AbstractThe nasal route offers many advantages for drug delivery: quick onset of action, better patient compliance, avoidance of first‐pass metabolism and bypassing the blood‐brain barrier. Despite the potential of this route, several challenges exist, such as the short drug retention time caused by mucociliary clearance (MCC). In situ forming gels, which undergo a sol‐to‐gel transition with specific triggers at the site of action, present real opportunities in this field. They combine the intrinsic characteristics of hydrogels (elasticity and water‐holding capacity) with responsiveness, allowing easy application of drugs (spraying or extruding through a nozzle), as well as prolonged retention in the nasal cavity. The incorporation of mucoadhesive polymers, additives and nanocarriers can further tune the properties of in situ gels as nasal delivery platforms. This review summarizes advances in in situ gels for nasal drug delivery. We first describe challenges of the nasal route, target properties of in situ nasal gels, and then present both “classic” gelling polymers (poloxamers and polysaccharides) – which form the bulk of reported studies on nasal gels – as well as novel bespoke materials; we review characterization methods, highlighting the lack of standardization and accepted target values, then discuss applications by spraying, and conclude with future prospects.

The field of mucoadhesion has grown from a niche interest to a central consideration for the optimisation of mucosal medicines. As new therapies progress through development pipelines there are constantly emerging conditions which would benefit from the ability to target prolonged residence at mucosal sites. As such, there continues to be expansive investigation into mucoadhesion and the design of novel mucoadhesive materials for dosage form design. In this perspective piece, we give consideration to the recent progress in the field of mucoadhesive materials and make suggestion for reconsideration of current focus. Opinion on risks around current approaches to the development of mucoadhesive materials are described. Furthermore, challenges with translation are discussed, focussing on sensitisation and incompatibilities. Finally, the state of data in this field is critically assessed with a focus to in vitro–in vivo correlation and the formulation state space. It is intended that this manuscript challenges some important areas currently under investigation in the field.

Emulsions are complex. Dispersing two immiscible phases, thus expanding an interface, requires effort to achieve and the resultant dispersion is thermodynamically unstable, driving the system toward coalescence. Furthermore, physical instabilities, including creaming, arise due to presence of dispersed droplets of different densities to a continuous phase. Emulsions allow the formulation of oils, can act as vehicles to solubilize both hydrophilic and lipophilic molecules, and can be tailored to desirable rheological profiles, including "gel-like" behavior and shear thinning. The usefulness of emulsions can be further expanded by imparting stimuli-responsive or "smart" behaviors by inclusion of a stimuli-responsive emulsifier, polymer or surfactant. This enables manipulation like gelation, breaking, or aggregation, by external triggers such as pH, temperature, or salt concentration changes. This platform generates functional materials for pharmaceuticals, cosmetics, oil recovery, and colloid engineering, combining both smart behaviors and intrinsic benefit of emulsions. However, with increased functionality comes greater complexity. This review focuses on the use of stimuli-responsive polymers for the generation of smart emulsions, motivated by the great adaptability of polymers for this application and their efficacy as steric stabilizers. Stimuli-responsive emulsions are described according to the trigger used to provide the reader with an overview of progress in this field. Emulsions, complex colloidal systems, serve as vehicles to solubilize hydrophilic and lipophilic molecules and can be tailored for desired rheological properties. However, their physical and thermodynamic instabilities are challenging. Stabilizing emulsions with stimuli-responsive macromolecules enables manipulation via pH, temperature or salt concentration changes, broadening applications in pharmaceuticals, cosmetics, and colloid engineering. This review highlights engineered emulsions stabilized by responsive polymers. image

Abstract It has been found that the thermoresponsive behavior of emulsions stabilized by block copolymer surfactants (BCSs) can induce either gelation or emulsion break‐up with mild temperature changes. A hydrophilic, steric‐stabilizing component of the BCS, polyethylene glycol methacrylate (PEGMA), is crucial to control the thermoresponsive behavior of the emulsions: longer PEG chains (950 g mol−1) lead to thermoregulation, whereas shorter PEGM chains (500 or 300 g mol−1) lead to emulsion break‐up upon mild heating. Additionally, the relative abundance of PEGMA to the thermoresponsive component in the BCS controls the gelation temperature of BCS‐stabilized emulsions. Small‐angle neutron scattering and transmission electron microscopy reveal that the BCS forms oblate ellipsoids which grow anisotropically with temperature. In samples that form a gel, there is evidence that these nano‐objects form supra‐colloidal structures, which are responsible for the gel mesophase formation. An optimal BCS can form emulsions that transition from a liquid to gel state when warmed above 32 °C. This makes the system ideal for in situ gelation upon contact with the body. Overall, this study highlights the great potential of BCSs in generating thermoresponsive emulsions for drug delivery and other healthcare applications.

