Formulation Dependent Pharmacokinetics–Does the Dosage Form Matter for Nifedipine?

Abstract

This was an open-label, randomized, 3-way crossover study that compared in 25 healthy male subjects, the pharmacokinetics of a single 60-mg dose of nifedipine GITS tablet versus (1) 20-mg doses of nifedipine prolonged action tablets given q12h for a total of two doses and (2) 2 x 10 mg doses of nifedipine capsules given q8h for a total of three doses. Following capsule administration, there was a rapid rise in plasma concentration of drug achieving a peak concentration of 196(35) ng/mL (mean and coefficient of variation) within 0.7 (105) hours and an AUC(infinity) of 973(39) ng.hr/mL. After nifedipine PA there was also a rapid rise in plasma concentration of drug achieving a Cmax of 85.5 (36) ng/mL with a tmax of 1.7(58) hours and an AUC(infinity) of 879(46) ng.hr/mL. For the nifedipine GITS formulation, there was a lag in the plasma concentration time profile for approximately 2 to 3 hours, then it rose gradually achieving a Cmax of of 686(54) 30.5(63) ng/mL with a tmax of 15.0(50) hours and an AUC(infinity) ng.hr/mL. The AUC(infinity) and Cmax were significantly (P = 0.0001) greater in the capsule and PA formulations than for the GITS; however, the tmax for the GITS formulation was significantly (P = 0.001) longer than for the other formulations. This study suggests marked formulation-dependent pharmacokinetics, which may have important clinical implications.

Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form

“…Nifedipine reference standard (batch number 516A051), sucrose octaacetate (C 28 H 38 O 19 ), pepsin (USP grade), and pancreatin (USP grade) were supplied by Sigma Aldrich (Steinheim, Germany). High-purity water used in analytical procedures was obtained from a Millipore Milli-Q plus ultrapure water system (Bedford, MA, USA).…”

“…Wonneman et al have postulated that the observed differences between these two products may have direct therapeutic relevance when substituting a given formulation by the other one (30). This should be particularly taken into consideration if administration conditions are changed in conjunction to the formulation (e.g., fasted to fed-state administration) since the pharmacological and therapeutic actions are closely associated to the drug plasma levels (19,30).…”

“…Commercially available formulations, e.g., polymer matrix systems with erosion-driven drug release or oral osmotic systems (OROS) with osmotically controlled drug delivery, involve various mechanisms to obtain appropriate drug dissolution. Besides indisputable advantages of such formulations, there are also some drawbacks with regards to high costs and complexity of the systems, limited usefulness for application with poorly soluble APIs, or risk of toxicity increase due to dose dumping (e.g., in the case of coating perforation (15,19,20)). For these reasons, there is still need to contemplate novel strategies for controlled delivery of poorly soluble drugs.…”

“…Nifedipine (NIF) is a widely used calcium channel blocker, whose efficiency and tolerability have been confirmed in a number of studies (19)(20)(21). Both forms of NIF, crystalline and amorphous, are available and the latter one shows significantly improved solubility kinetics and saturation solubility, but it is physically unstable.…”

“…It has been demonstrated that a rapid increase of nifedipine plasma concentrations results in an increased occurrence of undesirable effects, e.g., hearing problems (20,21). Consequently, it has become evident that improvement of efficiency and safety of the cardiovascular diseases treatment with nifedipine is required (19).…”