Oral Modified Release Drug Delivery (Part 2)

Drugs with what characteristics are undesirable for sustained-release products?

- Extremes of aqueous solubility

- Poor permeability

- Absorbed by regionally-expressed active or carrier-mediated uptake transporters

- High degree of GI degradation

- Very short or very long half-lives

- Absorption windows

Co

Concentration in oil

Cw

Concentration in water

P

Partition coefficient

What is the equation for permeability?

P = Co/Cw

For what is valacyclovir a substrate?

PEPT1 and PEPT2

For what is zidovudine a substrate?

CNT1

What are the intestinal efflux transporters?

- Pgp

- MRP

- BCRP

- MCT

What are the intestinal uptake transporters?

- PEPT

- OATP & OCT

- ASBT

- CNT

- OCTN

- ENT

What happens to bioavailability when drugs undergo extensive metabolism by intestinal and/or hepatic enzymes?

Lower bioavailability of SR formulations compared to IR formulations

SR performance of drugs transported by what may be difficult to predict?

Efflux transporters

What drugs are difficult to formulate into MR, as large doses would be necessary?

Half-life < 2 hours

What drugs are unnecessary to modify into MR systems?

Half-life > 8 hours

What are the parameters related to stability for SR systems?

- Acid hydrolysis

- Drug metabolizing enzymes

- Bacteria in colon

What is the acceptable dose size limit for an SR system?

Up to 1 g

What conditions reduce absorption of oral MR systems?

- Short bowel syndrome

- Ulcerative colitis

- Crohn's disease

What are the examples of drugs that induce hepatic metabolism?

- Phenytoin

- Barbiturates

What are the examples of drugs that inhibit hepatic metabolism?

- Verapamil

- Diltiazem

What are the examples of drugs that promote GI transit?

- Laxatives

- Metoclopramide

- Metformin

- Orlistat

What are the examples of drugs that slow GI transit?

- Anticholinergics

- Antihistamines

- Opiates

- Iron supplements

Multi-unit system

Dose of drug distributed among several units which can be filled into a capsule or compressed into a tablet

What are the advantages to multi-unit MR systems?

- More predictable gastric emptying and GI transit times

- Tailored drug release

- Less risk of dose dumping/high local drug concentration

- Ease of coating

- Suitable for pediatric/geriatric use

What is the most important counseling point about oral MR systems?

Swallow whole