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Journal Club Presentation On… The Influence of Non Disintegrating Tablet Dimensions and Density on Their Gastric Emptying in Fasted Volunteers:

Department of Pharmaceutics 1 Journal Club Presentation On… The Influence of Non Disintegrating Tablet Dimensions and Density on Their Gastric Emptying in Fasted Volunteers Presented By… Saiesh p phaldesai I st yr. M.Pharm Dept. Of P’ceutics , Srinivas college of pharmacy Manglore

Introduction:

Department of Pharmaceutics 2 Introduction Aim- to identify the influence of tablet density on their gastric emptying in fasted subjects and to compare the findings with those of a previous study using the same subjects with tablets of larger diameter. Tablets of 6.6 mm dia. & densities of 1.41 and 2.85gcm -3 were labelled with 99m Tc & 111 In. They were coated with ethyl cellulose. Their position was monitored with double headed gamma camera at 1 min time interval.

Need for present investigation:

Department of Pharmaceutics 3 Need for present investigation To determine whether the previous findings (Podczeck et al 1999), showing a significant difference between the gastric emptying of light (density 1.5 g cm -3 ) & heavy (density 2.85 g cm -3 ) tablets of 6.6mm diameter and whether the two tablet sizes differed in their gastric emptying properties. It is imp. To identified an appropriate time interval for observation of the tablet & also to ensure that the position of the tablet in GIT is clearly identified, to ensure a reliable estimate of the gastric emptying time.

Materials and Methods:

10/5/2013 Department of Pharmaceutics 4 Materials and Methods Materials- Dense tablet - Barium Sulfate BP (grade HR 10; sachtleben chemie Germany) & the ion exchange resin amberlite CG400 (Aldrich chemicals UK ) Light tablet – Lactose Monohydrate BP (Sheffield products, NJ) & ion exchange resin Dowex 50w-8h (BDH, Poole, UK) Binder – Polyvinyl Pyrrolidone BP (BDH, Poole, UK) Lubricant – 1% Magnesium Sterate (BDH, Poole, UK) Coating solution – Ethyl Cellulose BP(grade 50, colorcon, UK) plus 1.2% diethyl phthalate BP and 2.4% polyethylene glycol 4000 in a 70:30 mixture of methylene chloride-methanol

Preparation of Tablets:

Department of Pharmaceutics 5 Preparation of Tablets Wet granulation method. Powders were blended with a appropriate quantity of water in a planetary mixer. Wet mass was pushed by hand through a 1.7mm mesh screen and dried for 2 hrs. at 60 0 c in a hot air oven. Granules were blended with 1% magnesium sterate by tumbling in a round screw-capped jar on rollers. The tablets were compressed with 6.5 mm diameter normal concave punches at a fixed displacement setting on a rotary tablet machine. Coating was applied in a fluidized coater fitted with wurster column & bottom pneumatic spray.

Radiolabelling of tablets:

10/5/2013 Department of Pharmaceutics 6 Radiolabelling of tablets The radiolabel was attached to the tablets by immersing them for 5h in either a solution of sodium pertechnetate in 95% saline (dense tablets) or a 0.04 M hydrochloric acid solution of indium-111 (light tablets) After soaking excess solution was removed & the tablets washed with 2 separate 5 ml quantities of normal saline. They were further washed with 10 ml of normal saline for 1 hr. in an automatic shaker. The excess solution was removed and the tablets dried in a hot air oven at 40 0 c overnight. The radioactivity of tablets was measured with an isotope assay calibrator. The final activity provided on the day of study was 7.4MBq for 99m Tc and 2.6 MBq for the 111 In

Gamma camera study:

Department of Pharmaceutics 7 Gamma camera study Eight healthy male subjects, age range 22-56 (median age 24) took part in study, having provided written consent. They were fasted overnight from 20.00 h on the day before study. At the zero time the subjects swallowed a light and heavy tablet with 50 ml of water, while sitting between the heads of double-headed gamma camera fitted with medium energy collimators. Images of two isotopes were obtained sequentially at 30s intervals with both heads to give anterior and posterior images. The level of activity of 99m Tc & 111 In were measured at 140 & 208 keV resp.

