K. The ESEEM data reveal that H-bonding formation between the -NO group of the spin-label and the D2O molecules is favored in the intergitated phase with respect to the micellar phase and, in any lipid dispersion, the fraction of nitroxides that are singly H-bonded to deuterons is higher than the fraction that are doubly H-bonded. The overall results highlight the differences in the accessibility and properties of the solvent in the hydrocarbon region of lipid bilayers, interdigitated bilayers and micelles.

Lipid-shelled microbubbles for ultrasound-triggered release of bioactive gases to treat stroke and cardiovascular disease

Ischemia-reperfusion-induced neurological injury is a primary cause of stroke disability. Xenon (Xe), a bioactive gas, has potential as an effective and nontoxic neuroprotectant for the treatment of ischemic stroke. Nitric oxide (NO) is a potent bioactive gas capable of inducing vasodilatory, anti-inflammatory, neuroprotectant and bactericidal effects. The goal of this work was to develop lipid-shelled microbubbles for site-specific release of Xe or NO upon pulsed ultrasound exposure. Gas-loaded microbubbles were synthesized by high-shear mixing of a lipid dispersion in a vial that contained, Xe or NO, and octafluoropropane (OFP) in combination. Attenuation spectroscopy measurements demonstrate the feasibility of 6-MHz pulsed Doppler ultrasound-triggered release of Xe or NO from microbubbles. The addition of OFP in the lipid-shelled microbubbles increased the number density, size, and stability of the microbubbles, particularly in undersaturated saline. Gas chromatography mass spectrometry was employed to measure Xe dose (127 ± 29 μl Xe/mg lipid). The payload of NO in the microbubbles (97 ± 12 μl NO/mg lipid) was assessed using an amperometric sensor. Intravenous administration of microbubbles carrying a neuroprotective or a vasodilatory gas in combination with ultrasound exposure has potential as a novel noninvasive strategy for local therapeutic delivery to modulate the effects or duration of cerebral ischemia.

Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): physicochemical and solid-solution state characterizations

Amphotericin B (AmB) is one of the most effective systemic antifungal agents, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation, Fungizone®. Significantly lesser toxicity is obtained when AmB incorporated into the aqueous dispersion of lipid nanoparticles. The aim of this study was to develop and characterize AmB loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). NLC differed from SLN by the presence of liquid lipid, glyceryl tri(caprylate/caprate) in the lipid matrix. Various surfactants i.e. tween 20, cremophor RH40, poloxamer 407 (P407) and Myrj 52 were used to stabilize SLN and NLC. The effect of phospholipid incorporated in those lipid dispersions was also determined. Among surfactants tested, only P407 could stabilize AmB lipid dispersions. There was no chemical reaction occurred between AmB and other components that confirmed by Fourier transform infrared spectroscopy (FT-IR) spectra. The differential scanning calorimetry (DSC), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD) data showed that AmB was molecularly dispersed or in amorphous form in the lipid matrix. The proton nuclear magnetic resonance (1H-NMR) results showed that in the presence of phospholipid oil clusters within the lipid matrix are formed. These results indicate that SLN and NLC stabilized by P407 and/or phospholipid as the colloidal carrier for AmB were successfully developed.

A vesicle-to-sponge transition via the proliferation of membrane-linking pores in ω-3 polyunsaturated fatty acid-containing lipid assemblies

We investigate the nanostructure evolution and the membrane reorganization of diluted lipid dispersions of self-assembled monoolein (MO)/eicosapentaenoic acid (EPA, 20:5) mixtures by synchrotron small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) microscopy. The nonlamellar lipid phase containing a ω-3 polyunsaturated fatty acid was fragmented into stable nanoscale objects with the help of PEGylated lipids. The Cryo-TEM imaging revealed the transformation pathway of the vesicular bilayer membranes into sponge nanoparticles (spongosomes) in excess aqueous medium. At ambient temperature, the topological transition occurred through the proliferation of membrane-linking pores (MLP) within the individual lipid nanoparticles. The density of the MLP pores varied starting from the nanoparticle center toward the periphery. The generation of MLP is governed by the amphiphilic composition and leads to formation of 3D networks of aqueous channels inside the nanoparticles, i.e. spongosomes. A higher density of MLP pores was established at increasing fraction of EPA in the mixed lipid membranes. This corresponded to sponge particles of less hydrated internal structure, i.e. with smaller-size aqueous compartments. Synchrotron SAXS patterns characterized the overall structural transition from vesicles to sponge membranes in the studied lipid systems. It can be concluded that the incorporation of a ω-3 polyunsaturated fatty acid at increasing concentration causes swelling inhibition (dehydration) of the host liquid crystalline architectures.

