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In a previous paper a thermosensitive hydrogel formulation based on chitosan or its derivatives (TSOH), containing medicated chitosan nanoparticles (Ch NP) for transcorneal administration of 5-fluorouracil (5-FU) was described. The Ch NP-containing TSOH allowed a time-constant 5-FU concentration in the aqueous for 7 h from instillation. The aim of...
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Insulin-dependent diabetic patients have to count on the administration of painful and discomforting insulin injections. However, inadequate insulin absorption and the risk of insulin level escalation in the blood are some disadvantages associated with insulin therapy. Thus, the current study intends to formulate insulin-loaded chitosan nanoparticl...
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... However, its poor water solubility limits its further application. Fortunately, chitosan has a unique parental backbone structure with abundant active hydroxyl and amino groups in the molecular chain, which can be chemically modified [23,24]. For the first time, we synthesized a new amphiphilic chitosan (CS-SA-DA), which is safe, non-toxic, and has a high drug-carrying capacity, by grafting succinic anhydride (SA) and deoxycholic acid (DA) onto chitosan amino groups. ...
Curcumin (Cur) is a phytochemical with various beneficial properties, including antioxidant, anti-inflammatory, and anticancer activities. However, its hydrophobicity, poor bioavailability, and stability limit its application in many biological approaches. In this study, a novel amphiphilic chitosan wall material was synthesized. The process was carried out via grafting chitosan with succinic anhydride (SA) as a hydrophilic group and deoxycholic acid (DA) as a hydrophobic group; 1H-NMR, FTIR, and XRD were employed to characterize the amphiphilic chitosan (CS—SA—DA). Using a low-cost, inorganic solvent-based procedure, CS—SA—DA was self-assembled to load Cur nanomicelles. This amphiphilic polymer formed self-assembled micelles with a core–shell structure and a critical micelle concentration (CMC) of 0.093 mg·mL−1. Cur-loaded nanomicelles were prepared by self-assembly and characterized by the Nano Particle Size Potential Analyzer and transmission electron microscopy (TEM). The mean particle size of the spherical Cur-loaded micelles was 770 nm. The drug entrapment efficiency and loading capacities were up to 80.80 ± 0.99% and 19.02 ± 0.46%, respectively. The in vitro release profiles of curcumin from micelles showed a constant release of the active drug molecule. Cytotoxicity studies and toxicity tests for zebrafish exhibited the comparable efficacy and safety of this delivery system. Moreover, the results showed that the entrapment of curcumin in micelles improves its stability, antioxidant, and anti-inflammatory activity.
... 17,229,230 Among all the polymers utilized, chitosan nanoparticles with cationic characteristics confers powerful antimicrobial effects through interaction with the negatively charged microorganisms cell membranes. 231,232 Hydrogels encapsulating polymeric nanoparticles can be prepared using various methods, including physical mixing, in situ synthesis, and surface modication. The choice of method depends on the type of nanoparticles and the hydrogel matrix used. ...
The prevention and treatment of microbial infections is an imminent global public health concern due to the poor antimicrobial performance of the existing antimicrobial regime and rapidly emerging antibiotic resistance in pathogenic microbes. In order to overcome these problems and effectively control bacterial infections, various new treatment modalities have been identified. To attempt this, various micro- and macro-molecular antimicrobial agents that function by microbial membrane disruption have been developed with improved antimicrobial activity and lesser resistance. Antimicrobial nanoparticle-hydrogels systems comprising antimicrobial agents (antibiotics, biological extracts, and antimicrobial peptides) loaded nanoparticles or antimicrobial nanoparticles (metal or metal oxide) constitute an important class of biomaterials for the prevention and treatment of infections. Hydrogels that incorporate nanoparticles can offer an effective strategy for delivering antimicrobial agents (or nanoparticles) in a controlled, sustained, and targeted manner. In this review, we have described an overview of recent advancements in nanoparticle–hydrogel hybrid systems for antimicrobial agent delivery. Firstly, we have provided an overview of the nanoparticle hydrogel system and discussed various advantages of these systems in biomedical and pharmaceutical applications. Thereafter, different hybrid hydrogel systems encapsulating antibacterial metal/metal oxide nanoparticles, polymeric nanoparticles, antibiotics, biological extracts, and antimicrobial peptides for controlling infections have been reviewed in detail. Finally, the challenges and future prospects of nanoparticle–hydrogel systems have been discussed.
