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Background/objectives: Crickets are recognized as an alternative source of chitosan. This study aimed to assess the potential of cricket-derived chitosan as a natural source to develop chitosan nanoparticles (CNPs)., Methods: Chitosan were isolated from different cricket species, including Gryllus bimaculatus , Teleogryllus mitratus , and Acheta domesticus . The isolated chitosan were characterized by their functional groups, crystallographic and thermal properties, molecular structure, morphology, water solubility, molecular weight, binding capacity, irritation potential, and cytotoxicity in comparison to commercial shrimp-based chitosan. CNPs were developed through an ionotropic gelation method, followed by the evaluation of particle size, polydispersity index (PDI), and zeta potential., Results: The findings of this study indicate that chitosan can be successfully isolated from the three cricket species, with yields ranging from 4.35% to 5.22% w / w of the dried material. The characteristics of cricket-based chitosan were similar to those of commercial chitosan, except that the cricket-based chitosan displayed a higher crystallinity and a lower molecular weight. Additionally, CPNs were successfully produced from cricket-based chitosan using sodium citrate as a crosslinking agent. All cricket-based chitosan exhibited no irritation or cytotoxicity. Chitosan derived from A. domesticus however was found to be the most suitable to develop CPNs, as it produced the smallest particle size (522.0 ± 12.1 nm) with a comparatively narrow PDI (0.388 ± 0.026) and an acceptable positive zeta potential (34.2 ± 4.4 mV)., Conclusions: Cricket-derived chitosan compares favorably with crustacean-derived chitosan and showed potential for a range of applications, including the use as a nanocosmeceutical delivery system in topical and cosmetic formulations.

Coffee husks have been valorised by isolating humic materials before (HLS-Raw) or after (HS-Comp) composting them. Such substrates were reacted with chitosan at different ratios to synthesize novel nanoparticles (NP) with radical scavenging properties. Size and antioxidant activity of nanomaterials increased at higher HS/chitosan ratio, while zeta potential decreased. Our results furthermore highlighted that he molecular features of raw humic materials, as studied by solid-state NMR spectroscopy, affected the studied NP properties. Indeed, at equal reactant ratio, NP from HS-Comp had lower zeta potential due to their higher amount of carboxyl moieties contained, which counterbalanced a greater number of chitosan positive charges. Moreover, these NP showed lower antioxidant activity despite the greater phenolic content of the original HS. We hypothesized that the higher hydrophobicity of HS-Comp led to the partial partitioning of their phenolic components into the inner domains of the derived NP, lowering their antioxidant capacity. Additionally, in a short-term stability assay, NP coalescence was observed, especially at higher humic/chitosan ratio, with nanomaterial precipitation and consequent decrease in antioxidant capacity. Overall, we demonstrated that humic materials from raw or composted coffee husks could successfully crosslink chitosan chains to synthesize sustainable NP with tuneable physical-chemical and antioxidant properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Olive phenolic compounds like hydroxytyrosol (OH-Tyr), tyrosol (Tyr), and their precursors have different health-promoting properties, mainly based on their strong antioxidant capacity. However, their presence in extra-virgin olive oil (EVOO) is scarce since they are primarily contained in the by-products of oil production, such as olive pomace (OP). The aim of this work was to extract and encapsulate OP phenolic compounds into chitosan-tripolyphosphate nanoparticles (NPs) using an ionotropic gelation lyophilization approach to increase their resistance to environmental and chemical stress. NPs resulted in a monodisperse (PDI: 0.21) population of cationic NPs (ζ-potential: 33 mV, size: 229 nm) with an encapsulation efficiency (EE%), expressed as total phenolic content (TPC) and total OH-Tyr + Tyr content, of 64-65%. Mannitol and maltodextrin DE 19 (MD-19) were evaluated as lyoprotectants to counteract irreversible NP aggregation during lyophilization. The NP powder freeze dried using 0.7% of MD-19 showed the best performance, returning a monodispersed population of particles after rehydration. The antioxidant capacity of the obtained NPs was confirmed both in cell-free assays and in a THP-1 cell model of oxidative stress. This method represents a promising way to deliver health-promoting olive phenols for nutraceutical purposes and, hence, to valorize otherwise wasted by-products.

Objectives: In the recent years, in-situ hydrogel based on gellan gum has been investigated for delivery of various drug molecules particularly to treat neurological disorders via intranasal route. The major objective of the present manuscript is to review the recent research studies exploring gellan gum as ionic triggered in-situ gel for intranasal administration to enhance absorption of drugs and to increase their therapeutic efficacy., Methods: This review include literature from 1982 to 2023 and were collected from various scientific electronic databases like Scopus, PubMed and Google Scholar to review source, chemistry, ionotropic gelation mechanism, and recent research studies for gellan gum based in-situ hydrogel for intransasl administration.Keywords such as gellan gum, in-situ hydrogel, intranasal administration and brain targeting were used to search literature. The present review included the research studies which explored gellan gum based in-situ gel for intranasal drug delivery., Results: The findings have shown enhanced biavailability of various drugs upon intranasal administration using gellan-gum based in-situ hydrogel.Moreover, the review indicated that intranasal administration of in-situ hydrogel facilitate to overcome blood brain barrier effectively. Hence, significantly higher drug concentration was found to be achieved in brain tissues upon intranasal administration than that of other routes like oral and intravenous., Conclusion: The present work conducted a comprehensive review for gellan gum based in-situ hydrogel particularly for intransal administration to overcome BBB. The study concluded that gellan gum based in-situ hydrogel could be potential promising delivery system for intranasal administration to improve bioavailability and efficacy of drugs specifically to treat neurological disorders., Competing Interests: Declarations Ethical approval NA. Informed consent NA Conflict of interest Authors declared no conflict of interest., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Conventional oral vaccine delivery in poultry is challenging due to vaccine degradation in the gastrointestinal (GI) environment and the need for cold-chain storage. Microencapsulation offers a solution by protecting vaccines from GI degradation and improving stability. Natural polymers like alginate and cashew gum have mucoadhesive properties, making them promising candidates for oral vaccine delivery. This study developed cashew-alginate microbeads and a powdered dose form for oral vaccine delivery in chickens. The microbeads were created using ionotropic gelation, while the powdered form was obtained via freeze-drying. These formulations were characterized for size, shape, and stability using scanning electron microscopy (SEM), light microscopy, X-ray diffraction (XRD), and Energy Dispersive X-ray (EDX). Peak adhesion time (PAT) was determined using chicken intestinal and esophageal tissues, and antigenicity was assessed with in-vitro hemagglutination (HA) and hemagglutination inhibition (HI) assays. The microbeads exhibited a spherical shape with a porous structure, suggesting enhanced antigen accommodation. Hemagglutination Inhibition tests indicated that the experimental vaccine remained effective without cold-chain storage for three months. These findings suggest that cashew-alginate microbeads are promising for oral vaccine delivery in poultry.

In this study, the effect of desalinated lava seawater via electrodialysis (ED water) on the formation and properties of low methoxyl pectin (LMP) gels was investigated. Additionally, the syneresis, microstructure, gelation mechanism, and thermostability of the gel samples were analyzed. When the ED water content exceeded 25 %, pectin gels with viscosities and textures that differed from those of the sol were formed. The highest gel hardness (9.38 N) was observed when 50 % ED water was mixed with LMP. However, when 75 % ED water was added, the pore size of the LMP gel became the largest, and excess water was released from the gel, resulting in a weak gel strength (4.98 N). The formation and properties of the gel structure were found to be mainly due to the ionic bonds between the minerals in the ED water and the free carboxyl groups of pectin, and it was confirmed that the hydrogen bonds within the pectin chains also had an effect. These results suggest that the interaction between the ED water and LMP can be widely used in various industrial fields, including low-sugar gels or viscosity-enhancing agents with diverse rheological properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Improvement of nutritional value and reduction of antinutritional factors (ANFs) of soybean meal (SBM) for animal feed applications could be achieved by using bromelain immobilized onto bentonite (Bt)-carboxymethylcellulose (CMC) composites. The composite with mass ratio between CMC to calcium ion (Ca 2+ ) at 1:20 provided the highest enzyme activity, immobilization yield higher than 95%, with superior thermal and storage stabilities. Performance of the immobilized bromelain for soybean protein hydrolysis was further studied. The results showed that at 60 °C, the immobilized bromelain exhibited the highest efficiency in enzymatic hydrolysis to release free alpha amino nitrogen (FAN) as a product with high selectivity and to effectively reduce SBM allergenic proteins within 30 min. In conclusion, immobilization of bromelain onto Bt-CMC composites leads to stability enhancement of the enzyme, enabling effective improvement in SBM quality in a short treatment time and showing great potential for application in animal feed industries.

