Donald E. Chickering

Bioadhesive microspheres: I. A novel electrobalance-based method to study adhesive interactions between individual microspheres and intestinal mucosa

Abstract A simple electrobalance-based method has been developed to measure bioadhesive interactions between individual polymer microspheres and biological tissues. Environmental conditions, such as temperature and pH, are easily controlled to mimic physiological parameters. The technique is unique in that it allows the measurement of many parameters: compressive deformation, peak compressive load, yield point, peak tensile load, deformation to peak load, fracture strength, deformation to failure, compressive work, returned work, and tensile work in a single experiment. The method has been shown to be statistically reproducible and accurate. Using this technique, several hydrophobic, thermoplastic polymers and one hydrogel were studied. Co-polymers of fumaric and sebacic acid, of the polyanhydride family, produced bioadhesive fracture strengths greater than 50 mN/cm 2 with rat small intestinal mucosa, in vitro. We suggest that bioadhesion in these hard, bioerodible materials is not due to chain entanglement, as required by the diffusion theory of bioadhesion, but due to numerous hydrogen bonds generated between hydrophilic functional groups (-COOH) and mucus glycoproteins.

Bioadhesive microspheres : III. An in vivo transit and bioavailability study of drug-loaded alginate and poly(fumaric-co-sebacic anhydride) microspheres

Bioadhesive drug delivery systems (BDDSs) could improve bioavailability by protecting bioactive molecules from physical and chemical degradation, enhancing absorption rates by minimizing diffusion barriers, and increasing the period for absorption by prolonging residence time. The in vivo bioadhesive performance of calcium alginate microspheres and poly(fumaric-co-sebacic anhydride) 20:80 microspheres were evaluated in two ways. Firstly, effect on GI transit was measured in rats. P(FA:SA) 20:80 microspheres showed significantly prolonged retention in the gut when compared to alginate microspheres. Secondly, the ability of these polymers to improve relative bioavailability of a model drug, dicumarol, in rats was assayed. A significant increase was measured in the area under the plasma concentration-time curve for dicumarol encapsulated in P(FA:SA) 20:80 when compared to its controls. The results of this study suggest that polymers which have been shown to produce strong bioadhesive forces in vitro and delayed GI transit in vivo may be used to improve oral bioavailability of certain drugs.

Poly(fumaric-co-sebacic) microspheres as oral drug delivery systems.

The current study focuses on the development of bioadhesive oral delivery systems based on bioerodible polyanhydrides. The polymers were studied and characterized using a novel tensiometer based on a very sensitive electrobalance. The system was designed to mimic in vivo interactions, thus all experiments were conducted with freshly excised tissue immersed in physiological saline at 37 degrees C. Poly(fumaric-co-sebacic) [P(FA:SA)] was found to be the most bioadhesive polymer from a series of different thermoplastic materials evaluated. Correlation with in vivo performance was investigated by determining gastrointestinal (GI) residence time of barium-loaded microspheres. Residence times of 24 to 36 h provided a strong indication that these microspheres were good candidates for bioadhesive drug delivery systems. To evaluate the effect of these materials on bioavailability, the anticoagulant drug, dicumarol, was encapsulated. Systemic blood levels demonstrated increased bioavailability for the encapsulated dicumarol formulation as compared with unencapsulated drug. (c) 1996 John Wiley & Sons, Inc.

Bioadhesive microspheres, II. Characterization and evaluation of bioadhesion involving hard, bioerodible polymers and soft tissue

Abstract Several bioerodible polymers and one hydrogel were studied as potential bioadhesive materials. A microbalance-based method was used to measure bioadhesive interactions between individual polymer microspheres and rat intestinal tissue. In addition, surface and bulk properties of these microspheres were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and contact angle measurements. Polyanhydride microspheres composed of copolymers of fumaric and sebacic acid, produced bioadhesive fracture strengths greater than 50 mN/cm2 with rat small intestinal mucosa in vitro. We suggest that bioadhesion in these bioerodible materials is not attributable to chain entanglement, but instead to hydrogen bonding between hydrophilic functional groups (COOH) and mucus glycoproteins. We also believe that continuous degradation of these materials may enhance their bioadhesive properties by changing surface energy, and increasing both carboxylic acid concentration and surface roughness.