Optimization of the Technology for the Preparation of Cationic Liposomes for the Delivery of Nucleic Acids

Cationic liposomes based on the cationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)- 7,11,16-2-tetraazahexacosane tetrahydrochloride (2X3) and the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) have been prepared by two methods, namely ultrasonication and the extrusion of a lipid dispersion. The effect of the preparation method and the type of the water phase on the physicochemical characteristics of cationic liposomes and their biological activity has been studied. The optimization of the preparation of cationic liposomes made it possible to determine the technological parameters providing the reproducibility of physicochemical characteristics of liposomes from batch to batch.

Antioxidant activity of a winterized, acetonic rye bran extract containing alkylresorcinols in oil-in-water emulsions

Naturally derived antioxidants are in high demand as the food industry strives to meet consumer preferences for non-synthetic additives. Alkylresorcinols (ARs) represent a novel class of natural antioxidants that can be derived from a natural waste stream (bran) and have the potential to inhibit lipid peroxidation given their phenolic structure. The antioxidant activity of rye bran extract containing ARs was investigated in an oil-in-water emulsion and was found to inhibit lipid oxidation reactions. The concentration of ARs in the continuous phase of emulsions was measured to understand partitioning behavior, as this is known to impact antioxidant activity. It was found that a majority of the ARs were associated with the lipid phase and those in the continuous phase were associated with surfactant micelles, perhaps inhibiting their interaction with water-soluble pro-oxidants. These results show that a rye bran extract containing ARs can function as a radical scavenging antioxidant in lipid dispersions.

Amphotericin B-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): effect of drug loading and biopharmaceutical characterizations

The aim of this study was to further investigate the effect of drug loading, drug entrapment efficiency, the drug release profiles and biopharmaceutical point of views of amphotericin B (AmB) lipid formulations, that is, degree of aggregation by UV-spectroscopy, in vitro hemolytic and antifungal activities. The optimum drug loading was 2.5% by weight corresponded to lipid fraction in formulation. Increasing of the drug entrapment was achieved by blending small amount of phospholipid in solid lipid nanoparticle (SLN) dispersions. All AmB lipid dispersions were less aggregated species and hemolytic response than Fungizone® indicating that lipid nanoparticles could reduce its toxicity. The sustained release profiles of AmB formulations depended on its aggregated form and entrapment efficiency. Too high AmB loaded (5% w/w) showed a biphasic drug release profile probably due to some amounts of drug deposited on the nanosphere surface including in continuous phase which promptly released. For in vitro antifungal testing, all AmB lipid formulations were equal and more effective than both AmB itself and Fungizone®. These observations suggested that AmB loaded SLNs, nanostructured lipid carriers and modified SLNs by blending lecithin could enhance AmB solubility, prolong release characteristics, reduce toxicity and improve antifungal activity.

Mass-Producible Organic Nanocapsule with Water-Responsive Releasing Ability

An organic nanocapsule was obtained by mixing zinc acetate powder into a peptide lipid dispersion in ethanol. The nanocapsule was mass-produced at a scale of over 100 g L–1 within 1 h. Fourier transform infrared spectroscopy and scanning electron microscopy revealed that a zinc-peptide lipid complex was formed within 15 min, which subsequently transformed into a nanocapsule as a result of changes in the hydrogen bonding networks between the peptides. A variety of organic dyes could be encapsulated by simply adding them during the nanocapsule formation. We also confirmed their high stabilities in organic solvents, water-responsive morphological change, and resulting guest release. The water-responsive nanocapsule is expected to be useful in a variety of fields.

