Comparison of the bioavailability of MST Continus tablets and Oramorph SR tablets.
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Absorption↗
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In vivo/in vitro correlations for four differently dissolving ketorolac tablets.
This study assesses whether in vitro immediate release ketorolac tablet dissolution profiles (utilizing the recently proposed USP dissolution test for ketorolac tablets) can be correlated with in vivo plasma pharmacokinetic parameters. Four batches of ketorolac tablets were utilized: a ketorolac tablet batch that demonstrated a rapid dissolution rate during USP in vitro dissolution testing, two tablet batches that were manufactured such that they dissolved at moderate rates, and a tablet batch that was manufactured such that it dissolved at a distinctly slow rate. The single-dose mean pharmacokinetic characteristics and relative bioavailability of the four different 10 mg ketorolac tromethamine tablets were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The amount dissolved of the various tablets at 10, 20, and 30 min was in the order of fast-dissolving tablets > medium-1-dissolving tablets = medium-2-dissolving tablets > slow-dissolving tablets. In general, the profiles of the average plasma concentrations for ketorolac were similar for the fast- and the two medium-dissolving tablet batches (even though a statistically significant difference was found between the tmax of the fast-dissolving tablet and one of the medium-dissolving tablet batches). The mean plasma concentrations for the slow-dissolving tablet, however, reached peak levels much later, with the peak also being significantly smaller. There were no statistically significant differences in the total AUC or in the mean plasma half-lives among the four formulations. Good correlations were obtained for mean tmax versus the percentage dissolved at 20, 30, and 45 min. Correlations were generally weaker for percentage dissolved versus Cmax or percentage bioavailability. This indicates that in vitro dissolution testing for immediate release ketorolac tablets can be a useful indicator of in vivo time to maximum plasma concentration when comparing similarly formulated tablets. Further, the proposed USP dissolution test and specification would have appropriately failed the slow-dissolving tablet batch, which demonstrated a significantly slower rate of absorption as per tmax and Cmax.
Adult↗
A better dissolution method for ranitidine tablets USP.
Ranitidine tablets USP showed variable intra- and inter-lab dissolution results. In order to ascertain the reason for this behavior, ranitidine tablets USP produced by (BIPI) Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, and Zantac Tablets (brand of ranitidine USP), Glaxo Inc., Research Triangle, NC, were subjected to the compendia (USP) dissolution testing using paddle and basket apparatus. Two potencies of tablets 150 mg and 300 mg were tested. Comparison of BIPI tablets and matching Zantac tablets indicated that both brands of ranitidine tablets USP had similar dissolution behavior. When the basket apparatus was substituted for the paddle apparatus the overall rate and extent of tablet dissolution increased, while the individual tablet variability decreased. BIPI 150 mg tablets using the basket apparatus, but at reduced rotational speed of 30 rpm, showed increase in rate and extent of drug dissolved, with less individual tablet variability compared to the paddle apparatus at 50 rpm. The 300 mg tablet (30 rpm/basket apparatus) had an initial slower rate, but then rapidly equaled the paddle apparatus dissolution results, and had less individual tablet variability. Paddle apparatus tablet sinkers were used to prevent tablets from sticking to the bottom of the dissolution vessel. Overall dissolution for all tablets with sinkers showed a trend which was more rapid and complete than tablets without sinkers. Results showed that dissolution artifacts for ranitidine tablets could be reduced by the use of baskets or tablet sinkers.
Anti-Ulcer Agents↗
Effect of calcium tablets on interpretation of lumbar spine DXA scans.
