Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application.

AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.

A retrospective analysis of therapeutic drug exposures in New Zealand National Poisons Centre data 2018-2020.

OBJECTIVE: The New Zealand National Poisons Centre advises the general public and health professionals on management of exposures to various substances. The epidemiology of medicine exposures was used to characterise inappropriate use of medicines across age groups. METHODS: Data from contacts in 2018-2020 were analysed: patient demographics (age, gender), number of therapeutic substances, and advice given. The most frequent individual therapeutic substance exposures across age groups and the reasons for these occurring were determined. RESULTS: A total of 76% of children's (aged 0-12 or unknown child) exposures were exploratory in nature, involving a variety of medicines. Youth (aged 13-19) had frequently engaged in intentional self-poisoning (61% of their exposures), and most commonly by exposure to paracetamol, antidepressants, and quetiapine. Adults (aged 20-64) and older adults (aged 65 and over) were frequently affected by therapeutic errors (50% and 86% of their exposures, respectively). Adults were most frequently exposed to paracetamol, codeine, tramadol, antidepressants, and hypnotics, while older adults were exposed to paracetamol and various cardiac medications. CONCLUSIONS: Types of inappropriate medicine exposures vary in different age groups. IMPLICATIONS FOR PUBLIC HEALTH: Poisons centre data add to pharmacovigilance monitoring of potential harm from medicines and inform medication safety policies and interventions.

Chiral nematic liquid crystal droplets as a basis for sensor systems.

For a series of phospholipid coated calamitic nematic liquid crystal droplets (5CB, 6CB, 7CB, E7 and MLC7023) of diameter ∼18 µm, the addition of chiral dopant leaves the sign of surface anchoring unchanged. Herein we report that for these chiral nematic droplets an analyte induced transition from a Frank-Pryce structure (with planar anchoring) to a nested-cup structure (with perpendicular anchoring) is accompanied by changes in the intensity of reflected light. We propose this system as both a general scheme for understanding director fields in chiral nematic liquid crystal droplets with perpendicular anchoring and as an ideal candidate to be utilised as the basis for developing cheap, single use LC-based sensor devices.

Combined electric and photocontrol of selective light reflection at an oblique helicoidal cholesteric liquid crystal doped with azoxybenzene derivative.

An oblique helicoidal cholesteric liquid crystal Ch_{OH} represents a unique optical material with a single-harmonic periodic modulation of the refractive index and a pitch that can be tuned by an electric or magnetic field in a broad range from submicrometers to micrometers. In this work, we demonstrate that the oblique helicoidal cholesteric doped with azoxybenzene molecules can be tuned by both the electric field and light irradiation. The tuning mechanism is explained by the kinetics of trans-cis photoisomerization of the azoxybenzene molecules. At a fixed voltage, UV irradiation causes a redshift of the reflection peak by more than 200 nm. The effect is caused by an increase of the bend elastic constant of Ch_{OH} under irradiation. The demonstrated principle has the potential for applications such as smart windows, sensors, tunable lasers, and filters.

Hydrogen Sulfide-Responsive Bicontinuous Nanospheres.

Block copolymers (BCPs) that can self-assemble into particles and be triggered by disease-specific molecules such as hydrogen sulfide (H2S) have the potential to impact on drug delivery, decreasing off-target toxicities while increasing drug efficacy. However, the incorporation of H2S-responsive aryl azides into BCPs for self-assembly has been limited by heat, light, and radical sensitivities. In this study, a robust activator regenerated by the electron-transfer atom-transfer radical polymerization reaction was used to synthesize aryl-azide-containing BCPs under ambient conditions. Conditions controlling self-assembly of the BCPs into 150-200 nm particles and the physicochemical properties of the particles were investigated. The use of nanoprecipitation with tetrahydrofuran to promote self-assembly of the BCPs resulted in vesicle structures, while dimethylformamide or dimethylsulfoxide resulted in polymeric bicontinuous nanospheres (BCNs). Triggering of the BCPs and particles (vesicles or BCNs) via exposure to H2S revealed that unsubstituted aryl azides were readily reduced (by HS-), resulting in particle disruption or cross-linking. The relative polar nature of the particle bilayers containing unsubstituted aryl azides and the open structure of the BCNs did however limit encapsulation of small hydrophilic and hydrophobic payloads. Incorporation of a benzylamide substituent onto the aryl azide group increased the hydrophobicity of the particles and encapsulation of hydrophilic cargo but reduced sensitivity to H2S, likely due to the reduced penetration of HS- into the bilayer.