... The gelatin microbeads were modified with alginate and chitosan, both of which are natural polysaccharides, polyanionic and polycationic, respectively. They are well-known natural polymers and have been widely used in diverse bio-applications [25][26][27][28][29]. Figure 1 presents the schematical drawing of the GEL/SA/CS hydrogel microbeads attempted to be prepared in this study for phage delivery. ...
... The solution extrusion of sodium alginate within the dispersion medium containing divalent cations like Ca +2 is a very simple approach to producing alginate hydrogel beads with uniform spherical forms, which could be achieved at room temperature [25,26,29]. Alginate beads are pH-responsive: they exhibit a gel phase transition at around pH 2.5- The solution extrusion of sodium alginate within the dispersion medium containing divalent cations like Ca +2 is a very simple approach to producing alginate hydrogel beads with uniform spherical forms, which could be achieved at room temperature [25,26,29]. ...
... The solution extrusion of sodium alginate within the dispersion medium containing divalent cations like Ca +2 is a very simple approach to producing alginate hydrogel beads with uniform spherical forms, which could be achieved at room temperature [25,26,29]. Alginate beads are pH-responsive: they exhibit a gel phase transition at around pH 2.5- The solution extrusion of sodium alginate within the dispersion medium containing divalent cations like Ca +2 is a very simple approach to producing alginate hydrogel beads with uniform spherical forms, which could be achieved at room temperature [25,26,29]. Alginate beads are pH-responsive: they exhibit a gel phase transition at around pH 2.5-3.0 and they shrink (collapse) at values lower than this pH, such as the pH of the gastric juice, which is 1.5-2.0 in humans. ...
Bacterial infections are among the most significant health problems/concerns worldwide. A very critical concern is the rapidly increasing number of antibiotic-resistant bacteria, which requires much more effective countermeasures. As nature’s antibacterial entities, bacteriophages shortly (“phages”) are very important alternatives to antibiotics, having many superior features compared with antibiotics. The development of phage-carrying controlled-release formulations is still challenging due to the need to protect their activities in preparation, storage, and use, as well as the need to create more user-friendly forms by considering their application area/site/conditions. Here, we prepared gelatin hydrogel microbeads by a two-step process. Sodium alginate was included for modification within the initial recipes, and these composite microbeads were further coated with chitosan. Their swelling ratio, average diameters, and Zeta potentials were determined, and degradations in HCl were demonstrated. The target bacteria Escherichia coli (E.coli) and its specific phage (T4) were obtained from bacterial culture collections and propagated. Phages were loaded within the microbeads with a simple method. The phage release characteristics were investigated comparatively and were demonstrated here. High release rates were observed from the gelatin microbeads. It was possible to reduce the phage release rate using sodium alginate in the recipe and chitosan coating. Using these gelatin-based microbeads as phage carrier matrices—especially in lyophilized forms—significantly improved the phage stability even at room temperature. It was concluded that phage release from gelatin hydrogel microbeads could be further controlled by alginate and chitosan modifications and that user-friendly lyophilized phage formulations with a much longer shelf life could be produced.
... These approaches often involve the incorporation of additional polymers as well as low molecular weight compounds and the utilization of cross-linking techniques [9][10][11][12][13]. Cross-linking agents, such as citric acid, glutaric dialdehyde, genipin, and phenolic compounds, are widely utilized to improve the mechanical properties, water-sensitivity, barrier properties, oxygen/water vapor transmission rates, and antimicrobial properties of polymer films [14][15][16]. Cross-linking is a process that involves connecting polymer chains through covalent or non-covalent bonds, resulting in the formation of a three-dimensional network. This network reduces the mobility of the polymer chains and enhances their mechanical and barrier properties, as well as their water resistance. ...