Undissolved calcium (Ca) tablets in the gastrointestinal tract at the time of a dual-energy X-ray absorptiometry (DXA) scan could conceivably affect the accuracy of the lumbar spine bone mineral density (BMD) determination. We studied phantoms and volunteers to determine the effect of Ca tablets overlying bone, Ca tablets in the soft-tissue field, and Ca tablets overlapping both bone and soft tissue. For L1-4, a 500-mg Ca tablet taped to the phantom surface or the skin of volunteers resulted in <or=2.2% mean increase in measured BMD (less than the lumbar spine least significant change), changing the T-score for L1-4 very little. However, an overlying Ca tablet had a substantial effect on BMD of a single vertebral body. Greater effects were seen with higher amounts of tablet Ca and with lower BMD, resulting in as much as a 12.6% mean increase in single vertebral BMD in the in vivo series. Recent versions of DXA software successfully identified tablets in the soft-tissue field as artifact and eliminated the tablet pixels from the analysis. However, tablets overlapping bone and soft tissue necessitated operator intervention to either exclude the affected vertebral body or adjust edges by mapping the tablet as artifact and/or neutral field. A paraffin-coated Ca tablet swallowed by a volunteer was tracked serially by DXA during gastrointestinal transit. Similar effects were seen as with the phantom and volunteer studies using external tablets; there was little effect of the Ca tablet on L1-4 BMD either with the tablet overlying bone or in the soft-tissue field. We conclude that undissolved Ca tablets introduce small artifacts on L1-L4 BMD insufficient to alter diagnostic categorization of patients. However, if only two or three vertebral levels are available, misclassification of the patients may occur due to tablet artifact. The precision of monitoring BMD over time could also be adversely affected by tablet artifact if a tablet was directly overlying bone and undetected, especially with smaller regions of interest and with lower baseline BMD.
Absorptiometry, Photon↗
Composition profiling of seized ecstasy tablets by Raman spectroscopy.
Raman spectroscopy with far-red excitation has been investigated as a simple and rapid technique for composition profiling of seized ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine) tablets. The spectra obtained are rich in vibrational bands and allow the active drug and excipient used to bulk the tablets to be identified. Relative band heights can be used to determine drug/excipient ratios and the degree of hydration of the drug while the fact that 50 tablets per hour can be analysed allows large numbers of spectra to be recorded. The ability of Raman spectroscopy to distinguish between ecstasy tablets on the basis of their chemical composition is illustrated here by a sample set of 400 tablets taken from a large seizure of > 50,000 tablets that were found in eight large bags. The tablets are all similar in appearance and carry the same logo. Conventional analysis by GC-MS showed they contained MDMA. Initial Raman studies of samples from each of the eight bags showed that despite some tablet-to-tablet variation within each bag the contents could be classified on the basis of the excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag contained tablets with a glucose excipient. More extensive analysis of 50 tablets from each of a representative series of sample bags have distribution profiles that showed the contents of each bag were approximately normally distributed about a mean value, rather than being mixtures of several discrete types. Two of the sorbitol-containing sample sets were indistinguishable while a third was similar but not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration but had a slightly different MDMA/sorbitol ratio. The cellulose-based samples were badly manufactured and showed considerable tablet-to-tablet variation in their drug/excipient ratio while the glucose-based tablets had a tight distribution in their drug/excipient ratios. The degree of hydration in the MDMA feedstocks used to manufacture the cellulose-, glucose- and sorbitol-based tablets were all different from each other. This study, because it centres on a single seizure of physically similar tablets with the same active drug, highlights the fact that simple physical descriptions coupled with active drug content do not in themselves fully characterize the nature of the seized materials. There is considerable variation in the composition of the tablets within this single seizure and the fact that this variation can be detected from Raman spectra demonstrates that the potential benefits of obtaining highly detailed spectra can indeed translate into information that is not readily available from other methods but would be useful for tracing of drug distribution networks.
Hallucinogens↗
The effect of size and shape of tablets on their esophageal transit.
The esophageal transit times of small- and medium-sized barium sulfate tablets were measured using x-ray fluoroscopy in 50 patients after swallowing while in both erect and supine positions with a 15-mL drink, and the esophageal transit times of large round and oval barium sulfate tablets were similarly measured in 25 patients. When tablets were swallowed by subjects who were standing, no difference was found between the transit times of small and medium tablets, but large oval tablets had significantly shorter times than did large round tablets (P less than .04). The transit times of both small and medium tablets were significantly shorter than those of oval (P less than .05) and large round tablets (P less than .02). Retention of large oval and round tablets in the esophagus occurred in 20% of patients after swallowing while in the standing position. No medium-sized tablet was retained, but in 4% of patients, a small tablet remained in the esophagus. Tablets that were retained in the esophagus remained there for five minutes, when they were washed down by a further drink. When tablets were swallowed in the lying position, no significant differences in transit times were found between any of the four tablets. Retention of tablets within the esophagus occurred in over 60% of patients with all four tablets after ingestion while in the supine position. Tablets stuck mainly in the lower esophagus above the lower esophageal sphincter, but after swallowing in the standing position, a significant proportion (33% [P less than .01]) stuck in the upper esophagus.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Administration of crushed extended-release pentoxifylline tablets: bioavailability and adverse effects.
