Investigation of a novel method for measuring the hydrogel strength of controlled release tablets and the effect of this strength on in vitro/in vivo correlation.

摘要

Controlled release (CR) hydrogel tablets containing polymers hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo® lactose, to produce tablets with polymer content of 8%, 15%, and 30% w/w.; A novel method for measuring gel strength (Γ) of these tablets was developed by fixing the tablet to a glass plate, placing it in a dissolution apparatus, and subjecting it to dissolution conditions corresponding to 50% drug release. Γ was measured by shearing the external gelled layer of the tablet by a cone/plate rheometer. Γ is defined as the minimum energy increase/unit volume needed to cause shear failure of the tablet gel layer.; Results show significant differences (p ≤ 0.05) in Γ among tablets containing different polymers and in different dissolution media (DI H ₂O, 0.1 N HCl, pH 6.8 phosphate buffer). Γ values were in rank order Γ_{HPMC K100MP} > Γ_{HPC HXF} > Γ _{Carbomer 971P} (same % w/w) with Γ values at 30% w/w polymer in DI H₂O water of 6600, 4600, & 1600 ergs/cm3, respectively, even though all tablets demonstrated close and slow dissolution profiles.; In vivo testing of 30% w/w polymer formulations having different Γ from different polymers was performed. Drug profiles in plasma for 30% HPMC K100MP tablets were consistent with in vitro dissolution profiles and Γ values, while plasma profiles for the 30% carbomer 971P formulation showed higher peak drug concentrations (compared to HPMC or HPC) in vivo in all dogs, not consistent with slow drug release dissolution profiles but consistent with its low in vitro Γ values. Γ_{HPMC K100MP} was the largest and had the lowest prediction error (PE) for level A in vitro/in vivo correlation.; A pharmacokinetic equation to predict in vivo drug profiles for CR dosage forms having square root of time drug release kinetics was derived: Cp=p ks2kee ketVderfi &parl0;ket-tl &parr0;˙eketl ;&parl0;t≤tmax&parr0; Cp=Cpmaxe -ket;&parl0;ttmax&parr0; ; Results comparing predicted and observed plasma profiles, using the derived equation, showed a better fit than equations that assume first or zero order drug release. This equation can serve as a valuable aid in design of formulations to yield a desired plasma profile in vivo and provides support to interpreting the mechanism of drug release in vivo.