Incorporation of mRNA in Lamellar Lipid Matrices for Parenteral Administration.

Insertion of high molecular weight messenger RNA (mRNA) into lyotropic lipid phases as model systems for controlled release formulations for the mRNA was investigated. Low fractions of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) were used as an anchor to load the mRNA into a lamellar lipid matrix. Dispersions of zwitterionic lipid in the aqueous phase in the presence of increasing fractions of mRNA and cationic lipid were prepared, and the molecular organization was investigated as a function of mRNA and cationic lipid fraction. Insertion of both cationic lipid and mRNA was clearly proven from the physicochemical characteristics. The d-spacing of the lipid bilayers, as determined by small-angle X-ray scattering (SAXS) measurements, responded sensitively to the amount of inserted DOTAP and mRNA. A concise model of the insertion of the mRNA in the lipid matrices was derived, indicating that the mRNA was accommodated in the aqueous slab between lipid bilayers. Depending on the DOTAP and mRNA fraction, a different excess of water was present in this slab. Results from further physicochemical characterization, including determination of free and bound mRNA, zeta potential, and calorimetry data, were in line with this assumption. The structure of these concentrated lipid/mRNA preparations was maintained upon dilution. The functionality of the inserted mRNA was proven by cell culture experiments using C2C12 murine myoblast cells with the luciferase-encoding mRNA. The described lipid phases as carriers for the mRNA may be applicable for different routes of local administration, where control of the release kinetics and the form of the released mRNA (bound or free) is required.

Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers.

Secondary lung infections are the primary cause of morbidity associated with cystic fibrosis lung disease. Aerosolized antibiotic inhalation is potentially advantageous but has limited effectiveness due to altered airway aerodynamics and deposition patterns that limit drug access to infected regions. One potential strategy to better reach infected areas is to formulate aerosols with surfactants that induce surface tension gradients and drive postdeposition drug dispersal via Marangoni transport along the airway surface liquid (ASL). Since this relies on surfactant-induced surface tension reduction, the presence of endogenous lipid monolayers may hinder drug dispersal performance. Tobramycin solutions were formulated with dipalmitoylphosphatidylcholine (DPPC), a major component of endogenous pulmonary surfactant, to drive postdeposition aerosol dispersal across a model ASL based on a liquid layer or "subphase" of aqueous porcine gastric mucin (PGM) solution with predeposited DPPC monolayers to mimic the endogenous surfactant. In vitro subphase samples were collected from regions outside the aerosol deposition zone and assayed for tobramycin concentration using a closed enzyme donor immunoassay. The motion of a tracking bead across the subphase surface and the corresponding decrease in surface tension on aerosol deposition were tracked both with and without a predeposited DPPC monolayer. The surface tension/area isotherm for DPPC on PGM solution subphase was measured to aid in the interpretation of the tobramycin dispersal behavior. Transport of tobramycin away from the deposition region occurs in aerosols formulated with DPPC whether or not predeposited lipid is present, and tobramycin concentrations are similar in both cases across biologically relevant length scales (∼8 cm). When DPPC is deposited from an aerosol, it induces ultralow surface tensions (<5 mN/m), which drive Marangoni flows, even in the presence of a dense background layer of DPPC. Therefore, aerosolized phospholipids, such as DPPC, will likely be effective spreading agents in the human lung.