The pharmacokinetics of crushed and intact pentoxifylline tablets were compared, and the frequency of adverse effects was evaluated. Intact 400-mg extended-release pentoxifylline tablets, crushed 400-mg tablets, intact 600-mg tablets, and crushed 600-mg tablets were given sequentially to 10 healthy male volunteers. Blood samples were collected at time 0, at 30-minute intervals for the first three hours, and at 4, 6, 8, 12, and 24 hours after the dose and analyzed by capillary gas chromatography for pentoxifylline and three major metabolites. The bioavailability of the crushed tablets relative to the intact tablets was 156% for the 400-mg strength and 137% for the 600-mg strength. The area under the plasma drug concentration-time curve from 0 to 24 hours (AUC0-24) for the 400-mg tablets (crushed and intact) differed significantly from that for the 600-mg tablets; there was no significant difference between intact 400-mg and intact 600-mg tablets or crushed 400-mg and crushed 600-mg tablets. The maximum plasma drug concentration (Cmax) was significantly greater and the time to maximum concentration (t(max)) significantly shorter for crushed tablets than intact tablets. The 400-mg crushed tablet caused mild nausea in three subjects. The 600-mg crushed tablet caused both moderate nausea and dizziness in seven subjects and diaphoresis, headache, and vomiting in one subject each. Cmax was higher and tmax shorter when pentoxifylline tablets were administered crushed rather than intact, and the increase in maximum plasma concentrations appeared to cause dose-related adverse effects; crushing the tablets did not decrease the relative bioavailability.
Biological Availability↗
Punch geometry and formulation considerations in reducing tablet friability and their effect on in vitro dissolution.
The tablet friability resulting from formulation variations was studied under controlled granulation moisture content and tablet crushing strength. Tablets made with lactose were more friable than tablets made with microcrystalline cellulose. Replacement of 0.5% magnesium stearate with 0.5% stearic acid in the formula reduced tablet friability, whereas the combination of 0.5% stearic acid and up to 0.25% magnesium stearate did not increase tablet friability, decrease drug dissolution rate, or increase tablet-to-tablet variability in dissolution. Tablets compressed with extra deep concave punches resulted in lower friability compared with tablets compressed with standard concave or deep concave punches. The friabilities of the standard convex and deep convex tablets were similar, indicating that a critical level of punch tip curvature was important in reducing tablet friability. The dissolution rate was not affected by the punch tip geometry, but the tablet-to-tablet dissolution variability at the 0.5% stearic acid level for the extra deep convex tablets was higher compared with the standard convex tablets.
Chemical Phenomena↗
Evaluation of cellulose II powders as a potential multifunctional excipient in tablet formulations.
The use of UICEL-A/102 and UICEL-XL, the cellulose II powders, as a multifunctional direct compression excipient in the design of tablets containing hydrochlorothiazide (HCTZ) or ibuprofen (IBU), the model low and high dose drugs, respectively, has been reported. Commercial Oretic and Advil tablets containing HCTZ and IBU, respectively, and tablets made using Avicel PH-102 - the most commonly and widely used commercial direct compression excipient, were used in the study for comparison purposes. Tablets were made by first blending drug with the excipient and then with stearic acid, a lubricant, in a V-blender, followed by compressing into a tablet on a hydraulic press using 105 MPa of compression pressure and a dwell time of 30 s. The crushing strengths of HCTZ tablets decreased in the order Avicel PH-102>UICEL-XL, UICEL-A/102>Oretic and of IBU tablets in the order Avicel PH-102 > or = UICEL-XL approximately UICEL-A/102>Advil. The friability values for all tablets were well below the maximum 1% USP tolerance limit. UICEL-A/102 and UICEL-XL tablets containing HCTZ disintegrated rapidly (<25 s). Oretic tablets disintegrated in about 60 s, while Avicel PH-102 tablets remained intact during 1 h test period. The IBU tablets made using UICEL-A/102 disintegrated the fastest, UICEL-XL and Advil tablets the next, and Avicel PH-102 tablets remained intact. All tablets, except for those of Avicel PH-102, conformed to the USP drug release requirements. These results conclusively show that UICEL-A/102 and UICEL-XL have the potential to be used as filler, binder, and disintegrant, all-in-one, in the design of tablets containing either a low dose or high dose drug by the direct compression method.