Curcumin, a bioactive compound derived from the rhizome of Curcuma longa, has gained widespread attention for its potential therapeutic properties, including anti-inflammatory, antioxidant and anticancer effects. However, its poor aqueous solubility, instability and limited bioavailability have hindered its clinical applications. New beads formulations based on sodium alginate biopolymer (SA) and poly vinyl alcohol (PVA) were successfully prepared and evaluated as a potential drug vehicle for extended release of curcumin (Cur). Pristine and curcumin loaded calcium alginate/poly vinyl alcohol beads (CA/PVA and CA/PVA/Cur) at different compositions of SA and PVA were prepared by an ionotropic gelation method of SA followed by two freeze-thawing (FT) cycles for further crosslinking of PVA. Characterization techniques, such as scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), UV-Visible spectroscopy, thermogravimetric analysis (TGA) and x-ray diffraction (XRD) were used to confirm the successful microencapsulation of curcumin within the CA/PVA microcapsules. Furthermore, the swelling of pristine beads, pH-sensitive properties and in vitro release studies of curcumin loaded beads were investigated at 37 °C in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). The effect of the polymer blend ratio, the encapsulation efficiency (EE %) of curcumin, the loading capacity (LC μg/mg), the sphericity factor (SF), the antioxidant activity of the elaborated beads and their antimicrobial properties against bacteria and fungi were just as much evaluated. The obtained results indicate that the swelling and the behavior of the developed beads were influenced by the pH of the test medium and the PVA content. The introduction of PVA into the SA matrix greatly enhanced the physicochemical properties, the encapsulation efficiency and the loading capacity of the elaborated microparticles. Results also suggested that the antioxidant activity of the loaded beads (CA/PVA/Cur) showed a higher DPPH radical scavenging activity while the bacterial and fungal strains proved sensitive to the different formulations used in the assay. Moreover, the important drug encapsulation efficiency and the sustainable drug release of these materials make them promising for the development of new drug carrier systems for colon targeting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A natural polysacharide, gum odina was collected from Odina wodier tree and purified. Purified gum odina was used with sodium alginate for immobilization of α-amylase. Calcium alginate-gum odina (CA-GO) beads were prepared by ionotropic gelation method to find the improvement of immobilization efficiency and reusability of α-amylase over calcium alginate (CA) beads. XRD, SEM, FTIR, beads diameter, enzyme leaching from beads, moisture content, total soluble matter and swelling study have been carried out to understand the physical morphology and mechanism of immobilization of enzyme in beads matrix. It has been observed that if the polymer ratio changes (keeping enzyme conc. & calcium Chloride conc. constant) then the size and shape of the beads will vary and at a particular range of polymer ratio, the optimal beads forms. At a certain conc.(4%w/v of SA and 1%w/v GO), the immobilization efficiency of CA-GO and CA beads were 92.71 ± 0.85 % (w/w) and 89.19 ± 0.35 %(w/w) respectively. After 8th time use, the CA-GO beads remain (~4 fold) more active than that of CA beads. The FTIR confirms that GO does not interfere with α-Amylase and alginate. Here, it can be concluded that CA-GO beads show better efficiency in respect to immobilization, reusability than CA beads only., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Alginate is a biopolymer widely used on delivery systems when bioactive protection at acidic pH is required, while chitosan can enhance mucoadhesion and controlled release at alkaline pHs. In this work, alginate ionotropic gelation and electrostatic complexation to chitosan were evaluated concomitantly or in a two-step approach to improve the delivery properties of systems in different pHs. The effect of pH on alginate gelation and chitosan interactions were also evaluated. Alginate microspheres were prepared by ionotropic gelation in CaCl 2 at different pH values (2.5 and 6.0) by extrusion. Complexation with chitosan was carried out during alginate ionotropic gelation (one-step approach) or after alginate gel formation (two-step approach). Alginate microparticles without chitosan showed larger pores and lower mechanical strength. Extruded microspheres at pH 6.0 were more stable to pH and showed smaller pores than the formed at pH 2.5. One-step production retained a large amount of bioactive at pH 7.0 and resulted in lower release at the pH of intestinal digestion. The two-step approach retained less amount of bioactive but confer more protection to the pH of the stomach phase and higher release in pH of the intestinal phase than one-step samples. These results indicate that the formation of alginate gels by ionotropic gelation followed by the complexation with chitosan (in two-step) is promising for the transport and delivery of bioactives into intestinal conditions, whereas the ionotropic gelation concomitantly to electrostatic complexation (one-step approach) is indicated to the delivery of bioactives into lower pH environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Glucosamine (Glu) is a cartilage and joint fluid matrix precursor that modulates osteoarthritic joint changes. To improve the enzymatic stability, glucosamine was developed into nanoglucosamine by the ionic gelation method through sodium tripolyphosphate (TPP) as cross-linking agent. The optimized mass ratio of Glu:TPP was (3:1) with the particle size 163 ± 25 nm and surface charge -5 mV. Then Sinapic acid (SA) as a natural phenolic acid with strong antioxidant and antimicrobial activities has been grafted onto glucosamine nanoparticles (GluNPs) with grafting efficiency (73 ± 6 %). The covalent insertion of SA was confirmed by UV-Vis, FTIR, 1 HNMR, XRD, and FESEM analyses and the other physicochemical properties were also characterized. SA-g-GluNPs showed spherical shape with a mean diameter of 255 ± 20 nm and zeta potential +16 mV. The in vitro release profile of SA-g-GluNPs exhibited the sustained and pH-dependent drug release property. SA-g-GluNPs had a more pronounced effect on reducing the elevated levels of LPS-induced oxidative stress and pro-inflammatory cytokines than free SA in the human chondrocyte C28/I2 cell line. Furthermore, the antibacterial properties against E. coli and S. aureus were also improved by SA-g-GluNPs. This study demonstrated the potential of phenolic acid grafted GluNPs in therapeutic drug applications for chondroprotection and food industries., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The stability and release properties of all bioactive capsules are strongly related to the composition of the wall material. This study aimed to evaluate the effect of the wall materials during the encapsulation process by ionotropic gelation on the viability of Lactobacillus fermentum K73, a lactic acid bacterium that has hypocholesterolemia probiotic potential. A response surface methodology experimental design was performed to improve bacterial survival during the synthesis process and under simulated gastrointestinal conditions by tuning the wall material composition (gelatin 25% w / v , sweet whey 8% v / v , and sodium alginate 1.5% w / v ). An optimal mixture formulation determined that the optimal mixture must contain a volume ratio of 0.39/0.61 v / v sweet whey and sodium alginate, respectively, without gelatin, with a final bacterial concentration of 9.20 log 10 CFU/mL. The mean particle diameter was 1.6 ± 0.2 mm, and the experimental encapsulation yield was 95 ± 3%. The INFOGEST model was used to evaluate the survival of probiotic beads in gastrointestinal tract conditions. Upon exposure to in the vitro conditions of oral, gastric, and intestinal phases, the encapsulated cells of L. fermentum decreased only by 0.32, 0.48, and 1.53 log 10 CFU/mL, respectively, by employing the optimized formulation, thereby improving the survival of probiotic bacteria during both the encapsulation process and under gastrointestinal conditions compared to free cells. Beads were characterized using SEM and ATR-FTIR techniques.

