Thermo-responsive Diels-Alder stabilized hydrogels for ocular drug delivery of a corticosteroid and an anti-VEGF fab fragment

In the present study, a novel in situ forming thermosensitive hydrogel system was investigated as a versatile drug delivery system for ocular therapy. For this purpose, two thermosensitive ABA triblock copolymers bearing either furan or maleimide moieties were synthesized, named respectively poly(NIPAM-co-HEA/Furan)-PEG 6K-P(NIPAM-co-HEA/Furan) (PNF) and poly(NIPAM-co-HEA/Maleimide)-PEG 6K-P(NIPAM-co-HEA/-Maleimide) (PNM). Hydrogels were obtained upon mixing aqueous PNF and PNM solutions followed by incubation at 37 °C. The hydrogel undergoes an immediate (<1 min) sol-gel transition at 37 °C. In situ hydrogel formation at 37 °C was also observed after intravitreal injection of the formulation into an ex vivo rabbit eye. The hydrogel network formation was due to physical self-assembly of the PNIPAM blocks and a catalyst-free furan-maleimide Diels-Alder (DA) chemical crosslinking in the hydrophobic domains of the polymer network. Rheological studies demonstrated sol-gel transition at 23 °C, and DA crosslinks were formed in time within 60 min by increasing the temperature from 4 to 37 °C. When incubated at 37 °C, these hydrogels were stable for at least one year in phosphate buffer of pH 7.4. However, the gels degraded at basic pH 10 and 11 after 13 and 3 days, respectively, due to hydrolysis of ester bonds in the crosslinks of the hydrogel network. The hydrogel was loaded with an anti-VEGF antibody fragment (FAB; 48.4 kDa) or with corticosteroid dexamethasone (dex) by dissolving (FAB) or dispersing (DEX) in the hydrogel precursor solution. The FAB fragment in unmodified form was quantitatively released over 13 days after an initial burst release of 46, 45 and 28 % of the loading for the 5, 10 and 20 wt% hydrogel, respectively, due to gel dehydration during formation. The low molecular weight drug dexamethasone was almost quantitively released in 35 days. The slower release of dexamethasone compared to the FAB fragement can likely be explained by the solubilization of this hydrophobic drug in the hydrophobic domains of the gel. The thermosensitive gels showed good cytocompatibility when brought in contact with macrophage-like mural cells (RAW 264.7) and human retinal pigment epithelium-derived (ARPE-19) cells. This study demonstrates that PNF-PNM thermogel may be a suitable formulation for sustained release of bioactive agents into the eye for treating posterior segment eye diseases

Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids

© 2024 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/The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.Peer reviewe

Implants pour la délivrance de principes actifs

Les implants permettant de contrôler la libération d’un principe actif peuvent grandement améliorer l’efficacité d’un traitement médical tout en réduisant le risque d’apparition d’effets secondaires toxiques. Dans cet article, quatre stratégies différentes sont développées à titre d’exemple : des substituts osseux hybrides alliant de l’hydroxyapatite et des hydrogels de chitosan, des stents vasculaires recouverts d’un polymère bio-inspiré, des implants cochléaires pour la délivrance locale de dexaméthasone et des implants se formant in situ pour le traitement des parodontites. Mais cela ne représente qu’une petite sélection et de nombreuses autres approches et applications basées sur des implants libérant un principe actif (ou une combinaison d’actifs) existent. Comparés aux implants ou formes galéniques conventionnelles, ils peuvent offrir des avantages potentiellement décisifs

Crystalline Polymorphism Emerging From a Milling-Induced Amorphous Form: The Case of Chlorhexidine Dihydrochloride

International audienc

L'adolescent à travers deux cas au comptoir (l'acné et la contraception)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Les filtres UV et les nanoparticules de dioxyde de titane

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Le vieillissement cutané (intérêt de l'huile d'argan dans la prise en charge)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Problèmes posés par l'administration des médicaments en cardiologie infantile (exemple de la warfarine)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

PEO hot melt extrudates for controlled drug delivery: Importance of the type of drug and loading

International audienceA variety of poly(ethylene oxide) (PEO)-based matrix tablets loaded with theophylline, ibuprofen or metoprolol tartrate was prepared via hot melt extrusion. The initial drug loading was varied from 10 to 60 %, the PEO polymer molecular weight from 300 to 7,000 kDa. The extrudates were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C using optical and scanning electron microscopy, X-ray diffraction analysis and drug release measurements. In the case of metoprolol tartrate, the resulting drug release rates monotonically increased with increasing initial drug loading, irrespective of the PEO grade. This can be attributed to an “increased porosity effect” upon drug leaching, resulting in less hindrance for subsequent drug release. However, in the case of theophylline and ibuprofen, also “limited drug solubility effects” played a role and were even dominant in 7,000 kDa PEO-based extrudates: Upon water penetration into the system, not all of the drug was dissolved. Dissolved and non-dissolved drug co-existed. Importantly, only dissolved drug is available for diffusion. Thus, increasing the initial drug content did not increase the concentration gradients of dissolved drug (and the absolute drug release rates in the absence of porosity effects), but increased the 100 % reference values. Interestingly, in 300 kDa PEO-based extrudates, “increased porosity effects” dominated for all drugs, and the relative release rates always increased with increasing drug loading. At 1,000 and 7,000 kDa, the resulting released rate increased or decreased with increasing drug loading, depending of the type of drug

Towards a better understanding of the release mechanisms of caffeine from PLGA microparticles

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