Cellulose↗
Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen.
Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel, SLS, Avicel PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol ER tablets.
Acetaminophen↗
Magnetic resonance imaging for the in vivo evaluation of gastric-retentive tablets.
PURPOSE: To develop a magnetic resonance imaging (MRI) technique for assessing in vivo properties of orally ingested gastric-retentive tablets under physiologic conditions. METHODS: Tablets with different floating characteristics (tablet A-C) were marked with superparamagnetic Fe3O4 particles to analyze intragastric tablet position and residence time in human volunteers. Optimal Fe3O4 concentration was determined in vitro. Intragastric release characteristic of one slow-release tablet (tablet D) was analyzed by embedding gadolinium chelates (Gd-DOTA) as a drug model into the tablet. All volunteers underwent MRI in the sitting position. Tablet performance was analyzed in terms of relative position of tablet to intragastric meal level (with 100% at meal surface), intragastric residence time (min) and Gd-DOTA distribution volume (% of meal volume). RESULTS: Intragastric tablet floating performance and residence time of tablets (tablet A-D) as well as the intragastric Gd-DOTA distribution of tablet D could be monitored using MRI. Tablet floating performance was different between the tablets (A, 93%(95 - 9%); B, 80%(80 - 68%): C, 38%(63 - 32%); p < 0.05). The intragastric distribution volume of Gd-DOTA was 19.9% proximally and 35.5% distally. CONCLUSIONS: The use of MRI allows the assessment of galenic properties of orally ingested tablets in humans in seated position.
Delayed-Action Preparations↗
Chitosan and sodium sulfate as excipients in the preparation of prolonged release theophylline tablets.
The major objectives of this study were to monitor the effect of cross-linking of cationic chitosan in acidic media with sulfate anion during granules preparation by wet granulation method prior to tableting using theophylline (TPH) as a model drug. The prepared granules and the compressed tablets were subjected to in vitro evaluation. The properties of the prepared matrix granules and the compressed tablets were dependent on chitosan:sodium sulfate weight ratios, chitosan content, and molecular weight of chitosan. The prepared granules of all batches showed excellent to passable flowability and were suitable for compression into tablets. Most of the granules were hard and expected to withstand handling during the subsequent compression into tablets. Granules with high friabilities were only those prepared with a high amount of sodium sulfate or low amount of chitosan. Compression of granule batches yield nondisintegrating tablets that showed a decrease in tensile strength with the increase of sodium sulfate content at high chitosan:sodium sulfate weight ratio or with decrease of chitosan content. On the other hand, friability of tablets was increased in the presence of an excessive amount of sodium sulfate and low chitosan content as observed with granules. Slow TPH release from the formulated tablets was achieved at 1:0.5 and 1:1 chitosan:sodium sulfate weight ratios where all or most of the cationic chitosan and sulfate anions were used in a cross-linking reaction during wet granulation. Ratios of 1:2 and 1:3 showed fast drug release, which support the hypothesis that excessive unreacted water-soluble sodium sulfate might increase the porosity of the nondesintegrating tablets during dissolution. Slow drug release was also obtained with high molecular weight chitosan, whereas changing the hardness of the tablets did not significantly change the release profile of the drug as long as the tablets are intact during dissolution. Furthermore, slow drug release was observed as the total amount of chitosan was increased in the formulated tablets. A comparative in vivo study between the chosen formulated tablets (1:1 chitosan:sodium sulfate ratio that contains 10% high molecular weight chitosan) and the commercial Quibron tablets indicated prolonged appearance of the drug in dogs' plasma for both formulations with no significant differences (p > 0.05) in rate and extent of drug absorption. The formulated tablets showed 103.16% bioavailability relative to that of the commercial tablets.
Animals↗
Pharmacokinetics of acetaminophen from rapidly disintegrating compressed tablet prepared using microcrystalline cellulose (PH-M-06) and spherical sugar granules.