Ionotropic gelation (IG) is a highly attractive method for the synthesis of natural water-soluble polymeric nanoparticles (NPs) and sub-micron particles (sMP) due to its relatively simple procedure and the absence of organic solvents. The method involves the electrostatic interaction between two ionic species of opposite charge. Although it is well studied at the laboratory scale, the difficulty to achieve size control in conventional bench-top process is actually a critical aspect of the technology. The aim of this work is to study the membrane dispersion technology in combination with IG as a suitable scalable method for the production of chitosan sub-micron particles (CS-sMPs). The two phases, one containing chitosan (CS) and the other containing sodium tripolyphosphate (TPP), were put in contact using a tubular hydrophobic glass membrane with a pore diameter of 1 μm. TPP (dispersed phase) was permeated through the membrane pores into the lumen side along which the CS solution (the continuous phase) flowed in batch recirculation or continuous single-pass operation mode. The influence of chemical variables (i.e. pH, concentration and mass ratio of polyelectrolyte species, emulsifier) and fluid-dynamic parameters (i.e. polyelectrolyte solution flow rate and their relative mass ratio) was studied to precisely tune the size of CS-Ps., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Purpose: Wound healing is a biological process that can be difficult to manage clinically. In skin wound healing, the interaction of many cells, growth factors, and cytokines reveals an outstanding biological function mechanism. Wound healing that occurs naturally restores tissue integrity, however, it is usually restricted to wound repair. Curcumin synthesised in a chitosan matrix can be used to heal skin sores., Experimental Approach: The ionotropic gelation procedure required crosslinking chitosan with a tripolyphosphate (TPP) crosslinker to generate curcumin nanoparticles encapsulated in chitosan., Key Results: The nanoparticles were between 200 and 400 nm in size, with a strong positive surface charge and good entrapment efficacy, according to SEM and TEM investigations. Curcumin and chitosan compatibility was investigated using FTIR spectroscopy. All batches showed consistent drug release, with the F5 batch having the highest curcumin release, at 75% after 16 hours. On L929 cells, scratch assays were utilised to assess wound healing. Wound closure with widths of 59 and 65 mm with curcumin and 45 and 78 mm with curcumin-loaded chitosan nanoparticles was seen after 24 and 48 hours of examination., Conclusions: According to the findings, prepared curcumin chitosan nanoparticles are beneficial in healing skin damage., Competing Interests: Conflict of interest: The authors report no conflicts of interest in this work., (Copyright © 2023 by the authors.)

Phenolic compounds that are present in pineapple by-products offer many health benefits to the consumer; however, they are unstable to many environmental factors. For this reason, encapsulation is ideal for preserving their beneficial effects. In this work, extracts were obtained by the combined method of solid-state fermentation with Rhizopus oryzae and ultrasound. After this process, the encapsulation process was performed by ionotropic gelation using corn starch, sodium alginate, and Weissella confusa exopolysaccharide as wall material. The encapsulates produced presented a moisture content between 7.10 and 10.45% (w.b), a solubility of 53.06 ± 0.54%, and a wettability of 31.46 ± 2.02 s. The total phenolic content (TPC), antioxidant capacity of DPPH, and ABTS of the encapsulates were also determined, finding 232.55 ± 2.07 mg GAE/g d.m for TPC, 45.64 ± 0.9 µm Trolox/mg GAE for DPPH, and 51.69 ± 1.08 µm Trolox/mg GAE for ABTS. Additionally, ultrahigh performance liquid chromatography (UHPLC) analysis allowed us to identify and quantify six bioactive compounds: rosmarinic acid, caffeic acid, p-coumaric acid, ferulic acid, gallic acid, and quercetin. According to the above, using ionotropic gelation, it was possible to obtain microencapsulates containing bioactive compounds from pineapple peel extracts, which may have applications in the development of functional foods.

Chitosan is an abundant natural cationic polysaccharide with excellent biodegradability, bioadhesion, and biocompatibility. Chitosan is extensively researched for various particulate oral insulin drug delivery systems. Oral insulin is economically efficient and more convenient than injections, with greater patient compliance. Electrostatic ionic interaction between cationic chitosan and anionic polymer or insulin leads to the formation of spontaneously self-assembled nanoparticles. This simple technique attracted many researchers as it can be carried out quickly in mild conditions without harmful solvents, such as surfactants or chemical cross-linkers that might degrade the insulin structure. The formulated chitosan nanoparticles help to protect the core insulin from enzymatic degradation in the digestive system and improve paracellular intestinal uptake from the enterocytes due to mucoadhesion and reversible tight junction opening. Moreover, functionalized chitosan nanoparticles create newer avenues for targeted and prolonged delivery. This review focuses on modified chitosan-insulin nanoparticles and their implications on oral insulin delivery. Dependent variables and their optimal concentration ranges used in self-assembly techniques for chitosan-insulin nanoparticular synthesis are summarized. This review provides a comprehensive guide to fine-tune the essential factors to formulate stable insulin-chitosan nanoparticles using mild ionic interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

FucoPol, a fucose-rich polyanionic polysaccharide, was used for the first time for the preparation of hydrogel membranes (HMs) using Fe 3+ as a crosslinking agent. This study evaluated the impact of Fe 3+ and FucoPol concentrations on the HMs' strength. The results show that, above 1.5 g/L, Fe 3+ concentration had a limited influence on the HMs' strength, and varying the FucoPol concentration had a more significant effect. Three different FucoPol concentrations (1.0, 1.75 and 2.5 wt.%) were combined with Fe 3+ (1.5 g/L), resulting in HMs with a water content above 97 wt.% and an Fe 3+ content up to 0.16 wt.%. HMs with lower FucoPol content exhibited a denser porous microstructure as the polymer concentration increased. Moreover, the low polymer content HM presented the highest swelling ratio (22.3 ± 1.8 g/g) and a lower hardness value (32.4 ± 5.8 kPa). However, improved mechanical properties (221.9 ± 10.2 kPa) along with a decrease in the swelling ratio (11.9 ± 1.6 g/g) were obtained for HMs with a higher polymer content. Furthermore, all HMs were non-cytotoxic and revealed anti-inflammatory activity. The incorporation of FucoPol as a structuring agent and bioactive ingredient in the development of HMs opens up new possibilities for its use in tissue engineering, drug delivery and wound care management.

Gellan gum, a microbial exopolysaccharide, is biodegradable and has potential to fill several key roles in many fields from food to pharmacy, biomedicine and tissue engineering. In order to improve the physicochemical and biological properties of gellan gum, some researchers take advantage of numerous hydroxyl groups and the free carboxyl present in each repeating unit. As a result, design and development of gellan-based materials have advanced significantly. The goal of this review is to provide a summary of the most recent, high-quality research trends that have used gellan gum as a polymeric component in the design of numerous cutting-edge materials with applications in various fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ionotropic gelation technique was chosen to produce vitamin D3-loaded microparticles starting from oil-in-water (O/W) Pickering emulsion stabilized by flaxseed flour: the hydrophobic phase was a solution of vitamin D3 in a blend of vegetable oils (ω6:ω3, 4:1) composed of extra virgin olive oil (90%) and hemp oil (10%); the hydrophilic phase was a sodium alginate aqueous solution. The most adequate emulsion was selected carrying out a preliminary study on five placebo formulations which differed in the qualitative and quantitative polymeric composition (concentration and type of alginate selected). Vitamin D3-loaded microparticles in the dried state had a particle size of about 1 mm, 6% of residual water content and excellent flowability thanks to their rounded shape and smooth surface. The polymeric structure of microparticles demonstrated to preserve the vegetable oil blend from oxidation and the integrity of vitamin D3, confirming this product as an innovative ingredient for pharmaceutical and food/nutraceutical purposes.