Evaluating Phospholipid-Functionalized Gold Nanorods for In Vivo Applications.

Gold nanorods (AuNRs) have attracted a great deal of attention due to their potential for use in a wide range of biomedical applications. However, their production typically requires the use of the relatively toxic cationic surfactant cetyltrimethylammonium bromide (CTAB) leading to continued demand for protocols to detoxify them for in vivo applications. In this study, a robust and facile protocol for the displacement of CTAB from the surface of AuNRs using phospholipids is presented. After the displacement, CTAB is not detectable by NMR spectroscopy, surface-enhanced Raman spectroscopy, or using pH-dependent ζ-potential measurements. The phospholipid functionalized AuNRs demonstrated superior stability and biocompatibility (IC50  > 200 µg mL-1 ) compared to both CTAB and polyelectrolyte functionalized AuNRs and are well tolerated in vivo. Furthermore, they have high near-infrared (NIR) absorbance and produce large amounts of heat under NIR illumination, hence such particles are well suited for plasmonic medical applications.

Production of giant unilamellar vesicles and encapsulation of lyotropic nematic liquid crystals.

We describe a modified microfluidic method for making Giant Unilamellar Vesicles (GUVs) via water/octanol-lipid/water double emulsion droplets. At a high enough lipid concentration we show that the de-wetting of the octanol from these droplets occurs spontaneously (off-chip) without the need to use shear to aid the de-wetting process. The resultant mixture of octanol droplets and GUVs can be separated by making use of the buoyancy of the octanol. A simpler microfluidic device and pump system can be employed and, because of the higher flow-rates and much higher rate of formation of the double emulsion droplets (∼1500 s-1 compared to up to ∼75 s-1), it is easier to make larger numbers of GUVs and larger volumes of solution. Because of the potential for using GUVs that incorporate lyotropic nematic liquid crystals in biosensors we have used this method to make GUVs that incorporate the nematic phases of sunset yellow and disodium chromoglycate. However, the phase behaviour of these lyotropic liquid crystals is quite sensitive to concentration and we found that there is an unexpected spread in the concentration of the contents of the GUVs obtained.

Control of Director Fields in Phospholipid-Coated Liquid Crystal Droplets.

In liquid crystal (LC) droplets, small changes in surface anchoring energy can produce large changes in the director field which result in readily detectable optical effects. This makes them attractive for use as biosensors. Coating LC droplets with a phospholipid monolayer provides a bridge between the hydrophobic world of LCs and the water-based world of biology and makes it possible to incorporate naturally occurring biosensor systems. However, phospholipids promote strong perpendicular (homeotropic) anchoring that can inhibit switching of the director field. We show that the tendency for phospholipid layers to promote perpendicular anchoring can be suppressed by using synthetic phospholipids in which the acyl chains are terminated with bulky tert-butyl or ferrocenyl groups; the larger these end-group(s), the less likely the system is to be perpendicular/radial. Additionally, the droplet director field is found to be dependent on the nature of the LC, particularly its intrinsic surface properties, but not (apparently) on the sign of the dielectric anisotropy, the proximity to the melting/isotropic phase transition, the surface tension (in air), or the values of the Frank elastic constants.

High-Contrast and Fast Photorheological Switching of a Twist-Bend Nematic Liquid Crystal.

