George A. Digenis

Evaluation of the effect of food and specific gravity of tablets on gastric retention time

Abstract In the present study the effect of food and specific gravity on the gastric retention time of floating (spec. grav. 0.96) and non-floating (spec. grav. 1.59) tablet formulations was investigated using gamma scintigraphy in humans. The results obtained indicate that the presence of food in the stomach appears to significantly prolong gastric retention of both the floating and non-floating tablets while specific gravity does not seem to play an important role in the residency time of the tablets in the stomach.

An in vitro-in vivo investigation of oral bioadhesive controlled release furosemide formulations☆

Abstract The in vitro controlled release and bioadhesive properties of furosemide formulations were evaluated with standard dissolution tests and with a specially developed model using rabbit intestine. The results showed that the controlled release properties were not affected by the application of the bioadhesive polymer but that the bioadhesive properties were substantially different. In order to assess the gastrointestinal transit time in vivo, a γ-scintigraphy study was performed in six volunteers testing the same controlled release formulation with and without bioadhesive polymer. Plasma levels of furosemide, evaluation of urinary flux and measures of urinary excretion of furosemide in the six volunteers allowed correlations to be made between gastrointestinal transit and furosemide absorption.

Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time

During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80–120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 µCi 111InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.

Gastrointestinal Behavior of Orally Administered Radiolabeled Erythromycin Pellets in Man as Determined by Gamma Scintigraphy

The behavior of single 250‐mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron‐activated samarium‐153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points.

Disposition of radiolabelled suppositories in humans

The disposition of Witepsol H 15 suppositories radiolabelled with [99m Tc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5−7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the ‘first‐pass’ effect may be partially avoided by their rectal administration.

Vaginal distribution of Replens and K-Y Jelly using three imaging techniques

BACKGROUND Determination of vaginal distribution is important to the development of potential vaginal microbicidal or spermicidal products. STUDY DESIGN This was a descriptive study of three imaging techniques with a randomized crossover assignment of two gels and activity status within each technique. METHOD Each of three sites utilized one technique. Three nulligravid women and three parous women were to be enrolled at each site. We studied the effects of time, ambulation, parity and body mass index on vaginal spreading of two commonly used gels, K-Y Jelly and Replens. Imaging by magnetic resonance imaging and gamma scintigraphy was performed at 5, 20, 35 and 50 min after insertion of 3.5 mL of gel. Imaging with a fiberoptic probe was performed at 5 and 20 min after insertion. RESULTS Initial application of the gel resulted in approximately two thirds of maximum coverage possible, both in linear extent along the vaginal axis and in surface area covered. Over the next 45 min, spreading increased to about three quarters of the maximum possible. Ambulation generally increased linear spreading and the proportions of women with gel at the introitus and os. Effects of parity and body mass index (BMI) were similar on most measures of gel spreading, with nulligravid women tending toward greater spread than parous women and women of high BMI usually showing somewhat greater spread than women of normal weight. Differences between the two gels were not seen when all conditions of application were considered together. CONCLUSION In vivo imaging of gel distribution demonstrated that ambulation, parity and BMI affect vaginal gel spreading. The three imaging techniques have advantages and disadvantages and provide complementary information for microbicide development.

Kinetics of paclitaxel 2′-N-methylpyridinium mesylate decomposition

This study was designed to examine the kinetics of decomposition of paclitaxel 2′-N-methylpyridinium mesylate (PNMM), a derivative of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies of PNMM were conducted over a pH range of 4.0 to 8.0 at 25°C. The critical micelle concentration (CMC) of PNMM was determined by pulsating bubble surfactometry. Studies of the conversion of PNMM to paclitaxel were conducted in vitro in human plasma. Decomposition of PNMM followed apparent zero-order kinetics. The pH-rate profile exhibited no evidence of acid catalysis down to pH 4.0, while the rate was accelerated under base conditions. Surface tension studies suggested that PNMM formed micelles with a CMC of approximately 34 μg/mL. Conversion studies in phosphate buffer showed that no more than 5% of PNMM converted to paclitaxel, while in human plasma the conversion was about 25%. The degradation of PNMM was via apparent zero-order kinetics and was dependent upon pH. The observed apparent zero-order kinetics of decomposition of PNMM was consistent with the formation of micelles in phosphate buffer. In buffered aqueous media alone or in human plasma, PNMM did not convert quantitatively to paclitaxel. Thus, the limiting factor in the application of PNMM as a prodrug would appear to be the poor potential to convert to paclitaxel.

