Scintigraphic study to investigate the effect of food on a HPMC modified release formulation of UK-294,315.

The objective of the study was to use the combined approach of gamma scintigraphy and pharmacokinetics, in order to understand the mechanisms explaining the pharmacokinetic differences observed for a modified release (MR) formulation, when administered either in the fed or fasted state. Ten healthy subjects were recruited into a randomized three period single dose study, each subject receiving UK-294,315 40 mg IR (fasted), 100 mg MR (fasted) or 100 mg MR (after a high fat meal). C(max) values were markedly higher for the MR tablet in the fed state versus fasted and mean residence time was about 3 h longer for fasted versus fed; there was little difference in apparent oral clearance. In the fasted state, average gastric emptying of the intact tablet occurred at 1.2 h postdose, with gastric emptying of intact tablet observed in all subjects. In the fed state, rapid disintegration of the MR tablet was observed by scintigraphy, with 7/9 subjects showing complete disintegration in the stomach. Complete disintegration occurred 10.1 h postdose in the fasted state versus 5.9 h after a high fat meal. The study showed that in the fed state, the MR tablet eroded more rapidly than in the fasted state, leading to an overall increase in the rate of absorption.

Pharmaceutical design of a novel colon-targeted delivery system using two-layer-coated tablets of three different pharmaceutical formulations, supported by clinical evidence in humans.

Drug delivery systems to the colon are being actively investigated in order to develop oral preparations of peptides and treat local colonic diseases. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. To make a colonic delivery system practical for medical use, in vitro testing methods need to be established in order to determine the specifications of the preparations. To achieve this objective, three pharmaceutical preparations, designed to have different tablet disintegration times, were used to examine three buffers in seven combinations intended to simulate pH changes in the stomach, small intestine, and colon of humans. To validate the in vitro methodology, furthermore, the fate of all the formulations was examined in the gastrointestinal (GI) tract of healthy volunteers. A three-way crossover trial by scintigraphy revealed that the three formulations--in spite of presenting different in vitro tablet disintegration profiles--have comparable transit profiles and excellent colon-targeting properties in the human gastrointestinal tract regardless of gender and age. These facts strongly suggest that this novel delivery system may be useful for the delivery of drugs to the human colon.

Combined scintigraphic and pharmacokinetic investigation of enteric-coated mesalazine micropellets in healthy subjects.

BACKGROUND: There is a growing clinical trend to increase the daily dose of mesalazine, which leads to significant compliance issues associated with multiple dosings of current preparations. AIM: To examine the gastrointestinal performance and systemic exposure of a 1.5 g sachet (micropellets) mesalazine formulation, compared with three enteric-coated tablets (500 mg each, Claversal). METHODS: A randomized, two-way, cross-over pharmacoscintigraphic (scintigraphy plus pharmacokinetics) study and a two-way, cross-over, pharmacokinetic-only study were performed in 24 healthy volunteers (12 subjects per investigation). RESULTS: The relative bioavailability of mesalazine was 92% comparing micropellets with Claversal tablets, and the cumulative urine excretion was c. 26% for both preparations, suggesting comparable systemic exposure for the two types of preparation. In the majority of subjects, drug release from the micropellet formulation occurred predominantly in the terminal ileum and ascending colon. The Claversal tablets disintegrated in comparable intestinal sites, albeit at slightly later time points than the micropellets, principally due to slower gastric emptying for the single-unit formulation. CONCLUSION: The 1.5 g micropellet formulation offers comparable delivery properties to the marketed tablets, but with greater convenience of dosing.

A scintigraphic study to investigate the potential for altered gut distribution of loperamide from a loperamide-simethicone formulation in man.

A loperamide simethicone combination formulation has recently been demonstrated to have significant clinical advantages compared to loperamide alone in the relief of diarrhoea and related symptoms. The product visualisation technique of gamma scintigraphy has been used to investigate the interaction of the formulation with the heterogenous environment of the human gut in a group of 12 healthy volunteers. The results suggest that changes in the intestinal kinetics of loperamide from the combination product, e.g. jejunal coating, could be contributing to the improved efficacy.

Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon.

The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.

The role of gamma-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 gamma-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).

Oral drug absorption studies: the best model for man is man!

The Discussion Forum provides a medium for airing your views on any issues related to the pharmaceutical industry and obtaining feedback and discussion on these views from others in the field. You can discuss issues that get you hot under the collar, practical problems at the bench, recently published literature, or just something bizarre or humorous that you wish to share. Publication of letters in this section is subject to editorial discretion and company-promotional letters will be rejected immediately. Furthermore, the views provided are those of the authors and are not intended to represent the views of the companies they work for. Moreover, these views do not reflect those of Elsevier, Drug Discovery Today or its editorial team. Please submit all letters to Rebecca Lawrence, News & Features Editor, Drug Discovery Today, e-mail: rebeca.lawrence@current-trends.com

Human lung deposition data: the bridge between in vitro and clinical evaluations for inhaled drug products?

