Thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate)-ran-(polyethylene glycol methacrylate) graft copolymers exhibiting temperature-dependent rheology and self-assembly

© 2021 The Authors. Published by Elsevier B.V. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/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-diethylacrylamide and diethylene glycol methyl ether methacrylate. Thermoresponsive graftcopolymers containing di(ethylene glycol) methyl ether methacrylate (DEGMA) exhibited phase transition temperature close to physiological conditions (ca 30 °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 stablecolloidal structures above LCST, whereas those the hydroxy termini generally formed two phase sedimented systems when heated. Two thermoresponsive DEGMA-based graft polymers, poly(PEGMA7-ran-DEGMA170) and poly(PEGMA1-ran-DEGMA38), 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 heatPeer reviewe

A mucosa-mimetic material for the mucoadhesion testing of thermogelling semi-solids

Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi-solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow-through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type

The effect of erythrosine-B on the structuration of poloxamer 407 and cellulose derivative blends: in silico modelling supporting experimental studies

© 2021 Elsevier B.V. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.msec.2021.112440Erythrosine 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.Peer reviewe

Assessing mucoadhesion in polymer gels : The effect of method type and instrument variables

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The process of mucoadhesion has been widely studied using a wide variety of methods, which are influenced by instrumental variables and experiment design, making the comparison between the results of different studies difficult. The aim of this work was to standardize the conditions of the detachment test and the rheological methods of mucoadhesion assessment for semisolids, and introduce a texture profile analysis (TPA) method. A factorial design was developed to suggest standard conditions for performing the detachment force method. To evaluate the method, binary polymeric systems were prepared containing poloxamer 407 and Carbopol 971P®, Carbopol 974P®, or Noveon® Polycarbophil. The mucoadhesion of systems was evaluated, and the reproducibility of these measurements investigated. This detachment force method was demonstrated to be reproduceable, and gave different adhesion when mucin disk or ex vivo oral mucosa was used. The factorial design demonstrated that all evaluated parameters had an effect on measurements of mucoadhesive force, but the same was not observed for the work of adhesion. It was suggested that the work of adhesion is a more appropriate metric for evaluating mucoadhesion. Oscillatory rheology was more capable of investigating adhesive interactions than flow rheology. TPA method was demonstrated to be reproducible and can evaluate the adhesiveness interaction parameter. This investigation demonstrates the need for standardized methods to evaluate mucoadhesion and makes suggestions for a standard study design.Peer reviewedFinal Published versio

Thermoresponsive systems composed of poloxamer 407 and HPMC or NaCMC: mechanical, rheological and sol-gel transition analysis

© 2020 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/.Poloxamer 407 (polox407) is widely studied as thermogelling polymer, transitioning to a gel state when warmed Polox407 forms weak hydrogels with rapid dissolution in excess solvent. This study reports the development of binary systems composed of polox407 and hydroxypropyl methylcellulose (HPMC) or sodium carboxymethylcellulose (NaCMC) aiming to improve the rheological and mechanical properties of the hydrogel. The interaction between polox407 and cellulose derivatives was studied, and their interaction with biological surfaces predicted. The carbohydrates affected the mechanical and rheological behavior of polox407 in different ways, dependent on polymer type, concentration, and temperature. Tsol/gel and rheological interaction parameters were useful to select the most suitable formulations for topical or local application. Most of the binary systems exhibited plastic behavior, thixotropy and viscoelastic properties. Appropriate formulations were identified for local application, such as 17.5/3; 17.5/4; 20/3 and 20/4 (%, w/w) for polox407/HPMC; and 17.5/1; 17.5/1.5; 20/1 and 20/1.5 (%, w/w) for polox407/NaCMC.Peer reviewe

Interaction between mucoadhesive cellulose derivatives and Pluronic F127: investigation on the micelle structure and mucoadhesive performance