The aim of the present study was to evaluate the bioavailability of a drug from rapidly disintegrating tablets prepared using fine spherical crystalline cellulose (PH-M-06) and spherical sugar granules (Nonpareil, NP). Rapidly disintegrating tablets containing acetaminophen as the model drug in combination with a mixture of NP-108 (purified n-mannitol) and PH-M-06 were prepared. Plasma concentration profiles and pharmacokinetic parameters of acetaminophen in rabbits were investigated after oral administration of the prepared tablets. No significant difference in Cmax and AUC(0-infinity) of acetaminophen between rapidly disintegrating tablets and conventional tablets was observed after direct administration of these tablets into the stomach of rabbits. However, tmax (15 min) of acetaminophen from rapidly disintegrating tablets was significantly (p<0.05) shorter than that from conventional tablets (130 min). The same tmax was observed for rapidly disintegrating tablets and solution. When suitable excipients such as fine spherical microcrystalline cellulose (PH-M series) and spherical sugar granules (NP series) were used, rapidly disintegrating tablets could be prepared by the conventional direct compression method. According to the results of moment analysis, the mean residence time (MRT) obtained between both rapidly disintegrating and conventional tablets indicates that the mean absorption time (MAT) from these tablets is approximately 60 and 90 min, respectively. This difference in MAT between the two tablets may be caused by the difference in the sum of the mean dissolution time (MDT) and the mean disintegration time (MDIT) of these tablets. Rapidly disintegrating tablets allow rapid absorption of the drug compared with conventional tablets.
Acetaminophen↗
Statistical analysis of tablet breakability methods.
PURPOSE: Using a model tablet, the influence of breakability methodology on mass uniformity of half- and quarter-tablets as well as the comparison of different data acquisition and evaluation approaches were investigated. Moreover, different breakability evaluation criteria were compared based upon distribution as well as distribution-free models. METHODS: A cross-scored tablet, i.e. having two break-marks, was broken by different methods by different persons, and the masses determined for the whole (unbroken) tablets, the half-tablets and quarter-tablets. RESULTS: Beside the possible interaction between the methodology and the person breaking the tablets, the major factor significantly influencing the mass uniformity of broken tablets is the breakability methodology. The best results, i.e. smallest loss and smallest variability, are obtained when the breaking force applied by the thumbs is directed towards the score side of the tablet, i.e. by "opening" the score. Using our model tablet, significant differences between the different evaluation criteria are observed, with the USP/NF approach being best in line with the detailed analysis of all broken tablets. CONCLUSIONS: Assuming that for this model tablet the variance is a linear function of the break-line length, the standard deviation of quarter-tablets is theoretically calculated to be 0.87 times the standard deviation of the half-tablets. As the absolute standard deviation, expressed in mass units, will thus remain approximately identical, the relative standard deviation will nearly double as the mean mass of the quarter-tablets will be half of the mean mass of the half-tablets. This was experimentally confirmed.
Analysis of Variance↗
In vitro--in vivo evaluation of tableted caseinchitosan microspheres containing diltiazem hydrochloride.
Casein-chitosan microspheres containing diltiazem hydrochloride (DTZ.HCL) were prepared using aqueous coacervation technique. The formed microspheres were not suitable for tableting by direct compression due to their poor binding properties. The effect of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carbopol 940 and egg albumin as dry binders at different concentrations on the properties of the tablets was studied. Each blend of microspheres with dry binder and 2% w/w magnesium stearate as glidant was hand-filled into the die cavity of a single punch tablet machine to ensure constant amount of drug (90 mg) in each tablet. The compression force was adjusted to produce tablets with hardness value about 7.73 +/- 0.79 Kp. The prepared tablets showed good appearance and low friability. The tested binders HPMC (10 and 30% w/w) and EC (20 and 30% w/w) gave fast tablet disintegration with high initial drug release (burst effect) while, carbopol 940 (5 and 10% w/w) and egg albumin (30% w/w) gave non-disintegrating tablets with low initial drug release. Tableted microspheres prepared with 30% egg albumin showed drug release profile similar to one of the commercial tablets (Dilzem retard, 90 mg) and was chosen for in-vivo study. Tableted microspheres and commercial tablets were administered orally in different occasions to six beagle dogs and diltiazem was assayed in dog plasma. The pharmacokinetic parameters including maximum drug concentration (Cmax) and time to reach that maximum (Tmax) were 106.24 +/- 17.96 ng.ml-1 and 5.8 +/- 2.04 hours, respectively, for the commercial sustained release DTZ tablets while, those were 107.9 +/- 12.89 ng.ml-1 and 3.6 +/- 1.36 hours, respectively for tableted microspheres. The elimination half-lives were nearly the same for the commercial and the formulated tablets (8.22 +/- 4.19 and 7.95 +/- 4.28 hours, respectively). No statistical differences (P > 0.05) were found between the two treatments for area under the plasma concentration curve (AUC0 infinity), mean residence time (MRT) and rate of drug absorption (Cmax/AUC0 infinity) indicating comparable extent and rate of drug absorption for both formulations. It was concluded that the formulated tableted microspheres provide an acceptable delivery for DTZ over an extended period of time.
