Mucoadhesive Properties Research Articles

Chitosan-Coated SLN: A Potential System for Ocular Delivery of Metronidazole.

Ophthalmic drops for ocular delivery exhibit inadequate residence time, which often requires multiple daily dosing that may result in patient non-adherence. In this study, the development of a once-daily-dosed chitosan-coated metronidazole (MTZ)-loaded solid lipid nanoparticles (SLNs) for ocular delivery was undertaken. Melt emulsification and ultrasonication were used to manufacture MTZ-loaded SLN, which were subsequently coated with chitosan (CS) by mechanical stirring using a 0.1% w/v solution. Gelucire® 48/16 and Transcutol® HP were used as the solid lipid and synthetic solvent, respectively, with Tween® 20 included as a stabilizing agent. The critical quality attributes (CQA) of the optimized CS-coated SLN that was monitored included particle size, polydispersity index, Zeta potential, % entrapment efficiency, % MTZ loading, pH, and osmolarity. The optimized coated nanocarriers were evaluated using laser Doppler anemometry (LDA) and were determined to be stable, with particle sizes in the nanometre range. In vitro mucoadhesion, MTZ release and short-term stability, in addition to the determination of the shape of the optimized CS-coated SLN, were undertaken. The mucoadhesive properties of the optimized CS-coated MTZ-loaded SLN demonstrated increased ocular availability, which may allow dose reduction or longer intervals between doses by improving precorneal retention and ocular availability. Overall, our findings suggest that CS-coated MTZ-loaded SLNs have the potential for clinical application, to enhance ocular delivery through the release of MTZ.

The Impact of Hypromellose on Pharmaceutical Properties of Alginate Microparticles as Novel Drug Carriers for Posaconazole.

Fungal infections are a group of diseases which are challenging to treat because of drug-resistant fungi species, drug toxicity, and often severe patient conditions. Hence, research into new treatments, including new therapeutic substances and novel drug delivery systems, is being performed. Mucoadhesive dosage forms are beneficial to improving drug bioavailability by prolonging the residence time at the site of application. Sodium alginate is a natural polymer with favorable mucoadhesive and gelling properties, although its precipitation in acidic pH significantly disrupts the process of drug release in gastric conditions. Hypromellose is a hydrophilic, semi-synthetic cellulose derivative with mucoadhesive properties, which is widely used as a control release agent in pharmaceutical technology. The aim of this study was to evaluate the impact of hypromellose on alginate microparticles with posaconazole, designed to modify drug release and to improve their mucoadhesive properties for both oral or vaginal application.

Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies

Lisinopril (LIS) is antihypertensive drug, classified as a class III drug with high water solubility and low permeability. To overcome the low permeability, 32 factorial designs aimed to formulate LIS as a sustained-release (LIS-SR) matrix pellet by extrusion/spheronization. Matrix pellets were composed of wet mass containing Avicel® and polymeric matrix polymers (sodium alginate (SA) and chitosan (CS)). Evaluation of the effect of two independent variables, matrix-forming units (SA and CS) on mean line torque, on pellet size, dissolution rate after 6 h, and mucoadhesion strength of the pellets were assessed using Statgraphics software. The tested formulations (F1-F9) showed that mean line torque ranged from 1.583 to 0.461 Nm, with LIS content in the LIS-SR pellets ranged from 87.9 to 103%, sizes varied from 1906 to 1404 µm and high percentages of drug released from pellets formulations (68.48 to 74.18 %), while the mean zeta potential value of mucoadhesive range from −17.5 to –22.9 mV.The selection of optimized formulation must have the following desirability: maximum peak torque, maximum pellets’ particle size, and minimum % LIS release after 6hr. LIS optimized sustained release pellet formula composed of 2,159 % SA and 0.357 % CS was chosen as optimized formula. It’s showed a 1.055 Nm mean line torque was responsible for the increased pellet size to 1830.8 μm with decreased release rate 56.2 % after 6 hr, and −20.33 mV average mucin zeta potential.Ex-vivo mucoadhesion studies revealed that that the optimize formulation, exhibited excellent mucoadhesive properties, after 1 h, about 73% of the pellets were still attached to the mucus membrane. Additionally, ex-vivo permeation determination of LIS from the optimized LIS-SR formulation was found to be significantly higher (1.7-folds) as compared to free LIS.In conclusion: LIS-SR matrix pellets, prepared with an extrusion/spheronization have desirable excellent characteristics in-vitro and ex-vivo sustained-release pellet formulation of LIS-SR was able to sustain the release of LIS for up to 8 h.

