Chitosan films and hydrogels of chlorhexidine gluconate for oral mucosal delivery

Topical delivery of antimicrobial agents is the most widely accepted approach aimed at prolonging active drug concentrations in the oral cavity. As most antifungals do not posses inherent ability to bind to the oral mucosa, this is best achieved through improved formulations. Chitosan, a partially deacetylated chitin, which is a biologically safe biopolymer, prolongs the adhesion time of oral gels and drug release from them. Chitosan also inhibits the adhesion of Candida albicans to human buccal cells and has antifungal activity. The antifungal agent, chlorhexidine gluconate (Chx), also reduces C. albicans adhesion to oral mucosal cells. The aim of this study was to design a formulation containing chitosan for local delivery of Chx to the oral cavity. Gels (at 1 or 2% concentration) or film forms of chitosan were prepared containing 0.1 or 0.2% Chx and their in vitro release properties were studied. The antifungal activity of chitosan itself as well as the various formulations containing Chx was also examined. Release of Chx from gels was maintained for 3 h. A prolonged release was observed with film formulations. No lag-time was observed in release of Chx from either gels or films. The highest antifungal activity was obtained with 2% chitosan gel containing 0.1% Chx.     

Design and evaluation of chitosan films for transdermal delivery of glimepiride

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. However, its oral therapy is encountered with bioavailability problems due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glimepiride. Chitosan polymer was utilized in developing transdermal films for glimepiride. Chitosan has film forming ability, bioadhesive and absorption enhancing properties. Aiming at optimizing the drug delivery and circumventing the skin barrier function, inclusion complexation of glimepiride with beta-cyclodextrin (beta-CyD) as well as the use of several conventional penetration enhancers were monitored for augmenting the drug flux. The physical and mechanical properties of the prepared films were investigated using tensile testing, IR spectroscopy and X-ray diffractometry. Release studies revealed adequate release rates from chitosan films. Permeation studies through full thickness rat abdominal skin were conducted. High flux values were obtained from films comprising a combination of the drug with limonene and ethanol as well as from films containing glimepiride-beta-CyD complex. In vivo studies on diabetic rats for selected formulae revealed a marked therapeutic efficacy sustained for about 48 hours. The above-mentioned results shed light on feasibility of utilizing chitosan as an effective, safe transdermal delivery system for glimepiride characterized by increased patient compliance and better control of the disease.     

Development and physical characterization of a periodontal bioadhesive gel of metronidazole

To develop a localized drug delivery system that offers prolonged administration of metronidazole into the periodontal pocket, muccoadhesive gel formulations containing 5% w/w metronidazole were prepared using the bioadhesive polymers: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpirrolidone, and carbopol. Increased concentrations of the polymers decreased the drug release rate and enhanced syringeability, yield value, and adhesiveness but decreased the spreadability. The bioadhesive properties of the gels were affected by pH and Ca 2+ concentration. The gel containing 20% hydroxyethylcellulose, 20% polyvinylpirrolidone, and 1% carbopol exhibited zero-order drug release kinetics and suitable physical properties for drug delivery to the periodontal pocket.     

Development and Physical Characterization of a Periodontal Bioadhesive Gel of Metronidazole

To develop a localized drug delivery system that offers prolonged administration of metronidazole into the periodontal pocket, muccoadhesive gel formulations containing 5% w/w metronidazole were prepared using the bioadhesive polymers: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpirrolidone, and carbopol. Increased concentrations of the polymers decreased the drug release rate and enhanced syringeability, yield value, and adhesiveness but decreased the spreadability. The bioadhesive properties of the gels were affected by pH and Ca 2+ concentration. The gel containing 20% hydroxyethylcellulose, 20% polyvinylpirrolidone, and 1% carbopol exhibited zero-order drug release kinetics and suitable physical properties for drug delivery to the periodontal pocket.     

