In Vitro Dissolution as a Tool for Formulation Selection: Telmisartan Two-Step IVIVC.

The purpose of this investigation was to develop an exploratory two-step level A IVIVC for three telmisartan oral immediate release formulations, the reference product Micardis, and two generic formulations (X1 and X2). Correlation was validated with a third test formulation, Y1. Experimental solubility and permeability data were obtained to confirm that telmisartan is a class II compound under the Biopharmaceutic Classification System. Bioequivalence (BE) studies plasma profiles were combined using a previously published reference scaling procedure. X2 demonstrated in vivo BE, while X1 and Y1 failed to show BE due to the lower boundary of the 90% confidence interval for Cmax being outside the acceptance limits. Average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed ( fa). Fractions dissolved ( fdiss) were obtained in several conditions in USP II and USP IV apparatus, and later, the results were compared in order to find the most biopredictive model, calculating the f2 similarity factor. The apparatus and conditions showing the same rank order than in vivo data were selected for further refinement of conditions. A Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the different formulations of telmisartan employed the USP IV dissolution apparatus and a dissolution environment with a flow rate of 8 mL/min and a three-step pH change, from 1.2 to 4.5 and 6.8, with a 0.05% of Tween 80. Thus, these conditions gave rise to a biopredictive dissolution test. This new model is able to predict the formulation differences in dissolution that were previously observed in vivo, which could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.

Investigating the Discriminatory Power of BCS-Biowaiver in Vitro Methodology to Detect Bioavailability Differences between Immediate Release Products Containing a Class I Drug.

The purpose of this work is to investigate the discriminatory power of the Biopharmaceutics Classification System (BCS)-biowaiver in vitro methodology, i.e., to investigate if a BCS-biowaiver approach would have detected the Cmax differences observed between two zolpidem tablets and to identify the cause of the in vivo difference. Several dissolution conditions were tested with three zolpidem formulations: the reference (Stilnox), a bioequivalent formulation (BE), and a nonbioequivalent formulation (N-BE). Zolpidem is highly soluble at pH 1.2, 4.5, and 6.8. Its permeability in Caco-2 cells is higher than that of metoprolol and its transport mechanism is passive diffusion. None of the excipients (alone or in combination) showed any effect on permeability. All formulations dissolved more than 85% in 15 min in the paddle apparatus at 50 rpm in all dissolution media. However, at 30 rpm the nonbioequivalent formulation exhibited a slower dissolution rate. A slower gastric emptying rate was also observed in rats for the nonbioequivalent formulation. A slower disintegration and dissolution or a delay in gastric emptying might explain the Cmax infra-bioavailability for a highly permeable drug with short half-life. The BCS-biowaiver approach would have declared bioequivalence, although the in vivo study was not conclusive but detected a 14% mean difference in Cmax that precluded the bioequivalence demonstration. Nonetheless, these findings suggest that a slower dissolution rate is more discriminatory and that rotation speeds higher than 50 rpm should not be used in BCS-biowaivers, even if a coning effect occurs.

Effect of thickener on disintegration, dissolution and permeability of common drug products for elderly patients.

Dysphagia is a very common problem suffered by elderly patients. The use of thickeners during administration in these patients helps to prevent difficulties with swallowing larger solid dosage forms. However, there are several indications when the thickeners may influence disintegration and dissolution processes of solid dosage forms, potentially affecting therapeutic efficacy. In this paper the effects of a commonly used thickener on tablet disintegration, dissolution and subsequent absorption of 6 formulated drugs frequently used in elderly patients (Aspirin, Atenolol, Acenocumarol, Candesartan, Ramipril and Valsartan) in two different administration conditions (intact tablet and crushed tablet) are reported. Disintegration times were determined using a modified disintegration test device. The presence of thickener leads to a pseudoplastic behavior with clearly increased viscosity values. The thickener was also shown to significantly affect the release processes (dissolution and disintegration), but not the permeability of the studied drugs. When tablets are crushed the effect of the thickener on drug dissolution is avoided. Consequently, crushing the tablets would be a recommendation for these drugs if the use of a thickener is necessary in patients with dysphagia.

Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products.

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher Cmax. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f2, results reflected the Cmax rank order.

Assessment of the Regulatory Methods for the Comparison of Highly Variable Dissolution Profiles.

The objective is to compare the performance of dissolution-profile comparison methods when f 2 is inadequate due to high variability. The 90% confidence region of the Mahalanobis distance and the 90% bootstrap confidence interval (CI) of the f 2 similarity factor (f 2-bootstrap) were explored. A modification of the Mahalanobis distance (new D-Mahalanobis) in which those points >85% were not taken into account for calculation was also used. A population kinetic approach in NONMEM was used to simulate dissolution profiles with the first-order or Weibull kinetic models. The scenarios were designed to have clearly similar, clearly non-similar or borderline situations. Four different conditions of variability were established: high (CV = 20%) and low variability (CV = 5%) for inter-tablet (IIV) and inter-batch variability (IBV) associated to the dissolution parameters (k d or MDT) using an exponential model. Forty-four (44) scenarios were simulated, considering different combinations of IIV, IBV and typical dissolution parameters. The dissolution profiles simulated using a first-order model modified the profile slope. The Weibull model allows profiles with different shapes and asymptotes and crossing each other. The results show that the f 2-bootstrap is the most adequate method in cases of high variability. The method based on the 90% confidence region of the Mahalanobis distance (D-Mahalanobis) is not able to detect large differences that can be detected simply with f 2 (i.e. low specificity and positive predictive value due to false positives). The new D-Mahalanobis exhibits superior sensitivity to detect differences (i.e. specificity as a diagnostic test), but it is not as good as the f 2-bootstrap method.

Drug gastrointestinal absorption in rat: Strain and gender differences.

Predictive animal models of intestinal drug absorption are essential tools in drug development to identify compounds with promising biopharmaceutical properties. In situ perfusion absorption studies are routinely used in the preclinical setting to screen drug candidates. The objective of this work is to explore the differences in magnitude and variability on intestinal absorption associated with rat strain and gender. Metoprolol and Verapamil absorption rate coefficients were determined using the in situ closed loop perfusion model in four strains of rats and in both genders. Strains used were Sprague-Dawley, Wistar-Han, Wistar-Unilever, Long-Evans and CD∗IGS. In the case of Metoprolol only CD∗IGS and Wistar Unilever showed differences between males and females. For Verapamil, Wistar Han and Sprague-Dawley strains do not show differences between male and female rats. That means that in these strains permeability data from male and female could be combined. In male rats, which are commonly used for permeability estimation, there were differences for Metoprolol permeability between Sprague-Dawley (with lower permeability values) and the other strains, while for Verapamil Sprague-Dawley and Wistar-Han showed the lower permeability values. In conclusion, the selection of rat's strain and gender for intestinal absorption experiments is a relevant element during study design and data from different strains may not be always comparable.