Smart viscoelastic materials that respond to specific stimuli are one of the most attractive classes of materials important to future technologies, such as on-demand switchable adhesion technologies, actuators, molecular clutches, and nano-/microscopic mass transporters. Recently it was found that through a special solid-liquid transition, rheological properties can exhibit significant changes, thus providing suitable smart viscoelastic materials. However, designing materials with such a property is complex, and forward and backward switching times are usually long. Therefore, it is important to explore new working mechanisms to realize solid-liquid transitions, shorten the switching time, and enhance the contrast of rheological properties during switching. Here, a light-induced crystal-liquid phase transition is observed, which is characterized by means of polarizing light microscopy (POM), photorheometry, photo-differential scanning calorimetry (photo-DSC), and X-ray diffraction (XRD). The light-induced crystal-liquid phase transition presents key features such as (1) fast switching of crystal-liquid phases for both forward and backward reactions and (2) a high contrast ratio of viscoelasticity. In the characterization, POM is advantageous in offering information on the spatial distribution of LC molecule orientations, determining the type of liquid crystalline phases appearing in the material, and studying the orientation of LCs. Photorheometry allows measurement of a material's rheological properties under light stimuli and can reveal the photorheological switching properties of materials. Photo-DSC is a technique to investigate thermodynamic information of materials in darkness and under light irradiation. Lastly, XRD allows studying of microscopic structures of materials. The goal of this article is to clearly present how to prepare and measure the discussed properties of a photorheological material.

Distinct differences in the nanoscale behaviors of the twist-bend liquid crystal phase of a flexible linear trimer and homologous dimer.

We synthesized the liquid crystal dimer and trimer members of a series of flexible linear oligomers and characterized their microscopic and nanoscopic properties using resonant soft X-ray scattering and a number of other experimental techniques. On the microscopic scale, the twist-bend phases of the dimer and trimer appear essentially identical. However, while the liquid crystal dimer exhibits a temperature-dependent variation of its twist-bend helical pitch varying from 100 to 170 Å on heating, the trimer exhibits an essentially temperature-independent pitch of 66 Å, significantly shorter than those reported for other twist-bend forming materials in the literature. We attribute this to a specific combination of intrinsic conformational bend of the trimer molecules and a sterically favorable intercalation of the trimers over a commensurate fraction (two-thirds) of the molecular length. We develop a geometric model of the twist-bend phase for these materials with the molecules arranging into helical chain structures, and we fully determine their respective geometric parameters.

Augmenting Bragg Reflection with Polymer-sustained Conical Helix.

There has been a recent surge of interest in smart materials and devices with stimuli-responsive properties for optical modulations. Cholesteric liquid crystals (CLCs) are a unique class of light-manipulating materials, and strongly interact with light and other electromagnetic (EM) waves. Because of their intricate helical structure, new properties of CLC have emerged revealing unique optical behavior that has resulted in rewriting Braggs' law for how light interacts with soft materials. The aim of this work is to push the limits of spectral tuning with a new method of augmenting light-cholesteric interactions using a polymer-sustained conical helix (PSCH) structure. We experimentally explore the reversibility of reflective wavelength modulation and validate the mechanism enhanced by a polymer-sustained helicoidal structure via theoretical analyses. The conical helix structure of a CLC, formed by low-field-induced oblique orientation of cholesteric helices, is comprised of a chiral dopant, a conventional nematic, and bimesogenic and trimesogenic nematics. Polymerizing a small amount of a reactive mesogen in the CLC with an applied electric field produces a templated helical polymer network that enables three switched optical states, including light-scattering and transparent states as well as color reflection in response to an applied increasing or decreasing electric field. An electro-activated PSCH optical film covers a wide color space, which is appropriate for tunable color device applications. We envisage that this PSCH material will lead to new avenues for controlling EM waves in imaging and thermal control, smart windows and electronic papers.