Evaluation of the Safety and Gastrointestinal Migration of Guanidinylated Chitosan after Oral Administration to Rats.

Arginine-rich membrane-permeable peptides (APPs) can be delivered to cells by forming complexes with various membrane-impermeable bioactive molecules such as proteins. We recently reported on the preparation of guanidinylated chitosan (GCS) that mimics arginine peptides, using chitosan, a naturally occurring cationic polysaccharide, and confirmed that it enhances protein permeability in an in vitro cell system. However, studies on the in vivo safety of GCS are not available. To address this, we evaluated the in vivo safety of GCS and its translocation into the gastrointestinal tract in rats after a single oral administration of an excessive dose (500 mg/kg) and observed changes in body weight, major organ weights, and organ tissue sections for periods of up to 2 weeks. The results indicated that GCS causes no deleterious effects. The results of an oral administration of rhodamine-labeled chitosan and an evaluation of its migration in the gastrointestinal tract suggested that the disappearance of rhodamine-labeled GCS from the body appeared to be slower than that of the non-dose group and pre-guanidinylated chitosan due to its mucoadhesive properties. In the future, we plan to investigate the use of GCS to improve absorption using Class III and IV drugs, which are poorly water-soluble as well as poorly membrane-permeable.

Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation.

Mucoadhesive nanosized crystalline aggregates (NCs) can be delivered by the gastrointestinal, nasal, or pulmonary route to improve retention at particular sites. Itopride hydrochloride (ITH) was selected as a drug candidate due to its absorption from the upper gastrointestinal tract. For drug localization and target-specific actions, mucoadhesive polymers are essential. The current work aimed to use second-generation mucoadhesive polymers (i.e., thiolated polymers) to enhance mucoadhesive characteristics. An ITH-NC formulation was enhanced using response surface methodology. Concentrations of Tween 80 and Polyvinyl pyrrolidone (PVP K-30) were selected as independent variables that could optimize the formulation to obtain the desired entrapment efficacy and particle size/diameter. It was found that a formulation prepared using Tween 80 at a concentration of 2.55% and PVP K-30 at 2% could accomplish the goals for which an optimized formulation was needed. Either xanthan gum (XG) or thiolated xanthan gum (TXG) was added to the optimized formulation to determine how they affected the mucoadhesive properties of the formulation. Studies demonstrated that there was an initial burst release of ITH from the ITH/NC/XG and ITH/NC/TXG in the early hours and then a steady release for 24 h. As anticipated, the TXG formulation had a better mucin interaction, and this was needed to ensure that the drug was distributed to tissues that produce mucus. Finally, at the measured concentrations, the ITH/NC showed minimal cytotoxicity against lung cells, indicating that it may have potential for additional in vivo research. The enhanced bioavailability and mean residence time of the designed mucoadhesive NC formulations were confirmed by pharmacokinetic studies.

Formulation and In-Vitro/Ex-Vivo Characterization of Pregelled Hybrid Alginate-Chitosan Microparticles for Ocular Delivery of Ketorolac Tromethamine.