This investigation seeks to integrate LAPONITE® clay gels with thermoresponsive branched copolymer surfactants (BCSs) to develop advanced functional materials with temperature-induced sol-gel behaviour. It is known that a diverse range of molecules adsorb strongly to clays which may be used to control liberation of the species in healthcare applications, and as such the development of polymer/clay hybrid materials which can add function to the native clay behaviour are of great interest. BCS were synthesised with a structure that encompasses poly(ethylene glycol)methacrylate (PEGMA), ethylene glycol dimethacrylate (EGDMA), and dodecanethiol (DDT), conferring versatile and tuneable thermoresponsive attributes. Systematic modulation of the monomer : DDT/initiator ratio was used to facilitate the synthesis of BCS architectures spanning a range of molecular weights. Through application of small-amplitude oscillatory shear (SAOS) rheology and small-angle neutron scattering (SANS) in conjunction with controlled temperature variations, the sol-gel transition dynamics of these nanocomposite materials were elucidated. Complementary insights into the mechanisms underpinning this transition and temperature-induced alterations in the constituents are gleaned through the utilization of SANS techniques employing contrast-matching methodologies to mitigate clay and polymer scattering interference. It is found that heating systems from room- to body- temperature induces self-assembly of BCS in the bulk aqueous phase with concurrent structuration of clay in gel-forming samples with lower number average molecular weight (Mn). SANS study unpicks this phenomenon to find that gelation occurs with concurrent aggregation of BCS in the bulk, inducing clay-clay interactions only in lower Mn BCS systems with large nanoaggregates.

In situ gelling formulations are drug delivery systems which typically exist in a liquid form at room temperature and change into gel state after application to the body in response to various stimuli such as changes in temperature, pH and ionic composition. Their biomedical application can further be improved by incorporating drug nanoparticles into in situ gelling systems in order to prolong drug release, reduce dosing frequency and improve therapeutic outcomes of patients, developing highly functional but challenging dosage forms. The composition of in situ gelling formulations influence factors relating to performance such as their syringeability, rheology, drug release profile and drug bioavailability at target sites, amongst other factors. The inclusion of mucoadhesive polymeric constituents into in situ gelling formulations has also been explored to ensure that the therapeutic agents are retained at target site for extended period of time. This review article will discuss traditional techniques (water bath-based vial inversion and viscometry) as well as advanced methodology (rheometry, differential scanning calorimetry, Small Angle Neutron Scattering, Small Angle X-ray Scattering, etc.) for evaluating in situ gel forming systems for topical drug delivery. The clinical properties of in situ gelling systems that have been studied for potential biomedical applications over the last ten years will be reviewed to highlight current knowledge in the performance of these systems. Formulation issues that have slowed the translation of some promising drug formulations from the research laboratory to the clinic will also be detailed.

Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate monomer, [2-(acryloyloxy)ethyl]trimethylammonium chloride (TMAEA), and a co-monomer, 1-vinyl-2-pyrrolidone (NVP), were prepared to produce paracetamol-loaded printlets. 1H NMR spectroscopy analysis confirmed the integration of TMAEA and NVP in the polymer, and residual TMAEA monomers were found to be present only in trace amounts (0.71 - 1.37 %w/w). The apparent molecular mass of the photopolymerised polymer was found to exceed 300,000 Da with hydrodynamic radii of 15 - 20 nm, estimated based on 1H DOSY NMR measurements The loaded paracetamol was completely released from the printlets between 45 minutes to 5 hours. In vivo single-dose acute toxicity studies in rats suggest that the printlets did not cause any tissue damage. The findings reported in this study represent a significant step towards the adoption of vat photopolymerization-based 3DP to produce personalised medicines.

Branched copolymer surfactants (BCS) containing thermoresponsive polymer components, hydrophilic components, and hydrophobic termini allow the formation of emulsions which switch from liquid at room temperature to a gel state upon heating. These materials have great potential as in situ gel-forming dosage forms for administration to external and internal body sites, where the emulsion system also allows effective solubilisation of a range of drugs with different chemistries. These systems have been reported previously, however there are many challenges to translation into pharmaceutical excipients. To transition towards this application, this manuscript describes the evaluation of a range of pharmaceutically-relevant oils in the BCS system as well as evaluation of surfactants and polymeric/oligomeric additives to enhance stability. Key endpoints for this study are macroscopic stability of the emulsions and rheological response to temperature. The effect of an optimal additive (methylcellulose) on the nanoscale processes occurring in the BCS-stabilised emulsions is probed by small-angle neutron scattering (SANS) to better comprehend the system. Overall, the study reports an optimal BCS/methylcellulose system exhibiting sol-gel transition at a physiologically-relevant temperature without macroscopic evidence of instability as an in situ gelling dosage form.