Animals↗
Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies.
Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.
Biological Availability↗
Food effects on tablet disintegration.
The aims of the present study was to investigate if food components, as represented by a multi-component nutritional drink for tube feeding, could affect tablet disintegration of standard tablets in vitro as well as in vivo and propose a mechanism for potential food effects on tablet disintegration. The tablet disintegration was delayed between 5 min and more than 1h in the simulated gastric fed medium compared to a simple buffer. This effect was dependent on the tablet composition. A similar delay in tablet disintegration was also found in vivo after administration of the nutritional drink to three Labradors as observed by removing the tablet from the stomach at different times through a gastric fistula. The delay in tablet disintegration appeared to be caused by precipitation of a film, mainly consisting of protein, on the tablet surface as indicated by disintegration studies with pure nutrients, identification by IR spectroscopy of contents of precipitates obtained in a model study were the nutrients were incubated with different tablet excipients and visual observations of tablets exposed to the simulated fed medium. The drug dissolution of a soluble compound, metoprolol tartrate, from a standard tablet was also strongly delayed in the simulated fed medium. In conclusion, food, could significantly delay tablet disintegration and drug dissolution in the stomach by formation of a film around the tablets. This effect could be monitored by a simple in vitro disintegration test using a test medium based on a nutritional drink. More studies are needed to investigate the significance of the slow tablet disintegrations on bioavailability and for which types of food the present effect occurs.
Animals↗
Residue-free sodium phosphate tablets (OsmoPrep) versus Visicol for colon cleansing: a randomized, investigator-blinded trial.
BACKGROUND: The bowel purgative Visicol contains microcrystalline cellulose (MCC) residue, which may impair full visibility during a colonoscopy. An MCC residue-free sodium phosphate (RF-NaP; OsmoPrep) tablet was developed. OBJECTIVE: To investigate appropriate RF-NaP dosing. DESIGN: Phase 2, randomized, investigator-blinded study. SETTING: Six research centers in the United States. PATIENTS AND INTERVENTIONS: Patients undergoing a colonoscopy received Visicol (n = 34) or 1 of 6 RF-NaP regimens administered as either split (S) dosing (the evening before and the day of colonoscopy) or evening-only (E) dosing. Dosing regimens for RF-NaP were 40 tablets S, 3 every 15 minutes (n = 33); 40 tablets S, 4 every 15 minutes (n = 34); 32 tablets E, 4 every 15 minutes (n = 34); 32 tablets S, 4 every 15 minutes (n = 36); 28 tablets E, 4 every 15 minutes (n = 34); 28 tablets S, 4 every 15 minutes (n = 34). Visicol was administered as 40 tablets S, 3 every 15 minutes. MAIN OUTCOME MEASURE: Overall colon cleansing (OCC) was assessed by a physician questionnaire (4-point scale, based on colonic contents). An OCC rating of "excellent" or "good" was considered a response. Safety measures were also monitored. RESULTS: Split dosing with RF-NaP was associated with high OCC and achieved response rates of 90%, 97%, and 100% for 28, 32, and 40 tablets, respectively, compared with 86% for Visicol. In addition, RF-NaP evening-only regimen response rates were 90% (32 tablets) and 72% (28 tablets). Transient shifts in electrolyte levels were reduced, and GI adverse events were less common with lower RF-NaP dose regimens. CONCLUSIONS: Administration of RF-NaP retains the benefits of a tablet purgative but eliminates MCC issues. Split dosing and 32-tablet evening-only dosing of RF-NaP tablets were efficacious and well tolerated, and split dosing of RF-NaP tablets is recommended.
Adolescent↗