Innovative hybrid chitosan-sodium alginate (Ch-Ag) microparticles (MPs) were fabricated using both the ionic gelation method as well as the pre-gelation technique. The hybrid Ch-Ag MPs were studied for size, zeta potential, morphology, mucoadhesion, in-vitro release, corneal permeation, and ocular irritation using lens and corneal epithelial cell lines. The average particle size ranged from 1322 nm to 396 nm. The zeta potential for the prepared formulations showed an increase with increasing Ch concentrations up to a value of >35 mV; the polydispersity index (PDI) of some optimized MPs was around 0.1. Compared to drug-free MPs, ketorolac-loaded Ch-Ag MPs demonstrated a drug proportion-dependent increase in their size. SEM, as well as TEM of KT-loaded MPs, confirmed that the formed particles were quasi-spherical to elliptical in shape. The KT release from the MPs demonstrated a prolonged release profile in comparison to the control KT solution. Further, mucoadhesion studies with porcine mucin revealed that the KT-loaded MPs had effective mucoadhesive properties, and polymeric particles were stable in the presence of mucin. Corneal permeation was studied on bovine eyes, and the results revealed that Ch-based MPs were capable of showing more sustained KT release across the cornea compared with that for the control drug solution. Conclusively, the cytotoxicity assay confirmed that the investigated MPs were non-irritant and could confer protection from direct drug irritation of KT on the ocular surface. The MTT cytotoxicity assay confirmed that KT-loaded MPs showed acceptable and reasonable tolerability with both human lens and corneal epithelial cell lines compared to the control samples.

Evaluation of pilocarpine in situ forming buccal gels as potential formulations for the management of xerostomia

Buccally administrated pilocarpine (PIL) can be a unique formulation approach for the management of xerostomia. In this way the severity of systemically induced side effects can be effectively controlled, while maintaining a high level of therapeutic efficacy. The aim of the present study was to evaluate the sol–gel and mucoadhesive properties of an in situ thermoresponsive hydrogel designed for PIL's buccal administration. For this purpose, poloxamer 407 (P407) and 188 (P188) were used as in situ gel forming agents, while xanthan gum (XG) was added as a mucoadhesion enhancer. Implementation of a Box-Behnken experimental design, combined with multi-linear regression (MLR) fitting, unraveled the role of formulation factors on several critical product attributes (such as gel transition temperature, gelation time, solution viscosity and gel viscosity). Artificial neural networks (ANNs) showed excellent generalizing ability, with verification experiments showing good agreement between the ANN- predicted and the experimentally-obtained results. The optimum sol-gel formulations were sprayable at room/storage temperature, while forming a strong gel at temperatures prevailing in the buccal cavity. In vitro dissolution profiles of all optimum formulations exhibited a sustained release pattern (releasing almost 80% of the total dose in 360 min) characterized by an initial rapid release followed by a steady state plateau. The evaluation of drug release kinetics, by applying different release kinetic models, suggested that the drug release from the in situ gels predominantly follows Fick's law and is primarily diffusion-controlled. The in vitro studies were complemented with ex vivo studies, performed on a freshly excised porcine buccal mucosa, showing good mucoadhesion properties with approximately 27% of the total drug permeating the buccal porcine mucosa, while no damage to the epithelium was observed based on the histological evaluation.

Mucoadhesive 3D printed vaginal ovules to treat endometriosis and fibrotic uterine diseases

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1–3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells’ metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

Propranolol-Loaded Limonene-Based Microemulsion Thermo-Responsive Mucoadhesive Nasal Nanogel: Design, In Vitro Assessment, Ex Vivo Permeation, and Brain Biodistribution.

