Preprandial Conditions Research Articles

Biorelevant Dissolution Method Development For Dutasteride/Tamsulosin Hydrochloride Modified Release Capsule - A Prognostic Tool For Oral Drug Absorption

The research work was aimed to develop a biorelevant dissolution method for fixed dose combination containing Dutasteride 0.5 mg in immediate-release form and Tamsulosin 0.4 mg in modified-release form. Mean plasma concentration achieved after oral administration to human under pre-prandial condition are deconvoluted using Wagner-Nelson deconvolution method, to achieve target dissolution profile. The dissolution profile observed using office of generic drugs recommended dissolution media was observed to be faster than the target dissolution profile. Tamsulosin being a modified-release multiparticulate system, biorelevant dissolution method was developed with Fasted state simulated change over dissolution media, using USP Apparatus 3 (reciprocating cylinder). Dutasteride being an immediate-release form, dissolution method was developed with single dissolution media, by extending the dissolution run time upto C max . Dissolution media, media volume and Dips Per Minute (DPM) are optimized by performing full factorial design of experiment. The ANOVA result interprets the biorelevant dissolution media for Tamsulosin part is 250 ml of Fasted state simulated change over dissolution media with 15 DPM, based on desirability factor of 0.7768 and for Dutasteride part 250 ml of pH 6.5 Fasted state simulated intestinal fluids with 7 DPM, based on desirability factor of 0.8988. The regression co-efficient (R 2 ) value of 0.999 and 0.996 demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition for Tamsulosin and Dutasteride respectively. The developed method shall be used as a predictive in-vitro tool for evaluation of in-vivo performance under pre-prandial condition.

Prediction of In-vivo Performance of Naproxen and Esomeprazole Magnesium Delayed-Release Tablets using Biorelevant Dissolution Tests

Main objective of this research work was to develop a biorelevant dissolution method by correlating the in-vivo behavior of Naproxen and Esomeprazole magnesium delayed release tablets 500/20mg, when administered orally under pre-prandial condition. The target dissolution profile for bio-relevant dissolution media was derived, by deconvoluting mean blood plasma concentration time profile of Naproxen and Esomeprazole, achieved after oral administration under pre-prandial condition. The dissolution media volume and RPM were optimized using full factorial design of experiment. The dissolution profile observed with office of generic drugs recommended dissolution media was faster in release for Naproxen part and slower in release for Esomeprazole part in comparison to target release of bio-relevant dissolution method, with the F 2 value of 31 for Naproxen and 29 for Esomeprazole. USP Apparatus-I with fasted state simulated gastro intestinal change over dissolution media were used for method development. Based on ANOVA results, for Naproxen part, 250ml of fasting change over dissolution medium, and 50RPM, with the desirability factor of 0.508 was concluded as bio relevant dissolution medium. For esomeprazole part, the 900ml of fasting change over dissolution medium, and 100RPM, with the desirability factor of 0.479 was concluded as bio-relevant dissolution medium. The F 2 value observed between in-vitro and in-vivo dissolution profile is 64 and 63, the regression co-efficient (R 2 ) value of 0.987 and 0.997 for Naproxen and Esomeprazole respectively demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition. The developed method shall be used as a predictive in-vitro tool for evaluation Naproxen from Naproxen and Esomeprazole magnesium delayed release tablets, and also gives the advantage for claiming bio-waiver for remaining strengths.

Development of bio-relevant dissolution method for prognosis of In-vivo performance of Dipyridamole from modified release capsules

In-vitro biorelevant dissolution test method was developed for Dipyridamole in modified release multi-particulate dosage form, to simulate the product drug release after oral administration to human. The Dipyridamole concentration in blood plasma achieved after oral administration under pre-prandial (fasting) condition were used for deriving the target dissolution profile deconvoluting the plasma concentration using numerical deconvolution technique. The fraction of drug absorbed was considered as the target dissolution profile. The drug product was tested by using the dissolution method recommended by office of generic drugs, and the dissolution results observed are not comparable with the target dissolution profile. Dissolution method was developed using reciprocating cylinder, Bio-Dis (apparatus -3 as per USP), by simulating the pre-prandial conditions. A full factorial design of experiment was carried out to achieve the target dissolution profile. Media volume and dips per minute (DPM) are considered as main factors, in design of experiment. The dissolution results achieved with media volume 250ml and 10DPM were found to be comparable with target dissolution profile and observed with the F2 value (similarity factor) of 92%. The developed dissolution method demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition, and shall be used as a predictive in-vitro tool for evaluation Dipyridamole extended release capsules.