The design of nanoparticle formulations composed of biopolymers, that govern the physicochemical properties of orally delivered insulin, relies on improving insulin stability and absorption through the intestinal mucosa while protecting it from harsh conditions in the gastrointestinal (GI) tract. Chitosan/polyethylene glycol (PEG) and albumin coating of alginate/dextran sulfate hydrogel cores are presented as a multilayer complex protecting insulin within the nanoparticle. This study aims to optimize a nanoparticle formulation by assessing the relationship between design parameters and experimental data using response surface methodology through a 3-factor 3-level optimization Box-Behnken design. While the selected independent variables were the concentrations of PEG, chitosan and albumin, the dependent variables were particle size, polydispersity index (PDI), zeta potential, and insulin release. Experimental results showed a nanoparticle size ranging from 313 to 585 nm, with PDI from 0.17 to 0.39 and zeta potential ranging from -29 to -44 mV. Insulin bioactivity was maintained in simulated GI media with over 45% cumulative release after 180 min in a simulated intestinal medium. Based on the experimental responses and according to the criteria of desirability on the experimental region's constraints, solutions of 0.03% PEG, 0.047% chitosan and 1.20% albumin provide an optimum nanoparticle formulation for insulin oral delivery.

This study aims to develop hydrogels from apple pectin (AP) and hogweed pectin (HP) in multiple ratios (4:0; 3:1; 2:2; 1:3; and 0:4) using ionotropic gelling with calcium gluconate. Rheological and textural analyses, electromyography, a sensory analysis, and the digestibility of the hydrogels were determined. Increasing the HP content in the mixed hydrogel increased its strength. The Young's modulus and tangent after flow point values were higher for mixed hydrogels than for pure AP and HP hydrogels, suggesting a synergistic effect. The HP hydrogel increased the chewing duration, number of chews, and masticatory muscle activity. Pectin hydrogels received the same likeness scores and differed only in regard to perceived hardness and brittleness. The galacturonic acid was found predominantly in the incubation medium after the digestion of the pure AP hydrogel in simulated intestinal (SIF) and colonic (SCF) fluids. Galacturonic acid was slightly released from HP-containing hydrogels during chewing and treatment with simulated gastric fluid (SGF) and SIF, as well as in significant amounts during SCF treatment. Thus, new food hydrogels with new rheological, textural, and sensory properties can be obtained from a mixture of two low-methyl-esterified pectins (LMPs) with different structures.

Hydrogels have a tridimensional structure. They have the ability to absorb a significant amount of water or other natural or simulated fluids that cause their swelling albeit without losing their structure. Their properties can be exploited for encapsulation and modified targeted drug release. Among the numerous natural polymers suitable for obtaining hydrogels, gellan gum is one gaining much interest. It is a gelling agent with many unique features, and furthermore, it is non-toxic, biocompatible, and biodegradable. Its ability to react with oppositely charged molecules results in the forming of structured physical materials (films, beads, hydrogels, nanoparticles). The properties of obtained hydrogels can be modified by chemical crosslinking, which improves the three-dimensional structure of the gellan hydrogel. In the current review, an overview of gellan gum hydrogels and their properties will be presented as well as the mechanisms of ionotropic gelation or chemical crosslinking. Methods of producing gellan hydrogels and their possible applications related to improved release, bioavailability, and therapeutic activity were described.

The accumulation of chitin waste from the seafood industry is a serious environmental problem. However, this residue can be degraded by chitinases and its subproducts, such as chitosan, economically exploited. In this study, a chitinase producer bacteria, identified as Paenibacillus illinoisensis, was isolated from the Brazilian coastal city of Terra de Areia - Rio Grande Do Sul (RS) and was immobilized within alginate beads to evaluate its chitinase production. The alginate beads containing cells presented an average size of 4 mm, 99% of immobilization efficiency and increased the enzymatic activity in 40.71% compared to the free cells. The biomass during enzymatic production increased 62.01% and the total cells leaked from the alginate beads corresponded to 6.46% after 96 h. Immobilized cells were reused in a sequential batch system and remained stable for production for up to four 96-h cycles, decreasing only 21.04% of the initial activity at the end of the fourth cycle. Therefore, the methodology used for cell immobilization resulted in adequate beads to maintain cell viability during the enzymatic production, increasing enzymatic activity, showing low cell leakage from the support and appropriate recyclable capacity., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

In this work, novel bio-based hydrogel beads were fabricated by using soybean extract as raw waste material loaded with Lambrusco extract, an Italian grape cultivar. The phenolic profile and the total amount of anthocyanins from the Lambrusco extract were evaluated before encapsulating it in soybean extract-based hydrogels produced through an ionotropic gelation technique. The physical properties of the produced hydrogel beads were then studied in terms of their morphological and spectroscopic properties. Swelling degree was evaluated in media with different pH levels. The release kinetics of Lambrusco extract were then studied over time as a function of pH of the release medium, corroborating that the acidity/basicity could affect the release rate of encapsulated molecules, as well as their counter-diffusion. The pH-sensitive properties of wine extract were studied through UV-Vis spectroscopy while the colorimetric responses of loaded hydrogel beads were investigated in acidic and basic solutions. Finally, in the framework of circular economy and sustainability, the obtained data open routes to the design and fabrication of active materials as pH-indicator devices from food industry by-products.

The encapsulation of pesticides within nanoparticles is a promising approach of advanced technology in sustainable agriculture. Lambda-cyhalothrin (LC) was encapsulated by the ionotropic gelation technique into chitosan (CS)/tripolyphosphate (TPP) and CS/alginate (ALG) matrixes. CS-LC nanoparticles were characterized, and their efficacy was then evaluated against the key pest of soft fruits in Europe and the United States, Drosophila suzukii . The encapsulation efficiency (74%), nanoparticle yield (80%), polydispersity index (0.341), zeta potential (-23.1 mV) and particle size (278 nm) were determined at the optimum conditions. FTIR confirmed the cross-linkage between CS and TPP/ALG in the nanoparticles. The optimum formula recommended by the fractional factorial design was associated with the formulation variables of CS of high or low molecular weight, cross-linking agent (TPP), LC concentration (1.5% w/v ) and stirring rate (1500 rpm), showing the highest desirability value (0.5511). CS-LC nanoparticles of the lowest particle size (278 nm) exhibited the highest percent mortality of D. suzukii males (86%) and females (84%), exceeding that caused by the commercial product (Karate-zeon ® 10% CS) at 2 HAT. This is the first work to use the ionic gelation technique to make LC nanoparticles, to the best of our knowledge. The encapsulation of chemical pesticides within biodegradable polymeric nanoparticles could be helpful for establishing a sustainable IPM strategy with benefits for human and environmental health and the lifetime of pesticides.

The synthesis of hydrogel beads involving natural polymers is, nowadays, a leading research area. Among natural polymers, starch and chitosan represent two biomolecules with proof of efficiency and low economic impact in various utilization fields. Therefore, herein, the features of hydrogel beads obtained from chitosan and three sorts of starch (potato, wheat and rise starches), grafted with acrylonitrile and then amidoximated, were deeply investigated for their use as sorbents for heavy metal ions and dyes. The hydrogel beads were prepared by ionotropic gelation/covalent cross-linking of chitosan and functionalized starches. The chemical structure of the hydrogel beads was analyzed by FT-IR spectroscopy; their morphology was revealed by optical and scanning electron microscopies, while the influence of the starch functionalization strategies on the crystallinity changes was evaluated by X-ray diffraction. Molecular dynamics simulations were used to reveal the influence of the grafting reactions and grafted structure on the starch conformation in solution and their interactions with chitosan. The sorption capacity of the hydrogel beads was tested in batch experiments, as a function of the beads' features (synthesis protocol, starch sort) and simulated polluted water, which included heavy metal ions (Cu 2+ , Co 2+ , Ni 2+ and Zn 2+ ) and small organic molecules (Direct Blue 15 and Congo red).

Biopolymer beads can be used as carrier and encapsulation system for a wide variety of materials in food, medical, pharmaceutical, cosmetics, agricultural, and environmental applications. Beads of low acyl gellan gum (0.4-1.2% w/w) were produced using extrusion technique (dripping) followed by an ionotropic gelation step with calcium or potassium chloride. In this methodology, gel formation is accomplished by cations diffusion at room temperature and, as a consequence, different structure and gel properties could be obtained. Gellan beads were subjected to uniaxial compression measurements. The force-displacement curves showed that the occurrence of structural failure under tested conditions depended on beads formulation and was only observed at polysaccharide concentration above 0.8% (w/w). Maximum force or force at failure was mainly dependent on the type (monovalent or divalent cation) and salt concentration. Moreover, at fixed salt amounts, higher values of maximum force were reached using a concentration of 1% (w/w) gellan. Young modulus, determined using Hertz approach, showed values between 445 and 840 kPa depending on polysaccharide concentration and salt type added. Mechanical properties are critical features of gel beads and can define their suitability for a specific application. Therefore, the results obtained, mainly intrinsic properties such as Young modulus, could be a tool for comparing and choosing polysaccharides for specific uses., (© 2022 Wiley Periodicals LLC.)