Propranolol is the first-line drug for managing migraine attacks. D-limonene is a citrus oil known for its neuroprotective mechanism. Thus, the current work aims to design a thermo-responsive intranasal limonene-based microemulsion mucoadhesive nanogel to improve propranolol efficacy. Microemulsion was fabricated using limonene and Gelucire® as the oily phase, Labrasol®, Labrafil®, and deionized water as the aqueous phase, and was characterized regarding its physicochemical features. The microemulsion was loaded in thermo-responsive nanogel and evaluated regarding its physical and chemical properties, in vitro release, and ex vivo permeability through sheep nasal tissues. Its safety profile was assessed via histopathological examination, and its capability to deliver propranolol effectively to rats' brains was examined using brain biodistribution analysis. Limonene-based microemulsion was of 133.7 ± 0.513 nm diametric size with unimodal size distribution and spheroidal shape. The nanogel showed ideal characteristics with good mucoadhesive properties and in vitro controlled release with 1.43-fold enhancement in ex vivo nasal permeability compared with the control gel. Furthermore, it displayed a safe profile as elucidated by the nasal histopathological features. The nanogel was able to improve propranolol brain availability with Cmax 970.3 ± 43.94 ng/g significantly higher than the control group (277.7 ± 29.71 ng/g) and with 382.4 % relative central availability, which confirms its potential for migraine management.

Chitosan coated niosomes for nose-to-brain delivery of clonazepam: Formulation, stability and permeability studies.

Crossing the Blood Brain Barrier constitutes a challenge in drug administration to the brain. In this context, nose-to-brain delivery is explored as an alternative route in the treatment of central nervous system disorders, and nanotechnology constitutes a promising tool for drug delivery to the brain. In this work, we explored niosomes and chitosan-coated niosomes (chitosomes) as possible tools for nose-to-brain delivery of clonazepam. The formulations have been optimised using different chitosan concentrations and different preparation methods as Thin Layer Evaporation-paddle (TLE-P), Evaporation (E), and Solvent Displacement Technique (SDT). The most suitable formulations were loaded with clonazepam (CLZ) and a full physicochemical characterization was performed. Chitosomes presented a size of around 200 nm, PDI < 0.3, a positive surface charge, spherical shape and a CLZ encapsulation above 60%. Chitosomes were stable for 12 weeks under storage conditions at 4ºC, in simulated nasal fluid for 24 h as well as after a lyophilization-sonication process. A CLZ release of 50% was also achieved after 4 h in this media. The mucoadhesive properties of chitosomes were also confirmed, with a 1.5-fold reduction of CLZ toxicity after encapsulation and a 10-fold increase of its permeability.

Hydroxyethyl cellulose functionalised with maleimide groups as a new excipient with enhanced mucoadhesive properties

Hydroxyethylcellulose (HEC) is a non-ionic water-soluble polymer with poor mucoadhesive properties. The mucoadhesive properties of hydroxyethylcellulose can be improved by modifying it through conjugation with molecules containing maleimide groups. Maleimide groups interact with the thiol groups present in cysteine domains in the mucin via Michael addition reaction under physiological conditions to form a strong mucoadhesive bond. This will prolong the residence time of a dosage form containing this modified polymer and drug on mucosal surfaces. In this study HEC was modified by reaction with 4-bromophenyl maleimide in varying molar ratios and the successful synthesis was confirmed using 1H NMR and FTIR spectroscopies. The safety of the newly synthesised polymer derivatives was assessed with in vivo planaria assays and in vitro MTT assay utilising Caco-2 cell line. The synthesized maleimide-functionalised HEC solutions were sprayed onto blank tablets to develop a model dosage form. The physical properties and mucoadhesive behavior of these tablets were evaluated using a tensile test with sheep buccal mucosa. The maleimide-functionalised HEC exhibited superior mucoadhesive properties compared to unmodified HEC.

Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

AimThis study aims to compare the mucus permeating and mucoadhesive properties of three generations of thiolated cyclodextrins (CDs). MethodsFree thiol groups of thiolated γ-CDs (CD-SH) were S-protected with 2-mercaptonicotinic acid (MNA), leading to a second generation of thiolated CDs (CD-SS-MNA) and with 2 kDa polyethylene glycol (PEG) bearing a terminal thiol group leading to a third generation of thiolated CDs (CD-SS-PEG). The structure of these thiolated CDs was confirmed and characterized by FT-IR, 1H NMR and colorimetric assays. Thiolated CDs were evaluated regarding viscosity, mucus diffusion, and mucoadhesion. ResultsThe viscosity of the mixture of CD-SH, CD-SS-MNA, or CD-SS-PEG with mucus increased up to 11-, 16-, and 14.1-fold compared to unmodified CD within 3 hours, respectively. Mucus diffusion increased in the following rank order: unprotected CD-SH < CD-SS-MNA < CD-SS-PEG. The residence time of CD-SH, CD-SS-MNA, and CD-SS-PEG on porcine intestine was up to 9.6-, 12.55-, and 11.2-fold prolonged compared to native CD, respectively. ConclusionAccording to these results, S-protection of thiolated CDs can be a promising approach to improve their mucus permeating and mucoadhesive properties. Statement of significanceThree generations of thiolated cyclodextrins (CDs) with different types of thiol ligands have been synthesized to improve mucus interaction. 1st generation of thiolated CDs was synthesized by converting hydroxyl groups into thiols by reaction with Thiourea. For 2nd generation, free thiol groups were S-protected by reaction with 2-mercaptonicotinic acid (MNA), resulting in high reactive disulfide bonds. For 3rd generation, terminally thiolated short PEG chains (2 kDa) were used for S-protection of thiolated CDs. Mucus penetrating properties were found to be increased as follows: 1st generation < 2nd generation < 3rd generation. Furthermore, mucoadhesive properties were improved in the following rank order: 1st generation < 3rd generation < 2nd generation. This study suggests that the S-protection of thiolated CDs can enhance mucus penetrating and mucoadhesive properties.

Formulation and Evaluation of Oral Mucoadhesive Microspheres of Ofloxacin for Peptic Ulcer Use

A peptic ulcer is a disease that affects the stomach lining caused by Helicobacter pylori. The present research aimed to formulate and evaluate the mucoadhesive microsphere of ofloxacin for the effective and safe treatment of peptic ulcers. The mucoadhesive microspheres were developed using natural polymers like Guar gum, Sodium alginate, and Chitosan using the emulsification cross-linking method. A total of 8 batch formulations were prepared using 23 full factorial designs. The prepared microspheres were evaluated various parameters such as % yield, entrapment efficiency, drug release study, in vitro wash-off test, optimization was done by the design of expert which was further subjected to statistical analysis that was kinetic release mechanism, compatibility studies were performed such as FTIR and DSC. Using factorial design 23 for the maximum possible formulation, the optimized formulation was found to be F5 in terms of better release for a longer time and with better mucoadhesive properties on the use of guar gum, sodium alginate, and chitosan in ratio 1:1:2. Second-order polynomial equations were derived for absorbing responses after the application of ANOVA, after omitting the non-significant (p ≥ 0.05) coefficients. %CDR 56.10 % for an extended period of 8 h, % EE exhibited 86.25±1.16. The sustained release activity of F5 might be due to the adhesion of the polymer to the gastric mucosa for more extended periods of 71 % to 8 h. it is also favoured by the suitable particle size of the optimized formulation. The result indicated that the prepared mucoadhesive microspheres can release the ofloxacin in sustained manner and helps in the management of peptic ulcer. HIGHLIGHTS Ofloxacin loaded mucoadhesive microsphere was prepared for treatment of peptic ulcer The mucoadhesive microspheres were developed using natural polymers A total of 8 batch formulations were prepared using 23 full factorial designs Drug release from the optimized microsphere was 71 % to 8 h The developed microsphere can effectively deliver the drug in stomach part GRAPHICAL ABSTRACT

Thiolated chitosan hydrogel-embedded niosomes: A promising crocin delivery system toward the management of aphthous stomatitis