The full range of porphyrin-phthalocyanine hybrids can be synthesized by treatment of 1,4-dioctylphthalonitrile with varying equivalents of MeMgBr to produce mixtures favoring specific hybrid structures and the tetrabenzoporphyrin in the extreme case. The individual macrocycles can be isolated in pure form as their magnesium derivatives and subsequently demetallated to give the parent metal-free compounds. Insertion of lead proceeded smoothly with all hybrids using lead (II) acetate. In the case of monoaza- and triaza-hybrids, the resulting materials could be recrystallized to give crystals suitable for X-ray diffraction. The crystal structures are distinctive from previously reported examples of non-peripherally substituted octaalkyl phthalocyanines and hybrids (metal-free and metallated, including with lead) and they each present infinite stacks of cofacial macrocycles linked through bridging lead ions which, as expected, lie outside of the macrocycle plane.

Chronic wounds affect millions of people annually and have emotional and financial implications in addition to health issues. The current treatment for chronic wounds involves the repeated use of bandages and drugs such as antibiotics over an extended period. A cost-effective and convenient solution for wound healing is the development of drugincorporated bandages. This study aimed to develop a biocompatible bandage made of drug -incorporated poly (lactic-co-glycolic acid) (PLGA) microparticles (MPs) and eggshell membrane (ESM) for cornea wound healing. ESM has desirable properties for wound healing and can be isolated from eggshells using acetic acid or ethylenediaminetetraacetic acid (EDTA) protocols. Fluorescein isothiocyanate-labelled Bovine Serum Albumin (FITC-BSA) was used as a model drug, and the PLGA MPs were fabricated using a solvent extraction method. The MPs were successfully attached to the fibrous layer of the ESM using NaOH. The surface features of the ESM samples containing MPs were studied using a field emission scanning electron microscope (FESEM) and compared with blank ESM images. The findings indicated that the MPs were attached to the ESM fibres and had similar shapes and sizes as the control MPs. The fibre diameters of the MPs samples were assessed using Fiji-ImageJ software, and no significant changes were observed compared to the blank ESM. The surface roughness, Ra values, of the MPs incorporated ESM samples were evaluated and compared to the blank ESM, and no significant changes were found. Fourier transform infrared (FTIR) spectroscopy was used to analyse the chemical Composition of the bandage, and the spectra showed that the FBM were effectively incorporated into the ESM. The FTIR spectra identified the major peaks of the natural ESM and the PLGA polymer in the bandage. The bandage was transparent but had a reduced visibility in the waterproof test card method. The bandage achieved sustained drug release up to 10 days and was found to be biocompatible and non-toxic in a chorio-allantoic membrane (CAM) assay. Overall, the drugincorporated PLGA MPs-ESM bandage has great potential for treating chronic wounds.

Erythrosine displays potential photodynamic activity against microorganisms and unhealthy cells. However, erythrosine has high hydrophilicity, negatively impacting on permeation through biological membranes. Combining biological macromolecules and thermoresponsive polymers may overcome these erythrosine-related issues, enhancing retention of topically applied drugs. The aim of this work was to investigate the performance of adhesive and thermoresponsive micellar polymeric systems, containing erythrosine in neutral (ERI) or disodium salt (ERIs) states. Optimized combinations of poloxamer 407 (polox407) and sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) were used as platforms for ERI/ERIs delivery. The rheological and mechanical properties of the systems was explored. Most of the formulations were plastic, thixotropic and viscoelastic at 37 °C, with suitable gelation temperature for in situ gelation. Mechanical parameters were reduced in the presence of the photosensitizer, improving the softness index. Bioadhesion was efficient for all hydrogels, with improved parameters for mucosa in contrast to skin. Formulations composed of 17.5 % polox407 and 3 % HPMC or 1 % NaCMC with 1 % (w/w) ERI/ERIs could release the photosensitizer, reaching different layers of the skin/mucosa, ensuring enough production of cytotoxic species for photodynamic therapy. Functional micelles could boost the photodynamic activity of ERI and ERIs, improving their delivery and contact time with the cells.

