Evaluation of a Three Compartment In Vitro Gastrointestinal Simulator Dissolution Apparatus to Predict In Vivo Dissolution

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109359/1/jps24112.pd

In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113173/1/jps24460.pd

The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: Mechanistic modeling and application to progesterone

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility–permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability ( P m ) as well as the unstirred water layer (UWL) permeability ( P aq ), to predict the overall effective permeability ( P eff ) dependence on cyclodextrin concentration ( C CD ). The analysis reveals that: (1) UWL permeability markedly increases with increasing C CD since the effective UWL thickness quickly decreases with increasing C CD ; (2) membrane permeability decreases with increasing C CD , as a result of the decrease in the free fraction of drug; and (3) since P aq increases and P m decreases with increasing C CD , the UWL is effectively eliminated and the overall P eff tends toward membrane control, that is, P eff  ≈  P m above a critical C CD . Application of this transport model enabled excellent quantitative prediction of progesterone P eff as a function of HPΒCD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility–permeability balance in order to achieve optimal overall absorption. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2739–2749, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71376/1/22033_ftp.pd

Effects of Gravity on Gastric Emptying, Intestinal Transit, and Drug Absorption

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97246/1/j.1552-4604.1991.tb03658.x.pd

The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon

A physiological flow model is presented to account for plasma level double peaks based on cyclical gastric emptying and intestinal motility in the fasted state. Central to the model is the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Simulated curves clearly indicate that variable gastric emptying rates can result in variable absorption rates from the gastrointestinal tract and double peaks in the plasma level curves of cimetidine. Vital to the occurrence of double peaks are (i) dosing time relative to phasic activity, (ii) variability in flow out of the stomach, and (iii) a small emptying rate constant Q s /V s , for a period of time within the first hour after administration. Variability in intestinal flow rates alone does not cause a double peak in the plasma level curve. Results of the simulations, as well as experimental results, can be categorized according to the shapes of the plasma level curves into four types: type A, C pmax (1) C pmax (2); type D, C pmax (1)=C pmax (2). Assuming that the experimental results were obtained from fasted subjects, with the time of dose administration being a random variable, the frequency of the experimental curves having shape A, B, C, or D correlates extremely well with theoretical predictions. It is concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45037/1/10928_2005_Article_BF01061761.pd

Plasticizer-induced changes in the mechanical rate of response of film coatings: an approach to quantitating plasticizer effectiveness

The plasticization of Eudragit S100, a polymeric-based enteric coating with polyethylene glycol 200 and dibutyl phthalate was investigated by analyzing changes in the time scale of mechanical response. Since all polymeric film coating solutions pass through the rubber-to-glass transition as solvent evaporates, this study focuses on the plasticization-induced changes in the rate of mechanical response in this region. Solvent cast films were mechanically analyzed using a low strain elongational creep compliance procedure and intrinsic mechanical response was analyzed via the application of a phenomenological approach of retardation spectrum analysis. Results indicate that at constant temperature, the addition of plasticizer changes the time scale of response by shifting the spectra negatively within the experimental time window. Using a free volume analysis a plasticizing effectiveness term, [beta], was calculated for the plasticizers in this study with . The higher value of [beta] indicates a greater propensity to in the rubber-to-glass transition. The application of this technique may yield more relevant mechanical information for film coating systems without relying solely on glass transition temperature changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27717/1/0000105.pd

Particle diffusional layer thickness in a USP dissolution apparatus II: A combined function of particle size and paddle speed

This work was to investigate the effects of particle size and paddle speed on the particle diffuisonal layer thickness h app in a USP dissolution apparatus II. After the determination of the powder dissolution rates of five size fractions of fenofibrate, including <20, 20–32, 32–45, 63–75, and 90–106 µm, the present work shows that the dependence of h app on particle size follows different functions in accordance with the paddle speed. At 50 rpm, the function of h app is best described by a linear plot of $h_{{rm app}} = 9.91sqrt d - 23.31$ ( R 2  = 0.98) throughout the particle diameter, d , from 6.8 to 106 µm. In contrast, at 100 rpm a transitional particle radius, r , of 23.7 µm exists, under which linear relationship h app  = 1.59 r ( R 2  = 0.98) occurs, but above which h app becomes a constant of 43.5 µm. Thus, h app changes not only with particle size, but also with the hydrodynamics under standard USP configurations, which has been overlooked in the past. Further, the effects of particle size and paddle speed on h app were combined using dimensionless analysis. Within certain fluid velocity/particle regime, linear correlation of h app / d with the square-root of Reynolds number $(dvarpi /upsilon )^{1/2}$ , that is, $h_{{rm app}} /d = 1.5207 - 9.25 times 10^{ - 4} (dvarpi /nu )^{1/2}$ ( R 2  = 0.9875), was observed. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4815–4829, 2008Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61209/1/21345_ftp.pd

Intestinal Dipeptide Absorption Is Preserved During Thermal Injury and Cytokine Treatment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142293/1/jpen0520.pd

Role of Integrin Expression in Adenovirus-Mediated Gene Delivery to the Intestinal Epithelium

Overview summary Previous studies of adenovirus-mediated gene transfer of the interleukin-1 receptor antagonist protein to rat jejunum have produced limited gene expression. In the present study, we have shown that integrins play a significant role in efficient adenoviral infection of the intestinal epithelium. As enterocytes differentiate, integrin expression decreases. This coincides with significant reduction in adenoviral transduction efficiency. Results from two in vitro models of the intestinal epithelium (Caco-2 and IEC-18 cells) show that αvβ3 integrins have the most influence on adenoviral internalization. Results from screening of rat intestinal segments for expression of the αvβ5 integrin suggest that, based on integrin expression, the ileum is a prime target for efficient adenovirus-mediated gene transfer. We have also found that administration of immunomodulating agents and inflammatory disease states provide a favorable environment for efficient internalization of adenoviral vectors due to up-regulation of integrin receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63160/1/hum.1998.9.4-561.pd

Biopharmaceutics and pharmacokinetics of [D-ala2, D-leu5]enkephalin after various routes of administration

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31917/1/0000870.pd