Combinations of polymers can improve the functional properties of microspheres to achieve desired therapeutic goals. Hence, the present study aimed to formulate Prunus armeniaca gum (PAG) and sodium alginate microsphere for sustained drug release. Blended and coated microspheres were prepared using the ionotropic gelation technique. The effect of polymer concentration variation was studied on the structural and functional properties of formulated microspheres. FTIR, XRD, and thermal analysis were performed to characterize the microspheres. All the formulations were well-formed spherical beads having an average diameter from 579.23 ± 07.09 to 657.67 ± 08.74 μm. Microspheres entrapped drugs within the range 65.86 ± 0.26-83.74 ± 0.79%. The pH-dependent swelling index of coated formulations was higher than blended. FTIR spectra confirmed the presence of characteristic peaks of entrapped Tramadol hydrochloride showing no drug-polymer interaction. In vitro drug release profile showed sustained release following the Korsmeyer-Peppas kinetic model with an R 2 value of 0.9803-0.9966. An acute toxicology study employing the oral route in Swiss albino mice showed no signs of toxicity. It can be inferred from these results that blending PAG with sodium alginate can enhance the stability of alginate microspheres and improve its drug release profile by prolonging the release time.

Nucleic acid vaccines have become a revolutionary technology to give a fast, safe, cost-effective and efficient response against viral infections, such as SARS-CoV-2 or Human papillomavirus (HPV). However, to ensure their effectiveness, the development of adequate methods to protect, carry, and deliver nucleic acids is fundamental. In this work, nanoparticles (NPs) of chitosan (CS)-tripolyphosphate (TPP)-plasmid DNA (pDNA) were thoroughly modulated and characterized, by measuring the charge and size through dynamic light scattering (DLS) and morphology by scanning electron microscopy (SEM). Stability, cytotoxicity and cellular uptake of NPs were also evaluated. Finally, the effect of polyplexes on the expression of HPV E7 antigen in human fibroblast and RAW cells was investigated through polymerase chain reaction (PCR) and real-time PCR. The results showed NPs with a spherical/oval shape, narrow size distribution <180 nm and positive zeta potentials (>20 mV) and good stability after one month of storage at 4 °C in formulation buffer or when incubated in culture medium and trypsin. In vitro studies of NPs cytotoxicity revealed that the elimination of formulation buffers led to an improvement in the rate of cell viability. The E7 antigen transcription was also increased for NPs obtained with high pDNA concentration (60 μg/mL). The analyzed CS-TPP-pDNA polyplexes can offer a promising vehicle for nucleic acid vaccines, not only in the prevention or treatment of viral infections, but also to fight emergent and future pathogens.

Purpose: In the performed study, the rheological and textural parameters of gellan-based hydrogels were investigated and their dependence on three factors was taken into consideration: ( i ) The presence of the model drug, ( ii ) The presence and type of the ionic crosslinking agent, and ( iii ) the composition of the polymer network. The objective was to compare two analytical methods, regarded as complementary, and define to what extent the obtained results correlate with each other., Methods: The hydrogels contained low-acyl gellan gum or its mixtures with hydroxyethyl cellulose or κ-carrageenan. CaCl 2 and MgCl 2 were used as gelling agents. Mesalazine was used as a model drug. The rheological analysis included oscillatory stress and frequency sweeping. The texture profile analysis was performed to calculate texture parameters., Results: Placebo gels without the addition of gelling agents had the weakest structure. The drug had the strongest ability to increase the stiffness of the polymer network. The weakest structure revealed the placebo samples without the addition of gelling agents. Texture analysis revealed no significant influence of the drug on the strength of the gels, while rheological measurements indicated clear differences., Conclusions: It can be concluded that in the case of some parameters methods correlate, that is, the effect related to gelling ions. However, the rheological analysis seems to be more precise and sensitive to some changes in the mechanical properties of the gels.

Background: Ellagic acid (EA), a potent dietary antioxidant, has limited bioavailability owing to its rapid absorption in the stomach and small intestine, and EA is transformed to more bioavailable compounds - urolithins - in the colon. An encapsulation system that sustains the release of EA in the gastrointestinal system and delivers more EA into the colon could improve the oral bioavailability of EA. Electrosprayed EA-loaded alginate-pectin beads were produced and coated with low- (LC) and high-molecular-weight chitosan (HC). The EA release from uncoated and coated beads under simulated gastrointestinal conditions was evaluated. The samples were characterized by particle size, gel strength, scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) analysis., Results: The encapsulation efficiency (EE%) of EA ranged from 49.53% to 69.85% for uncoated beads, which was elevated up to 86.50% by coating, and LC coating provided higher EE%. Pectin addition to alginate and chitosan coating reduced the gel strength and changed the size depending on the molecular weight of chitosan. SEM images of pectin-added beads showed fewer cracks but more wrinkles, and chitosan coating presented more aggregated surfaces. The ionic interaction of alginate-pectin-chitosan and the entrapment of EA were confirmed by FTIR. In the gastric medium, EA release was very low from uncoated beads (15.2-19.8%), and totally restricted by chitosan coating. In the intestinal stage, EA release from LC-coated alginate-pectin beads was only 18%, and it was between 55% and 65% for uncoated or HC-coated counterparts., Conclusion: The LC-coated alginate-pectin beads could be further explored as a potential system for colon-targeted delivery of EA. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Background: Aceclofenac is a non-steroidal anti-inflammatory drug and a potent analgesic. However, its oral ingestion may cause gastrointestinal problems, including dyspepsia, abnormal pain, nausea, diarrhea, and ulcerative colitis., Objective: This study aimed to prepare vesicular-based enteric microspheres containing aceclofenac by ionotropic gelation technique to minimize gastric irritation in rats., Methods: The micron-size vesicles were prepared by the ionic-orifice gelation method. Three types of vesicularbased microcapsules containing aceclofenac were prepared by employing sodium alginate as the coating material in combination with Eudragit L100, Eudragit S100, and polyvinylpyrrolidone PVP K90. The drug to sodium alginate to polymer ratios were 1:0.5:0.5, 1:1:1, and 1:1.5:1.5, respectively. Gelation of sodium alginate was induced by the dropwise addition of calcium chloride solution (10 % w/v). Aceclofenac-loaded microspheres were evaluated in terms of aceclofenac content and in vitro drug release, and FTIR, DSC, and XRD were used for physicochemical evaluation of some selected formulae. The effects of microencapsulation on aceclofenac-induced ulcerative activity in male Wistar rats were also investigated., Results: The results indicated no interaction between aceclofenac and microcapsules forming polymers. In addition, microcapsules formulations M1, M4, and M7 gave maximal protection in acidic pH and optimal release in alkaline pH. The histopathological studies revealed that the reduction of ulceration is evident from the macroscopic and microscopic studies, which showed complete protection of the tissue morphology with no ulcers, indicating the effectiveness of the microcapsules system against aceclofenac-induced gastric ulceration in rats again., Conclusion: Ionotropic gelation seems to be a simple, efficient technique to prepare aceclofenac-loaded microspheres with a reduced risk of gastric ulceration. It is possible to overcome the problem of gastric damage while utilizing aceclofenac by avoiding the exposure of the drug to the ulcer-prone area of the gastrointestinal tract., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Throughout the past decade, Pickering emulsion has been increasingly utilized for the encapsulation of bioactive compounds due to its high stability and biocompatibility. In the present work, palm tocotrienols were initially encapsulated in a calcium carbonate Pickering emulsion, which was then subjected to alginate gelation and subsequent chitosan coating. The effects of wall material (alginate and chitosan) concentrations, gelation pH and time, and chitosan coating time on the encapsulation efficiency of palm tocotrienols were explored., Results: Our findings revealed that uncoated alginate microcapsules ruptured upon drying and exhibited low encapsulation efficiency (13.81 ± 2.76%). However, the addition of chitosan successfully provided a more complex and rigid external wall structure to enhance the stability of the microcapsules. By prolonging the crosslinking time from 5 to 30 min and increasing the chitosan concentration from 0.1% to 0.5%, the oil encapsulation efficiency was increased by 28%. Under the right gelation pH (pH 4), the extension of gelation time from 1 to 12 h resulted in an increase in alginate-Ca 2+ crosslinkings, thus strengthening the microcapsules., Conclusion: With the optimum formulation and process parameters, a high encapsulation efficiency (81.49 ± 1.75%) with an elevated oil loading efficiency (63.58 ± 2.96%) were achieved. The final product is biocompatible and can potentially be used for the delivery of palm tocotrienols. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Microfluidics is emerging as a promising tool to control physicochemical properties of nanoparticles and to accelerate clinical translation. Indeed, microfluidic-based techniques offer more advantages in nanomedicine over batch processes, allowing fine-tuning of process parameters. In particular, the use of microfluidics to produce nanoparticles has paved the way for the development of nano-scaled structures for improved detection and treatment of several diseases. Here, ionotropic gelation is implemented in a custom-designed microfluidic chip to produce different nanoarchitectures based on chitosan-hyaluronic acid polymers. The selected biomaterials provide biocompatibility, biodegradability and non-toxic properties to the formulation, making it promising for nanomedicine applications. Furthermore, results show that morphological structures can be tuned through microfluidics by controlling the flow rates. Aside from the nanostructures, the ability to encapsulate gadolinium contrast agent for magnetic resonance imaging and a dye for optical imaging is demonstrated. In conclusion, the polymer nanoparticles here designed revealed the dual capability of enhancing the relaxometric properties of gadolinium by attaining Hydrodenticity and serving as a promising nanocarrier for multimodal imaging applications.