Regulatory dossiers for new inhaled drug products generally contain in vitro data, which assess delivered dose and particle size distribution, together with clinical efficacy and safety data. Human lung deposition data may be generated using radionuclide imaging techniques or appropriate pharmacokinetic methods, and can act as a 'bridge' via which a seamless transition can be made between in vitro testing in the laboratory and efficacy/safety testing in the clinic. By enabling informed decisions to be made about the evaluation of new devices or formulations in man, lung deposition data permit a long and expensive clinical trials programme to be commenced with much greater certainty of a successful outcome. Human lung deposition data should be considered for supplementing the information required for regulatory dossiers.

Development of a new engineering-based capsule for human drug absorption studies.

Over recent years, there has been a significant growth in the number of new drugs entering development with challenging pharmaceutical (e.g. solubility) and biopharmaceutical (e.g. permeability) properties. As a consequence, there is an increasing number of pharmaceutical companies using human absorption studies to provide a 'route map' for development. These projects are typically undertaken early in clinical development and utilize engineering-based capsules to provide non-invasive drug delivery to the selected sites of the human gut. The Enterion capsule has recently been developed to provide for the delivery of a wide range of different drug formulations, for example, solution, powder and granulate, into any region of the gut, both easily and efficiently.

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.

AIMS: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. METHODS: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings. RESULTS: Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. CONCLUSIONS: Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form.

Does the site of intestinal delivery of oleic acid alter the ileal brake response?

Previous work has demonstrated that high doses of oleic acid can activate the ileal brake but the importance of site of delivery has yet to be investigated. The objective of this study was to use modified release capsules to release oleic acid in different regions of the intestine. When tested by in vitro dissolution in pH 6.8 phosphate buffer, one batch released the contents almost immediately, another after around 30 min and the last batch after around 60-70 min. The effect of oleic acid release site on the ileal brake was assessed by the measurement of transit time of radiolabelled non disintegrating tablets by gamma scintigraphy. The results demonstrated that the transit of tablets could be slowed down by oleic acid and therefore it appears the ileal brake can be activated along the entirety of the small intestine.

Gastrointestinal spread of oral prolonged-release mesalazine microgranules (Pentasa) dosed as either tablets or sachet.

BACKGROUND: There is increasing interest in using higher dosages of mesalazine for the treatment of inflammatory bowel disease; however, with current mesalazine products this involves the use of 8-16 tablets per day. AIM: To evaluate the disposition, dispersion and movements of Pentasa prolonged-release microgranules following single dosing of either tablets (2 x 500 mg) or a new 1 g sachet (unit dose, microgranules in a foil bag). METHODS: A randomized crossover study in eight healthy volunteers was undertaken. Both formulations were radiolabelled by neutron activation and dosed in the fasted state. Location of the preparations in the bowel was assessed over 24 h by scintigraphy. RESULTS: Dissolution testing at pH 7.5 showed comparable in vitro mesalazine release properties for the tablet and sachet preparations. In vivo disposition of the microgranules administered as either tablets or sachet was comparable in terms of gastric emptying, small intestinal transit and colon arrival. CONCLUSIONS: Pentasa sachets 1 g unit dose offers the same release of mesalazine as Pentasa 500 mg tablets. Drug release occurs throughout the gastrointestinal tract from stomach to colon, with the advantage of fewer oral doses and ease of swallowing.

Site-specific drug delivery in the gastrointestinal tract.

In recent years there has been a significant increase in available strategies for site-specific delivery in the gastrointestinal tract both to maximize a therapeutic response and to reduce side effects. However, in only a few instances has there been close attention paid to how these products will perform in the heterogeneous environment of the human gut. Targeted oral delivery requires a multidisciplinary approach to research, involving contributions not only from polymer and pharmaceutical scientists but also from experts in gastroenterology and product evaluation. The objective of this article is, therefore, to examine our current understanding of human gastrointestinal physiology and to review the current "state of the art" of available targeting strategies. Emphasis will be placed on human data and, in particular, the interaction between the delivery system and the gastrointestinal tract, as assessed by product visualization studies.

Evolution of the biopharmaceutics classification system (BCS) to oral modified release (MR) formulations; what do we need to consider?

The Biopharmaceutics Classification System (BCS) has provided a mechanistic framework for understanding the concept of drug absorption in terms of permeability and solubility. Regulatory guidance for Immediate Release (IR) products incorporating the BCS has appeared over recent months. Extrapolation of the approach to oral Modified Release (MR) formulations is therefore inevitable, however, further evolution of our thinking is first required. MR products can deliver drug throughout the gastrointestinal tract and it is important that we recognise there is significant heterogeneity in permeability, lumenal pH/contents and gut wall metabolism from stomach to colon.

