M. Frier

Evaluation of the clearance characteristics of bioadhesive systems in humans.

This paper describes the characterisation, radiolabelling and clearance characteristics of three bioadhesive nasal delivery systems; starch microspheres, chitosan microspheres and chitosan solution. The time taken for 50% of these bioadhesive materials and a control to be cleared from the nasal cavity, after nasal administration to human volunteers, was evaluated using gamma scintigraphy. The data show that the control was cleared rapidly, with a half life of 21 min, whereas the bioadhesive delivery systems had much longer half lives. The clearance of the chitosan solution almost doubled to 41 min, whilst the half life of clearance for the starch microspheres more than tripled to 68 min and for the chitosan microspheres the half life of clearance quadrupled to 84 min. From the results reported in this study it is possible to determine that both chitosan systems and the starch microspheres have good bioadhesive characteristics. The results have supported the hypothesis that chitosan delivery systems can reduce the rate of clearance from the nasal cavity, thereby increasing the contact time of the delivery system with the nasal mucosa, providing the potential for increasing the bioavailability of drugs incorporated into these systems.

Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.

Pulsincap formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for time of release from Pulsincap preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.

Effect of bran particle size on gastric emptying and small bowel transit in humans : a scintigraphic study

Bran is an effective treatment for constipation but its use is often limited by heartburn and bloating. This study examined the effect of fine and coarse bran (15 g) on the gastric emptying and small bowel transit of a 325 kcal rice test meal. Twelve healthy volunteers underwent a three way cross over study, ingesting the technetium-99m labelled rice meal with or without 15 g of indium-111m labelled fine or coarse bran, in random order. Serial scintigraphic images were obtained to define gastric emptying and colonic arrival of label. Compared with control values (99 (9) minutes) (mean (SEM)), the time to 50% gastric emptying was significantly delayed by coarse but not fine bran, being 121 (6) and 104 (9) minutes respectively, p < 0.05, n = 12. Fundal emptying was unchanged but both brans seemed to increase the proportion of isotope in the antrum at 90 minutes. Small bowel transit was slightly faster with both bran types but in this study the difference was not significant. Both the bran and rice labels moved down the gut without significant separation. Fine bran causes less disturbance of gastric physiology than coarse bran.

Regional differences in quinine absorption from the undisturbed human colon assessed using a timed release delivery system.

AbstractPurpose. To investigate the regional absorption characteristics of the distal gut using two markers of permeability, quinine (a transcellular probe) and 51CrEDTA (a paracellular probe). Methods. The permeability markers were delivered to the undisturbed gastrointestinal tract in 39 healthy volunteers using an oral timed-release delivery vehicle which allowed pulsed release within a particular site of the gut. Site of release was identified using gamma scintigraphy. Absorption of quinine and 5lCrEDTA was assessed by measuring the percent excretion in the urine using HPLC and gamma counting respectively. Serial plasma samples allowed time-concentration curves for quinine to be plotted. Results. There was a significant trend for diminished absorption with more distal delivery of the transcellular probe, quinine, which was: 6.26 ± 0.87% (small intestine, n = 10); 4.65 ± 0.93% (ascending colon, n = 16); and 2.59 ± 0.52% (transverse colon, n = 10) of the ingested dose excreted respectively (p < 0.001). No such gradient was seen with the paracellular marker, 5lCrEDTA. Conclusions. These results suggest that delayed release formuations should aim for release in the distal small bowel and proximal colon if absorption is to be miximised. Absorption by the transcellular route diminishes in the more distal colon, a fact which has implications for delayed or sustained release formulations.

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations

Risedronate sodium is an orally active antiresorptive agent and a member of the pyridinyl class of bisphosphonates. It has been approved for the treatment of Pagets disease of the bone and is under development as a chronic therapy for the treatment and prevention of osteoporosis. A novel cellulose film-coated tablet formulation was developed to optimize esophageal transit of this bisphosphonate. The aim of the present study was to compare the esophageal transit of the film-coated tablet formulation of risedronate with its original gelatin capsule dose form. A total of 25 elderly, healthy volunteers (mean 66 years), who were dysphagia-free, participated in this randomized cross-over study. On separate occasions, volunteers swallowed radiolabeled placebo formulations with 50 ml water. Dynamic images with participants in a sitting position were recorded for 10 min using a gamma camera. Scintigraphic imaging showed a delay in esophageal transit (greater than 15 s) in 28% of patients in the capsule group but in none of the tablet group (P<0.05). The mean transit times of the capsules and tablets were 23.8 and 3.3 s, respectively. Esophageal transit of film-coated tablets was faster than gelatin capsules, suggesting that film-coated tablets would be the appropriate formulation for all pivotal trials with risedronate and for subsequent commercialization.