Aphthous stomatitis is a common inflammatory oral disease with challenging management. Crocin is a natural carotenoid that has shown great anti-inflammatory properties. The aim of this study was to develop thiolated chitosan (TCS)-based hydrogels containing niosomes to serve as a mucoadhesive crocin delivery system for aphthous stomatitis. Crocin-loaded niosomes were prepared and the impact of surfactant type, cholesterol content, and lipid to drug ratio on the characteristics of niosomes was evaluated. TCS was synthesized and the success of thiolation was investigated. The optimum niosomal formulation was loaded into the hydrogel and the hybrid system was characterized regarding the morphology, mucoadhesive properties, viscosity, chemical structure, in vitro drug release, and in vivo efficacy. The optimized niosome formulation showed 77% crocin entrapment, a particle diameter of 59 nm, and a zeta potential of −18 mV. The niosome-containing hydrogel exhibited pseudoplastic rheological behavior, mucoadhesive properties, suitable swelling, and sustained release of crocin. In vivo study revealed that the niosome-containing hydrogel improved ulcer healing and decreased the expression of tumor necrosis factor-alpha (TNF-α) and p53 while increasing the expression of vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA). Collectively, TCS hydrogel-embedded crocin-loaded niosomes is a promising therapeutic option for aphthous stomatitis. Chemical compounds studied in this articleCrocin (PubChem CID: 5281233)Chitosan (PubChem CID: 71853)Thioglycolic acid (PubChem CID: 1133)1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (PubChem CID: 2723939)5,5′-dithiobis (2-nitrobenzoic acid) (PubChem CID: 6254)Cholesterol (PubChem CID: 5997)

Reactive oxygen species-responsive thymine-conjugated chitosan: Synthesis and evaluation as cryogel

Chitosan (CS) is a biodegradable, biocompatible cationic polysaccharide based natural polymer with antibacterial and anti-inflammatory properties. Hydrogels made from CS have found their applications in wound healing, tissue regeneration and drug delivery. Although, mucoadhesive properties are resulted from the polycationic nature of CS, in hydrogel form amines are engaged in interactions with water leading to decrease in mucoadhesive properties. In case of injury, presence of elevated level of reactive oxygen species (ROS) has inspired many drug delivery platforms to conjugate ROS responsive linkers for on demand drug delivery. In this report we have conjugated a reactive oxygen species (ROS) responsive thioketal (Tk) linker and nucleobase thymine (Thy) with CS. Cryogel from this doubly functionalized polymer CS-Thy-Tk was prepared through crosslinking with sodium alginate. Inosine was loaded on the scaffold and studied for its release under oxidative condition. We anticipated that the presence of thymine shall retain the mucoadhesive nature of the CS-Thy-Tk polymer in hydrogel form and when placed at the site of injury, due to the presence of excessive ROS at inflammatory condition, loaded drug shall release due to degradation of the linker. Porous cryogel scaffold was prepared via chemical crosslinking of amine functional group of chitosan with carboxylic acid containing polysaccharide sodium alginate. The cryogel was evaluated for porosity (FE-SEM), rheology, swelling, degradation, mucoadhesive properties and biocompatibility. Resulted scaffold was found to be porous with average pore size of 107 ± 23 μm, biocompatible, hemocompatible and possesses improved mucoadhesive property (mucin binding efficiency of 19.54 %) which was found to be 4 times better as compared to chitosan (4.53 %). The cumulative drug release found to be better in the presence of H2O2 (∼90 %) when compared to that of PBS alone (∼60–70 %). Therefore, the modified CS-Thy-TK polymer may hold potential as interesting scaffold in case of conditions associated with elevated ROS level such as injury and tumor.