The effect of oleic acid on the human ileal brake and its implications for small intestinal transit of tablet formulations.

PURPOSE: A human volunteer study was carried out to investigate whether activation of the ileal brake mechanism affects the transit of tablets through the small intestine. METHODS: Oleic acid, which has previously been shown to activate the brake, was delivered to the small intestine in a modified release capsule at doses of 300 mg, 600 mg and 1200 mg. The effect of the oleic acid was determined by measuring the transit of two sets of radiolabelled tablets by gamma scintigraphy. One set of tablets was dosed with the capsule and the other one hour later. RESULTS: The results show that in the majority of the volunteers small intestinal residence time was greater with the oleic acid than control. The effect was most pronounced in the tablets given concomitantly with the capsule and with the higher doses of oleic acid. CONCLUSIONS: The ileal brake, activated by oleic acid, can slow the transit of tablets through the small intestine.

The effect of cross-linking on the in vivo disintegration of hard gelatin capsules.

PURPOSE: To evaluate if the cross-linking of gelatin affects in vivo capsule disintegration. METHODS: Scintigraphic investigation in nine healthy volunteers to provide for a real time visualisation of capsule disintegration. RESULTS: The moderately stressed capsules failed the USP dissolution specification for acetaminophen capsule when tested in water and conventional SGF but passed with the addition of pepsin. Moderately stressed capsules started to disintegrate at 10 +/- 6 minutes (range 6 to 24 minutes) compared to 8 +/- 2 minutes (range 5 to 11 minutes) for the unstressed capsule. CONCLUSIONS: The results of the study clearly demonstrate that with the incisive technique of gamma scintigraphy there are no differences in the in vivo disintegration properties of moderately stressed and unstressed capsules.

The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir).

PURPOSE: To evaluate mechanistically the effect of food on the absorption and gastrointestinal transit of the protease inhibitor saquinavir. METHODS: Pharmacoscintigraphic investigation in eight healthy volunteers. RESULTS: Gastric emptying occurred rapidly in the fasted state with some capsules leaving the stomach prior to disintegration. Unmeasurable plasma concentrations were observed in several subjects when dosed under fasted conditions. Following post-prandial administration the radioactive marker became re-distributed within the stomach contents and consequently slower gastric emptying resulted. Plasma concentrations under fed conditions were measurable up to 12 hrs after administration in seven of the eight subjects. Six of the eight plasma profiles showed secondary peaks at c. 4 hours post-dose; two of which coincided with the gastrocolonic response following ingestion of lunch. CONCLUSIONS: Bioavailability of saquinavir is significantly improved in the presence of food. Emptying of intact capsules in the fasted state may further reduce bioavailability. In the fed state, capsules disintegrate rapidly and gastric emptying is prolonged which may improve exposure of the drug to target absorption sites. Saquinavir may be absorbed from the colon. Second peaks in the absorption profile can only be attributed to gastrocolonic response following ingestion of a meal in some cases. Increased absorption is more likely to be due to an increase in dissolved drug being available for absorption due to general increased motility and secretion stimulated by ingestion of a meal.

Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers.

Colonic drug delivery is intended for local or systemic therapies. The lack of predictive in vitro or animal model leads to considerable time delays in colonic product development. The objective of this scintigraphic study was to provide "proof of concept" for a novel capsule-type colonic delivery system (Colon-Targeted Delivery Capsule) in healthy volunteers. The human data validates the design concept behind the release mechanism, in that capsule disintegration, and hence drug release, did not start until 5 h after gastric emptying, irrespective of whether the product was administered to fasted or fed subjects. However, the potential for prolonged gastric residence for large enteric coated products intended for intestinal targeting was also observed; overall, the study provides a focus for subsequent product development and highlights the role of scintigraphy in dynamically visualizing the drug delivery process.

Is the pig a good animal model for studying the human ileal brake?

This study was designed to investigate the existence of an ileal brake mechanism in the pig model. The test substances used (oleic acid, deoxycholic acid, taurocholic acid) had all been previously shown to affect the ileal brake mechanism in other species including man. The substances were infused directly into the terminal ileum of surgically modified pigs, 45 min after the pigs had ingested a meal containing a drug marker. The marker used was sulfasalazine, which is cleaved to form a metabolite, sulfapyridine, when it reaches the colon. The subsequent HPLC analysis of collected blood samples allowed the appearance of sulfapyridine in the plasma and hence the arrival of sulfasalazine in the colon to be determined. Any differences in transit between control and test could be evaluated from a profile of plasma concentrations and corresponding values of AUC. The findings from this study show that the various substances did not affect transit of a test meal in the pig and suggest that it is not possible to use this pig model to make predictions about the human ileal brake.