Lipid coated liquid crystal droplets for the on-chip detection of antimicrobial peptides.

We describe a novel biosensor based on phospholipid-coated nematic liquid crystal (LC) droplets and demonstrate the detection of Smp43, a model antimicrobial peptide (AMP) from the venom of North African scorpion Scorpio maurus palmatus. Mono-disperse lipid-coated LC droplets of diameter 16.7 ± 0.2 µm were generated using PDMS microfluidic devices with a flow-focusing configuration and were the target for AMPs. The droplets were trapped in a bespoke microfluidic trap structure and were simultaneously treated with Smp43 at gradient concentrations in six different chambers. The disruption of the lipid monolayer by the Smp43 was detected (<6 µM) at concentrations well within its biologically active range, indicated by a dramatic change in the appearance of the droplets associated with the transition from a typical radial configuration to a bipolar configuration, which is readily observed by polarizing microscopy. This suggests the system has feasibility as a drug-discovery screening tool. Further, compared to previously reported LC droplet biosensors, this LC droplet biosensor with a lipid coating is more biologically relevant and its ease of use in detecting membrane-related biological processes and interactions has the potential for development as a reliable, low-cost and disposable point of care diagnostic tool.

Spherical-cap droplets of a photo-responsive bent liquid crystal dimer.

Using a photo-responsive dimer exhibiting the transition between nematic (N) and twist-bend nematic (NTB) phases, we prepared spherical cap-shaped droplets on solid substrates exposed to air. The internal director structures of these droplets vary depending on the phase and on the imposed boundary conditions. The structural switching between the N and NTB phases was successfully performed either by temperature control or by UV light-irradiation. The N phase is characterized by an extremely small bend elastic constant K3, and surprisingly, we found that the droplet-air interface induces a planar alignment, in contrast to that seen for typical calamitic liquid crystals. As a consequence, the director configuration was stabilized in a structure substantially different from that normally found in conventional nematic liquid crystalline droplets. In the twist-bend nematic droplets characteristic structures with macroscopic length scales were formed, and they were well controlled by the droplet size. These results indicated that a continuum theory is effective in describing the stabilization mechanism of the macroscopic structure even in the twist-bend nematic liquid crystal droplets exhibiting director modulations on a scale of several molecular lengths.

Is the Skin Absorption of Hydrocortisone Modified by the Variability in Dosing Topical Products?

Fingertip units have been proposed as a tool to standardize topical therapy with semisolid formulations. However, no studies to date have characterized the variability in dosing by patients using this concept and whether this variability ultimately affects the topical absorption of drugs. This work aimed to answer these two questions. A first study determined the dose measured, the area of spread and the area-normalized dose for a 1% hydrocortisone cream and ointment applied by members of the public using this dosing approach before and after brief counselling. Then, in vivo tape-stripping and in vitro permeation studies investigated whether the variability in the area-normalized dose altered the skin absorption of hydrocortisone. Participants applied greater doses and spread them over larger areas after a short counselling intervention leading to smaller area-normalized doses. In vivo hydrocortisone uptake by the stratum corneum was significantly greater for the higher normalized dose and the differences were further supported by the in vitro permeation studies. However, these differences were relatively small and not proportional to the increase in normalized dose. This work shows that, following brief advice, patients and carers can apply consistent and sufficient doses of corticosteroids whilst minimizing risks and variability in hydrocortisone absorption.

Electrically tunable laser based on oblique heliconical cholesteric liquid crystal.