AbstractThe last decade has seen an increasingly large number of studies reporting on the development of novel small organic conjugated systems for mitochondrial imaging exploiting optical signal transduction pathways. Mitochondria are known to play a critical role in a number of key biological processes, including cellular metabolism. Importantly, irregularities on their working function are nowadays understood to be intimately linked to a range of clinical conditions, highlighting the importance of targeting mitochondria for therapeutic benefits. In this work we carry out an in‐depth evaluation on the progress to date in the field to pave the way for the realization of superior alternatives to those currently existing. The manuscript is structured by commonly used chemical scaffolds and comprehensively covers key aspects factored in design strategies such as synthetic approaches as well as photophysical and biological characterization, to foster collaborative work among organic and physical chemists as well as cell biologists.

This study describes thermo-rheological properties of branched copolymer surfactants (BCSs) stabilizing oil-in-water emulsions to generate materials exhibiting temperature-dependent gelation with the ability to solubilize a broad range of molecules. Four poly(N-isopropylacrylamide-ran-poly(ethylene glycol) methacrylate) (poly(NIPAM-ran-PEGMA)) BCSs with varying molecular weight (M-n), 4.7; 7.0; 7.8 and 9.0 kg mol(-1), are investigated via oscillatory shear rheology, small angle neutron scattering (SANS), and neutron reflectivity (NR). Rheological thermoscans show that emulsions stabilized by the BCS with the lowest M-n (4.7 kg mol(-1)) are thermo-thinning, while with the other BCSs the emulsions display a thermo-thickening behavior. Emulsions stabilized with the BCS with M-n = 7.8 kg mol(-1) form gels within a precise temperature window depending on BCS concentration. Small angle neutron scattering data analysis suggests that the BCS is present in two forms in equilibrium, small aggregates dispersed in the bulk water and an adsorbed polymeric layer at the oil/water interface. Changes in dimensions of these structures with temperature correlate with the macroscopic thermo-thinning/thermo-thickening behavior observed. Neutron reflectivity is conducted at the oil/water interface to allow further elucidation of BCS behavior in these systems.

The exploitation of vibrational spectroscopy towards the understanding of molecular-level events in polymers, such as poloxamers, is highly warranted. This would facilitate the development of real-time approaches to monitor processes as well as the rational realisation of superior architectures. To date, studies on poloxamer based systems are restricted to low concentration materials and the evaluation of vibrational frequencies involving C-H stretching motions. We carry out an in-depth analysis of thermally-induced micellization processes employing technologically relevant 20% w/w P407 aqueous formulations. Our results, coupling Raman spectroscopy to computational approaches, are unequivocally consistent with such temperature-controlled events not being restricted to molecular re-arrangements involving C-H stretching motions. In fact, the synergistic approach of all key spectral regions was observed to yield optimum delineation of formulations at different temperatures. Vibrational envelopes were deconvoluted and it was observed that vibrational analysis of convoluted spectra can often be misleading. Individual contributions were assigned to either PEO or PPO building blocks by means of quantum-mechanical calculations. Temperature-induced changes to both intensity and vibrational frequencies were statistically evaluated and identified variations rationalised based on intermolecular interactions and structural order/disorder of the polymer units. Such observations were identified to be critically different depending on the nature of the vibrations. (C) 2022 Published by Elsevier B.V.

Graft copolymers with brush-type architectures are explored containing poly(ethylene glycol) methacrylates copolymerized with "thermoresponsive" monomers which impart lower critical solution temperatures to the polymer. Initially, the chemical structure of the thermoresponsive polymer is explored, synthesizing materials containing N-isopropyl acrylamide, N,N-diethyl acrylamide and diethylene glycol methyl ether methacrylate. Thermoresponsive graft-copolymers containing di(ethylene glycol) methyl ether methacrylate (DEGMA) exhibited phase transition temperature close to physiological conditions (ca 30 degrees C). The effect of polymer composition was explored, including molecular weight, PEG-methacrylate (PEGMA) terminal functionality and PEGMA/DEGMA ratios. Molecular weight exhibited complex relationships with phase behavior, where lower molecular weight systems appeared more stable above lower critical solution temperatures (LCST), but a lower limit was identified. PEGMA/DEGMA feed was able to control transition temperature, with higher PEGMA ratios elevating thermal transition. It was found that PEGMA terminated with methoxy functionality formed stable colloidal structures above LCST, whereas those the hydroxy termini generally formed two-phase sedimented systems when heated. Two thermoresponsive DEGMA-based graft polymers, poly(PEGMA(7)-ran-DEGMA(170)) and poly(PEGMA(1)-ran-DEGMA(38)), gave interesting temperature-dependent rheology, transitioning to a viscous state upon heating. These materials may find application in forming thermothickening systems which modify rheology upon exposure to the body's heat. (C) 2021 The Authors. Published by Elsevier B.V.