Estimation of the Effects of Food on the Pharmacokinetic Results in Bioequivalence Studies

Paper presents the effect of food on the pharmacokinetics of omeprazole and on the extraction yield of its internal standard, lansoprazole. The experimental data were obtained over three bioequivalence studies performed by the authors. Statistical analysis of plasma level curves of omeprazole indicated that food induces a delay of the time of maximum concentrations, but had a lower effect on maximum concentration and area under curves. Peak areas of lansoprazole were not constant, presenting a similar pattern in all seven periods of the clinical experiment, both in feeding and fasting conditions: an increase after the standard meal at four hours from the administration of drug followed by relatively constant, but higher areas afterwards. Statistical analysis of data (1500 points) in the 3 - 6 h interval, i.e. from immediately before until two hours after food intake revealed a two phase effect: an initial decrease of areas followed by an increase to a higher level than in the preprandial conditions, leading to the appearance of a minimum in curves one hour after food intake. In almost all cases a good parabolic fitting of data was obtained, which is in agreement with authors previous results on extraction of ketoconazole from pasma in methylene chloride in the presence of bile salts. The increase of peak areas of lansoprazole from two hours after meal by 24 h lead to an artificial decrease of calculated omeprazole concentrations. This effect could explain the unexpected lack of food effect on the area under curve of omeprazole, observed in the comparison between areas in fasting and fed conditions.

Prandial States Modify the Reactivity of the Gustatory Cortex Using Gustatory Evoked Potentials in Humans.

Previous functional Magnetic Resonance Imaging studies evaluated the role of satiety on cortical taste area activity and highlighted decreased activation in the orbito-frontal cortex when food was eaten until satiation. The modulation of orbito-frontal neurons (secondary taste area) by ad libitum food intake has been associated with the pleasantness of the food's flavor. The insula and frontal operculum (primary taste area) are also involved in reward processing. The aim was to compare human gustatory evoked potentials (GEP) recorded in the primary and secondary gustatory cortices in a fasted state with those after food intake. Fifteen healthy volunteers were enrolled in this observational study. In each of two sessions, two GEP recordings were performed (at 11:00 am and 1:30 pm) in response to sucrose gustatory stimulation, and a sucrose-gustatory threshold was determined. During one session, a standard lunch was provided between the two GEP recordings. During the other session, subjects had nothing to eat. Hunger sensation, wanting, liking, and the perception of the solution's intensity were evaluated with visual analog scales. GEP latencies measured in the Pz (p < 0.001), Cz (p < 0.01), Fz (p < 0.001) recordings (primary taste area) were longer after lunch than in the pre-prandial condition. Fp1 and Fp2 latencies (secondary taste area) tended to be longer after lunch, but the difference was not significant. No difference was observed for the sucrose-gustatory threshold regardless of the session and time. Modifications in the primary taste area activity during the post-prandial period occurred regardless of the nature of the food eaten and could represent the activity of the frontal operculum and insula, which was recently shown to be modulated by gut signals (GLP-1, CCK, ghrelin, or insulin) through vagal afferent neurons or metabolic changes of the internal milieu after nutrient absorption. This trial was registered at clinicalstrials.gov as NCT02472444.

Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update

The aim of this study was to update the compositions of biorelevant media to represent the composition and physical chemical characteristics of the gastrointestinal fluids as closely as possible while providing physical stability during dissolution runs and short-term storage. Media were designed to reflect postprandial conditions in the stomach and proximal small intestine in the "early", "middle", and "late" phases of digestion. From these "snapshot" media, general media for simulating postprandial conditions were devised. Additionally, media reflecting preprandial conditions in the stomach and small intestine were revisited. A set of four media is presented. A recently published medium to represent the fasted stomach, FaSSGF, needed no further revision. To simulate the postprandial stomach, a new medium, FeSSGF, is presented. Media representing the upper small intestine in the fed and fasted states were fine-tuned according to physicochemical and biochemical characteristics in vivo. All four media proved to be stable under ambient storage conditions for at least 72 h as well as under usual dissolution test conditions. The updated dissolution media can be used to predict formulation performance and food effects in vivo. These media are more physiologically relevant and show better physical stability than their corresponding predecessors.

Octreotide potentiates PKC-dependent vasoconstrictors in portal-hypertensive and control rats.

The effect of octreotide on vascular tone in the superior mesenteric artery (SMA) was studied in portal-hypertensive (portal vein-ligated) and sham-operated rats. In vitro-perfused SMA vascular beds were tested for the cumulative dose-response to octreotide at baseline conditions and after preconstriction with different vasoconstrictors (alpha1-agonist methoxamine, endothelin [ET-1], phorbol ester [PdBu], and potassium chloride [KCl]). Octreotide did not affect baseline perfusion pressures (without preconstriction). alpha1-Adrenergic-, ET-1-, and PdBu-, but not KCl-, induced vasoconstriction was significantly potentiated by octreotide. This effect was dose-dependent and not different in portal vein-ligated and sham rats. Amplification of alpha1-adrenergic vasoconstriction by octreotide was significantly enhanced by nitric oxide inhibition (N(W)-nitro-L-arginine, 10(-4) mol/L) as well as by removal of the endothelium, and was completely suppressed by inhibition of protein kinase C (calphostin C, 1 micromol/L), phospholipase A2 (quinacrine, 5 micromol/L), and cyclooxygenase (indomethacin, 20 micromol/L). Not directly, but in the presence of vasoconstrictors involving activation of protein kinase C, octreotide exerts a local vasoconstrictive effect on vascular smooth muscle of SMA. This potentiation is equipotent in portal vein-ligated and sham rats, immediate in onset, and mediated via phospholipase A2 and cyclooxygenase-derived prostanoids. This indicates that in preprandial conditions octreotide enhances the vasoconstrictive effect of dependent vasoconstrictors.

