Background: Diabetes Mellitus is a multisystem chronic pandemic, wound inflammation, and healing are still major issues for diabetic patients who may suffer from ulcers, gangrene, and other wounds from uncontrolled chronic hyperglycemia. Marshmallows or Althaea officinalis (A.O.) contain bioactive compounds such as flavonoids and phenolics that support wound healing via antioxidant, anti-inflammatory, and antibacterial properties. Our study aimed to develop a combination of eco-friendly formulations of green synthesis of ZnO-NPs by Althaea officinalis extract and further incorporate them into 2% chitosan (CS) gel. Method and Results: First, develop eco-friendly green Zinc Oxide Nanoparticles (ZnO-NPs) and incorporate them into a 2% chitosan (CS) gel. In-vitro study performed by UV-visible spectrum analysis showed a sharp peak at 390 nm, and Energy-dispersive X-ray (EDX) spectrometry showed a peak of zinc and oxygen. Besides, Fourier transforms infrared (FTIR) was used to qualitatively validate biosynthesized ZnO-NPs, and transmission electron microscope (TEM) showed spherical nanoparticles with mean sizes of 76 nm and Zeta potential +30mV. The antibacterial potential of A.O.-ZnO-NPs-Cs was examined by the diffusion agar method against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Based on the zone of inhibition and minimal inhibitory indices (MIC). In addition, an in-silico study investigated the binding affinity of A.O. major components to the expected biological targets that may aid wound healing. Althaea Officinalis, A.O-ZnO-NPs group showed reduced downregulation of IL-6, IL-1β, and TNF-α and increased IL-10 levels compared to the control group signaling pathway expression levels confirming the improved anti-inflammatory effect of the self-assembly method. In-vivo study and histopathological analysis revealed the superiority of the nanoparticles in reducing signs of inflammation and wound incision in rat models. Conclusion: These biocompatible green zinc oxide nanoparticles, by using Althaea Officinalis chitosan gel ensure an excellent new therapeutic approach for quickening diabetic wound healing.

Pioglitazone Hydrochloride (PGZ) suffers from poor aqueous solubility. The aim of this research was to design orally disintegrating tablets with self-nanoemulsifying properties (T-SNEDDS) to improve the Pioglitazone solubility and dissolution rate. Three liquid self-nanoemulsifying systems (L-SNEDDS) were formulated and evaluated for transmittance percentage, emulsification time, particle size, Poly dispersity index (PDI), percentage of content, solubility and stability. The optimum L-SNEDDS formula was converted to a solidified self-nanoemulsifying drug delivery system (S-SNEDDS) by adsorption on Syloid (SYL). Powder characterization tests, such as flowability tests, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM), were performed for the selected S-SNEDDS formulation. Orally disintegrating tablets (ODT) were formulated by blending S-SNEDDS with tableting excipients. The ODT tablet batch composed of Prosolv was selected for tablet quality control tests, such as hardness, friability, disintegration time, content uniformity, weight variation, in vitro release, in vivo studies and accelerated stability studies. ODT tablets showed accepted mechanical properties and rapid disintegration time ( 0.05). In vivo pharmacokinetic and pharmacodynamic evaluation of ODTs showed better behavior compared to the raw drug suspension and the commercial tablet (p > 0.05). Orally disintegrating tablets revealed a promising potential to improve Pioglitazone poor aqueous solubility, dissolution profile and bioavailability.

Background: Diabetic foot ulcers present a formidable challenge due to colonization by biofilm-forming microorganisms, heightened oxidative stress, and continuous wound maceration caused by excessive exudation. Methods: To address these issues, we developed a robust, stretchable, electro-conductive, self-healing, antioxidant, and antibiofilm hydrogel. This hydrogel was synthesized through the crosslinking of polyvinyl alcohol (PVA) and chitosan (CH) with boric acid. To enhance its antimicrobial efficacy, graphene oxide (GO), produced via electrochemical exfoliation in a zinc ion-based electrolyte medium, was incorporated. For optimal antibiofilm performance, GO was functionalized with cranberry (CR) phenolic extracts, forming a graphene oxide-cranberry nanohybrid (GO-CR). Results: The incorporation of GO-CR into the hydrogel significantly improved its stretchability (280% for PVA/CH/GO-CR compared to 200% for PVA/CH). Additionally, the hydrogel demonstrated efficient photothermal conversion under near-infrared (NIR) light, enabling dynamic exudate removal, which is expected to minimize retained exudate between the wound and the dressing, reducing the risk of wound maceration. The hydrogel effectively reduced levels of lipopolysaccharide (LPS)-induced skin inflammation markers, significantly lowering the expression of NLRP3, TNF-α, IL-6, and IL-1β by 39.2%, 31.9%, 41%, and 52.3%, respectively. Histopathological and immunohistochemical analyses further confirmed reduced inflammation and enhanced wound healing. Conclusion: The PVA/CH/GO-CR hydrogel exhibits multifunctional properties that enhance wound healing ulcers. Its superior mechanical, antibacterial, and anti-inflammatory properties and ability to promote angiogenesis make it a promising candidate for effective wound management in diabetic patients.

