Sevda Şenel

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.

Drug permeation enhancement via buccal route: possibilities and limitations.

Over the last decade, there has been a particular interest in delivering drugs, especially peptides and proteins via the buccal route. It provides direct entry into the systemic circulation thus avoiding the hepatic first-pass effect and degradation in the gastrointestinal tract, ease of administration, and the ability to terminate delivery when required. However membrane permeation can be a limiting factor for many drugs administered via the buccal route, and the epithelium that lines the oral mucosa is a very effective barrier to the absorption of drugs. In order to deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue must be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators, cyclodextrins and chitosan. Among these chemicals used for the drug permeation enhancement, bile salts are most common. The first part of this paper focuses on work related to the elucidation of mechanisms of action of bile salts in buccal permeation enhancement of various drugs and mucosal irritation. In the second part, results showing the enhancing effect of chitosan on buccal permeation of hydrocortisone, a commonly used topical oral anti-inflammatory agent, and transforming growth factor beta (TGF-beta), which is a bioactive peptide to which the oral mucosa is relatively impermeable is presented.

Enhancing effect of chitosan on peptide drug delivery across buccal mucosa

The buccal mucosa represents a potentially important topical route for delivery of peptide or protein drugs with some unique advantages such as the avoidance of hepatic first-pass metabolism and the acidity and protease activity encountered in the gastrointestinal tract. However, the bioavailabilities or relative potencies of intraorally administered peptides are usually quite low, unless permeabilizers are employed. Chitosan, a mucopolysaccharide of marine origin, has been claimed to act both as a bioadhesive and permeabilizer, making it a candidate system for mucosal drug delivery. In this study, the enhancement effect of chitosan in gel form for oral mucosa was investigated with a large bioactive peptide, transforming growth factor-beta (TGF-beta). Chitosan gel was prepared at 2% concentration in dilute lactic acid and TGF-beta was incorporated into the gel. The effect of chitosan as a permeabilizer was determined by measuring the flux of TGF-beta across porcine oral mucosa in an in vitro system. The localization of TGF-beta within the oral mucosa was determined by horizontal sectioning and counting. Chitosan was found to exert a marked permeabilizing effect on buccal mucosa for peptide drug.

Chitosan-based systems for the delivery of vaccine antigens.

This review discusses the current status of chitosan and its derivatives as adjuvants and delivery systems in vaccine delivery, and their future possibilities and challenges. After a brief introduction to adjuvants and delivery systems, chitosan will be described in detail in regard to vaccine formulation. Applications of chitosan and its derivatives will be reviewed and their proposed mechanisms in the enhancement of immune responses will be discussed.

Recent developments in buccal and sublingual delivery systems

Introduction: There have been several advances in the delivery of drugs through the buccal mucosa over the last 5 years, which have resulted in a number of new buccal delivery products appearing on the market. Areas covered: This review discusses the most recent developments in the area of buccal and sublingual drug delivery, with a focus on marketed drugs. Likely future directions are also considered and reported. Expert opinion: The future potential of buccal and sublingual delivery systems looks favorable. It is envisaged that in the future, buccal and sublingual delivery technologies will provide a platform for the successful delivery of vaccines and antigens. It is also foreseen that physical means of enhancing drug uptake (e.g., sonophoresis, iontophoresis and electroporation) will be commercialized for buccal delivery, thereby expanding the current drug candidate list for this area. The formulation of delivery systems for photosensitizers in photodynamic therapy is a potential emerging area, while buccal and sublingual delivery, in general, is attractive for the development of intellectual property.

Enhancement of transbuccal permeation of morphine sulfate by sodium glycodeoxycholate in vitro

Abstract In this study, enhancement of transbuccal permeation of morphine sulfate was studied in the presence of sodium glycodeoxycholate (GDC). The permeability of the bovine buccal mucosa to morphine sulfate was determined in vitro in the absence and presence of GDC at 10 mM and 100 mM concentrations. Light and electron microscopy studies were performed to determine the histological and ultrastructural changes resulting from transepithelial permeation enhancement. In addition, infrared spectroscopy (IR) was used to investigate the interaction of GDC with the epithelial lipids of bovine buccal mucosa. The permeation of morphine sulfate across the bovine buccal epithelium was enhanced in the presence of 100 mM GDC by a factor of five whereas at lower concentrations, no significant enhancement was obtained. After 4 h treatment with 100 mM (5% w/v) GDC, significant changes were observed in the epithelium at histological and ultrastructural levels which can be defined as formation of vacuoles, swelling of the cells and a possible increase in intercellular space. Furthermore, by means of IR spectroscopy, it was possible to show the effect of GDC on bovine buccal epithelial lipid domains which was in good correlation with the permeation results. In the light of the results obtained by permeation, histological and IR spectroscopy studies, it is concluded that GDC at 100 mM concentration significantly enhances the permeation of MS across the buccal epithelium and the mechanism of this action appears to involve an interaction with the epithelial lipids.