The Role of Chitosan in Drug Delivery

Chitosan, obtained by deacetylation of chitin, is a natural, hydrophilic, nontoxic, biocompatible, and biodegradable polysaccharide suitable for applications in pharmaceutical technology. Its role in drug delivery systems was examined by considering the chemical and biologic properties of the polymer. Chitosan is a nonbranched homopolymer formed by β-(1,4)-linked glucosamine units; hydroxyls and the amino groups are substrates for chemical modifications aimed at obtaining suitable materials for different purposes. Chitosan is soluble at acidic pH, forming gels; hydrogels are also formed in the presence of negatively charged drugs or polyanions, and represent a sustained drug release form. The bioadhesive nature of chitosan can be attributed to the same type of ionic interactions with mucosal membrane components. Mucoadhesive formulations have been developed for ocular, nasal, buccal, gastrointestinal, and vaginal drug administration. Chitosan is able to promote transmucosal absorption of small polar drugs, including peptides, inducing a transient opening of the tight junctions of the cell membrane. Due to its polymeric nature, chitosan has been widely investigated for a variety of microparticulate pharmaceutical forms. Chitosan is also a candidate for potential applications in the delivery of radiopharmaceuticals, genes and peptides.     

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation,rheological, textural,mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76?±?0.07 and 1.14?±?0.01 (mg/cm²?±?SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (?′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.     

5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Development of mucoadhesive buccal films for the treatment of oral sub-mucous fibrosis: a preliminary study

The objective of the present study was to develop the mucoadhesive buccal film of valdecoxib for the treatment of oral sub mucous fibrosis, a localized buccal disease. Valdecoxib, a novel COX-2 inhibitor has been reported to be used in various osteopathic and rheumatoid conditions as oral therapy. The films were made out of chitosan and HPMC K4M as polymers. Sodium taurocholate was used as a permeation enhancer. All the formulations were examined for film thickness, swelling properties, drug content, weight variation, in vitro release studies, bioadhesive force, tensile strength, diffusion studies using pig mucosa and pharmacokinetic study in healthy male volunteers. Prepared films were thin, flexible, smooth and transparent. Bioadhesive force and tensile strength of the optimized formulation were found to be 75 ± 4 kg m^?1 S^?2 and more than 2.5 kg/3 cm², respectively. The percent drug content was 98.5 ± 1.3%. The in vitro drug release from the selected formulation showed that about 69.34% of the drug payload was released up to 6 hours. The drug permeation through the dialysis sac and pig buccal mucosa was found to be 62.70% and 54.39%, respectively. Pharmacokinetic studies of the buccal mucoadhesive film showed that the drug was released locally at the target site of action, and a very small amount might have absorbed systemically.     

Development and Characterization of Bioadhesive Vaginal Films of Sodium Polystyrene Sulfonate (PSS), a Novel Contraceptive Antimicrobial Agent

No HeadingPurpose. Polystyrene sulfonate (PSS) is a novel noncytotoxic antimicrobial contraceptive agent. A gel formulation of PSS was found safe for vaginal administration in phase I clinical trials. The purpose of the current study was to develop and evaluate novel bioadhesive vaginal film formulations of PSS.Methods. PSS films were prepared by solvent evaporation and optimized for various physical, mechanical, and aesthetic properties. Further, films were evaluated for various biological activities and safety.Results. Vaginal films containing 300 mg PSS per unit have been developed, using generally regarded as safe (GRAS) listed excipients. The films are colorless, transparent, thin, soft, and tough, dissolve rapidly in physiologic fluid to form a smooth, viscous and bioadhesive solution that could be retained in the vagina for prolonged intervals. Sperm function inhibition (hyaluronidase and cervical mucus penetration) and antimicrobial activities against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) by PSS films were found comparable to PSS. Also, films did not inhibit normal vaginal microflora (Lactobacillus) and were noncytotoxic as indicated by negligible sperm immobilization and cytotoxicity to host cell assays.Conclusions. Rapidly dissolving bioadhesive vaginal film formulation of PSS with desired physical, mechanical, aesthetic, and biological properties is a suitable candidate vaginal microbicide for prevention of sexually transmitted disease (STDs) and is ready for toxicological and clinical evaluation.     

