Purpose: Nifedipine drug product was first introduced in the mid-1970s for the prevention of angina symptoms and later for the treatment of hypertension. The development of the extended release (ER) formulation aimed to delay and flatten the attainment of the peak plasma concentrations of nifedipine in the pharmacokinetic profiles and result in a smooth, more gradual onset of the antihypertensive effect, which can be sustained throughout 24 hours without discernible cardio acceleration. When passing through the stomach and small intestine, oral dosage forms are normally subjected to physical shear and grinding forces as well as pressure exerted by peristaltic movements. The complex physical forces exerted by the gastrointestinal (GI) tract are not well simulated by USP dissolution methods in a stirred medium. As a result, the in vitro dissolution data based on USP methods may not be correlated to in vivo drug release. Since the delivery rate of nifedipine into the systemic circulation is a direct determinant of the onset rate of the vasodilator effect, there may be potential risks to the patients if the in vitro dissolution testing is not discriminative as a quality control method. The objective of this study focuses on the effect of simulated GI contractions on drug release.
Methods: 60 mg of osmotic pump product A and polymer matrix based product B and C were tested in this study. An in-house system was used for dissolution testing in 350 mL of pH 6.8 buffer with 1% sodium laurel sulfate (SLS) under various mechanical compression forces (0.1, 50, 100, 200 and 400 gram). Both the drug release profile and sample mechanical responses were obtained simultaneously from tests using the in-house system. Dissolution testing was also conducted as a control using USP II apparatus in 37°C 900 mL pH 6.8 buffer with 1% sodium laurel sulfate (SLS) for 24 hours.
Results: Dissolution results from the USP II method showed that Product B and C exhibited faster release than Product A. Product C showed higher variability than the other two products. Product A showed similar dissolution behavior under various levels of applied mechanical compressions. The deformation of Product A tablet resulted in ~ 7.5% decrease in tablet height under 400 gram force compression. Product B and C showed drug release rate increases as the mechanical compression forces were increased. The Product B deformed about 22%, 58% and 84% under 100, 200 and 400 gram force compressions, respectively. The Product C had about 20%, 59% and 78% deformations under 50, 100 and 200 gram force compressions, respectively.
Conclusion: The various mechanical compression forces during dissolution testing could be used to simulate physiological GI contraction. The osmotic pump formulation (Product A) delivered drug substance at a constant rate, largely independent of the mechanical compression applied in this study. The shape and the size of the Product A tablets were almost unchanged compared to the intact tablets after testing in dissolution medium. Compared to the osmotic pump formulation, the mechanical response of the matrix based formulation (Products B and C) deformed significantly under compression. The various levels of simulated GI compressions resulted in different drug release profiles. The mechanical response during dissolution could be used as one of the parameters to assure product quality.