Clinical and radiographic evaluations of chitosan gel in periodontal intraosseous defects: A pilot study

Periodontitis is a chronic infection in the supportive tissue of the teeth which eventually leads to tooth loss. Various grafting materials and barrier membranes have been used to repair periodontal intraosseous lesions. Chitosan is a derivative of chitin, a natural biopolymer, which is biologically safe, biodegradable, and nontoxic and has been applied in a variety of forms in dentistry. It also exerts bioactive properties such as wound healing, antimicrobial, tissue regeneration, and hemostatic activities. The aim of this study was to evaluate effects of chitosan on periodontal regeneration. Twenty chronic periodontitis patients were recruited. Following initial therapy, the patients were divided into four groups: group A, receiving chitosan gel (1% w/v); group B, receiving chitosan gel + demineralize bone matrix; group C: receiving chitosan gel + collagenous membrane; and group D, receiving flap only (control group). Clinical and radiographic measurements were recorded at baseline, day 90 (3rd month), and day 180 (6th month) after surgery. For clinical data, no significant differences were obtained among the treatment groups. However, radiographic data revealed that except control group, all the other groups showed statistically significant bone fills when compared with baseline indicating that chitosan gel alone or its combination with demineralize bone matrix/collagenous membrane is promising for periodontal regeneration.

In vitro studies on enhancing effect of sodium glycocholate on transbuccal permeation of morphine hydrochloride

During the perioperative period, gastric emptying rate and first-pass metabolism limit the use of peroral morphine. Buccal mucosa appears to be a potential site for delivery of morphine as it provides direct entry into the system circulation thereby avoiding the hepatic first-pass effect. However, the low permeability of the buccal epithelium results in a low flux of the drug. The use of a penetration enhancer is required to improve the bioavailability of the drug via buccal route. In this study, the enhancing effect of sodium glycocholate (GC) used at 10 mM and 100 mM concentrations on permeation of morphine hydrochloride (MPH) across the porcine buccal mucosa was studied in vitro. Furthermore, in conjunction with its permeation, accumulation of GC in the tissue with time was also studied in order to elucidate the relationship between GC and enhanced mucosal permeation of the drug. Franz diffusion cells were used in the experiments. Permeation of MPH was increased in the presence of 100 mM GC with an enhancement factor of 9.3 whereas no enhancement was obtained with 10 mM GC. The calculated permeability coefficient for MPH in the presence of 100 mM GC was 2.35 x 10(-5) cm/s. Accumulation of GC at 100 mM in the tissue appears to be more significant at 100 mM concentration which correlated well with the increased permeation of the drug. GC was diffused through the buccal epithelium significantly at 100 mM concentration. Interaction of GC with the tissue appears to be more significant at 100 mM concentration compared to 10 mM concentration, thus resulting in a significant enhancing effect.

Chitosan based delivery systems for mucosal immunization against bovine herpesvirus 1 (BHV-1)

Bovine herpesvirus 1 (BHV-1), is a major pathogen of cattle which causes serious infections, including infectious bovine rhinotracheitis (IBR)/infectious pustular vulvovaginitis (IPV). At present, BHV-1 is still a serious threat to animal health and productivity in Turkey, hence to develop a more efficient and economical vaccine system against BHV-1 is certainly an important necessity. A mucosal vaccination strategy would provide both mucosal and systemic immune responses to protect disease progression and transmission. However, vaccination through mucosal membranes requires adjuvants/delivery systems in order to enhance the immunogenicity of the antigens. Chitosan, which is a biodegradable, biocompatible and bioadhesive natural polysaccharide, has been shown to be promising both as a delivery system and an adjuvant for mucosal vaccination. In this study, microparticles with appropriate size (<10μm), positive surface charge and high loading efficiency (∼95%) were prepared for mucosal delivery of BHV-1, using various types of chitosan with different molecular weight and solubility. Particles were shown to be taken up by the cells, mostly around the nucleus, whereas with aggregates which were bigger in size were adsorbed at the surface. Furthermore, gel formulations with a suitable viscosity which would provide easy application and remain on the mucosa for extended period of time were also developed with a high zeta potential indicating a stable system. Both the BHV-1 loaded microparticle and gel formulations were shown to maintain cell viability and antigen integrity. Chitosan-based formulations are suggested as promising adjuvant/delivery systems for mucosal immunization against BHV-1.

Histological and bioadhesion studies on buccal bioadhesive tablets containing a penetration enhancer sodium glycodeoxycholate

Abstract For many drugs, buccal route offers many advantages over conventional routes of delivery with an improved bioavailability due to the avoidance of degradation in the gastrointestinal tract and hepatic first-pass metabolism. However, the major limitation to buccal drug delivery is the permeability barrier in the buccal mucosa. Use of penetration enhancers appears to be a pertinent approach to increase the drug permeation through the buccal epithelium. Buccal bioadhesive tablet formulations enable a delivery with a plasma drug level of the desired therapeutic response for a defined period of time, and also provides a means of confining the drug and penetration enhancer to a defined region of the mucosa. In this study, a bioadhesive tablet formulation for buccal delivery was designed using a mixture of hydroxypropyl methylcellulose and carbomer, incorporated with a penetration enhancer, sodium glycodeoxycholate (GDC). In vitro bioadhesion property of the formulated tablet was examined and histological study was carried out to examine an in vivo interaction between the tablet and tissue. GDC did not affect the adhesiveness of the tablet which makes it an acceptable excipient for a buccal bioadhesive drug delivery system. Histological changes such as loss of upper cell layers and formation of vacuoles as well swelling in the cells were observed in the buccal epithelium, after 4 h contact with the tablets containing GDC. Studies on reversibility of the interaction are in progress.