In the context of the growing interest in biopolymer-based materials for various applications, this study aimed to enhance the properties of chitosan (CS, a derivative of chitin) films by incorporating caffeic acid, a polyphenol compound known for its multiple health benefits. The objective was to improve the mechanical parameters of the resulting films, including surface roughness and elasticity. CS was combined with caffeic acid and then underwent a neutralization process. The modified films exhibited potential for use in soft tissue engineering, where increased elasticity and surface roughness are desirable characteristics. The main methods employed to evaluate the structure and properties of the films included mechanical analysis, infrared spectroscopy, scanning electron microscopy, atomic force microscopy, thermogravimetric analysis, contact angle measurement, and swelling behavior. The study’s main findings revealed significant alterations in the mechanical properties and surface morphology of the films. The main conclusions drawn from the study suggest that interactions between caffeic acid and CS hold promise for the development of advanced biomaterials in medicine, tissue engineering, and cosmetic formulations. However, a deeper understanding of these interactions is necessary to optimize the material properties and unlock their full potential.
... Carriers for drug delivery systems can be classified based on various parameters, such as their composition, structure, size, and mechanism of drug release. Some common classifications include liposomes [68,104,143], polymer micelles [63,144,145], microspheres [157][158][159], inorganic nanoparticles [148,160,161], dendrimers [99,142,162], hydrogels [11,12], and others [163][164][165][166][167][168]. ...
... Nanoparticle polymer-based hydrogels are hydrogel materials that incorporate nanoparticles within their polymer network [166][167][168]. These hydrogels combine the properties of both hydrogels and nanoparticles, offering unique characteristics and functionalities. ...
... First, nanoparticles can enhance the mechanical properties of hydrogels, improving their strength, elasticity, and stability [62,124,126]. This is particularly important in applications where robustness is required, such as tissue engineering or drug delivery [153,163,[166][167][168]. Second, the incorporation of nanoparticles can provide additional functionalities to the hydrogel [11,23]. ...
Polymer-based hydrogels are hydrophilic polymer networks with crosslinks widely applied for drug delivery applications because of their ability to hold large amounts of water and biological fluids and control drug release based on their unique physicochemical properties and biocompatibility. Current trends in the development of hydrogel drug delivery systems involve the release of drugs in response to specific triggers such as pH, temperature, or enzymes for targeted drug delivery and to reduce the potential for systemic toxicity. In addition, developing injectable hydrogel formulations that are easily used and sustain drug release during this extended time is a growing interest. Another emerging trend in hydrogel drug delivery is the synthesis of nano hydrogels and other functional substances for improving targeted drug loading and release efficacy. Following these development trends, advanced hydrogels possessing mechanically improved properties, controlled release rates, and biocompatibility is developing as a focus of the field. More complex drug delivery systems such as multi-drug delivery and combination therapies will be developed based on these advancements. In addition, polymer-based hydrogels are gaining increasing attention in personalized medicine because of their ability to be tailored to a specific patient, for example, drug release rates, drug combinations, target-specific drug delivery, improvement of disease treatment effectiveness, and healthcare cost reduction. Overall, hydrogel application is advancing rapidly, towards more efficient and effective drug delivery systems in the future.
... The assembly of ILs into nanoaggregates is also necessary to observe a mucoadhesive effect, producing over twofold increases in the values of the complex viscosity, G , and G of mucin samples. This effect is indicative of an interconnected microstructure between mucin and the assembled ionic liquids [40], indicative of a prolonged ocular residence time of the IL-containing eye drops and, thus, increased bioavailability [19]. ...
The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL–DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.
