A Novel Approach to Serving Plant-Based Confectionery-The Employment of Spray Drying in the Production of Carboxymethyl Cellulose-Based Delivery Systems Enriched with Teucrium montanum L. Extract.

In this study, spray drying was used as a technological solution for the valorization of Teucrium montanum extract into carboxymethyl cellulose-based delivery systems (CMC), individually or in combination with collagen, guar gum, gum arabic, and kappa-carrageenan. The results showed that the process yield and morphological properties were positively influenced by the introduction of CMC binary blends. The employment of CMC resulted in a high encapsulation efficiency (77-96%) for all phenylethanoid glycosides (PGs) analyzed. Due to the low wettability of the microparticles, a relatively gradual in vitro release of the PGs was achieved. Infusion of the filling with hydrophilic T. montanum extract encapsulated in microparticles with high hydrophobic surface area proved to be a practical route for significant confectionery fortification (5-9 mg PGs per dw serving), ensuring prolonged interaction between the food matrix used and the extract under simulated gastrointestinal conditions. Based on sensory evaluation, the introduction of kudzu starch into the jelly matrix has shown a texture-modifying potential.

In situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nose-to-brain delivery: development, characterization and deposition studies in a 3D-printed human nasal cavity model.

The nasal route has been investigated as a promising alternative for drug delivery to the central nervous system, avoiding passage through the blood-brain barrier and improving bioavailability. In this sense, it is necessary to develop and test the effectiveness of new formulations proposed for the management of neurological disorders. Thereby, the aim of this work was to develop and characterize an ion sensitive in situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nasal delivery in the treatment of epilepsy. Physical characterization of the developed formulations was performed and included the evaluation of rheological features, particle size, polydispersity index (PDI) and zeta potential (ZP) of an in situ hydrogel containing DZP-NLC. Afterwards, in vitro drug release, in vitro mucoadhesion and biocompatibility studies with RPMI 2650 nasal cells were performed. The in situ hydrogel containing DZP-NLC was aerosolized with a nasal spray device specifically designed for nose-to-brain delivery (VP7 multidose spray pump with a 232 N2B actuator) and characterized for droplet size distribution and spray cone angle. Finally, the deposition pattern of this hydrogel was evaluated in a 3D-printed human nasal cavity model. The developed in situ hydrogel containing DZP-NLC presented adequate characteristics for nasal administration, including good gelling ability, mucoadhesiveness and prolonged drug release. In addition, after inclusion in the hydrogel net, the particle size (81.79 ± 0.53 nm), PDI (0.21 ± 0.10) and ZP (-30.90 ± 0.10 mV), of the DZP-NLC remained appropriate for nose-to-brain delivery. Upon aerosolization in a nasal spray device, a suitable spray cone angle (22.5 ± 0.2°) and adequate droplet size distribution (Dv (90) of 317.77 ± 44.12 µm) were observed. Biocompatibility studies have shown that the developed formulation is safe towards RPMI 2650 cells in concentrations up to 100 µg/mL. Deposition studies on a 3D-printed human nasal cavity model revealed that the best nasal deposition profile was obtained upon formulation administration without airflow and at an angle from horizontal plane of 75°, resulting in 47% of administered dose deposited in the olfactory region and 89% recovery. The results of this study suggested that the intranasal administration of the developed in situ hydrogel containing DZP-NLC could be a promising alternative to the conventional treatments for epilepsy.

Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile.

Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer's disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.

Hydroxypropyl-ß-Cyclodextrin-Based Helichrysum italicum Extracts: Antioxidant and Cosmeceutical Activity and Biocompatibility.

Two Helichrysum italicum extracts, OPT-1 (rich in phenolic acids) and OPT-2 (rich in total phenols and flavonoids), were prepared using hydroxypropyl-ß-cyclodextrin (HP-ß-CD)-assisted extraction. The prepared extracts were rich in phenolic compounds, including flavonoids and phenolic acids. GC-MS analysis of the extracts identified neryl acetate, neo-intermedeol, ß-selinene, γ-curcumene, italidione I, and nerol as the main volatile components of the extracts, as well as plant sterols, γ-sitosterol, campesterol, and stigmasterol. The antioxidant (DPPH radical scavenging, reducing power, and a carotene linoleic acid assay) and cosmeceutical (anti-hyaluronidase, anti-tyrosinase, anti-lipoxygenase, ovalbumin anti-coagulation, and a UV-absorption assay) activity of the extracts in most of the assays was better than the activity of the applied positive controls. Especially low were the IC50 values of the extracts in the anti-hyaluronidase (14.31 ± 0.29 µL extract/mL and 19.82 ± 1.53 µL extract/mL for OPT-1 and OPT-2, respectively) and the anti-lipoxygenase (0.96 ± 0.11 µL extract/mL and 1.07 ± 0.01 µL extract/mL for OPT-1 and OPT-2, respectively) assays. The extracts were non-toxic to HaCaT cells in concentrations of up to 62.5 µL extract/mL assuring their status as excellent candidates for cosmeceutical product development appropriate for direct use in cosmetic products without solvent evaporation.

