Ian R. Wilding

Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects

The variability in the gastrointestinal transit of a multiple-unit and single-unit dosage form was investigated following a light breakfast in six, healthy, male volunteers after repeated weekly administration. The dosage forms were labeled with gamma-emitting radionuclides and the transit of the formulations was monitored on 4 separate study days using the technique of dual-isotope gamma scintigraphy. Gastric emptying times and small intestinal transit times were calculated and compared statistically within and between subjects using the standard deviation and coefficient of variance. The variability in gastric emptying of single- and multiple-unit systems was large; the intrasubject variation being less than the intersubject. There was less variation in small intestinal transit times for the single- and multiple-unit formulations than in gastric emptying, intrasubject variation again being less than intersubject variation.

The role of γ-scintigraphy in oral drug delivery

The gastrointestinal tract is usually the preferred site of absorption for most therapeutic agents, as seen from the standpoints of convenience of administration, patient compliance and cost. In recent years there has been a tendency to employ sophisticated systems that enable controlled or timed release of a drug, thereby providing a better dosing pattern and greater convenience to the patient. Although much about the performance of a system can be learned from in vitro release studies using conventional and modified dissolution methods, evaluation in vivo is essential in product development. The non-invasive technique of γ-scintigraphy has been used to follow the gastrointestinal transit and release characteristics of a variety of pharmaceutical dosage forms. Such studies provide an insight into the fate of the delivery system and its integrity and enable the relationship between in vivo performance and resultant pharmacokinetics to be examined (pharmacoscintigraphy).

Enteric coated HPMC capsules designed to achieve intestinal targeting

The enteric coating of HPMC capsules containing paracetamol was investigated. Two enteric polymers, Eudragit L 30 D-55 and Eudragit FS 30 D were studied, which are designed to achieve enteric properties and colonic release, respectively. The capsules were coated in an Accela Cota 10, and, as shown by optical microscopy, resulted in capsules with a uniform coating. Scanning electron microscopy of the surface of the capsules illustrate that, in contrast to gelatin, HPMC has a rough surface, which provides for good adhesion to the coating. Dissolution studies demonstrated that capsules coated with Eudragit L 30 D-55 were gastro resistant for 2 h at pH 1.2 and capsules coated with Eudragit FS 30 D were resistant for a further 1 h at pH 6.8. The product visualisation technique of gamma scintigraphy was used to establish the in vivo disintegration properties of capsules coated with 8 mg cm(-2) Eudragit L 30 D-55 and 6 mg cm(-2) Eudragit FS 30 D. For HPMC units coated with Eudragit L 30 D-55, complete disintegration occurred predominately in the small bowel in an average time of 2.4 h post dose. For HPMC capsules coated with Eudragit FS 30 D, complete disintegration did not occur until the distal small intestine and proximal colon in an average time of 6.9 h post dose.

Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes

OBJECTIVES To evaluate the effect of exenatide on gastric emptying (GE) in type 2 diabetes using scintigraphy. METHODS Seventeen subjects with type 2 diabetes participated in a randomized, single-blind, 3-period, crossover study. In each 5-day period, 5 or 10 microg exenatide or placebo was administered subcutaneously BID. Oral antidiabetic treatments were continued. The presence of cardiac autonomic neuropathy was assessed during screening. On day 5, after the morning dose, subjects consumed a 450-kcal breakfast containing (99m)Tc-labeled eggs and (111)In-labeled water, and GE was measured by scintigraphy. Plasma glucose and insulin, perceptions of appetite, and plasma exenatide were also quantified. RESULTS Exenatide slowed GE of both solid and liquid meal components [solid (T(50)(90% confidence interval [CI]); placebo, 60(50-70) min; 5 microg exenatide, 111(94-132) min; 10 microg exenatide, 169(143-201) min; both P<0.01); liquid (T(50)(90% CI), placebo, 34(25-46) min; 5 microg exenatide, 87(65-117) min; 10 microg exenatide, 114(85-154) min; both P<0.01)]. GE was not different between subjects with cardiac autonomic neuropathy (n=7), compared with those without (n=10) (P>/=0.68). Exenatide reduced postprandial glucose (area under the curve [AUC((0-6 h))]) by 69-76% and peak insulin (C(max)) by 84-86% compared with placebo. There was an inverse relationship between the postprandial rise in glucose (AUC((0-3 h))) and GE (solid T(50), r=-0.49, P<0.001). CONCLUSIONS Exenatide slows GE substantially in type 2 diabetes, which could be an important mechanism contributing to the beneficial effect of exenatide on postprandial glycemia.

Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed-Release Formulation

Captopril has been administered to eight healthy male subjects by means of a pulsatile delivery system that was designed to release the drug in the colonic region of the intestine. The gastrointestinal transit and pulsatile release were followed using gamma scintigraphy. A pulsatile capsule system with release after a nominal 5-hr period was found to perform reproducibly in vitro and in vivo. In six of the eight subjects, the drug was delivered to the colon, and in the remaining two subjects, to the terminal ileum. Measurable blood levels of free captopril were found in three subjects. Variable instability of the drug in the distal intestine is suggested as a possible reason for the lack of absorption of the drug in the majority of subjects.