PowerPoint Presentation:

Department of Pharmaceutics 8 With the levels of imaging, it was possible to define the time when tablet first appeared out of stomach to the nearest minute. Once the tablet had emptied from stomach, images were taken at 15 min intervals until 9h. A 0.5 MBq 99m Tc point source was taped on the right side at the base of the ribs as a reference marker to allow position subject between the heads of camera. The standard lunch consisting of McDonalds quarter pounder, French fries and an apple was consumed after 3.5h

Statistical data evaluation:

Department of Pharmaceutics 9 Statistical data evaluation The median & inter quartile range values for the gastric emptying time, using the Bernoulli random event probability distribution approach, were determined using the method described by Podczeck et al (1999). The statistical comparison between emptying times were undertaken with the Wilcoxon signed-rank test.

Results and discussion:

Department of Pharmaceutics 10 Results and discussion Gastric emptying of tablets depends on the contractile state of the stomach, pyloric sphincter and the peristaltic waves over the stomach. The migrating motor/myoelectric complex is the main source of contractile events in fasted state. The MMC occurs cyclically about every two hrs & is considered to act as a transport of waste material along the intestine. The anatomy of fasted stomach indicates that the surface of stomach will consist of folds or rugae, for which there is no particular pattern.

PowerPoint Presentation:

Department of Pharmaceutics 11 The folds run longitudinally from fundus to pyloric antrum The illustration of the fasted stomach clearly showed that when fasted, the posterior/inferior surface will be less curved, with an axis that is nearly vertical. This will result in the tablets moving towards pyloric antrum rather than becoming lodged in the lower portion of J shape, which develops as the stomach is distended when in fed state.

Gastric Emptying Time of Light & Dense Tablets of 6.6 mm:

Department of Pharmaceutics 12 Gastric Emptying Time of Light & Dense Tablets of 6.6 mm Subject Gastric emptying times (min.) Light tablet Dense tablets 1 23 37 2 114 198 3 92 191 4 51 82 5 65 69 6 42 44 7 181 191 8 58 >540

Median and Inter Quartile Range (IQR) of Gastric Emptying of Light & Dense 6.6 mm & 12 mm Diameter Range:

Department of Pharmaceutics 13 Median and Inter Quartile Range (IQR) of Gastric Emptying of Light & Dense 6.6 mm & 12 mm Diameter Range 6.6 mm diameter 12 mm diameter Light Dense Light Dense Median 58.0 82.0 14.8 24.6 IQR 72.0 154.0 16.8 21.0

PowerPoint Presentation:

10/5/2013 Department of Pharmaceutics 14 The median value for gastric emptying time was shorter for the light tablets than the dense tablets. The median value for 6.6 mm tablets were considered longer than those for the 12 mm tablets. Comparing the ranking of the gastric emptying values of the individuals for the two different densities of tablets, using the spearman rank correlation coefficient (0.755 for 6.6mm tab & 0.786 for 12.0 mm tab) does indicate that the ranking was statistically the same for both light & dense tablets on each of the two occasions the tablets were administered. On every occasion higher density tablet left the stomach after the light tablet

PowerPoint Presentation:

Department of Pharmaceutics 15 Considering the findings that the light tablets emptied in a shorter time than the dense tablets, there is clear support for the more rapid emptying of the larger light tablets. 12 mm tablet can empty from stomach agrees with the observations of Munk et al (1978) that the mean resting diameter of the pylorus sphincter is 12.8 + 8.7 mm.

conclusion:

Department of Pharmaceutics 16 conclusion Under fasted conditions, increasing the density of a 6.6 mm tablet from 1.41 to 2.85 g cm -3 extends gastric emptying time. There is clear evidence that irrespective of tablet density, a 12.0 mm tablet has a shorter emptying time than a tablet of 6.6mm.

PowerPoint Presentation:

Department of Pharmaceutics 17 Thank You

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