Evaluating Potential of Pharmaceutical Excipients Used in Formulations of Oral Drugs to Improve Bioavailability of Certain BCS Class III/IV Drugs
Parnali Chatterjee, College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences; Graduate Student: Mohammed M. Alvi
Biopharmaceutical Classification System (BCS) is a system used by the FDA and Pharmaceutical Industry to classify drugs on the basis of their aqueous solubility and intestinal permeability. In vitro studies that demonstrate similar biopharmaceutical properties including aqueous solubility, intestinal permeability and drug dissolution between immediate- release (IR) solid dosage forms can claim biowavers from conducting in vivo Bioequivalence (BE) studies. For BCS class I drugs that are highly soluble and highly permeable, BE studies for different IR solid dosage forms have been biowaived based on supporting data from in-vitro biopharmaceutical studies. BCS class III drugs have high dissolution rates hence high solubility and low permeability whereas class IV drugs exhibit poor solubility as well as low permeability. A major efflux transporter, P-glycoprotein (P-gp), is known for permeability of most of the drug molecules in the human intestinal membrane. Membrane permeability can be altered by the excipients added to the drug formulation; they may show interactions with efflux transporters thereby reducing drug bioavailability. Certain excipients such as Labrasol, Tween-80, PEG have shown to inhibit P-glycoprotein (P-gp) in the gastrointestinal tract (GIT). Investigating the potential of certain formulation excipients: Lauroglycol 90, Labrasol, Transcutol, Peceol, Maisine-35 to inhibit P-gp in the GIT thereby elevating absorption of certain BCS Class III/IV drugs is of major interest to the group. Metformin HCl is a BCS class III drug which is freely soluble in water and most organic solvents, but suffers from poor permeability across the cell membrane.
Specific Aims (1) Determine cytotoxicity of excipients on MDCK-MDR1 cell line and primary human hepatocytes (2) Determine permeability coefficient of the formulation excipients on MDCK-MDR1 and primary hepatocytes, (3) Determine membrane fluidity by using fluorescent dye, rhodamine, with 14-C labeled metformin to predict the interaction of excipients and efflux transporters in affecting permeability of metformin across biological membrane.