We propose to develop novel oral drug delivery systems based on microspheres capable of increased bioadhesion with mucus. The bioadhesive phenomenon has been classically attributed to the use of polymers containing high concentrations of carboxyl groups (believed to form hydrogen bonds with mucus) and the presence of flexible polymer chains (thought to interpenetrate biological structures). We found that hydrophobic bioerodible thermoplastics exhibit very high bioadhesive -properties despite the lack of flexible polymer chains. The strongest example of thermoplastic bioadhesion occurred with polyanhydride copolymers. We believe the mechanism for adhesion is the high density of carboxylic groups exposed during degradation, and that other hydrophobic polymers with high concentrations of surface hydrophilic moieties will exhibit strong bioadhesive measurements. It is our hypothesis that performance of these novel drug delivery systems can be predicted by in vitro measurements of bioadhesive forces using four different methods: everted sac biaossay and measurements from CAHN, EMFT and contact angle studies. The four methods can be utilized to predict the performance of polymer systems in both rats and in larger animals (pigs). The end goal is to overcome the trans-species barrier in order to potentiate our drug delivery systems for use in humans. The significance of the proposed research is that it seeks to apply fundamental findings, derived from basic research into microsphere bioadhesion, to the development of new drug delivery systems and apply this to in vivo experiments in different species. The end goal is to move these novel drug delivery systems from research to clinical applications for treatment of diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047636-06
Application #
6179412
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Lewis, Catherine D
Project Start
1994-05-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$292,501
Indirect Cost
Name
Brown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Thanos, Chris G; Liu, Zhi; Goddard, Moses et al. (2003) Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer. J Pharm Sci 92:1677-89
Thanos, C G; Liu, Z; Reineke, J et al. (2003) Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride. Pharm Res 20:1093-100
Santos, C A; Freedman, B D; Ghosn, S et al. (2003) Evaluation of anhydride oligomers within polymer microsphere blends and their impact on bioadhesion and drug delivery in vitro. Biomaterials 24:3571-83
Santos, C A; Freedman, B D; Leach, K J et al. (1999) Poly(fumaric-co-sebacic anhydride). A degradation study as evaluated by FTIR, DSC, GPC and X-ray diffraction. J Control Release 60:11-22
Santos, C A; Jacob, J S; Hertzog, B A et al. (1999) Correlation of two bioadhesion assays: the everted sac technique and the CAHN microbalance. J Control Release 61:113-22
Chickering 3rd, D E; Harris, W P; Mathiowitz, E (1995) A microtensiometer for the analysis of bioadhesive microspheres. Biomed Instrum Technol 29:501-12