Risedronate sodium (RS) is used in osteoporosis for bone reabsorption. It is a BCS class III drug having poor oral bioavailability (<0.63%) due to low permeability. In the present study, RS-loaded chitosan nanoparticles were developed to increase oral bioavailability and evaluated for various parameters. The DSC study indicated compatibility of RS with excipients in their physical mixture. The nanoparticles were prepared by ionotropic gelation technique and lyophilized. The optimized batch (RS-CNs) was found to have particles of size 268.7 nm and zeta potential of 24.9 mV. The TEM image of RS-CNs revealed discrete spherical particles. Angle of repose of 27.02 indicates good flow property of nanoparticles. FT-IR spectra of RS-CNs showed characteristic peaks of RS indicating compatibility of RS with the excipients. The mucin binding efficiency of RS-CNs was obtained as 63.42%. The in vitro release study of RS indicated controlled delivery from RS-CNs over 22 h. The release mechanism was found to be diffusion- and erosion-controlled release. Ex vivo study using rat intestine revealed faster permeation of 32.78% in 6 h from RS-CNs compared to plain drug solution. In vivo pharmacokinetic study in rats showed increased C max (1.8 fold) from RS-CNs compared to marketed formulation. The relative bioavailability of 193% from RS-CNs indicated significant enhancement in bioavailability upon nanoparticle formulation. The RS-CNs were found to be stable at room and refrigerated conditions. In conclusion, developed RS-loaded chitosan nanoparticles seem to be a promising approach to increase oral bioavailability and can avoid upper GI tract side effects., (© 2021. American Association of Pharmaceutical Scientists.)

This article provides a systematic review of the crosslinking strategies used to produce microgel particles in microfluidic chips. Various ionic crosslinking methods for the gelation of charged polymers are discussed, including external gelation via crosslinkers dissolved or dispersed in the oil phase; internal gelation methods using crosslinkers added to the dispersed phase in their non-active forms, such as chelating agents, photo-acid generators, sparingly soluble or slowly hydrolyzing compounds, and methods involving competitive ligand exchange; rapid mixing of polymer and crosslinking streams; and merging polymer and crosslinker droplets. Covalent crosslinking methods using enzymatic oxidation of modified biopolymers, photo-polymerization of crosslinkable monomers or polymers, and thiol-ene "click" reactions are also discussed, as well as methods based on the sol-gel transitions of stimuli responsive polymers triggered by pH or temperature change. In addition to homogeneous microgel particles, the production of structurally heterogeneous particles such as composite hydrogel particles entrapping droplet interface bilayers, core-shell particles, organoids, and Janus particles are also discussed. Microfluidics offers the ability to precisely tune the chemical composition, size, shape, surface morphology, and internal structure of microgels by bringing multiple fluid streams in contact in a highly controlled fashion using versatile channel geometries and flow configurations, and allowing for controlled crosslinking.

The aim of the present study was to prepare a leflunomide (LFD) sustained release transdermal delivery system for the treatment of psoriasis. In this context, LFD-loaded nanoparticles (NPs) based on either neat chitosan (CS) or CS modified with [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SDAEM, a sulfobetaine zwitterionic compound) were initially prepared via ionotropic gelation and characterized in terms of in vitro dissolution, physicochemical, and antibacterial properties. Results showed that the use of the SDAEM-modified CS resulted in the formation of LFD-loaded NPs with improved wetting and solubilization properties, better in vitro dissolution profile characteristics (i.e., higher dissolution rate and extent), and improved (enhanced) antibacterial properties. The resultant LFD-loaded NPs were then embedded in suitable thin-film skin patches, prepared via spin-coating, utilizing two different biodegradable polyesters, namely methoxy polyethylene glycol- b- poly(L-lactide) (mPEG- b -PLA, at a ratio of 25/75 mPEG to PLA) and poly(lactic-co-glycolic acid) (PLGA at a ratio of 75/25 DL-lactide/glycolide copolymer). Results showed the formation of polymeric thin-films with no agglomeration (or trapped air) and uniform structure in all cases, while the LFD-loaded NPs were successfully embedded in the polymeric matrix. Analysis of the obtained in vitro dissolution profiles revealed a sustained release profile of the drug for up to approximately twelve days, while between the two proposed systems, the use of CS-SDAEM NPs (independently of the polyester type) was the most promising formulation approach.

The capability of some polymers, such as chitosan, to form low cost gels under mild conditions is of great application interest. Ionotropic gelation of chitosan has been used predominantly for the preparation of gel beads for biomedical application. Only in the last few years has the use of this method been extended to the fabrication of chitosan-based flat structures. Herein, after an initial analysis of the major applications of chitosan flat membranes and films and their usual methods of synthesis, the process of ionotropic gelation of chitosan and some recently proposed novel procedures for the synthesis of flat structures are presented.