... The idea is to alkylate the amine groups of chitosan in order to prepare quaternized ammonium derivatives with a permanent positive charge, which results in a greater solubility in the aqueous medium, appearing in a wide range of pH (Liu et al. 2016). Furthermore, in order to study the impact of surface properties on the ocular bioavailability of 5-fluorouracil (5-FU) Fabiano et al. (2019) prepared nanoparticles based on chitosan. The presence of permanent positive charges in these materials increased the contact of the nanoparticles with the ocular surface, while the negative charges slowed the release of 5-FU. ...
Hydroxyethyl cellulose (HEC) is considered one of the most important hydro-soluble cellulose derivatives, thanks to its biocompatibility and biodegradability profile. In this work, a facile synthesis methodology was developed to graft ionic liquids onto the HEC ester. Firstly, a low Tg (glass transition temperature) glassy brominated hydrophobic ester based on HEC was prepared. By regioselective nucleophilic substitution of bromine with imidazole and pyridine derivatives, HEC-ILs (ionic liquids) with a high degree of substitution were elaborated in a second step. The synthesized HEC-ILs were characterized by nuclear magnetic resonance (¹H, ¹³C NMR), elemental analysis (CHNO), Fourier transform infrared spectroscopy-Attenuated total reflection (FTIR-ATR), X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry and scanning electron microscopy. Zeta potential was used to verify the presence of permanent positive charge. Contact angle measurements were exploited to follow the reorganization of the surface of HEC-ILs in contact with water. A theoretical study was carried out to investigate the intra- and intermolecular interactions of polymer chains. The prepared cationic HEC derivatives have attractive properties such as their amphiphilic and glassy character, solubility in water, and a permanent positive charge. Such properties open a wide range of applications in the field of drug delivery and the complexation of anionic molecules.
Graphical Abstract
... The measurements were performed by using the Nano Zetasizer ZS instrument as previously reported [17,18]. The microrheological characterization of MβCD and MβCD-SH was performed using type II porcine gastric mucin. ...
... In general, cyclodextrins do not significantly change the viscosity of mucus control samples [23]; however, cyclodextrin can act as a rheology modifier with respect to the interacting molecule [24]. The effect of thiol moieties is greatly reflected on the increasing values of both complex viscosity (η*) and G" module, indicating a direct interaction between mucin and thiolated cyclodextrin molecules [12,17]. Table 2. Complex viscosity (η*), elastic modulus (G ), viscous modulus (G ) of MβCD and MβCD-SH, with respect to the plain mucin dispersion. ...
Thiolated cyclodextrins are structurally simple mucoadhesive macromolecules, which are able to host drugs and increase their apparent water solubility, as well as interact with the mucus layer prolonging drug residence time on the site of absorption. The aim of this study was to synthesize through green microwave-assisted process a freely soluble thiolated 2-methyl-β-cyclodextrin (MβCD-SH). Its inclusion complex properties with dexamethasone (Dex), a poor water soluble drug, and mucoadhesive characteristics were also determined. The product was deeply characterized through NMR spectroscopy (2D COSY, 2D HSQC, 1D/2D TOCSY, and 1D ROESY), showing a thiolation degree of 67%, a selective thiolation on the C6 residues and a monomeric structure. The association constant of MβCD and MβCD-SH with Dex resulted in 2514.3 ± 32.3 M−1 and 2147.0 ± 69.3 M−1, respectively, indicating that both CDs were able to host the drug. Microrheological analysis of mucin in the presence of MBCD-SH showed an increase of complex viscosity, G′ and G″, due to disulphide bond formation. The cytotoxicity screening on fibroblast BALB/3T3 clone A31 cells indicated an IC50 of 27.7 mg/mL and 30.0 mg/mL, for MβCD and MβCD-SH, respectively. Finally, MβCD-SH was able to self-assemble in water into nanometric structures, both in the presence and absence of the complexed drug.