Mucoadhesive Films Containing Chitosan‐Coated Nanoparticles: A New Strategy for Buccal Curcumin Release

Mucoadhesive films containing curcumin‐loaded nanoparticles were developed, aiming to prolong the residence time of the dosage form in the oral cavity and to increase drug absorption through the buccal mucosa. Films were prepared by the casting method after incorporation of curcumin‐loaded chitosan‐coated polycaprolactone nanoparticles into plasticized chitosan solutions. Different molar masses of mucoadhesive polysaccharide chitosan and concentrations of plasticizer glycerol were used to optimize the preparation conditions. Films obtained using medium and high molar mass chitosan were found to be homogeneous and flexible. Curcumin‐loaded nanoparticles were uniformly distributed on the film surface, as evidenced by atomic force microscopy and high‐resolution field‐emission gun scanning electron microscopy (FEG‐SEM) images. Analyses of film cross sections using FEG‐SEM demonstrate the presence of nanoparticles inside the films. In addition, films proved to have a good rate of hydration in simulated saliva solution, displaying a maximum swelling of around 80% and in vitro prolonged‐controlled delivery of curcumin. These results indicate that the mucoadhesive films containing nanoparticles offer a promising approach for buccal delivery of curcumin, which may be particularly useful in the treatment of periodontal diseases that require a sustained drug delivery.     

Antibacterial activity of triclosan chitosan coated graft on hernia graft infection model

The use of mesh in hernia repair has become common, because of lower recurrence rate and simple application. Data from the meta-analysis and the multi-central studies support the use of meshes in hernia repair. One of the complications due to the hernia repair with mesh is the infection. The incidence range is between 1 and 10%. Triclosan embedded commercial absorbable suture materials are used to reduce surgical site infection rate. This study was planned on mesh infection model, because of the low incidence rate. The agent isolated from mesh infections was mostly Staphylococcus aureus and thus it was used as the infecting agent in this research. To achieve a better therapeutic efficacy, triclosan was formulated in chitosan gels. Chitosan is an attractive biopolymer because of its biocompatible, biodegradable, bioadhesive properties. Gel formulations using chitosans (low, medium and high molecular weight) were prepared in 1% (v/v) acetic acid solution and in vitro release profiles were evaluated. Gel formulations showed release profile extended up to 7 days and high molecular weight chitosan gel formulation was released higher quantity drug than other formulations. Meshes coated with triclosan loaded chitosan gel were used to reduce bacterial count and to prevent mesh infection in the study. 24 h and simultaneous bacteria inoculation was used to model mesh infection. The rats were observed for 8 days by means of surgical site infection. On the eighth day, the animals were sacrificed and the grafts were removed. Tissue squeezers were used to liberate bacterias from removed grafts. The isolated suspensions were cultured on blood agar plates and colony-forming units were counted overnight. Grafts coated with triclosan loaded chitosan gel presented satisfactory preventive effect against graft infection.     

Chitosan: a potential polymer for colon-specific drug delivery system

INTRODUCTION: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties. AREAS COVERED: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug. EXPERT OPINION: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

Development of an ex vivo retention model simulating bioadhesion in the oral cavity using human saliva and physiologically relevant irrigation media

In recent years, there has been a particular interest in bioadhesive formulations for oromucosal drug delivery as this may promote prolonged local therapy and enhanced systemic effect. Saliva plays a vital role in oromucosal drug absorption by dissolving the drug and presenting it to the mucosal surface. However, the rheological, chemical, and interfacial properties of this complex biological fluid may strongly affect the adhesion of bioadhesive formulations. There is a need for well characterized in vitro models to assess the bioadhesive properties of oral dosage forms for administration in the oral cavity. Thus we aimed at developing an advanced ex vivo buccal retention model, with focus on choosing a physiologically relevant irrigation media closely resembling human saliva. Spray dried chitosan microparticles containing metformin hydrochloride as an example of a small hydrophilic drug, were employed as bioadhesive formulations. Chewing-stimulated human whole saliva was collected and characterized for use in retention studies in comparison with four artificial irrigation media; phosphate buffer, Saliva Orthana^®, porcine gastric mucin base media (PGM3), and xanthan gum based media (XG2). Retention of metformin, applied as spray dried microparticles on porcine buccal mucosa, greatly depended on the characteristics of the irrigation media. When rheology of the irrigation media was examined, changes in retention profiles could be interpreted, as irrigation media containing mucin and xanthan gum possessed a higher viscosity than phosphate buffer, which led to longer retention of the drug due to better hydration of the mucosa and the spray dried microparticles. Metformin retention profiles were comparable when human saliva, Saliva Orthana^®, or PGM3 were used as irrigation media. Moreover, PGM3 displayed physico-chemical properties closest to those of human saliva with regard to pH, protein content and surface tension. Saliva Orthana^® and PGM3 are therefore considered as suitable irrigation media for further retention studies.     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