Natural polysaccharides have been investigated as vehicles for oral insulin administration. Because of their non-toxic, renewable, low cost and readily available properties, gums find multiple applications in the pharmaceutical industry. This work aimed to develop a Sterculia striata gum-based formulation associated with additional biopolymers (dextran sulfate, chitosan, and albumin), a crosslinking agent (calcium chloride) and stabilizing agents (polyethylene glycol and poloxamer 188), to increase the oral bioavailability of proteins. Insulin was used as a model drug and the methods used to prepare the formulation were based on ionotropic pregelation followed by electrolytic complexation of oppositely charged biopolymers under controlled pH conditions. The developed formulation was characterized to validate its efficacy, by the determination of its average particle size (622 nm), the insulin encapsulation efficiency (70%), stability in storage for 30 days, and the in vitro mucoadhesion strength (92.46 mN). Additionally, the developed formulation preserved about 64% of initial insulin dose in a simulated gastric medium. This study proposed, for the first time, a Sterculia striata gum-based insulin delivery system with potential for the oral administration of protein drugs, being considered a valid alternative for efficient delivery of those drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polymeric nanoparticulate systems allow the encapsulation of bio-active substances, giving them protection against external agents and increasing the drug's bioavailability. The use of biocompatible and biodegradable polymers usually guarantees the harmless character of the formulation, and a controlled drug release is also assured. A relatively easy procedure to obtain polymeric formulations of bioactive agents is ionotropic gelation, which allows the synthesis of chitosan (CS) - sodium tri-polyphosphate nanoparticles (NPs) loading encapsulated proteins. In this work, Bovine serum albumin (BSA) model protein and a recombinant porcine alpha interferon variant were used to obtain nanoparticulate formulations. The internalization of the encapsulated material by cells was studied using a BSA-fluorescein system; the fluorescent conjugate was observable inside the cells after 20 h of incubation. The therapeutic CS-alpha interferon formulation showed a maximum of protein released in vitro at around 90 h. This system was found to be safe in a cytotoxicity assay, while biological activity experiments in vitro showed antiviral protection of cells in the presence of encapsulated porcine alpha interferon. In vivo experiments in pigs revealed a significant and sustained antiviral response through overexpression of the antiviral markers OAS2 and PKR. This proves the preservation of porcine alpha interferon biological activity, and also that a lasting response was obtained. This procedure is an effective and safe method to formulate drugs in nanoparticulate systems, representing a significant contribution to the search for more effective drug delivery strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polysaccharide-based hydrogel particles (PbHPs) are very promising carriers aiming to control and target the release of drugs with different physico-chemical properties. Such delivery systems can offer benefits through the proper encapsulation of many drugs (non-steroidal and steroidal anti-inflammatory drugs, antibiotics, etc) ensuring their proper release and targeting. This review discusses the different phases involved in the production of PbHPs in pharmaceutical technology, such as droplet formation (SOL phase), sol-gel transition of the droplets (GEL phase) and drying, as well as the different methods available for droplet production with a special focus on prilling technique. In addition, an overview of the various droplet gelation methods with particular emphasis on ionic cross-linking of several polysaccharides enabling the formation of particles with inner highly porous network or nanofibrillar structure is given. Moreover, a detailed survey of the different inner texture, in xerogels, cryogels or aerogels, each with specific arrangement and properties, which can be obtained with different drying methods, is presented. Various case studies are reported to highlight the most appropriate application of such systems in pharmaceutical field. We also describe the challenges to be faced for the breakthrough towards clinic studies and, finally, the market, focusing on the useful approach of safety-by-design (SbD)., Competing Interests: The authors declare no conflict of interest.

(1) Background: Ionotropic gelation of cost-effective and eco-friendly biopolymer chitosan (Chit) is a novel and promising approach to the one-step synthesis of proton-conducting fuel cell bio-membranes.The method discovered by the author in 2011 and subsequently drowned among very few papers. This work aimed to relaunch this method through clear and effective communication of new unpublished results emphasizing the key aspects of this topic for successful dissemination of the results and significant future developments. (2) Methods and results: The mechanism of in-situ ionotropic gelation of Chit on an alumina substrate by phosphotungtate anions (PWA 3- ) was discussed and analyzed. The study sheds light on the effect of prolonged post-treatment in phosphotungstic acid (PWA) solution on the obtained chitosan/phosphotungstate (Chit-PWA) flat structures. Methods used included combined structural (XRD), thermal-gravimetric (DTG), electrochemical (in-situ EIS), compositional (EDX),morphological analysis (SEM), as well as the performances in a low temperature H 2 /O 2 fuel cell(4) Conclusions: This contribution discloses novel possibilities aimed at increasing the impact of ionotropic gelation of chitosan on the scientific community working on the synthesis of novel proton conductive bio-composite membranes and structures.

Chitosan nanoparticles (NPs) are widely studied as vehicles for drug, protein, and gene delivery. However, lack of sufficient stability, particularly under physiological conditions, render chitosan NPs of limited pharmaceutical utility. The aim of this study is to produce stable chitosan NPs suitable for drug delivery applications. Chitosan was first grafted to phthalic or phenylsuccinic acids. Subsequently, polyphosphoric acid (PPA), hexametaphosphate (HMP), or tripolyphosphate (TPP) were used to achieve tandem ionotropic/covalently crosslinked chitosan NPs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). Thermal and infrared traits confirmed phosphoramide bonds formation tying chitosan with the polyphosphate crosslinkers within NPs matrices. DLS and TEM size analysis indicated spherical NPs with size range of 120 to 350 nm. The generated NPs exhibited excellent stabilities under harsh pH, CaCl 2 , and 10% FBS conditions. Interestingly, DLS, NPs stability and infrared data suggest HMP to reside within NPs cores, while TPP and PPA to act mainly as NPs surface crosslinkers. Drug loading and release studies using methylene blue (MB) and doxorubicin (DOX) drug models showed covalent PPA- and HMP-based NPs to have superior loading capacities compared to NPs based on unmodified chitosan, generated by ionotropic crosslinking only or covalently crosslinked by TPP. Doxorubicin-loaded NPs were of superior cytotoxic properties against MCF-7 cells compared to free doxorubicin. Specifically, DOX-loaded chitosan-phthalate polyphosphoric acid-crosslinked NPs exhibited 10-folds cytotoxicity enhancement compared to free DOX. The use of PPA and HMP to produce covalently-stabilized chitosan NPs is completely novel., (Copyright © 2020 Saeed, Dmour and Taha.)

The effectiveness of ionotropic gelation method (by combining alginate and chitosan) vaccine against Lactococcus garvieae and Streptococcus iniae was examined in rainbow trout. Fish were separated into four groups and fed the distinctive examined feeds. Our groups were included: A) fish immunized by chitosan-alginate coated vaccine, B) fish immunized by non-coated vaccine, C) fish feed by chitosan-alginate coated pellets without vaccine and D) fish feed by basic diet (non-coated and without vaccine). In groups A and B, the vaccination was carried out for 14 days. Fish of group C, like groups A and B were fed 14 days with pellets covered with chitosan-alginate without vaccine and a short time later they were fed with control diet. On day 0, 20, 40 and 60 of the trial, serum samples were extracted. Fish were challenged with L. garvieae and S. iniae after 60 days of research. Innate immunity components containing complement activity, total protein and IgM appeared no significant changes nearly in all groups during the 60 days that the examination finished. Although, bactericidal activity and lysozyme activity demonstrated a significant increase on days 20, 40 and 60 in group A compared to control groups (C and D) (P < 0.05) and similar results about the blood respiratory burst activity just on days 20 and 40 were obtained. Also, the relative expression of IL-6 of group A, was significantly higher compared to all of other groups (B, C and D) on days 20 and 60 of experiment (P < 0.05). The same results were obtained about the relative expression of IgM. The serum ELISA antibody titer against L. garvieae, increased significantly on days 20 and 40 of experiment in fish immunized by chitosan-alginate coated vaccine (Group A) compared to control groups (C and D)(P < 0.05) while the result of ELISA test against S. iniae was significantly higher on days 40 and 60 of experiment in group A compared to groups B, C and D (P < 0.05). After challenge with these two live bacteria (S. iniae and L. garvieae), a survival rates of 76.67 ± 5.77% (challenged with S. iniae) and 66.67 ± 5.77% (challenged with L. garvieae) were seen in group immunized with chitosan-alginate coated vaccine (Group A), which were higher than survival rates gotten in other trial groups (P < 0.05). The consequences of the present experiment show that the oral vaccination of rainbow trout with improved chitosan-alginate (via ionotropic procedure) (group A) properly secures this important fish against Lactococcus garvieae and Streptococcus iniae., (Copyright © 2019. Published by Elsevier Ltd.)