Preparation of mucoadhesive methacrylated chitosan nanoparticles for delivery of ciprofloxacin

Mucoadhesive polymers and their nanoparticles have attracted a lot of attention in pharmaceutical applications, especially transmucosal drug delivery (TDD). Mucoadhesive polysaccharide-based nanoparticles, particularly chitosan, and its derivatives, are widely used for TDD owing to their outstanding features such as biocompatibility, mucoadhesive, and absorption-enhancing properties. Herein, this study aimed to design potential mucoadhesive nanoparticles for the delivery of ciprofloxacin based on methacrylated chitosan (MeCHI) using the ionic gelation method in the presence of sodium tripolyphosphate (TPP) and compared them with the unmodified chitosan nanoparticles. In this study, different experimental conditions including the polymer to TPP mass ratios, NaCl, and TPP concentration were changed to achieve unmodified and MeCHI nanoparticles with the smallest particle size and lowest polydispersity index. At 4:1 polymer /TPP mass ratio, both chitosan and MeCHI nanoparticles had the smallest size (133 ± 5 nm and 206 ± 9 nm, respectively). MeCHI nanoparticles were generally larger and slightly more polydisperse than the unmodified chitosan nanoparticles. Ciprofloxacin-loaded MeCHI nanoparticles had the highest encapsulation efficiency (69 ± 13 %) at 4:1 MeCHI /TPP mass ratio and 0.5 mg/mL TPP, but similar encapsulation efficiency to that of their chitosan counterpart at 1 mg/mL TPP. They also provided a more sustained and slower drug release compared to their chitosan counterpart. Additionally, the mucoadhesion (retention) study on sheep abomasum mucosa showed that ciprofloxacin-loaded MeCHI nanoparticles with optimized TPP concentration had better retention than the unmodified chitosan counterpart. The percentage of the remained ciprofloxacin-loaded MeCHI and chitosan nanoparticles on the mucosal surface was 96 % and 88 %, respectively. Therefore, MeCHI nanoparticles have an excellent potential for applications in drug delivery.

Anti-inflammatory IL-8 Regulation via an Advanced Drug Delivery System at the Oral Mucosa.

Oral inflammatory diseases are highly prevalent in the worldwide population. Topical treatment of inflammation is challenging due to dilution effects of saliva and crevicular fluid. Thus, there is a great medical need to develop smart anti-inflammatory drug delivery systems for mucosa treatment. We compared two promising anti-inflammatory dendritic poly(glycerol-caprolactone) sulfate (dPGS-PCL) polymers for their applicability to the oral mucosa. Using an ex vivo porcine tissue model, cell monolayers, and full-thickness 3D oral mucosal organoids, the polymers were evaluated for muco-adhesion, penetration, and anti-inflammatory properties. The biodegradable dPGS-PCL97 polymers adhered to and penetrated the masticatory mucosa within seconds. No effects on metabolic activity and cell proliferation were found. dPGS-PCL97 revealed a significant downregulation of pro-inflammatory cytokines with a clear preference for IL-8 in cell monolayers and mucosal organoids. Thus, dPGS-PCL97 exhibits excellent properties for topical anti-inflammatory therapy, suggesting new therapeutic avenues in the treatment of oral inflammatory diseases.

Chitosan and chito-oligosaccharide: a versatile biopolymer with endless grafting possibilities for multifarious applications.

Chito-oligosaccharides (COS), derived from chitosan (CH), are attracting increasing attention as drug delivery carriers due to their biocompatibility, biodegradability, and mucoadhesive properties. Grafting, the process of chemically modifying CH/COS by adding side chains, has been used to improve their drug delivery performance by enhancing their stability, targeted delivery, and controlled release. In this review, we aim to provide an in-depth study on the recent advances in the grafting of CH/COS for multifarious applications. Moreover, the various strategies and techniques used for grafting, including chemical modification, enzymatic modification, and physical modification, are elaborated. The properties of grafted CH/COS, such as stability, solubility, and biocompatibility, were reported. Additionally, the review detailed the various applications of grafted CH/COS in drug delivery, including the delivery of small drug molecule, proteins, and RNA interference therapeutics. Furthermore, the effectiveness of grafted CH/COS in improving the pharmacokinetics and pharmacodynamics of drugs was included. Finally, the challenges and limitations associated with the use of grafted CH/COS for drug delivery and outline directions for future research are addressed. The insights provided in this review will be valuable for researchers and drug development professionals interested in the application of grafted CH/COS for multifarious applications.

