Pharmacoscintigraphy studies to assess the feasibility of a controlled release formulation of ziprasidone.

Ziprasidone, like many BCS Class II drugs with low intrinsic solubility and a strong tendency to crystallize from supersaturated solutions, presents significant technical challenges when developing an oral controlled release dosage form. In order to achieve acceptable bioavailability and prolonged exposures for once-daily dosing, good colonic absorption and a reliable controlled release (CR) technology are necessary. To this end, a novel solubilized drug form--coated crystals made by spray drying (CCSD), was formulated and progressed into human clinical studies. This report describes studies of colonic absorption for the CCSD using the Enterion™ capsule and a pharmacoscintigraphy study in which the CCSD was orally administered via a radiolabelled osmotic tablet formulation. These studies demonstrated that the probability of achieving the required drug solubilization in the colon with the CCSD concept and thereby the desired once daily pharmacokinetic profile was extremely low.

In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

In vitro and in vivo pharmacoscintigraphic evaluation of ibuprofen hypromellose and gelatin capsules.

PURPOSE: To evaluate the in vitro and in vivo characteristics of hypromellose (HPMC) capsules prepared using a gellan gum and potassium gelling system compared to conventional hard gelatin capsules. METHODS: The in vitro dissolution of ibuprofen gelatin and HPMC capsules was determined using the USP and TRIS buffers at pH 7.2. The effect of pH and composition of the media was determined using a model drug that is soluble throughout the pH range 1.2 to 7.2. In an 11 subject four-way crossover study, the gastrointestinal performance of ibuprofen gelatin and HPMC capsule formulations was evaluated using scintigraphy and pharmacokinetics following fasted and fed dosing. RESULTS: Acid conditions and the presence of K+ cations hinder HPMC capsule opening, whereas in water, dissolution is identical to that of gelatin. These effects are related to the nature of the gel network that is formed in the presence of cations. No significant difference in esophageal transit was observed. Although the in vivo opening times of HPMC capsules were longer than for their gelatin counterparts, no significant difference in the regulatory important pharmacokinetic metrics of C(max) and AUC was found between ibuprofen, gelatin and HPMC capsules. CONCLUSIONS: The in vitro performance of HPMC capsules differ from gelatin, which will require modification to dissolution testing methodology for certain drugs. However, for the class II BCS drug ibuprofen, the two capsule types were not statistically different when comparing AUC and C(max) values, which suggests that the in vitro differences have reduced in vivo relevance.

Assessment of lumiracoxib bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy.

PURPOSE: To determine the bioavailability and pharmacokinetic profile of lumiracoxib from different sites in the gastrointestinal tract. METHODS: Subjects (11 healthy adult males) were randomized to receive a 100 mg lumiracoxib dose, via a site-specific radiolabeled delivery capsule, to the stomach (internal reference), proximal small bowel, distal small bowel, or ascending colon. Gamma scintigraphy was used for real-time visualization of capsule location, and a radiofrequency signal was used to activate capsules at target site. RESULTS: Ten subjects completed the study. The mean capsule activation times for the stomach, proximal small bowel, distal small bowel, and ascending colon were 0.22, 1.52, 3.43, and 11.46 h post dose, respectively. Lumiracoxib was well absorbed from the proximal and distal small bowel, with AUC(0-infinity) ratios 104% (86, 127)% and 110% (89, 136)%, respectively. The highest Cmax (2413 ng/ml) and AUC(0-infinity) for lumiracoxib were in the distal small bowel (6842 ng x h/ml). Effective absorption was observed from the ascending colon, with an AUC(0-infinity) ratio of 85% (69, 104)% vs. the reference. CONCLUSIONS: Lumiracoxib is rapidly and efficiently absorbed throughout the gastrointestinal tract.

Scintigraphic evaluation of a novel colon-targeted delivery system (CODES) in healthy volunteers.

The purposes of this study are to investigate the gastrointestinal transit and release properties of a novel, colon-targeted delivery system (CODES) administered to healthy volunteers using gamma scintigraphy and to confirm that lactulose functions to promote disintegration in the colon. Two placebo formulations were studied: one was CODES, which consisted of a lactulose containing core overcoated with both Eudragit E and Eudragit L designed to rapidly disintegrate in the colon, the other was lactulose-free reference formulation (LFRF) that consisted of lactulose-free tablet core overcoated with the same materials. Transit and disintegration of the radiolabeled formulations were followed by gamma scintigraphy. In the fasted state, scintigraphic images indicated that CODES started to disintegrate in the ascending colon in the majority of subjects at 7.11 +/- 2.01 h post-dose. Disintegration was complete within 1 h following commencement of in vivo release. In contrast, LFRF presented with prolonged in vivo disintegration properties. In the fed state, the disintegration period of CODES was almost comparable to that observed in the fasted state. Gamma scintigraphic studies clearly showed that CODES provides for rapid target site release in the colon regardless of the ingestion of food.

Remote controlled capsules in human drug absorption (HDA) studies.

The biopharmaceutical complexity of today's new drug candidates provides significant challenges for pharmaceutical scientists in terms of both candidate selection and optimizing subsequent development strategy. In addition, life cycle management of marketed drugs has become an important income stream for pharmaceutical companies, but the selection of least risk/highest benefit strategies is far from simple. The proactive adoption of human drug absorption (HDA) studies using remote controlled capsules offers the pharmaceutical scientist significant guidance for planning a route through the maze of product development. This review examines the position of HDA studies in drug development, using a variety of case histories and an insightful update on remote controlled capsules to achieve site-specific delivery.

The effect of ileal brake activators on the oral bioavailability of atenolol in man.

A study was carried out in human volunteers to investigate whether ileal brake activators could alter the bioavailability of atenolol from the small intestine by slowing intestinal transit and thereby increasing the time available for absorption. Oleic acid and a monoglyceride were formulated into modified release capsules that were targeted to the small intestine. Atenolol was either dosed separately or incorporated into one of the capsules. Radiolabelled non-disintegrating tablets were dosed at the same time in order to determine the small intestinal transit time (SITT). Plasma concentrations of atenolol were determined by HPLC. The results showed that in some volunteers an increase in SITT did lead to an increase in the quantity of drug absorbed. However, drug absorption was related not only to the total time spent by the drug in the small intestine but other factors such as the proportion of such time spent at the ileocaecal junction. The study highlights the complexities of exploiting natural gastrointestinal processes to enhance the oral bioavailability of drugs.

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.