Adhesion bioadhesion

The preparation of a bioadhesive drug delivery system based upon gelatin/polyacrylic acid microspheres loaded with a model drug (oxprenolol hydrochloride) is described. The effects of preparation and formulation variables on the physicochemical properties and pharmaceutical characteristics of the microspheres are examined and the in-vitro adhesion, bioadhesion, drug release and drug bioavailability behaviour of the drug delivery system evaluated. 15 refs. 

A number of the water-soluble polymers also have adhesive properties which are being extensively evaluated for drug delivery (9). These polymers will adhere to the mucous coating in the gastrointestinal tract, the nose, and the mouth to delay passage and sustain drug release. Those polymers with the best adhesive properties are those with hydroxyl and carboxyl groups. Table II lists some of the bioadhesive polymers and their adhesive properties. 

Another approach is that of bioadhesive materials. The principle is to administer a device with adhesive polymers having an affinity for the gastric surface, most probably the mucin coat [12]. Bioadhesives have demonstrated utility in the mouth, eye, and vagina, with a number of commercially available products. To date, use of bioadhesives in oral drug delivery is a theoretical possibility, but no promising leads have been published. 

The adsorption theory states that the bioadhesive bond formed between an adhesive substrate and tissue or mucosae is due to van der Waals interactions, hydrogen bonds, and related forces. Alternatively, when mucus or saliva are interacting with a solid dosage form, the molecules of the liquid are adsorbed on the solid surface. This is an exothermic process. The free energy of adsorption is given by Eq. (1). 

The diffusion theory states that interpenetration and entanglement of polymer chains are additionally responsible for bioadhesion. The intimate contact of the two substrates is essential for diffusion to occur, that is, the driving force for the interdiffusion is the concentration gradient across the interface. The penetration of polymer chains into the mucus network, and vice versa, is dependent on concentration gradients and diffusion coefficients. It is believed that for an effective adhesion bond the interpenetration of the polymer chain should be in the range of 0.2-0.5 pm. It is possible to estimate the penetration depth (/) by Eq. (5),... 

Mikos A., and Peppas, N.A., Bioadhesive analysis of eontrolled-release systems. IV. An experimental method for testing the adhesion of microparticles with mucus, J. Control. Rel, 12 31-37 (1990). 

Chickering, D.E.lll, and Mathiowitz, E., Bioadhesive microspheres. 1. A novel electrobalance-based method to study adhesive interactions between individual microspheres and intestinal mucosa, J. Control. Rel., 34 251-262 (1995). 

Concentration of the polymeric adhesive. In general, the more concentrated the poly-merie adhesive, the lower its bioadhesive strength. The coiled molecules become solvent poor in a concentrated solution which, in turn, reduces the available chain length for interpenetration into the mueus layer. Therefore, a critical concentration of the polymeric adhesive is required for optimum bioadhesion [37]. 

In general, both physical and weak chemical bonds are responsible for mucoadhesion. Physical/mechanical bond formation can be explained as the entanglement of the adhesive polymer and the extended mucin chains. When this diffusion is mutual, it leads to maximum bioadhesive strength. 

Measurement of tensile or shear stress is the most commonly used in vitro method to determine bioadhesion. All in vitro measurements provide a rank order of bioadhesive strength for a series of candidate polymers. Measurement of tensile strength involves quantitating the force required to break the adhesive bond between the test polymer... 

In the preparation of adhesive patches by direct milling on a two-roll mill, the drug and the bioadhesive are homogeneously mixed with or without the aid of a solvent. The polymer/drug mixture may then be compressed to its desired thiekness and patches of appropriate size may be cut or punched out. The polymer/drug mixture prepared with a solvent may require an additional drying step by air or in an oven. 

Recently, a monolayer of human alveolar epithelial cells was used to study the bioadhesive properties of lectins [37]. Lectins are sugar-recognizing adhesive molecules (they bind to epithelial cells) and are thought to increase the bioavailability of larger molecules by triggering vesicular transport processes. 

Namre has evolved many excellent materials, including both organic and polymeric materials such as silks (Oroudjev et al. 2002), adhesion proteins (Law et al. 2003), bioadhesives (Lin et al. 2007 Waite et al. 2005 Zhao et al. 2006), and connective... 

For bioadhesive applications, anionic polymers appear to provide the most effective balance between adhesiveness and toxicity, with carboxylic materials preferred over sulfonic polymers [400]. Polyfacrylic acid) microparticles have been identified as particularly effective bioadhesive materials [402]. Studies with poly(acrylic acid) microparticles have indicated that, while water-swollen particles exhibit good bioadhesion, dry polymer particles give no adhesion at all. In addition, adhesive strength increases as the degree of ionization of the polymer is increased [402]. Thus the expanded nature of the polymer network is important to mucoadhesion, probably via polymer interdiffusion and entanglement with mucin [403],... 