A cholesteric liquid crystal (CLC) formed by chiral molecules represents a self-assembled one-dimensionally periodic helical structure with pitch [Formula: see text] in the submicrometer and micrometer range. Because of the spatial periodicity of the dielectric permittivity, a CLC doped with a fluorescent dye and pumped optically is capable of mirrorless lasing. An attractive feature of a CLC laser is that the pitch [Formula: see text] and thus the wavelength of lasing [Formula: see text] can be tuned, for example, by chemical composition. However, the most desired mode to tune the laser, by an electric field, has so far been elusive. Here we present the realization of an electrically tunable laser with [Formula: see text] spanning an extraordinarily broad range (>100 nm) of the visible spectrum. The effect is achieved by using an electric-field-induced oblique helicoidal (OH) state in which the molecules form an acute angle with the helicoidal axis rather than align perpendicularly to it as in a field-free CLC. The principal advantage of the electrically controlled CLCOH laser is that the electric field is applied parallel to the helical axis and thus changes the pitch but preserves the single-harmonic structure. The preserved single-harmonic structure ensures efficiency of lasing in the entire tunable range of emission. The broad tuning range of CLCOH lasers, coupled with their microscopic size and narrow line widths, may enable new applications in areas such as diagnostics, sensing, microscopy, displays, and holography.

Understanding the twist-bend nematic phase: the characterisation of 1-(4-cyanobiphenyl-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl)hexane (CB6OCB) and comparison with CB7CB.

The synthesis and characterisation of the nonsymmetric liquid crystal dimer, 1-(4-cyanobiphenyl-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl)hexane (CB6OCB) is reported. An enantiotropic nematic (N)-twist-bend nematic (NTB) phase transition is observed at 109 °C and a nematic-isotropic phase transition at 153 °C. The NTB phase assignment has been confirmed using polarised light microscopy, freeze fracture transmission electron microscopy (FFTEM), (2)H-NMR spectroscopy, and X-ray diffraction. The effective molecular length in both the NTB and N phases indicates a locally intercalated arrangement of the molecules, and the helicoidal pitch length in the NTB phase is estimated to be 8.9 nm. The surface anchoring properties of CB6OCB on a number of aligning layers is reported. A Landau model is applied to describe high-resolution heat capacity measurements in the vicinity of the NTB-N phase transition. Both the theory and heat capacity measurements agree with a very weak first-order phase transition. A complementary extended molecular field theory was found to be in suggestive accord with the (2)H-NMR studies of CB6OCB-d2, and those already known for CB7CB-d4. These include the reduced transition temperature, TNTBN/TNI, the order parameter of the mesogenic arms in the N phase close to the NTB-N transition, and the order parameter with respect to the helix axis which is related to the conical angle for the NTB phase.

Reversible Isothermal Twist-Bend Nematic-Nematic Phase Transition Driven by the Photoisomerization of an Azobenzene-Based Nonsymmetric Liquid Crystal Dimer.

The liquid crystal nonsymmetric dimer, 1-(4-butoxyazobenzene-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl) hexane (CB6OABOBu), shows enantiotropic twist-bend nematic, NTB, and nematic, N, phases. The NTB phase has been confirmed using polarized light microscopy, freeze fracture transmission electron microscopy, and X-ray diffraction. The helicoidal pitch in the NTB phase is 18 nm. The NTB-N (TNTBN) and N-I (TNI) transition temperatures are reduced upon UV light irradiation, with the reduction in TNTBN being much larger than that in TNI. An isothermal, reversible NTB-N transition may be driven photochemically. These observations are attributed to a trans-cis photoisomerization of the azobenzene fragment on UV irradiation, with the cis isomers stabilizing the standard nematic phase and the trans isomers stabilizing the NTB phase. The dramatic changes in TNTBN provide evidence that the transition between the normal nematic and twist-bend nematic with spontaneous breaking of chiral symmetry is crucially dependent on the shape of molecular dimers, which changes greatly during the trans-cis isomerization.

Electrically tunable selective reflection of light from ultraviolet to visible and infrared by heliconical cholesterics.

Electrical tuning of selective reflection of light is achieved in a very broad spectral range from ultraviolet to visible and infrared by an oblique helicoidal state of a cholesteric liquid crystal in a wide temperature range (including room temperature). The phenomenon offers potential applications in tunable smart windows, lasers, optical filters and limiters, as well as in displays.