John D. Smart

An in‐vitro investigation of mucosa‐adhesive materials for use in controlled drug delivery

An in‐vitro test system was developed to investigate the adhesiveness of various materials to mucus. The results obtained showed good agreement with the findings of previous in‐vivo evaluations of mucosa‐adhesives. Further investigations found that these materials become adhesive on hydration. Chain length, and the presence of ionizable groups in the molecule, were found to be determinate factors. The physical nature of the gel, and the location at which the mucoadhesive materials hydrated, were of less importance.

Bioadhesion of hydrated chitosans : an in vitro and in vivo study

Abstract The (bio)adhesivity of several chitosan chloride samples was screened in vitro and compared with hydroxypropyl-methylcellulose (HPMC), Carbopol 934P and polycarbophil by a force of detachment method. This revealed differences between samples, but was judged to be insufficient to describe the bioadhesive behaviour of fully hydrated chitosan. Therefore, an ex vivo method was designed, where freshly excised cattle corneas were treated with tritiated chitosan in solution. The contact time, pH, ionic strength and chitosan molecular weight were investigated by means of factorial design, and were shown to have significant effects on the adsorption. In addition, interactions were seen between the parameters. These effects were not seen when chitosan was incubated with polycarbonate membranes instead of corneas. It is concluded that fully hydrated chitosan has a specific bioadhesive activity towards biological surfaces. In the in vivo study, liposomes and chitosan-coated liposomes containing 125I-labelled bovine serum albumin (BSA) as a marker were applied to the eyes of anaesthetised rats and their retention at 10, 30 and 90 min compared. Both formulations showed significantly longer retention than a solution of the free 125I-BSA, but coating the liposomes with chitosan did not significantly improve their retention. It is concluded that the adhesive interaction between chitosan and a biological substrate is dependent on formulation factors as well as the chitosan quality.

AN INVESTIGATION INTO THE ROLE OF WATER MOVEMENT AND MUCUS GEL DEHYDRATION IN MUCOADHESION

Abstract Water transfer between mucoadhesive formulations and mucus gels was investigated. The water up-take by compacts and gels, measured in terms of weight gain, was evaluated at 37 ° C by placing each onto a section of dialysis membrane which was then placed in contact with a sample of porcine gastric mucus. Water transfer occurred for all the dry (and concentrated gel) formulations and was evident after only 1 min, with anionic polymers dehydrating the mucus gel more than the neutral polymer. As the concentration of gels containing Carbopol 934P decreased, so the extent of water uptake decreased, with water being lost from the 4% gels. The effect of dehydration on the physical properties of the mucus gel was evaluated using a modified tensiometer and dynamic oscillatory rheology. The adhesive and cohesive nature of the mucus gel was seen to increase when the water content decreased, which would be predicted to result in the strengthening of the weakest component of a mucoadhesive joint. It was concluded that water movement would be a significant factor in mucoadhesion involving dry and partially hydrated dosage forms, and this may be more important than molecular interpenetration.

An investigation of some factors influencing the in vitro assessment of mucoadhesion

Abstract The ultimate aim of this research is to develop in vitro systems that allow the prediction of in vivo performance of a mucoadhesive drug delivery system. In this novel approach a modified Dia-Stron rheometer was used that was capable of measuring the maximum force required, as well as the total work necessary, to detach a mucoadhesive containing disc from a model mucosal surface. Some of the factors that may affect the in vitro assessment of mucoadhesion were investigated, namely the method of measuring the adhesive strength, the nature of the mucosal surface, and the means of applying stress to the adhesive joint. A mucus gel, rat small intestine and, as a control, the non-adhesive surface of poly(vinyl chloride) tape were used as model mucosal surfaces. Test discs of various mucosa-adhesive materials were left in contact with the model mucosal surface for 2 min in a pH 6.0 isotonic phosphate buffer at 37°C, prior to testing. The model mucosal surface was then pulled away from the test disc at a rate of 2 mm min −1 until adhesive failure occurred. The attempt to apply and measure shear forces met with limited success. The results obtained on application of tensile stresses indicated that both the maximum detachment force and the total work of adhesion provided very similar measures of the relative adhesive strength for each test material. The discs were found to adhere to the control poly(vinyl chloride) tape stronger than rats small intestine, with the weakest adhesion being obtained with the mucus gel. It was concluded that these mucoadhesive materials on hydrating are capable of adhering to a variety of different surfaces and a specific mucus/mucoadhesion interaction is not an important factor.

Factors Influencing Gel‐strengthening at the Mucoadhesive‐mucus Interface

Abstract— Mechanical spectroscopy was used to examine some of the factors that may affect mucus gel strengthening: the effect of adding various concentrations of sodium chloride; mucoadhesive polymer molecular weight and its concentration; and the introduction of anionic, cationic and neutral polymers. A reduction in the storage modulus of the mucus/mucoadhesive mixture was observed with the introduction of sodium chloride. A poly(acrylic acid) with a molecular weight of 750 kDa gave the optimum mucus gel strengthening effect relative to other molecular weights. An anionic polymer was found to strengthen the mucus gel much more than a neutral or cationic polymer. It was proposed that the gel strengthening effect could be due to the formation of hydrogen bonded intermolecular complexes between the mucoadhesive and the mucus molecules. Furthermore, the complex formed is influenced by the ionic strength of the environment, and the molecular weight, nature and concentration of the mucoadhesive. In all cases the changes in the rheological properties of the mixes could be correlated directly to the strength of mucoadhesion reported in previous studies.