Spreading and Retention of Vaginal Formulations in Post-Menopausal Women as Assessed by Gamma Scintigraphy

AbstractPurpose. In this paper we report on the first scintigraphic evaluation of vaginal dosage forms in post-menopausal women. To date, almost nothing is known about the in vivo performance of pharmaceutical formulations in the human vagina, which is a major deficiency in the rational design of drug delivery systems for both existing and new indications. Methods. The vaginal spreading and clearance of a radiolabelled pessary formulation and Replens® (polycarbophil) gel, was assessed in six healthy, post-menopausal female volunteers over a six hour period using the technique of gamma scintigraphy. Results. In five out of the six subjects studied, clearance of the two formulations exhibited very little intra-subject variation. However, there was considerable inter-subject variability in clearance; in Subject 5 circa 80% of the products were retained whilst in Subject 2 less than 2% was present at the end of the six hour imaging period. Importantly, there was no evidence to suggest that either of the formulations dispersed material beyond the cervix, into the uterus, in any of the subjects studied. Conclusions. The lack of significant retention of these products in most of the volunteers has obvious implications for the delivery of therapeutic agents. This study shows that gamma scintigraphy is an invaluable technique with which to assess novel formulations aimed at optimising retention in the vagina for topical or systemic drug delivery.

Colonic transit of different sized tablets in healthy subjects

Abstract The gastrointestinal transit of single unit dosage forms (tablets) of different sizes (3 mm, 6 mm, 9 mm and 12 mm) was investigated in eight healthy male volunteers. The volunteers followed a strictly controlled diet containing 28 g dietary fibre (18.5 g non-starch polysaccharide), per day, starting six days prior to the start of the study and continuing until the study was completed. On each of the three study days, following an overnight fast, each volunteer received five control tablets (6 mm diameter) labelled with indium-111, and five variable sized tablets (3 mm, 9 mm or 12 mm diameters) labelled with technetium-99m. Tablet transit was followed using the technique of dual isotope gamma scintigraphy. Gastric emptying times, small intestinal transit times, colon arrival times and total transit times were calculated. The transit of tablets through the ileo-caecal junction was unaffected by tablet size. All tablets entered into the colon as a bolus. The 3 mm and 6 mm tablets were retained in the ascending colon for the longest period of time. Tablet streaming does not appear to be controlled solely by the diameter of the tablet. Differences in tablet volume also appear to have an effect.

Correlation of the gastric emptying of nondisintegrating tablets with gastrointestinal motility

The aim of the present study was to correlate the gastric emptying (GE) of nondisintegrating tablets with changes in gastrointestinal (GI) motility. Eight, healthy, male subjects each received 5 × 7-mm radiolabeled tablets, a radiolabeled meal, and a radiotelemetry capsule (RTC). Transit of the radiolabeled formulations was followed by gamma scintigraphy and the RTC detected contractile activity in the GI tract. The study demonstrated that 7-mm tablets can empty from the fed stomach, prior to the onset of interdigestive activity. Those tablets that were not emptied during fed activity were retained through the period of quiescence associated with the onset of the migrating myoelectric complex (MMC) and left the stomach during contractions associated with phase 2 and 3 activity. The RTC was retained in the stomach and was emptied only by large phase 3 contractions commonly termed the “housekeeper” wave. However, in one subject, the RTC was retained in the stomach for over 12 hr, during which time three distinct phase 3 complexes were monitored.

Localization of Drug Release Sites from an Oral Sustained-Release Formulation of 5-ASA (Pentasa®) in the Gastrointestinal Tract Using Gamma Scintigraphy

Release of 5‐ASA from a sustained release formulation (Pentasa®, Ferring A/S, Copenhagen, Denmark) was monitored with plasma sampling for up to 24 hours in nine volunteers under both fasted and fed conditions. Drug absorption was correlated with location of the sustained‐release microgranules in the gastrointestinal tract by gamma scintigraphy. Disintegration of the labeled tablet preparation occurred in the stomach within 20 minutes and acetylated 5‐ASA was detectable in the plasma less than 60 minutes after ingestion. No significant differences were detected in either transit times through the small intestine, peak plasma acetylated 5‐ASA concentration or lag time to absorption between fasted and fed individuals. Peak plasma concentration of acetylated 5‐ASA usually occurred when the microgranules were present in the small intestine or ascending colon. The pharmacoscintigraphic study confirmed that 5‐ASA release from the formulation occurred throughout the gastrointestinal tract, and that food effects on the in vivo behavior of the preparation were minimal.

The use of pharmacoscintigraphy to focus the development strategy for a novel 5-ASA colon targeting system (“TIME CLOCK®” system)

Abstract In the early stages of product development for novel colonic delivery systems, considerable time can be lost in establishing the likely potential of any given research strategy because of a lack of suitable in vitro or animal models. We therefore report on the utility of pharmacoscintigraphic evaluation in man to gauge the suitability of three prototype enteric coated 5-ASA “TIME CLOCK®” systems for possible development as front line therapies for treatment of inflammatory bowel disease. The clinical investigation involved the simultaneous assessment of transit/disintegration using scintigraphic imaging and drug absorption via traditional pharmacokinetic evaluation, for the three formulations (20%, 35% and 50% w/w hydrophobic coating) in a group of eight healthy volunteers. Initial tablet disintegration occurred at 5.91±1.47 h post-dose, 8.85±0.90 h post-dose and 12.03±1.25 h post dose for the 20%, 35% and 50% formulations, respectively. There was a clear differentiation between the three prototype 5-ASA “TIME CLOCK®” formulations in terms of in vivo lag time, anatomical location of disintegration, and subsequent 5-ASA absorption. The pharmacoscintigraphic findings provide “proof of concept” data for the colonic delivery of 5-ASA using enteric coated “TIME CLOCK®” technology and help focus the development strategy for subsequent clinical studies in the patient population.