Background/Objectives: Hesperidin (HSP) is a potent phytochemical antioxidant and anti-inflammatory agent that protects against otitis media. However, due to its low solubility and bioavailability, a suitable delivery method is needed to overcome these problems. A hydrogel is a promising nanocarrier for controlled drug delivery in response to external stimuli, such as pH variations. Methods: Graphene oxide (GO)-based nanocarriers that encapsulate hesperidin (HSP) were further coated with a polylactic-co-glycolic acid/alginate (PLGA-Alg) hydrogel before being integrated into a green neem oil (N.O.) double emulsion to produce a synergistic effect and then characterized by different assays. Results: The nanocarriers exhibited a substantial particle size (168 ± 0.32 nm), with high encapsulation (89.86 ± 0.23%) and a zeta potential of 37 ± 0.43 mV. In vitro release studies conducted over 96 h indicated a sustained HSP release of 82% at pH 5.4 and 65% at pH 7.4. The GO-HSP-loaded neem oil double emulsion formulation exhibits substantial antibacterial activity, as evidenced by inhibition zones of 39 ± 0.02 mm against Staphylococcus epidermidis, and considerable antifungal activity against Candida albicans, with an inhibition zone of 43 ± 0.13 mm, along with biofilm inhibition activity. The formulation demonstrated antioxidant activity (5.21 µg/mL) and increased cell viability (90–95%) while maintaining low cytotoxicity in HSE-2 cells. A histopathological analysis confirmed that treatment with the nanocarriers reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, TLR4, IL-6) and raised the levels of antioxidant markers (Nrf-2, SOD) in an in vivo rat model of otitis media. Conclusions: GO-based nanocarriers integrated into a neem oil double emulsion and coated with PLGA-Alg hydrogel deliver hesperidin with sustained release and enhanced antibacterial, antifungal, and antioxidant properties. This formulation may be used to treat otitis media and other oxidative stress diseases.

Background: Fungal keratitis (FK), a major cause of blindness, remains challenging to treat due to poor drug penetration and antifungal resistance. Amphotericin-B (AmB), a water-insoluble and low-permeability, necessitates innovative delivery systems to improve its therapeutic efficacy. Methods: AmB was encapsulated within oleosomes (Ole) prepared using the ethanol injection method, using phosphatidylcholine (Lipoid S100) and sodium oleate, resulting in nanosized spherical globules. The optimized Ole were characterized, then the selected Ole were incorporated into sodium polyacrylate/PEG/chitosan-based microneedles (AmB-Ole/MNs) to improve ocular delivery by creating transient microchannels on the eye surface. Results: The optimized Ole showed a droplet size of (175 ± 0.78 nm), polydispersity index of (0.33 ± 0.04), zeta potential of (31 ± 0.43 mV), high entrapment efficiency (91± 0.63%), and improved stability, bioavailability, and controlled drug release. The AmB-Ole/MNs system increases corneal penetration and contact time via transient microchannels in the eye surface, achieving sustained drug delivery over 72 hours with 70% ex vivo permeation over 80 hours compared to AmB. In vitro antifungal activity and histopathological examination showed that the AmB-Ole/MNs system has potent biofilm disruption (> 90%) and 27 mm and 32 mm zones of inhibition against Candida albicans and Aspergillus niger, respectively. The Cytotoxicity test showed reduced AmB toxicity with biocompatibility and in vivo rabbit model, ocular tolerance by targeting TLR4/NLRP3 pathways and histopathological studies. Conclusion: The AmB-Ole/MNs system as an innovative ocular delivery platform for fungal keratitis offers sustained drug release, enhanced permeation, potent antifungal activity, and reduced toxicity. AmB-Ole/MNs showed promise for ocular AmB delivery for FK.

Background/Objectives: Dry eye disease (DED), also known as “keratoconjunctivitis sicca”, is a common chronic ocular surface disease accompanied by inflammation and diminished tear production. Bovine Lactoferrin (BLF), a multi-functional iron-binding glycoprotein found in tears, decreased significantly in patients with DED, used for the treatment of dry eye, conjunctivitis, and ocular inflammation. BLF has limited therapeutic efficacy due to poor ocular bioavailability. Methods: This study developed and optimized a BLF-loaded nanosuspension (BLF-NS) using the Box–Behnken Design (BBD). Optimized BLF-NS was then incorporated with polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) dissolving microneedles (MNs). The formulations were characterized by Scanning and transmission microscopy, DSC, FTIR, ex vivo studies in corneal tissue from sheep and tested for its antibacterial and antifungal efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Aspergillus niger, respectively. Moreover, they were tested for their Benzalkonium chloride (BCL) dry eye in a rabbit model. Results: The optimized nanosuspension showed a vesicle size of (215 ± 0.45) nm, a Z.P (zeta potential) of (−28 ± 0.34) mV, and an Entrapment Efficiency (EE%) of (90 ± 0.66) %. The MNs were fabricated using a ratio of biodegradable polymers, PVP/HPMC. The resulting BLF-NS-MNs exhibited sharp pyramidal geometry with high mechanical strength, ensuring ocular insertion. In vitro release showed 95% lactoferrin release over 24 h, while ex vivo permeation achieved 93% trans-corneal delivery. In vivo, BLF-NS-MNs significantly reduced pro-inflammatory cytokines (TNF-α, IL-6, MMP-9, IL-1β, MCP-1) and upregulated antioxidant and anti-inflammatory genes (PPARA, SOD 1), restoring their levels to near-normal (p < 0.001). Conclusions: The nanosuspension combined with MNs has shown higher ocular tolerance against DED ensured by the Draize and Schirmer Tear Test.