A study on the diagnostic value of tear film objective scatter index in dry eye

Objective: To study the sensitivity and specificity of tear film objective scatter index to the diagnosis dry eye disease (DED). Methods: A prospective case-controlled study. Fifty-three patients with DED and 32 healthy age- and sex-matched control subjects were included from July to October 2016. All subjects underwent the examinations sequentially as follows: evaluation of ocular surface disease symptoms using the Ocular Surface Disease Index, optical quality detection, lipid layer thickness, tear film breakup time and SchirmerⅠtest. With Optical Quality Analysis SystemⅡ, the values of modulation transfer function cut off, basic objective scatter index (OSI) and total OSI were measured. To eliminate the influence of other refractive media, the tear film OSI (TF-OSI) was calculated, and the difference in TF-OSI between two groups was analyzed with the independent-samples t test. Spearman's correlation analysis was used to detect the correlation of each parameter in the DED group. With the receiver operating characteristic curve and the area under the curve (AUC), the specificity and sensitivity of TF-OSI and other parameters were described to differentiate DED from normal eyes. Results: In the dry eye group, the value of modulation transfer function cut off (32.07±11.95) was significantly lower than the normal group (39.38±9.44, t=-3.096, P=0.003) , and the mean value and dispersion of TF-OSI (0.50±0.43, 0.52±0.81) were higher than the normal group (0.21±0.16, 0.12±0.01) (t=4.300, P=0.000, t=3.546, P=0.001) . The mean value of TF-OSI had a positive correlation with lipid layer thickness (r=0.365, P=0.007) and dispersion of TF-OSI (r=0.581, P=0.000), and a negative correlation with MTF cut off (r=-0.368, P=0.007). To the diagnostic value of DED, the mean value of TF-OSI had a sensitivity of 0.736, a specificity of 0.762, and the AUC was 0.764. The dispersion of TF-OSI had a sensitivity of 0.811 and a specificity of 0.810, and the AUC was 0.900. Conclusion: In the DED group, the mean value and dispersion of TF-OSI were higher than the normal group. With its advantages, the TF-OSI may be a new method for the auxiliary diagnosis of dry eye. (Chin J Ophthalmol, 2017, 53: 668-674).

Nanostructured lipid systems modified with waste material of propolis for wound healing: Design, in vitro and in vivo evaluation

Propolis, a natural compound that can accelerate the wound healing process, is mainly used as ethanolic extract. The extractive solution may also be obtained from the propolis by-product (BP), transforming this waste material into a pharmaceutical active ingredient. Even if propolis does not show toxicity, when used as an extract over harmed skin or mucosa, the present ethanol content may be harmful to the tissue recovering, besides hindering the drug release. This study describes the development of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) as topical propolis delivery systems and the investigation of their in vitro and in vivo activities. The extracts were evaluated to guarantee their quality, and the lipid dispersions were characterized with respect to morphology (cryo-TEM), size and diffractometry (X-ray) properties. The occlusive capacity of formulations was also evaluated by an in vitro technique, which determines the occlusion factor. The drug entrapment efficiency (EE), as well as the in vitro drug release profile from the nanoparticulate systems was investigated as well. The size analysis performed through 90days was favorable to a topical administration and the polydispersity index, though not ideal in all cases due to the high content of resins and gums from the extracts, were relatively stable for the SLN. The propolis extract contributes to the occlusive potential of the formulations. The human immortalized keratinocytes presented good cell viability when tested with both extracts (propolis and BP) freely or entrapped in the systems. SLN modified with propolis material provided an acceleration of the in vivo wound healing process.

Cubosomes as Carriers for MRI Contrast Agents.

Cubosomes are self-assembled nanostructures that often form on dispersion of polar lipids in aqueous environments. The nanoparticles are analogous to liposomes but contain a complex internal self-assembled structure providing a point of difference to relatively simple liposomes. They exhibit a range of attractive properties such as having a high surface area, being able to incorporate both hydrophobic and hydrophilic molecules and controlled release. Consequently cubosomes are of increasing interest in fields such as drug delivery, and diagnostic imaging, in particular as a carrier for magnetic resonance imaging contrast agents. Over the last decade the incorporation of various contrast agents into the cubic mesophases has demonstrated improved relaxivity and resolution, as well as addressing other limitations of commercially available agents by increasing circulation time, stability and targeting. This minireview provides a brief overview of what cubosomes are, how they can be made, how they are characterised and also summarise the findings from the studies that have used cubosomes to develop better contrast agents for MRI, as well as highlight some potential for future developments.