Extraction Optimization, Antioxidant, Cosmeceutical and Wound Healing Potential of Echinacea purpurea Glycerolic Extracts.

Echinacea purpurea is a plant with immunomodulating properties, often used in topical preparations for treatment of small superficial wounds. In the presented study, the best conditions for ultrasound-assisted extraction of caffeic acid derivatives (caftaric and cichoric acid) (TPA-opt extract), as well as the conditions best suited for preparation of the extract with high radical scavenging activity (RSA-opt extract), from E. purpurea aerial parts were determined. A Box-Behnken design based on glycerol content (%, w/w), temperature (°C), ultrasonication power (W) and time (min) as independent variables was performed. Antioxidant, antiaging and wound healing effects of the two prepared extracts were evaluated. The results demonstrate that glycerol extraction is a fast and efficient method for preparation of the extracts with excellent radical scavenging, Fe2+ chelating and antioxidant abilities. Furthermore, the extracts demonstrated notable collagenase, elastase and tyrosinase inhibitory activity, indicating their antiaging properties. Well-pronounced hyaluronidase-inhibitory activities, with IC50 values lower than 30 µL extract/mL, as well as the ability to promote scratch closure in HaCaT keratinocyte monolayers, even in concentrations as low as 2.5 µL extract/mL (for RSA-opt), demonstrate promising wound healing effects of E. purpurea. The fact that the investigated extracts were prepared using glycerol, a non-toxic and environmentally friendly solvent, widely used in cosmetics, makes them suitable for direct use in specialized cosmeceutical formulations.

Tailoring functional spray-dried powder platform for efficient donepezil nose-to-brain delivery.

Shortcomings of oral donepezil administration in the treatment of Alzheimer's disease have paved the way for ongoing investigations towards more efficient and safe donepezil nose-to-brain delivery. Herein we present the development of advantageous powder platform for donepezil nose-to-brain delivery, coupling careful design of chitosan and mannitol-based carrier matrix with spray-drying technology advantages and early consideration of adequate nasal administration mode, employing QbD approach. Unprecedentedly, ultrasonic nozzle was used to atomise the drying feed in response to size-related requirements for nasal aerosol particles. The optimised spray-drying process resulted in free-flowable dry powder with a great majority of particles larger than 10 µm, ensuring localised nasal deposition upon aerosolization, as evidenced by using 3D-printed nasal cavity model. QbD approach coupling formulation, process and administration parameters enabled optimisation of drug deposition profile reaching tremendously high 65.5 % of the applied dose deposited in the olfactory region. The leading formulation exhibited favourable swelling, mucoadhesion, drug release and permeation-enhancing properties, suiting the needs for efficient brain-targeted delivery. Results of in vitro biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient donepezil nose-to-brain delivery. The obtained results encourage extending the study to an appropriate in vivo model needed for the final proof-of-concept.

In situ gelling nanosuspension as an advanced platform for fluticasone propionate nasal delivery.

In this work we present the development of in situ gelling nanosuspension as advanced form for fluticasone propionate nasal delivery. Drug nanocrystals were prepared by wet milling technique. Incorporation of drug nanocrystals into polymeric in situ gelling system with pectin and sodium hyaluronate as constitutive polymers was fine-tuned attaining appropriate formulation surface tension, viscosity and gelling ability. Drug nanonisation improved the release profile and enhanced formulation mucoadhesive properties. QbD approach combining formulation and administration parameters resulted in optimised nasal deposition profile, with 51.8% of the dose deposited in the middle meatus, the critical region in the treatment of rhinosinusitis and nasal polyposis. Results obtained in biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient nasal corticosteroid delivery.

A Dry Powder Platform for Nose-to-Brain Delivery of Dexamethasone: Formulation Development and Nasal Deposition Studies.

Nasal route of administration offers a unique opportunity of brain targeted drug delivery via olfactory and trigeminal pathway, providing effective CNS concentrations at lower doses and lower risk for adverse reactions compared to systemic drug administration. Therefore, it has been recently proposed as a route of choice for glucocorticoids to control neuroinflammation processes in patients with severe Covid-19. However, appropriate delivery systems tailored to enhance their efficacy yet need to emerge. In this work we present the development of sprayable brain targeting powder delivery platform of dexamethasone sodium phosphate (DSP). DSP-loaded microspheres, optimised employing Quality-by-Design approach, were blended with soluble inert carriers (mannitol or lactose monohydrate). Powder blends were characterized in terms of homogeneity, flow properties, sprayability, in vitro biocompatibility, permeability and mucoadhesion. Nasal deposition studies were performed using 3D printed nasal cavity model. Mannitol provided better powder blend flow properties compared to lactose. Microspheres blended with mannitol retained or enlarged their mucoadhesive properties and enhanced DSP permeability across epithelial model barrier. DSP dose fraction deposited in the olfactory region reached 17.0% revealing the potential of developed powder platform for targeted olfactory delivery. The observed impact of nasal cavity asymmetry highlighted the importance of individual approach when aiming olfactory region.