Long term objectives are to provide colon specific delivery for actives ranging from small molecules to macromolecules. Drug delivery to the colon is critical in the local treatment of Crohn's disease and ulcerative colitis. These unpreventable conditions affect 7 of every 10,000 people. The most effective treatment is oral 5-aminosalicylic acid (5-ASA) and glucocorticosteroids. Therapeutic efforts are hampered because these drugs, and even 5-ASA prodrugs, are absorbed from the small intestine, resulting in systemic concentrations high enough to cause side effects, with lower doses reaching the colon. The proposed studies examine chitosan as its acetate salt in an Aquacoat. coating applied to 5-ASA-containing extruded and spheronized beads to (i) limit drug release under small intestine conditions and (ii) achieve colon delivery of the remainder of the drug content. Chitosan will hydrate but not dissolve in small intestine fluid, a unique feature to this study in comparison to other studies utilizing a polymer in a coated bead. Hydration of chitosan facilitates colon delivery because hydrated chitosan is susceptible to enzyme-catalyzed degradation in the colon, but not in the upper gastrointestinal tract. Ethylcellulose, the polymer and primary component in Aquacoat., has not revealed a sensitivity to degradation by colon enzymes. Preliminary studies indicate that a rugged, smooth coat containing chitosan can be applied using a fluid bed coater to drug-containing beads and that this coat modifies both the drug release lag time and release rate based on chitosan type and the coating level on the beads when drug release is studied in simulated intestinal fluid. The molecular weight and degree of deacetylation determine the type of chitosan and its susceptibility to degradation in the presence of rat cecum and colon enzymes. Rat enzymes were chosen because they should be similar in type and levels to those found in the human colon. The proposed studies explore the effects of chitosan type, its content in the coat, and the level of coat on the beads on bead ruggedness and the drug release profile. The products that exhibit less than 10% release in small intestine fluid in 6 h will be assessed for success in colon specific delivery by measuring drug release in media containing rat cecum and colon enzymes. Those beads assessed will be considered successful if they release the remainder of the drug in less than 12 h in this media that mimics the colon environment. This project lays the foundation for future studies on colon specific delivery of other actives, such as anticancer agents, and therapeutic peptides and proteins. ? Public Health Relevance: Therapeutic efforts in the treatment of Crohn's disease and ulcerative colitis are hampered because glucocorticoids, 5-aminosalicylic acid (5-ASA), and even prodrug versions of 5-ASA are absorbed from the upper gastrointestinal tract, with systemic concentrations high enough that the patient experiences the resultant side effects. Since lowered amounts of drug reach the colon where drug action is desired, a higher dose must be administered to accomplish a therapeutic drug level at the colon. If the goals of this project are achieved, then lower doses can be administered with the therapeutic benefits of more effective treatment and far lower incidences of systemic side effects. ? ? ?
| Omwancha, Wycliffe S; Mallipeddi, Rama; Valle, Brenda L et al. (2013) Chitosan as a pore former in coated beads for colon specific drug delivery of 5-ASA. Int J Pharm 441:343-51 |
