Biomedical subjects

Roger L Schnaare

Publications and source records attributed to Roger L Schnaare.

9 recordsLinked to original sources

PubMed2007

Biophysical analysis of prototype microbicidal gels.

The objective of this study was to evaluate the distribution and retention (deployment) of four prototype vehicles for delivery of prophylactic microbicides against vaginal HIV transmission. Study gels were created with different molecular compositions, producing different biophysical properties governing vaginal deployment. The study employed three techniques: direct rheological measurement of gel properties, direct observation of gel surface coating erosion, and dissolution by a vaginal fluid simulant, and mathematical modeling of gel squeezing flow processes. Results suggest significant differences in extent of vaginal coating after gel application and in erosion of these gel layers due to contact with ambient vaginal fluid and shearing. The relationships between gel rheological properties, coating flow and erosion of coating were not always anticipated from differences in gel molecular composition.

Administration, Intravaginal↗

PubMed2005

In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials.

The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.

Animals↗

PubMed2004

In vitro test to evaluate the interaction between synthetic cervical mucus and vaginal formulations.

The interaction and mixing between a bilayer sample of mucus and vaginal formulation was evaluated through viscosity measurements with respect to time and shear. Physical mixtures of mucus and vaginal formulation were used as controls. Three test protocols were designed: (1) constant shear, (2) intermittent shear, and (3) delayed shear. Several marketed vaginal products (Gynol II, KY Plus, KY, and Advantage-S) and experimental formulations (C31G with hydroxyethylcellulose [HEC]) were evaluated and compared by these tests. The results of the constant shear test showed that the shear stress profile of the bilayer approached that of the corresponding physical mixture, consistent with complete mixing of the bilayer under shear. The time taken for the bilayer to mix completely was in the following order: KY Plus > Gynol II and C31G > KY > Advantage-S. Under the intermittent shear protocol, the following order for complete mixing was observed: KY Plus > C31G > Gynol II > KY > Advantage-S. The 2 products evaluated by the delayed shear test, C31G and Gynol II, were both completely mixed at 180 minutes. The development of an in vitro test, when coupled with in vivo data, should serve in the screening and evaluation of future vaginal formulations.

Administration, Intravaginal↗

PubMed2003

A multimechanistic drug release approach in a bead dosage form and in vitro predictions.

The objective of this study was to prepare a combination of immediate release, enteric coated, and controlled release (CR) beads and to mathematically model in vitro drug release characteristics of the combination based on the release profiles of individual beads. Uncoated beads were manufactured by using extrusion/spheronization technology. Fluid-bed bottom spraying was used for coating: Eudragit-L-30D for enteric coating and Eudragit-NE-30D for CR coating. In vitro drug release profiles for uncoated and coated beads were each fitted to appropriate mathematical equations. The drug release from the bead combination dosage form was predicted from the individual mathematical models and verified experimentally in vitro. The in vitro dissolution was conducted in 0.1 N HCl for 2 hr and then in buffer (pH 6.5 phosphate, 0.05 M) to mimic in vivo conditions using USP dissolution apparatus I. The results showed that uncoated beads gave similar release profiles in water, acid, and buffer with complete release within 2 hr. The release from CR beads was about 50% at 10 hr and was independent of the dissolution medium. As expected, enteric coated beads showed drug release < 5% at 2 hr in water and acid, whereas the release in buffer was comparable to that of uncoated beads. Exposure of enteric coated beads to acid for 2 hr produced a slower release rate in buffer compared with the release from beads added directly in the buffer. The release characteristics of the three beads can be described by square root and zero-order kinetics. The release characteristics from the combination dosage form were 39%, 69%, and 81% at 1, 4, and 8 hr, respectively. The experimental and predicted profiles agreed to within +/- 6% (residuals at individual data points). Our results suggest that release from the combined multimechanism oral dosage form can be predicted from the performance of individual beads.

Algorithms↗

PubMed2003

A multi-mechanistic drug release approach in a bead dosage form and in vitro/in vivo correlations.

An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.

Administration, Oral↗

PubMed2003

A multi-mechanistic drug release approach in a bead dosage form and in vivo predictions.