In this study, gellan gum (GG), a natural polysaccharide, was used to fabricate spherical porous beads suitable as sustained drug delivery systems for oral administration. GG was cross-linked with calcium ions to prepare polymeric beads. Rheological studies and preliminary experiments of beads preparation allowed to identify the GG and the CaCl 2 concentrations suitable for obtaining stable and spherical particles. GG beads were formed, through ionotropic gelation technique, with and without the presence of the synthetic clay laponite. The resultant beads were analyzed for dimensions (before and after freeze-drying), morphological aspects and ability to swell in different media miming biological fluids, namely SGF (Simulated Gastric Fluid, HCl 0.1 M) and SIF (Simulated Intestinal Fluid, phosphate buffer, 0.044 M, pH 7.4). The swelling degree was lower in SGF than in SIF and further reduced in the presence of laponite. The GG and GG-layered silicate composite beads were loaded with two model drugs having different molecular weight, namely theophylline and cyanocobalamin (vitamin B12) and subjected to in-vitro release studies in SGF and SIF. The presence of laponite in the bead formulation increased the drug entrapment efficiency and slowed-down the release kinetics of both drugs in the gastric environment. A moving-boundary swelling model with "diffuse" glassy-rubbery interface was proposed in order to describe the swelling behavior of porous freeze-dried beads. Consistently with the swelling model adopted, two moving-boundary drug release models were developed to interpret release data from highly porous beads of different drugs: drug molecules, e.g., theophylline, that exhibit a typical Fickian behavior of release curves and drugs, such as vitamin B12, whose release curves are affected by the physical/chemical interaction of the drug with the polymer/clay complex. Theoretical results support the experimental observations, thus confirming that laponite may be an effective additive for fabricating sustained drug delivery systems.

Alginates, being linear anionic co-polymers of 1,4-linked residues β-d-ManA (M) and α-l-GulA (G), are widely applied as hydrogel biomaterials due to their favourable in vivo biocompatibility and convenient ionic crosslinking. The "egg-box" model is the prevailing description of the local structure of junction zones that form between the alginate chains and divalent cations, such as Ca 2+ , when ionic gelation occurs. In the present study we address to what extent signatures of lateral dimerization and further lateral association of junction zones also represent a valid model for the gelation of alginate using the recently reported method of competitive ligand exchange of chelated Ca 2+ ions as a method for introducing gelling ions at constant pH. Small angle X-ray scattering with a q range from 0.1 to 3.3 nm -1 was employed to determine local structure in the hydrogel, using a custom-made fluid sample cell inserted in the X-ray beam. The scattering volume was intended to be localized to the contact zone between the two injected aqueous alginate solutions, and data was captured to resolve the kinetics of the structure formation at three different conditions of pH. The data show evolution of the local structure for the Ca 2+ induced formation of junction zones in an alginate with 68% G residues, characterized by cross-sectional radii that could be accounted for by a two-component, broken rod like model. The evolution of the two component weight fractions apparently underpinned the connectivity, as reflected in the rheological data.

Background: The turmeric (Curcuma longa) plant, a perennial herb of the ginger family, is an agronomic crop in the south and southeast tropical Asia. Turmeric an Indian yellow gold and universal spice is described in Ayurveda, an ancient treatise on longevity and quality life for the treatment of various inflammatory disorders. The oral bioavailability of curcumin is low due to poor aqueous solubility, alkaline instability and speedy elimination., Objective: The present study is designed to prepare alginate polysorbate 80 nanoparticles to enhance aqueous solubility/dispersibility, hence bioavailability., Method: Curcumin-loaded alginate - polysorbate 80 nanoparticles were prepared by ionotropic gelation technique., Results: The optimized nano particles exhibited higher encapsulation efficiency (95%), particle size of 383 nm and Zeta potential of +200 mV. Formulations exhibited very low dissolution in Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF), but the major portion released in SCF which is attributed to the digestibility of alginate in Simulated Colonic Fluid (SCF) under the influence of colonic micro flora. FTIR and DSC observations revealed the successful entrapment of curcumin in alginate polysorbate-80 nanoparticles. The nanoparticles were more spherical, discrete and homogeneous. In healthy human volunteers, the oral bioavailability (AUC) of curcumin increased 5-fold after the consumption of curcumin nanosuspension compared to curcumin suspension. Maximum plasma concentration Cmax- 636 ± 122 ng/ml was observed at tmax- 2h for nanosuspension, whereas Cmax-87.7 ± 17.9ng/ml at tmax- 4h for suspension., Conclusion: Curcumin-loaded alginate - polysorbate 80 nanoparticles prepared by ionotropic gelation method, successfully entrapped curcumin. Both curcumin suspension and curcumin nanosuspension were safe and well tolerated and may thus be useful in the prevention or treatment of various inflammatory diseases of mankind., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aim of this study was to formulate a novel dual crosslinked hydrogel bead using Portulaca mucilage for colon-targeted delivery of 5-fluorouracil (5-FU) and evaluate its safety, specificity and efficacy. The ionotropic gelation technique was employed to prepare the hydrogel beads of Portulaca mucilage. For this, the mucilage was initially crosslinked with alginate and calcium ions. Epichlorohydrin was employed as a crosslinker in the second crosslinking step. The formulation was subjected to in vitro and in vivo studies to evaluate morphology, size, cytotoxicity, and organ distribution. Human HT-29 colon cancer cell-line was used for in vitro assays and in vivo studies were performed in Wistar rats to assess the usefulness and effectiveness of the formulation for colon cancer therapy. Microsphere sizes ranged from 930 to 977μm and possessed a high level of drug encapsulation efficiency (ca. 78% w/w). Compared with 5-FU solution (Tmax = 1.2 h, mean resident time: MRT = 3.3h) the dual crosslinked Portulaca microspheres exhibited sustained drug release after oral administration to rats (Tmax = 16h, MRT = 14h). The relative bioavailability of 5-FU solution and the microspheres were 100 and 93.6% respectively. Tissue distribution studies indicated high concentration of 5-FU in colon. In-vitro anticancer assay demonstrated IC50 value of 11.50 μg/ml against HT-29 colon cancer cell line. The epichlorohydrin cross-linked Portulaca microspheres prepared in this study provided sustained release of 5-FU up to 16h in the colonic region and enhanced the antitumor activity of the neoplastic drug. The formulation is hence an ideal carrier system for colon-targeted drug delivery.

This work reports the development of different types of alginate hydrogel microparticles designed specifically for the esculin (ESC) payload. Negatively charged alginate (ALG) microspheres were prepared by the ionotropic gelation technique, and an oppositely charged polyelectrolyte (PE) shell as a compatible polycation (chitosan (CHIT) or gelatin (GEL)) or a synthetic PEs (poly(allylamine hydrochloride) (PAH) and poly(4-styrenesulfonate) (PSS)) were adsorbed using electrostatic complexation. Thorough characterization of microparticles was performed with advanced microscopic techniques (scanning electron, fluorescence and confocal), followed by stability studies, ESC encapsulation efficacy determination and in vitro release kinetics measurements. We provide an in-depth investigation of the relationships between the properties (thickness, viscosity, areal mass, zeta potential) of the outer shell and the retaining and release abilities of the fabricated microcarriers, using quartz crystal microbalance with dissipation monitoring technique (QCM-D), spectroscopic ellipsometry and streaming potential measurements, combined in a new approach that was not attempted before for micrometric particles. The PAH-PSS and GEL coatings provided sufficient protection against ESC release under simulated gastric conditions that followed a two-stage Corrigan-Gallagher model with a marginal release rate in the first (lag) stage. This seems to be an interesting outcome, since it is rather peculiar for a low-molecular weight hydrophilic compound encapsulated in a highly porous microhydrogel to be released in such a manner., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Microencapsulation of lipase from Yarrowia lipolytica IMUFRJ 50682 was performed by ionotropic gelation with sodium alginate. Sodium alginate, calcium chloride and chitosan concentrations as well as complexation time were evaluated through experimental designs to increase immobilization yield (IY) and immobilized lipase activity (ImLipA) using p -nitrophenyl laurate as substrate. To adjust both parameters (IY and ImLipA), the desirability function showed that microcapsule formation with 3.1%( w / v ) sodium alginate, 0.19%( w / v ) chitosan, 0.14 M calcium chloride, and 1 min complexation time are ideal for maximal immobilization yield and immobilized lipase activity. A nearly twofold enhancement in Immobilization yield and an increase up to 280 U/g of the lipase activity of the microcapsules were achieved using the experimental design optimization tool. Chitosan was vital for the high activity of this new biocatalyst, which could be reused a second time with about 50% of initial activity and for four more times with about 20% of activity.