Recent developments in the use of bioadhesive systems for delivery of drugs to the oral cavity

The delivery of therapeutic agents to, or via, the oral cavity is limited by the efficient removal mechanisms that exist in this area. Bioadhesive formulations have been developed to allow prolonged localized therapy and enhanced systemic delivery. The oral mucosa however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for "biopharmaceutical" products arising from the recent innovations in genomics and proteomics. Bioadhesive polymers are typically hydrophilic macromolecules containing numerous hydrogen-bonding groups. Second-generation bioadhesives include modified or new polymers that allow enhanced adhesion and/or drug delivery, along with site-specific ligands such as lectins. Over the last 20 years, a range of bioadhesive formulations have been developed for the oral cavity, but only comparatively few have found their way onto the market. This review will consider some recent developments in the use of bioadhesive buccal systems, notably the development of new polymers, advanced delivery systems, and the exploitation of the multifunctional properties of some bioadhesives.     

Chitosan and its salts for mucosal and transmucosal delivery

This review considers the application of chitosan and its salts in the delivery of drugs intended to act locally towards diseases of the mucosa itself (mucosal delivery), and to undergo systemic absorption by means of transmucosal routes (transmucosal delivery). Those chitosan properties that are particularly useful in mucosal and transmucosal delivery have been reviewed, such as mucoadhesion, penetration enhancement and peptidase inhibition behaviour. Chitosan bioactive properties have also been considered, such as anti-infective, haemostatic, wound healing and immune-stimulating activity. Chitosan is available with a wide range of molecular mass and deacetylation degree: the influence of these properties on polymer performance and solubility has been taken into account. As solubility in particular can strongly limit the results obtained at pH values close to neutrality, particular attention has been paid to chitosan salts and derivatives with modified solubility. Thanks to the presence of positively charged amino groups of the polymer, a subject of increasing interest is the exploitation of its interaction with acidic molecules having potential synergistic behaviour towards bioactive properties, or even with acidic drugs. The aim of the review is to describe not only some properties of chitosan, but also the way they can be modified by the acidic moiety.     

Stabilizing protein formulations during air-jet nebulization

Whilst some proteins can be effectively administered to the lungs using a nebulizer, others, such as lactate dehydrogenase (LDH) are degraded during air-jet nebulization. In order to deliver LDH by nebulization a protective delivery system or carrier may therefore be appropriate. The aim of this study was to produce and characterize a formulation of LDH, which retains enzyme activity during nebulization. Chitosan, a biocompatible, biodegradable and bioadhesive polysaccharide polymer, was included in the formulations studied as a potential protective agent. Complexes of LDH with chitosan of different molecular weights and concentrations were assessed for size, zeta potential, aerosol droplet size and delivery from a jet nebulizer. The highest molecular weight chitosan had the greatest complex size and a net positive charge of +29.7mV. Jet nebulization resulted in aerosol droplets with median size in the range 2.36-3.52μm. Nebulization of LDH solution resulted in enzyme denaturation and reduced activity. The stability of LDH was greatly improved in formulations with chitosan; with greater than 50% total LDH available in a nebulizer delivered to the lower stage of a two-stage impinger, with up to 62% retained enzyme activity. The nonionic surfactant Tween 80 also improved the stability of LDH to nebulization and had an additive protective effect when included, with chitosan, in formulations. These findings suggest chitosan may be a useful excipient in the preparation of stable protein formulations for jet nebulization.     

Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.     

Periodontal delivery of ipriflavone: new chitosan/PLGA film delivery system for a lipophilic drug

The aim of the present work was to design a film dosage form for sustained delivery of ipriflavone into the periodontal pocket.For this purpose, monolayer composite systems made of ipriflavone loaded poly(D,L-lactide-co-glycolide) (PLGA) micromatrices in a chitosan film form, were obtained by emulsification/casting/evaporation technique. Multilayer films, made of three layers of polymers (chitosan/PLGA/chitosan), were also prepared and compared to monolayer films for their "in vitro" characteristics. Morphology and physico-chemical properties of the different systems were evaluated. The influence of pH, ionic strength and enzymatic activity on film degradation, was also investigated. Significant differences in swelling, degradation and drug release were highlighted, depending on film structure and composition. In vitro experiments demonstrated that the composite micromatricial films represent a suitable dosage form to prolong ipriflavone release for 20 days.