ColoPulse tablets perform comparably in healthy volunteers and Crohn's patients and show no influence of food and time of food intake on bioavailability.

ColoPulse tablets are an innovative development in the field of oral drug delivery and are characterized by a colon-specific release. Until now ColoPulse dosage forms (only capsules) have been studied in healthy volunteers having a standardized breakfast three hours after administration but not in specific patient groups and not with a shorter interval between administration and breakfast. Information on bioavailability and release characteristics of ColoPulse tablets in Crohn's patients and the influence of food and time of food intake is a prerequisite to properly design future clinical studies with active substances in these patients. In the current cross-over study bioavailability and drug release characteristics of ColoPulse tablets were compared in healthy volunteers and in Crohn's patients in remission. Furthermore the influence of food and time of food intake on the in vivo drug release behavior of ColoPulse tablets was investigated. In this study the dual label isotope strategy was used which means that a ColoPulse tablet containing (13)C-urea and an uncoated, immediate release tablet containing (15)N2-urea were taken simultaneously. Breath and urine samples were collected during the test day for isotope analysis. The appearance of the stable isotopes in breath and/or urine provides information on the site of release from the dosage form, release characteristics and bioavailability. Both tablets were administered on two different days in a cross-over design: the first day with a breakfast (non-standardized) one hour after administration and the second day with a standardized breakfast three hours after administration of the tablets. There was no difference in instructions for administration between both days. Results of 16 healthy volunteers and 14 Crohn's patients were evaluated. At least 86% (51 out of 59) of all ColoPulse tablets administered in this study released their contents at the desired intestinal region. There was no significant difference in bioavailability between healthy volunteers and Crohn's patients on both days (day 1 75.8% vs 90.2%, p=0.070 and day 2 83.4% vs 91.4%, p=0.265). There was also no significant influence of food and time of food intake on bioavailability in healthy volunteers (75.8% and 83.4%, p=0.077) and in Crohn's patients (90.2% and 91.4%, p=0.618) when day 1 and day 2 were compared. Release characteristics did not significantly differ between healthy volunteers and Crohn's patients. However, food and time of food intake had some, clinically non-relevant, influence on the release characteristics within both groups which is in line with the fact that food affects gastro-intestinal transit times. This study shows that ColoPulse tablets enable the site-specific delivery of drugs or other compounds (e.g. diagnostics) deep in the ileo-colonic region of the intestine of Crohn's patients in a comparable amount and rate as in healthy volunteers. Food and time of food intake had no relevant influence on bioavailability. In conclusion ColoPulse delivery systems are promising and deserve further research for local therapy with immunosuppressive drugs in Crohn's patients in the near future.

Oral ileocolonic drug delivery by the colopulse-system: a bioavailability study in healthy volunteers.

The release profile of a novel oral ileocolonic drug delivery technology (ColoPulse-technology) was assessed by a combination of conventional kinetics of a marker substance in blood and site-specific signaling by stable isotope technology. Since ileocolonic delivery involves the drug release in a region in which bacteria are highly present, a prolonged lag time should coincide with proven bacterial enzyme activity. The latter can be tested using 13C-urea as the marker substance. The study was designed as a two period (uncoated versus coated capsule) crossover single dose bioavailability study in healthy subjects. The 13C-recovery data after oral administration of 13C-urea using the ColoPulse delivery system showed a delayed sigmoid release in all subjects with a lag time of > 3h (median: 330 min). Release was achieved in a urease-containing intestinal segment in all healthy subjects. Complete release in the ileocolonic region was achieved in 10 of 11 subjects. The ColoPulse-technology therefore enables specific and reliable drug delivery in the ileocolonic region in healthy volunteers.

Proof-of-concept study on the suitability of 13C-urea as a marker substance for assessment of in vivo behaviour of oral colon-targeted dosage forms.

BACKGROUND AND PURPOSE: (13)C-urea may be a suitable marker to assess the in vivo fate of colon-targeted dosage forms given by mouth. We postulated that release in the colon (urease-rich segment) of (13)C-urea from colon-targeted capsules would lead to fermentation of (13)C-urea by bacterial ureases into (13)CO(2). Subsequent absorption into the blood and circulation would lead to detectable (13)C (as (13)CO(2)) in breath. If, however, release of (13)C-urea occurred in the small intestine (urease-poor segment), we expected detectable (13)C (as (13)C-urea) in blood but no breath (13)C (as (13)CO(2)). The differential kinetics of (13)C-urea could thus potentially describe both release kinetics and indicate the gastrointestinal segment of release. EXPERIMENTAL APPROACH: The in vivo study consisted of three experiments, during which the same group of four volunteers participated. KEY RESULTS: The kinetic model was internally valid. The appearance of (13)C-in breath CO(2) (F(fermented)) and the appearance of (13)C in blood as (13)C-urea (F(not fermented)) show a high inverse correlation (Pearson's r=-0.981, P= 0.06). The total recovery of (13)C (F(fermented)+F(not fermented)) averaged 99%, indicating complete recovery of the administered (13)C via breath and blood. (13)CO(2) exhalation was observed in all subjects. This indicates that (13)C-urea was available in urease-rich segments, such as the caecum or colon. CONCLUSIONS AND IMPLICATIONS: In this proof-of-concept study, (13)C-urea was able to provide information on both the release kinetics of a colon-targeted oral dosage form and the gastrointestinal segment where it was released.

Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings.

Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope (13)C(6)-glucose as the test compound were administered and the occurrence of (13)CO(2) in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines.

A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products.

Mesalazine (5-ASA) is a compound being used in the therapy of inflammatory bowel disease (IBD). Considering the fact that 5-ASA is locally active and that the location of inflammation in IBD may vary, it is recognized that the release profile of 5-ASA drugs is the dominant factor for adequate local bioavailability. Furthermore, it is hypothesized that systemic absorption of 5-ASA (mainly in the upper intestinal segments) increases the risk of side effects. These facts relate to the conclusion that a method determining the dissolution profile under biorelevant conditions is a valuable tool for evaluation and comparison of 5-ASA-products. We tested several commercially available products (Salofalk tablets, Salofalk granules, Asacol tablets, Pentasa tablets and granules) in a gastro-intestinal simulation system (GISS). The GISS is based on the pharmacopeial dissolution test. The release profiles of all products are in agreement with their technological concepts. The percentage of the dose released in the simulated colon is small in all products. The GISS is a robust system able to discriminate between products which apply different modified-release technologies. Colon-selectivity of modified-release 5-ASA products might further be improved. The commercially available 5-ASA containing oral dosage forms exhibit different release profiles, which suggests that the optimal product may differ per patient.