Scintigraphic assessment of the in vivo dissolution rate of a sustained release tablet

Abstract The release of [ 99m Tc]diethylenetriaminepentaacetic acid ([ 99m Tc]DTPA) from a matrix tablet formulation was measured by external scintigraphy in 4 healthy male volunteers. The rate determined was compared with that observed in vitro using a U.S.P. dissolution apparatus. The in vitro release rate of [ 99m Tc]DTPA was similar to that of chlorpheniramine, and therefore the labelled compound was used to model the release of this drug in vivo. The in vitro release of [ 99m Tc]DTPA was pH-independent.

Ocular contact time of a carbomer gel (GelTears) in humans

BACKGROUND/AIMS Carbomers are widely used in products for the treatment of dry eye; however, the polymer gel thins on addition of probes (for example, fluorescein salt) confounding the comparison of products by objective clinical tests such as spectrophotofluorimetry or scintigraphy. A novel method of radiolabelling carbomer gels, with minimum change to their rheology, has permitted the non-invasive evaluation of precorneal residence of the gel in volunteers using gamma scintigraphy. The technique was used to evaluate the precorneal clearance of the liquid phase and of a suspended particulate in GelTears. METHODS Low sodium technetium-99m labelled diethylenetriaminepentacetic acid (99mTc-DTPA) was used to label carbomer 940 gel, either adsorbed onto sterile charcoal to model an entrapped drug, or added directly to the gel to a final activity of 1 MBq per 25 μl dose. The clearance of the labelled gels was then compared with 99mTc-DTPA labelled saline in 12 volunteers. RESULTS The addition of the low sodium radiopharmaceutical produced insignificant rheological changes in the gel compared with conventional 99mTc-DTPA labelling. The residence times on the eye of the gel formulations were significantly greater than that of the saline control. At 8 minutes postdosing, the label levels retained (mean (SD)) on the ocular surface were: saline, 7% (7%); 99mTc-DTPA gel, 42% (27%); and 99mTc-carbon gel, 42% (20%) of administered dose. There was no difference observed in the precorneal distribution between 99mTc-DTPA solution and particulate markers. CONCLUSIONS These data demonstrate that carbomer based gels significantly extend contact of solutes or suspended solids with the corneal surface. The method of labelling does not significantly change the initial viscosity and is superior to previous methods which have used sodium salts (for example, sodium fluorescein) and therefore underestimate contact time.

The use of scintigraphy to demonstrate the rapid esophageal transit of the oval film-coated placebo risedronate tablet compared to a round uncoated placebo tablet when administered with minimal volumes of water.

As our population ages, and the consumption of pharmaceutical products rises, the incidence of solid oral dosage forms lodging in the esophagus is likely to increase and may be formulation dependent. The aim of this study was to compare the esophageal transit of the commercial film-coated risedronate tablet and a round uncoated tablet resembling the alendronate 10 mg tablet which is reported to cause esophagitis if ingested with little to no water. Water volumes of 30 ml and 50 ml were selected as these volumes can detect formulations prone to esophageal adhesion and a habits and practice study showed that these volumes are within the range preferred by women (7-385 ml). A total of 28 healthy postmenopausal women completed the four-way crossover scintigraphy study. For both volumes of water, the film-coated placebo risedronate tablet had a statistically significant faster esophageal transit time than the uncoated placebo tablet (P=0.002 for 30 ml water and P<0.001 for 50 ml water). Among those taking the round, flat, uncoated tablet, five subjects had esophageal stasis (transit >20 s) and in three subjects the tablet remained in the esophagus at the end of the 10-min imaging period. No stasis was observed for the oval film-coated placebo risedronate tablet. This study demonstrates that tablet size, shape and coating are pharmaceutical parameters which can be controlled to minimize esophageal contact of a dosage form with esophageal tissue.

Radionuclide imaging in drug research

This book is based on the proceedings of a symposium Applications of Radionuclides in Drug Formulation Studies held at the University of Nottingham in April, 1981. Other than one from France and two from the USA, the contributing groups are English. Four general divisions of the book are discernible. The first part deals with basic aspects of radiopharmaceuticals and diagnostic imaging and is followed by chapters on the applications of external scintigraphy in studies of drug behavior in animal models and in man. Section Three consists of topics concerned with the formulation and targeting of labeled materials, and the final portion is made up of abstracts from the symposiums poster sessions, which covered a variety of topics.

Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects

Risedronate sodium is a pyridinyl bisphosphonate, proven effective for the treatment and prevention of postmenopausal osteoporosis and glucocorticoid‐induced osteoporosis and Paget’s disease of the bone.