... Fabiano et al. prepared a thermosensitive ophthalmic gel based on a CS-β-glycerophosphate mixture, containing 5-Fluorouracil either as such, or loaded into CS-hyaluronate nanoparticles, and also evaluated the effect of partially replacing the unmodified CS with quaternized or thiolated derivatives; the best formulations (containing 20% quaternized CS) after instillation in rabbits gave a 3.5 times increase of 0-8h AUC compared to the simple eye drops, but the nanoparticle containing gel showed a prolonged zero-order release during 7 h, in contrast to the rapid peak followed by a slow release given by the gel containing the free drug [209]. In a following paper, the authors studied the impact of using different CS derivatives for preparing the nanoparticles to load into the thermosensitive gel: the best results were obtained with quaternary ammonium-CS conjugate and sulfobutyl-CS, both allowing a zero-order release up to 10 h, with around a 1.5-fold AUC increase compared to the nanoparticles based on unmodified CS [210]. This finding was attributed, in the case of the quaternized derivative, to the increased contact of the positively charged nanoparticles with the negatively charged ocular surface, and in the other case, to a slowed down release of the drug from the negatively charged nanoparticles, both resulting in improved ocular bioavailability [210]. ...
... In a following paper, the authors studied the impact of using different CS derivatives for preparing the nanoparticles to load into the thermosensitive gel: the best results were obtained with quaternary ammonium-CS conjugate and sulfobutyl-CS, both allowing a zero-order release up to 10 h, with around a 1.5-fold AUC increase compared to the nanoparticles based on unmodified CS [210]. This finding was attributed, in the case of the quaternized derivative, to the increased contact of the positively charged nanoparticles with the negatively charged ocular surface, and in the other case, to a slowed down release of the drug from the negatively charged nanoparticles, both resulting in improved ocular bioavailability [210]. ...
Chitosan (CS) is a linear polysaccharide obtained by the deacetylation of chitin, which, after cellulose, is the second biopolymer most abundant in nature, being the primary component of the exoskeleton of crustaceans and insects. Since joining the pharmaceutical field, in the early 1990s, CS attracted great interest, which has constantly increased over the years, due to its several beneficial and favorable features, including large availability, biocompatibility, biodegradability, non-toxicity, simplicity of chemical modifications, mucoadhesion and permeation enhancer power, joined to its capability of forming films, hydrogels and micro- and nanoparticles. Moreover, its cationic character, which renders it unique among biodegradable polymers, is responsible for the ability of CS to strongly interact with different types of molecules and for its intrinsic antimicrobial, anti-inflammatory and hemostatic activities. However, its pH-dependent solubility and susceptibility to ions presence may represent serious drawbacks and require suitable strategies to be overcome. Presently, CS and its derivatives are widely investigated for a great variety of pharmaceutical applications, particularly in drug delivery. Among the alternative routes to overcome the problems related to the classic oral drug administration, the mucosal route is becoming the favorite non-invasive delivery pathway. This review aims to provide an updated overview of the applications of CS and its derivatives in novel formulations intended for different methods of mucosal drug delivery.
... This was further investigated in a later paper to enhance the permeation of 5-fluorouracil to the eye by varying the surface properties of the nanoparticles. The findings suggested that enhanced ocular residence of the drug and slower release is due to the interaction between the opposite charges of the nanoparticles and chitosan derivates (negative and positive respectively) [103]. ...
Ocular diseases have serious implications on patients’ lives, with the majority causing blindness if left untreated. In 2020 it was estimated that 43 million people were blind worldwide which is expected to increase to 61 million by 2050. Due to the eye’s complex structure and defence mechanisms, there has been an ongoing challenge to deliver drugs which can penetrate the eyes’ barrier and reside at the site of action. Recent advances focus on the use of hydrogels, in particular temperature-responsive hydrogels, ‘thermogels’, to improve the properties of current therapies. Formulating a hydrogel-based system has shown to increase the bioavailability and biodegradability, provide a sustained release profile, enhance the drug permeation and residence time, as well as reduce the frequency of applications. This article provides a review of progress made over the past 5 years (2017-2021) using ‘thermogels’ for the treatment of some common or life-threatening ophthalmic conditions.