Polymer architecture allows control of thermoreversible gelation in branched copolymer-stabilised emulsions.

Erythrosine is a dye approved for medical use that has shown promising photodynamic activity, allowing for the inactivation of microorganisms and activity against malignant cells. Despite the great photodynamic potential, erythrosine exhibits hydrophilicity, negatively impacting its action in biological membranes. Therefore, the incorporation of erythrosine in micellar polymeric systems, such as poloxamers, may overcome this limitation. Moreover, using bioadhesive and thermoresponsive polymers to combine in situ gelation and bioadhesion may enhance retention of this topically applied drug. In this work, mucoadhesive and thermoresponsive micellar systems were prepared containing erythrosine in two states: the native form (ERI) and the disodium salt (ERIs). The systems were evaluated based on the effect of ERI/ERIs on the micellar structure of the binary polymer mixtures. Optimised combinations of poloxamer 407 (polox407) and mucoadhesive sodium carboxymethylcellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) were used as micellar systems for ERI or ERIs delivery. The systems were studied with respect to theoretical interactions, qualitative composition, morphology, and micellar properties. In silico modelling indicated a higher interaction of the drug with poly(ethylene oxide) (PEO) than poly(propylene oxide) (PPO) fragments of polox407. Systems containing NaCMC displayed a repulsive effect in the presence of erythrosine, due to the polymer's charge density. Both systems could convert the photosensitizer in its monomeric form, ensuring photodynamic activity. In these mixtures, crystallinity, critical micellar temperature and enthalpy of polox407 micellisation were reduced, and micellar size, evaluated by transmission electron microscopy (TEM), showed low impact of ERI/ERIs in HPMC preparations. Aiming toward photodynamic applications, the findings showed how ERI or ERIs can affect the micellar formation of gels composed of 17.5% (w/w) polox407 and 3% (w/w) HPMC or 1% (w/w) NaCMC, important for understating their behaviour and future utilisation as erythrosine delivery systems.

The ability to trigger changes to material properties with external stimuli, so-called "smart" behavior, has enabled novel technologies for a wide range of healthcare applications. Response to small changes in temperature is particularly attractive, where material transformations may be triggered by contact with the human body. Thermoreversible gelators are materials where warming triggers reversible phase change from low viscosity polymer solution to a gel state. These systems can be generated by the exploitation of macromolecules with lower critical solution temperatures included in their architectures. The resultant materials are attractive for topical and mucosal drug delivery, as well as for injectables. In addition, the materials are attractive for tissue engineering and 3D printing. The fundamental science underpinning these systems is described, along with progress in each class of material and their applications. Significant opportunities exist in the fundamental understanding of how polymer chemistry and nanoscience describe the performance of these systems and guide the rational design of novel systems. Furthermore, barriers to translating technologies must be addressed, for example, rigorous toxicological evaluation is rarely conducted. As such, applications remain tied to narrow fields, and advancements will be made where the existing knowledge in these areas may be applied to novel problems of science.

Temperature-responsive nanomaterials have gained increasing interest over the past decade due their ability to undergo conformational changes in situ, in response to a change in temperature. One class of temperature-responsive polymers are those with lower critical solution temperature, which phase separate in aqueous solution above a critical temperature. When these temperature-responsive polymers are grafted to a solid nanoparticle, a change in their surface properties occurs above this critical temperature, from hydrophilic to more hydrophobic, giving them a propensity to aggregate. This study explores the temperature induced aggregation of silica nanoparticles functionalised with two isomeric temperature-responsive polymers with lower critical solution temperature (LCST) behavior, namely poly(N-isopropyl acrylamide) (PNIPAM), and poly(2-n-propyl-2-oxazoline) (PNPOZ) with similar molecular weights (5000 Da) and grafting density. These nanoparticles exhibited striking differences in the temperature of aggregation, which is consistent with LCST of each polymer. Using a combination of small-angle neutron scattering (SANS) and dynamic light scattering (DLS), we probed subtle differences in the aggregation mechanism for PNIPAM- and PNPOZ-decorated silica nanoparticles. The nanoparticles decorated with PNIPAM and PNPOZ show similar aggregation mechanism that was independent of polymer structure, whereby aggregation starts by the formation of small aggregates. A further increase in temperature leads to interaction between these aggregates and results in full-scale aggregation and subsequent phase separation.