The bioadhesive characteristics of tablets for oral use made from modified starch, poly(acrylic acid), polyethylene glycol) and sodium carboxymethyl cellulose were recently investigated [406]. In this work, the force and energy adhesion were determined in vitro, and maximum adhesion times were evaluated in vivo in humans [406], In the in vitro, studies, the poly(acrylic add) gave the best performance, however in vivo bioadhesion was not strongly correletated with... 

Milled wood lignin was mixed with the crude enzyme solution of Tram-ties versicolor extracellular phenoloxidases produced on spent sulfite liquor in a ratio of approximately 2 1. This comprised the main part of the two-component bio-adhesive. Industrial particles were bonded with 15% bioadhesive under conventional pressing conditions to have 19 mm particle boards (40 x 50 cm) of the properties described in Table IV. The bonding reaction (crosslinking) took place in aqueous solution at room temperature. If conventional pressing technology is applied, the temperature should be elevated in order to maintain water evaporation within a reasonable press time. 

In conclusion, the remarkable influence on DAP activity exerted by the low-viscosity PGA vehicles is an issue deserving further attention, in view of the possible implication of a muco-adhesive mechanism. A closer study of the potential interactive properties of polyuronic acids and of their drug salts with the precorneal mucin might lead to a better understanding of the bioadhesive properties of these and other similar anionic polymeric materials, and of their influence on ocular drug bioavailability. 

Korbonits M, Slawik M, Cullen D, Ross RJ, Stalla G, Schneider H, Reincke M, Bouloux P.M, Grossman AB. A comparison of a novel testosterone bioadhesive buccal system, Striant, with a testosterone adhesive patch in hypogonadal males. J Clin Endocrinol Metab 2004 89 2039-43. 

Buccoadhesive-controlled release tablets for delivery of nifedipine were prepared by direct compression of carboxymethyl cellulose (CMC) with carbomer (CP) and compared to those prepared with PVP, PVA, HPMC, and acacia by a modified tensiometry method in vitro. It was found that the adhesion force was significantly affected by the mixing ratio of CP CMC in the tablets. CMC is necessary for controlling the release rate, whereas CP is important in providing bioadhesion. The tablets containing 15% CMC and 35% CP were found to have optimum drug release rate and bioadhesion [81]. 

The term bioadhesion refers to any bond formed between two biological surfaces or to a bond between a biological and a synthetic surface [44]. In the case of bioadhesive drug delivery systems, the term bioadhesion is typically used to describe the adhesion between polymers, either synthetic... 

Two steps have been described in adhesive bond formation (1) intimate contact of the mucoadhesive agent and of mucus or mucosa consequent to wetting and (2) formation of physical or chemical bonds between the biological substrate and the mucoadhesive agent, preceded, in the case of polymeric materials, by interpenetration and diffusion between the bioadhesive and the mucin glycoprotein. 

The same theories relevant to adhesion, developed to explain and predict the performance of glues, adhesives, and paints, have also been applied to bioadhesive systems [44], These include the electronic, absorption, wetting, diffusion, and fracture theories. 

Polycarbophil-based bioadhesive tablets of metronidazole were tested for adhesion on bovine submaxillary mucin [74]. In a more recent study, metronidazole tablets based on a mixture of modified starch-polyacrylic acid showed an increased potential for the treatment of bacterial vaginosis [75]. 

Various mechanical testing methods have been used to assess the bioadhesive properties of materials and formulations. Review of the literature reveals that the technique most commonly used is the tensile test [82,85]. This test provides the measure of the force needed to detach a layer of the tested material or formulation from a mucosal substrate as a function of the displacement occurring at the bioadhesive interface. Besides maximum force of detachment, another parameter provided by tensile test is the work of adhesion calculated as the area under the force versus displacement curve. Such a parameter gives more complete... 

Another design one could take for retention in the upper GI tract has been bioadhesive microparticles that stick to the mucus or the mucosa in the upper GI tract, particularly in the duodenum and jejunum.19-21 Charged polymers and even antibodies have demonstrated adhesion to the mucosa quite successfully in vitro,22,23 but these bioadhesives have been less successful in vivo owing to two physiological limitations. The turnover of mucus is rapid and limits the duration of adhesion.24 Moreover, approximately 2 percent of even the most bioadhesive microparticles with either specific antibody interactions or nonspecific interactions are retained along the stomach or intestinal wall (unpublished data by the authors). 

Mucus. The cells of internal epithelia throughout the body are surrounded by an intercellular ground substance known as mucus. The principal components of mucus are complexes composed of proteins and carbohydrates. These complexes may be free of association or may be attached to certain regions on cell surfaces. This matrix may play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another.99 Moreover, mucus is believed to play a role in bioadhesion of mucoadhesive drug delivery systems.100... 

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