An investigation of mucus/polymer rheological synergism using synthesised and characterised poly(acrylic acid)s

A range of poly(acrylic acid)s with different average degrees of polymerisation and cross-linking densities were synthesised using a solution polymerisation process. The rheological characteristics of aqueous dispersions of these materials and those of mixtures with homogenised pigs gastric mucus were investigated using dynamic oscillatory rheology, and compared to the known mucoadhesive Carbopol 934P. From the storage moduli, the rheological synergy and relative rheological synergy were calculated, and the effects of concentration and pH on this considered. Generally, the larger the molecular weight (and degree of cross-linking), the greater the rheological synergy, with Carbopol 934P giving the most pronounced effect. Rheological synergy was seen to be concentration-dependent, and a maximum concentration to produce an optimum effect was evident. Acid pHs were seen to favour synergy, although in marked contrast to previous literature reports, the optimum mucus-polymer interaction was not observed at the half ionised value (pH = pKa) but at pH regimes that were unique to each polymer type. This could be influenced by the structural constrains imposed on potential hydrogen bonded interactions. It was concluded that synthesising poly(acrylic acid)s with better defined physicochemical properties than commercially available polymers will advance the study of the phenomenon of rheological synergy.

A rheological assessment of the nature of interactions between mucoadhesive polymers and a homogenised mucus gel

The ability of mucoadhesive materials to produce a large increase in the resistance to deformation when incorporated into a mucus gel, relative to when the mucus gel and test materials are evaluated separately at the same concentration, has been reported in several previous studies. It has been proposed that this phenomenon, termed rheological synergism, can be used as a measure of the strength of the mucoadhesive interaction. This study investigated the interactions between four putative mucoadhesive polymers (Noveon, Pemulen TR-2, carageenan and sodium carboxymethylcellulose) and a homogenised mucus gel, using dynamic oscillatory rheology. It was shown that, with the exception of sodium carboxymethylcellulose, incorporating a mucoadhesive polymer into a mucus gel produces rheological behaviour indicative of a weakly cross-linked gel network, which suggested a structure containing physical chain entanglements and non-covalent (probably hydrogen) bonds. Optimum gel strengthening occurred in a weakly acidic environment, suggesting an optimum conformation and degree of ionisation of the polymer and mucus molecules. Subsequent work suggested that the macromolecular interactions between polymer and mucus are sensitive to temperature, with the dynamic moduli decreasing with increasing temperature, further indicating bonding of a non-covalent nature. This work provide further evidence that rheological methods can be used as a tool to evaluate the interactions between a mucoadhesive macromolecule and a mucus gel. It also adds to the perception that molecular interpenetration may be an important factor in mucoadhesion by strengthening the mucus in the mucoadhesive/mucosal interfacial layer.

DRUG DELIVERY USING BUCCAL - ADHESIVE SYSTEMS

Abstract The buccal mucosa has been investigated for local drug therapy and the systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass metabolism or are unstable within the rest of the gastrointestinal tract. The mucosa of the oral cavity presents a formidable barrier to drug penetration, and one method of optimising drug delivery is by the use of adhesive dosage forms. Mucosal-adhesive materials are hydrophilic macromolecules containing numerous hydrogen-bond-forming groups. They have been called “wet” adhesives in that they require moisture to become adhesive and this may be supplied by the saliva; the latter may also act as the dissolution medium. Various buccal-adhesive formulations have been investigated with a view to delivering drugs locally or systemically. If the buccal route is to be used for the systemic delivery of large macromolecules, then a penetration enhancer incorporated into an adhesive dosage form may be a possible approach.

An in-vitro method for assessing the duration of mucoadhesion

Abstract A novel in-vitro test system was designed for measuring the duration of adhesion of discs containing various putative mucoadhesive materials to a mucosal surface on application of a constant tensile stress. Rat small intestine was used as the model mucosal surface and all experiments were completed in pH 6.0 isotonic phosphate buffer at 37°C. In all cases adhesive joint failure resulted from a cohesive failure within the hydrating dosage form. As expected, increasing the force applied to the mucoadhesive joint resulted in shortening of the duration of adhesion. A rank order of duration of adhesion for various mucoadhesive materials was obtained, which differed markedly from the rank order of adhesive strength reported in the literature. The neutral polymer hydroxypropylmethyl cellulose, reported to have moderate mucoadhesive properties, showed the longest duration of adhesion when subjected to a constant stress of 0.0846 N. Generally, the greater the reported rate of swelling, the shorter the duration of adhesion. It is suggested that a mucoadhesive dosage form capable of rapidly forming strong interactions with the mucosal surface, but only allowing limited hydration to form a rigid gel, would be the ideal candidate for stable long term mucoadhesion.

A direct-staining method to evaluate the mucoadhesion of polymers from aqueous dispersion.

A novel technique to evaluate polymer adhesion to human buccal cells following exposure to aqueous polymer dispersion, both in vitro and in vivo, is described. Adhering polymer has been visualised by staining with 0.1% (w/v) of either Alcian blue (60 min) or Eosin (10 min) solution, uncomplexed dye being removed by 0.25 M sucrose washings. The extent of polymer adhesion was quantified by measuring the relative staining intensity of control and polymer-treated cells by image analysis. In vitro, Carbopol 974P, polycarbophil (Noveon AA-1) and chitosan (CL 113) were found to adhere to human buccal cells from 0.10% (w/w) aqueous dispersions of these polymers. Following in vivo administration as a mouthwash, these polymers persisted upon the human buccal mucosa for at least 1 h.