Determination of Extent of Formaldehyde-Induced Crosslinking in Hard Gelatin Capsules by Near-Infrared Spectrophotometry

AbstractPurpose. To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR). Methods. HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25,4.60,9.42, 16.0 and 24.0 hours. The capsules were filled with fresh amoxicillin, placed in a 90° conical reflector cone, and scanned in a NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the intact capsules. Dissolution profiles were then obtained for each experimental group. Results. The dissolution of amoxicillin from the capsules at pH 1.2 was found to decrease with increasing time of exposure to the formaldehyde atmosphere. A set of principal components (PCs) was formed by a linear combination of the absorbance values at each wavelength scanned. A good correlation was established (r2 = 0.963) when PC values from the NIR spectra of the HGCs were regressed against percentage of amoxicillin dissolved at 45 minutes, at pH 1.2. Water content of the capsules was found to be the largest determinant in the variation between HGC spectra at each exposure time. Conclusions. NIR spectrophotometry, combined with PCR, was successful at not only predicting dissolution of HGCs exposed to formaldehyde, but also at determining which wavelengths contributed most to spectral variation of these stressed HGCs.

Preparation and preliminary tissue studies of optically active 11C-d- and l-phenylalanine

Abstract A rapid method for the preparation of l -phenylalanine-1-11C and d -phenylalanine-1-11C is described. dl -Phenylalanine-1-11C (375 mCi) was synthesized from 11C-cyanide (2.4 Ci) by a modified Bucherer- Strecker reaction with a chemical yield of 65% in 40 min (including purification). The resolution of the d - and l -isomers was accomplished in 35 min (including purification) by oxidative deamination using immobilized l - and d -amino acid oxidase, respectively; the yields for d - and l -phenylalanine-1-11C were 19 mCi and 27 mCi. Preliminary tissue distribution studies of these labeled isomers in the rat showed that the pancreas-to-liver ratio for the l -isomer increased throughout the first hour of observation following i.v. administration while that of the d -isomer decreased after 30 min. Whole body retention data revealed that the loss of radioactivity from dl - or d -phenylalanine-1-11C was less than 2% during the first hour of observation after i.v. administration.

Bioequivalence Study of Stressed and Nonstressed Hard Gelatin Capsules Using Amoxicillin as a Drug Marker and Gamma Scintigraphy to Confirm Time and GI Location of In Vivo Capsule Rupture

AbstractPurpose: Evaluate if crosslinked hard gelatin capsules (HGCs) havingdifferent in vitro dissolution profiles changed in vivo release times oraltered bioavailability of a drug marker; assess if a two-tier dissolutiontest (with and without enzyme) predicted in vivo performance. Methods. Two classifications of stressed HGCs were artificiallyproduced by exposure to formaldehyde (HCHO). HGCs were categorizedas, a) pass/pass (p/p) which met in vitro dissolution criterion (75%drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p)which failed dissolution criterion in the absence of enzymes and passedin the presence of enzymes, and c) severely crosslinked fail/fail (f/f)which failed in vitro standards with or without enzymes. A six-way,single dose bioequivalence study (n = 10) administered the three HGCsunder the fasted and fed condition. In vivo capsule rupture and GItransit were monitored via gamma scintigraphy, and blood sampleswere collected through six hours. Results. Each crosslinked HGC was bioequivalent to the control p/pcapsule when using AUC(0−∞) and Cmax for comparison. Meanin vivo disintegration of the p/p capsule was 7 ± 5 min for the fastedcondition and 11 ± 7 min for the fed condition. In vivo rupture forthe f/p capsule was 22 ± 12 min and 23 ± 11 min for the fasted andfed studies, respectively, while the f/f HGC ruptured at 31 ± 15 minand 71 ± 19 min under the fasted and fed condition, respectively.Onset of amoxicillin absorption was dependent on in vivo HGC ruptureand subsequent entry of the released radioactive marker into the smallintestine. Consequently, fasted Tmax values were significantly laterfor the f/p HGC (1.62 ± 0.53 hr) and f/f HGC (1.85 ± 0.58 hr) ascompared to the p/p HGC (1.17 ± 0.30 hr). Fed Tmax values werestatistically different only for the f/f capsule (2.55 ± 0.44 hr) whereTmax values for the p/p and f/p HGCs under the fed condition were1.50 ± 0.47 hr and 1.60 ± 0.46 hr, respectively. Conclusions. A two-tier dissolution procedure that retested across-linked hard gelatin capsule with addition of gastric or intestinal enzymesprovided an adequate in vitro indicator of the formulationsin vivo performance. The observed delays in the onset of amoxicillin absorptionand Tmax for the severely crosslinked f/f HGC was attributed todelayed in vivo capsule rupture, however, this delay did not adverselychange AUC(0−∞) nor Cmax.