1 Abu Alam Ph.D. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology July 23, 2008

2 Locally Acting Oral Drugs For the Treatment of Gastrointestinal Conditions

3 Drug Substance Purity Impurity Molecular Size Solubility (pH 1 to 8) Permeability Degradation Analytical Method Specification Stability

4 Dosage Form Formulation Excipients Manufacturing process Dosage form design Tablet Capsule Specifications Stability

5 Schematic of GI Transit Oral Dosage Stomach pH 1.2 Duodenum pH 4.5 Elimination Feces Colon pH 7.5 Jejunum pH 6.8

6 Dissolution Illustrations USP Method I or II pH 1.2 (Sodium Chloride)

7 Dissolution Illustrations USP Method I or II pH 4.5 (Acetate Buffer)

8 Dissolution Illustrations USP Method I or II pH 6.8 (Phosphate Buffer)

9 Schematic of Disposition Oral Dosage Dissolution GI Tract Local Action GI Tract Elimination Feces Systemic Absorption Elimination Systemic Toxicity

10 Criteria Not specifically absorbed Local action Dissolution is pH independent Freely available at site of action No permeation Vancomycin capsule fits the criteria

11 Conclusion Comparative, superimposable dissolution profile Rate and extent of dissolution are same In Vivo bioequivalency is unnecessary Clinical trial to prove safety and efficacy are unnecessary