Feeding-induced changes in temporal patterning of muscle activity in the lobster stomatogastric system

In the lobster Homarus gammarus, rhythmic masticatory movements of the foregut gastric mill are generated by a small neural network in the stomatogastric ganglion. We have used EMG recordings from intact animals to analyse gastric network output in relation to cycle period before and after feeding. In pre-prandial conditions, muscles controlling lateral teeth closure and medial tooth protraction (driven by MG and GM motor neurons, respectively) express relatively constant, return stroke-like burst durations, but change to a variable-duration power stroke-like phenotype after feeding. In contrast, the LPG neuron-innervated lateral teeth opener muscle switches from power stroke to return stroke-like behavior. Thus alternate phases within a single motor program may invert their temporal properties according to the behavioral situation.

Comparison of Blood Alcohol Concentrations After Beer and Whiskey

To determine whether blood alcohol concentrations achieved by ingestion of various alcoholic beverages differ as a function of prandial state, healthy male volunteers, aged 24 to 48 years, were given the same amount of alcohol (0.3 g/kg) as different beverages. The alcohol was consumed in three prandial states: postprandial (1 hr after a meal, n = 10), prandial (during the meal, n = 10), and preprandial (after an overnight fast, n = 9). Each subject was tested with both beer and whiskey, and in the postprandial state also with wine and sherry, in a within-subjects design. Blood alcohol concentrations were estimated by breath analysis for 4 hr or until concentrations reached zero. Peak blood alcohol levels were higher with beer than with whiskey in the postprandial and prandial conditions (p < 0.01), whereas the opposite was true in the preprandial state (p < 0.05). Similarly, the area under the blood alcohol curve was higher with beer in the prandial state (p < 0.05), and higher with whiskey in the preprandial condition (p < 0.01). Wine and sherry yielded peak concentrations intermediate between those of beer and whiskey in the postprandial state. The results indicate that a dilute alcoholic drink can yield either higher or lower blood alcohol levels than a concentrated beverage, depending on the prandial state.

Gastrointestinal blood flow and oxygen consumption in awake newborn piglets: effect of feeding.

Regional and total gastrointestinal (GI) blood flow, O2 delivery, and whole-gut O2 extraction and O2 consumption were measured before and 30, 60, and 120 min after feeding in nonanesthetized, awake 2-day-old piglets. Cardiac output and blood flow to kidneys, heart, brain, and liver were also determined. Blood flow was measured using the radiolabeled microsphere technique. In the preprandial condition, total GI blood flow was 106 +/- 9 ml X min-1 X 100 g-1, while O2 extraction was 17.2 +/- 0.9% and O2 consumption was 1.99 +/- 0.19 ml O2 X min-1 X 100 g-1. Thirty minutes after slow gavage feeding with 30 ml/kg artificial pig milk, O2 delivery to the GI tract and O2 extraction rose significantly (P less than 0.05) by 35 +/- 2 and 33 +/- 2%, respectively. The increase in O2 delivery was effected by a significant increase in GI blood flow, which was localized to the mucosal-submucosal layer of the small intestine. O2 uptake by the GI tract increased 72 +/- 4% 30 min after feeding. Cardiac output and blood flow to non-GI organs did not change significantly with feeding, whereas arterial hepatic blood flow decreased significantly 60 and 120 min after feeding. The piglet GI tract thus meets the oxidative demands of digestion and absorption by increasing local blood flow and tissue O2 extraction.

Meal related effects of IV glucose, glucagon and insulin on blood glucose level: Role in glucoregulation exhibited by self-injecting rats

In previous works, it was demonstrated that rats self-injected with (IV) glucose, insulin and/or glucagon and that the self-administration pattern was related to the meal. It was suggested that the different preprandial or postprandial blood glucose level (B.G.L) determinated the meal and were dependent on it. Previously self-injected amounts of glucose, glucagon and insulin were here injected by an automatic device and their effect on B.G.L. were compared in the post and preprandial conditions. Results indicated that the effects of insulin, glucagon and glucose on B.G.L., which were different during the postprandial hyperglycemia compared to the preprandial normoglycemia, accounted for the different self-injection patterns. Furthermore successive injection of glucose and insulin or glucagon and insulin suggest that rats, by pressing alternatively two levers performed a regulatory correction of variations of their B.G.L. It is concluded that rats may learn to perform a behavioral regulation of their B.G.L. by IV self-injections of glucose and glucoregulatory hormones.