Systems composed of bioadhesive and thermoresponsive polymers can combine in situ gelation with bio/mucoadhesion, enhancing retention of topically applied drugs. The effect of bioadhesive sodium carboxymethylcellulose (NaCMC) and hydroxypropyl methylcellulose cellulose (HPMC) on the properties of thermoresponsive Pluronic® F127 (F127) was explored, including micellization and the mucoadhesion. A computational analysis between these polymers and their molecular interactions were also studied, rationalising the design of improved binary polymeric systems for pharmaceutical and biomedical applications. The morphological characterization of polymeric systems was conducted by SEM. DSC analysis was used to investigate the crystallization and micellization enthalpy of F127 and the mixed systems. Micelle size measurements and TEM micrographs allowed for investigation into the interference of cellulose derivatives on F127 micellization. Both cellulose derivatives reduced the critical micellar concentration and enthalpy of micellization of F127, altering hydrodynamic diameters of the aggregates. Mucoadhesion performance was useful to select the best systems for mucosal application. The systems composed of 17.5% (w/w) F127 and 3% (w/w) HPMC or 1% (w/w) NaCMC are promising as topical drug delivery systems, mainly on mucosal surfaces. They were biocompatible when tested against Artemia salina, and also able to release a model of hydrophilic drug in a controlled manner.Peer reviewe

Boosting the photodynamic activity of erythrosine B by using thermoresponsive and adhesive systems containing cellulose derivatives for topical delivery

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

Thermo and Photoresponsive Emulgel Loaded with Copaifera reticulata Ducke and Chlorophylls: Rheological, Mechanical, Photodynamic and Drug Delivery Properties in Human Skin

Recently, the number of new cases of cutaneous leishmaniasis has been of concern among health agencies. Research that offers new therapeutic alternatives is advantageous, especially those that develop innovative drugs. Therefore, this paper presents the incorporation of Copaifera reticulata Ducke and chlorophyll extract into Pluronic®® F127 and Carbopol gels, under optimized polymer quantities. The chlorophyll extract (rich in photosensitizing compounds) was obtained by continuous-flow pressurized liquid extraction (PLE), a clean, environmentally friendly method. The system aims to act as as a leishmanicidal, cicatrizant, and antibiotic agent, with reinforcement of the photodynamic therapy (PDT) action. Rheological and mechanical analyses, permeation studies and bioadhesiveness analyses on human skin, and PDT-mediated activation of Staphylococcus aureus were performed. The emulgels showed gelation between 13° and 15 °C, besides pseudoplastic and viscoelastic properties. Furthermore, the systems showed transdermal potential, by releasing chlorophylls and C. reticulata Ducke into the deep layers of human skin, with good bioadhesive performance. The application of PDT reduced three logarithmic colony-forming units of S. aureus bacteria. The results support the potential of the natural drug for future clinical trials in treating wounds and cutaneous leishmania

Design and Optimization of a Natural Medicine from Copaifera reticulata Ducke for Skin Wound Care

In this study, we developed a bioadhesive emulsion-filled gel containing a high amount of Copaifera reticulata Ducke oil-resin as a veterinary or human clinical proposal. The phytotherapeutic system had easy preparation, low cost, satisfactory healing ability, and fly repellency, making it a cost-effective clinical strategy for wound care and myiasis prevention. Mechanical, rheological, morphological, and physical stability assessments were performed. The results highlight the crosslinked nature of the gelling agent, with three-dimensional channel networks stabilizing the Copaifera reticulata Ducke oil-resin (CrD-Ore). The emulgel presented antimicrobial activity, satisfactory adhesion, hardness, cohesiveness, and viscosity profiles, ensuring the easy spreading of the formulation. Considering dermatological application, the oscillatory responses showed a viscoelastic performance that ensures emulgel retention at the action site, reducing the dosage frequencies. In Vivo evaluations were performed using a case report to treat ulcerative skin wounds aggravated by myiasis in calves and heifers, which demonstrated healing, anti-inflammatory, and repellent performance for the emulsion-filled gel. The emulgel preparation, which is low in cost, shows promise as a drug for wound therapy