Our previous study has successfully prepared a combination of immediate release, enteric coated, and controlled release (CR) beads and mathematically modeled in vitro drug release characteristics of the combination based on the release profiles of individual beads. The objectives of the present study are to evaluate the combination and individual beads in vivo and to mathematically model in vivo drug input characteristics of the combination based on the in vivo input of individual beads. Beagle dogs were used as an animal model, and theophylline as a model drug. In vivo percent drug absorbed at different times (input function) after administration of a capsule bead dosage form was calculated using the Wagner-Nelson deconvolution method using intravenous injection of theophylline in each dog as a reference. The in vivo input functions of individual beads were each fitted to appropriate mathematical equations. The in vivo input function of the bead combination dosage form was calculated based on the individual mathematical equations (expected), and verified experimentally in vivo (experimental). The results showed that all bead dosage forms behave in vivo as defined in vitro. Enteric coated beads significantly delay the time to reach the maximum concentration of drug (tmax=4.9 h) compared to uncoated immediate release beads (2 h). The lag time of enteric coated beads is 1.1 h. CR beads showed both longer tmax (6 h) and mean residence time (MRT=9.7 h) compared to the uncoated immediate release beads (tmax=2 h and MRT=7.1 h) as designed in vitro. The in vivo input functions for the three individual beads can be fitted to equations as a function of square root of time. The combined bead dosage form showed tmax of 2.4 h and MRT of 7.9 h. The experimental and expected in vivo input profiles agreed to within +/- 12% (residues at individual data points). Our results suggest that the drug input function of a combined multi-mechanism oral dosage form can be predicted from the in vivo performance of individual formulations using the dog as an in vivo model.

Administration, Oral↗

PubMed2002

Synthetic cervical mucus formulation.

A synthetic formulation has been developed with viscosity, spinnbarkeit, and pH comparable to that reported for human cervical mucus. The formulation contains guar gum crosslinked with borate ion, mucin (dried porcine gastric), and a mixed preservative system in pH 7.4, 0.1M phosphate buffer. The guar gum source, mucin concentration, and method of preparation were shown to be critical factors in the performance of the formulation.

Borates↗

PubMed2002

The effect of controlled release tablet performance and hydrogel strength on in vitro/in vivo correlation.

The impact of controlled release (CR) formulations having different gel strength values (gamma) on in vivo tablet performance and the in vitro/in vivo correlation of the formulations was investigated. The CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose to produce tablets with a polymer content of 8 and 30% w/w. gamma was measured using a previously reported method. Male beagle dogs were utilized. Results showed that dissolution profiles were similar for all three polymers at the same % w/w level of polymer, irrespective of media (DI H2O, 0.1 N HCl, and pH 6.8 phosphate buffer). Mean gamma values were significantly different (p < or = 0.05) and were in order of HPMC K100MP > HPC HXF > carbomer 971P (same 30% w/w) with absolute gamma values at 30% w/w in DI H2O of 6600, 4600, and 1600 ergs/cm3, respectively. Drug profiles in plasma for the 30% HPMC K100MP tablets were consistent with in vitro dissolution profiles and gamma values. Plasma profiles for the 30% HPC HXF tablets were similar in vivo as the HPMC tablets. Plasma profiles for the 30% carbomer 971P formulation showed much higher drug concentrations (compared to HPMC and HPC) in vivo in all dogs. This findings is not consistent with the slow drug release found in the dissolution profiles but consistent with its low in vitro gamma values. Assessment of the predictability of a level A in vitro/in vivo correlation was quantified by absolute mean percent prediction error (PE). Formulations having gamma approximately 6000 ergs/cm3 have acceptable PE < 20%, and low standard deviation (sigma). Results showed that gamma values of CR hydrogel tablets in vitro will affect the in vivo performance (i.e., absorption kinetics of the drug) of the tablets and were also found to better assess (compared to in vitro dissolution profiles alone) the predictability of in vitro/in vivo correlations (level A and multiple level C).

Acrylic Resins↗

PubMed2002

An adjusted pharmacokinetic equation for predicting drug levels in vivo based on in vitro square root of time release kinetics.

An adjusted pharmacokinetic equation that predicts in vivo plasma drug profiles for controlled release (CR) dosage forms having square root of time drug release kinetics has been derived. The CR hydrogel tablets containing hydroxypropyl methylcellulose (HPMC) were formulated with theophylline and Fast Flo lactose, to produce tablets with HPMC K100MP content of 30% w/w. Plasma profiles in vivo were determined from four male beagle dogs. Tablet gel strength (gamma) was measured as previously reported. Results show drug release in vitro follows square root of time kinetics for the formulation in all media (purified H2O, 0.1 N HCl, and pH 6.8 phosphate buffer). The gamma values were not significantly different (p > 0.05) among the tablets in different dissolution media, with absolute values in DI H2O of 6600 erg/cm3, which is above the minimum threshold value of gamma (approximately 6000 erg/cm3) needed for acceptable in vitro/in vivo correlation. Comparison of predicted and observed plasma profiles in vivo, using the adjusted square root pharmacokinetic equation, showed a better fit of the overall pattern and absolute values of the in vivo data as compared to equations that assume first- or zero-order drug release from the HPMC based tablets. The adjusted square root pharmacokinetic equation can serve as a valuable aid in the design of formulations to yield a desired plasma profile in vivo and provides supporting evidence to the mechanism of drug release in vitro.

Gels↗