Comparison of beclomethasone dipropionate delivery by easyhaler dry powder inhaler and pMDI plus large volume spacer.

Dry powder inhalers (DPIs) provide a means of delivering inhaled asthma drugs without the use of propellants. Easyhaler is a multidose DPI, delivering 200 doses of beclomethasone dipropionate (BDP), 200 microg/dose. A gamma scintigraphic study has been carried out in 10 healthy volunteers to compare the deposition of BDP from Easyhaler with that from a pressurized metered dose inhaler (pMDI) coupled to a Volumatic spacer device delivering 250 microg BDP per dose. The spacer was used without any pretreatment to reduce static charge on the spacer walls. The study was conducted according to an open, randomized, crossover design. The volunteers inhaled the study drug using optimal inhalation technique for both devices. Lung deposition of 99mTc-labeled BDP averaged 18.9% (SD 9.5%) of the metered dose for Easyhaler, and 11.2% (SD 5.3%) for pMDI plus spacer (p < 0.05); when the data were expressed as mass of BDP deposited in the lungs, the difference in lung deposition just failed to reach statistical significance (Easyhaler 37.8 microg; pMDI plus spacer 28.0 microg). Oropharyngeal deposition was significantly reduced by use of the spacer. The results of this study show that Easyhaler delivers drug more efficiently to the lungs than pMDI plus Volumatic spacer when no measures are taken to eliminate static charge on the spacer walls.

The use of scintigraphy to provide "proof of concept" for novel polysaccharide preparations designed for colonic drug delivery.

PURPOSE: The aim of the present study was to provide "proof of concept" data in man for novel polysaccharide preparations designed for colonic drug delivery using gamma scintigraphy. METHODS: Two placebo calcium pectinate matrix tablet formulations were studied: one contained calcium pectinate and pectin (CaP/P) and was designed to rapidly disintegrate in the ascending colon, the other contained calcium pectinate and guar gum (CaP/GG) and was designed to disintegrate more slowly, releasing its contents throughout the ascending and transverse colon. Both formulations were enteric coated in order to protect them from the stomach. Ten healthy volunteers received either a CaP/P or CaP/GG tablet, in a randomised cross-over study. Transit and disintegration of the radiolabelled formulations was followed by gamma scintigraphy. Rat studies were conducted in order to verify that the expected colonic degradation of the polysaccharide formulations was as a consequence of bacterial enzyme attack. RESULTS: The in vivo clinical study confirmed the results obtained in the rat and bench in vitro fermentation models; complete tablet disintegration for Formulation CaP/GG appeared to be slower than that of Formulation CaP/P and the time and the location of complete tablet disintegration was more reproducible with Formulation CaP/P compared to Formulation CaP/GG. CONCLUSIONS: These results provide "proof of concept" data for the use of calcium pectinate preparations for drug delivery to the colon and highlight the value of scintigraphy in focusing the development strategy for colonic targeting preparations.

The effect of mannitol on the oral bioavailability of cimetidine.

The aim of the study was to investigate whether mannitol at amounts relevant to pharmaceutical formulations would alter the oral bioavailability of cimetidine, a drug primarily absorbed from the small bowel. Seven healthy male subjects each received four formulations, a chewable tablet or a solution, containing 0.200 g of cimetidine and either 2.264 g of mannitol or sucrose, in a randomized four-way cross-over study. Frequent blood samples were taken over a 24 h period to allow a cimetidine plasma profile to be obtained for each formulation. Transit of the radiolabeled formulations was followed by gamma scintigraphy. Statistically significant reductions in the AUC0-24 and maximum plasma concentration values were observed with the mannitol dosage forms compared to the sucrose controls. The mean small intestinal transit times were shortened after administration of the mannitol solution and tablet; the transit time of the solution was significantly shorter with values 23% of those for the sucrose solution. The implication of the study findings is that excipients cannot always be regarded as "inert" substances that can be incorporated into a formulation without having any deleterious effect on the overall in vivo behaviour of the product.

Echo-planar magnetic resonance imaging to assess water volume in the distal small bowel.

PURPOSE: Assessment of fluid volumes and flow through the small intestine has in the past only been possible by means of invasive intubation studies on human volunteers. Intubation very likely disturbs gut motility and stimulates secretion. METHODS: The aim of this study was to utilise the new technique of echo-planar magnetic resonance imaging in order to non-invasively visualise the changing volume of water in the small intestinal lumen. 200 mls of test solution was ingested and water volume assessed using a multi-slice scanning technique on 3 separate days. The solutions were pure water, pure water plus 2.264 or 10 g of mannitol. These were taken on separate days by 8 healthy male volunteers. Regions of interest were constructed in the area of the lower pelvis excluding retroperitoneal structure. RESULTS: The water content of the lower small intestine did not change significantly over the 4 hours after the control solution. By contrast after both mannitol solutions there was an increase in the amount of water in the distal intestine as assessed by the area under the curve of the volume time profile (Control 51 ml.h (SD +/- 47); mannitol 2.264 g/200 ml 72 ml.h (SD +/- 57); 10 g/200 ml mannitol 115 ml.h (SD +/- 56)). Page's L Trend test showed that the trend for the volume to increase with increasing mannitol concentration to be statistically significant at the 1% level (L = 108). CONCLUSIONS: The study highlights the potential of echo-planar magnetic resonance imaging to visualise changes in gastrointestinal physiology in a noninvasive manner.

The effects of pharmaceutical excipients on small intestinal transit.

1. The effect of three iso-osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non-disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11-14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39-94-149 min, and 40-82-124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non-disintegrating tablet preparations, when co-administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of different concentrations of mannitol in solution on small intestinal transit: implications for drug absorption.

The aim of the present study was to investigate the effect that different concentrations of mannitol have on small intestinal transit, and whether any observed effect was concentration dependent. Eight, healthy male subjects each received 200ml of radiolabelled purified water, or a 200ml solution of mannitol at three different concentrations; 0.755g/200ml, 1.509g/200ml and 2.264g/200ml, in a randomised, four way cross-over study. Transit of the radiolabelled solutions was followed by gamma scintigraphy. The study demonstrated no significant differences between the gastric emptying times of the four solutions. Rapid gastric emptying was observed in most cases. The mean small intestinal transit times for the 0.755g/200ml, 1.509g/200ml and 2.264g/200ml mannitol solutions was reduced by 11%, 23% and 34% respectively, when compared to the control solution. The intestinal transit data of the four solutions demonstrate that mannitol has a concentration dependent effect on small intestinal transit. Small concentrations of mannitol included in a pharmaceutical formulation could therefore lead to reduced uptake with any drug exclusively absorbed from the small intestine.