Development of Thermoresponsive Hydrogels with Mucoadhesion Properties Loaded with Metronidazole Gel-Flakes for Improved Bacterial Vaginosis Treatment.

Bacterial vaginosis is an infectious disease that has significantly affected women's health. Metronidazole has been widely used as a drug for treating bacterial vaginosis. Nevertheless, the currently available therapies have been found to be inefficient and inconvenient. Here, we developed the combination approach of gel flake and thermoresponsive hydrogel systems. The gel flakes were prepared using gellan gum and chitosan, showing that the incorporation of metronidazole was able to provide a sustained release pattern for 24 h with an entrapment efficiency of >90%. Moreover, the gel flakes were incorporated into Pluronics-based thermoresponsive hydrogel using the combination of Pluronic F127 and F68. The hydrogels were found to exhibit the desired thermoresponsive properties, showing sol-gel transition at vaginal temperature. Following the addition of sodium alginate as a mucoadhesive agent, the hydrogel was retained in the vaginal tissue for more than 8 h, with more than 5 mg of metronidazole retained in the ex vivo evaluation. Finally, using the bacterial vaginosis infection model in rats, this approach could decrease the viability of Escherichia coli and Staphylococcus aureus with reduction percentages of more than 95% after 3 days of treatment, with the healing ability similar to normal vaginal tissue. In conclusion, this study offers an effective approach for the treatment of bacterial vaginosis.

The role of high molecular weight hyaluronic acid in mucoadhesion on an ocular surface model

Hyaluronic acid (HA) is frequently formulated in eye drops to improve the stability of the tear film by hydration and lubrication. Mucoadhesion is related to the ocular residence time and therefore to the effectiveness of the eye drops. The ocular residence time of the HA formulation is correlated with the ability of HA to create specific strong interactions in the ocular surface with the mucus layer, mainly composed of a mixture of secreted mucins (MUC; gel forming MUC5AC and MUC2) and shed membrane-bound soluble mucins (MUC1, MUC4, and MUC16). Dry eye disease (DED) is a multifactorial pathology of the preocular tear film with possible damage to the ocular surface classified in two types: (1) aqueous-deficient dry eye and (2) evaporative dry eye, caused by a decrease in goblet cell density that reduces MUC expression and/or by meibomian gland dysfunction, that results in a drop in the lipidic fraction of the tear film.In this work, the binding affinity between HA and MUC2 has been evaluated with three complementary approaches because the secreted MUCs play a pivotal role in the viscoelastic properties of the tear film: 1. Rheological analysis, measuring the mucoadhesive index and the complex viscosity in relation to MM (Molecular Mass) and concentration; 2. Fluorescence analysis, using a fluorescent hydrophobic probe, to investigate the conformational change of MUC2 during the interaction with the HA polymer; 3. Surface plasmon resonance analysis, used to measure the affinity between MUC2 (immobilized on the surface of a sensor chip) and the HA polymers that flowed on it at the molecular level.For all these tests, the mucoadhesive performance of the natural HA linearly increases with the MM, whereas cross-linked HA and other emollient and gelling agents (formulated in artificial tears) do not show the same mucoadhesive properties (with the exception of xanthan gum). The mucoadhesive performance of high MM HA has also been confirmed in conditions that simulate the pathological condition of the tear film during DED by decreasing the MUC2 or oleic acid concentration. Physico-chemical analysis of a series of marketed artificial tears confirms the linear correlation between the MM of the HA used in the products and the mucoadhesive index measured on the ocular surface model.